ALBERT

Description: 〈p〉Publication date: 15 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 16〈/p〉 〈p〉Author(s): Tao Li, Jing Li, Yang Yang, Yilin Han, Dirong Wu, Tao Xiao, Yang Wang, Ting Liu, Yonglong Zhao, Yongjun Li, Zeqin Dai, Xiaozhong Fu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The deficiency of nucleos(t)ide analogues (NAs) as anti-hepatitis B virus (HBV) drugs in clinical use is attributable to their insufficient enrichment in liver and non-target organ toxicity. We aimed to develop potent anti-HBV adefovir derivatives with hepatotrophic properties and reduced nephrotoxicity. A series of adefovir mono 〈span〉l〈/span〉-amino acids, mono cholic acid-drug conjugates were designed and synthesized, and their antiviral activity and uptake in rat primary hepatocytes and Na〈sup〉+〈/sup〉-dependent taurocholate co-transporting polypeptide (NTCP)-HEK293 cells were evaluated. We isolated compound 〈strong〉6c〈/strong〉 as the optimal molecular candidate, with the highest antiviral activity (EC〈sub〉50〈/sub〉 0.42 μmol/L, SI 1063.07) and highest cellular uptake in primary hepatocytes and NTCP-HEK293 cells. In-depth mechanistic studies demonstrated that 〈strong〉6c〈/strong〉 exhibited a lower toxicity in HK-2 cells when compared to adefovir dipivoxil (ADV). This is because 〈strong〉6c〈/strong〉 cannot be transported by the human renal organic anion transporter 1 (hOAT1). Furthermore, pharmacokinetic characterization and tissue distribution of 〈strong〉6c〈/strong〉 indicates it has favorable druggability and pharmacokinetic properties. Further docking studies suggested compounds with ursodeoxycholic acid and 〈span〉l〈/span〉-amino acid groups are better at binding to NTCP due to their hydrophilic properties, indicating that 〈strong〉6c〈/strong〉 is a potential candidate as an anti-HBV therapy and therefore merits further investigation.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619309034-ga1.jpg" width="327" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Bo Hou, Ze Liu, Xiao-Bei Yang, Wen-Fei Zhu, Jin-Yu Li, Liu Yang, Fu-Cai Reng, Yong-Feng Lv, Jiang-Miao Hu, Guo-Yang Liao, Jun Zhou〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The stems of 〈em〉Dryopteris crassirhizoma〈/em〉, one of the main components of Lianhua-Qingwen Formula (LQF) was traditionally used for heat-clearing and detoxifying. Dryocrassin 〈strong〉ABBA〈/strong〉 is a key antiviral component in the herbal medicine while the compound is hard to get in large amounts with the features of homologous compounds, polyphenol groups, and low contents. Therefore, the present work aims to seek influenza H7N9 virus inhibitors from natural source by synthesis of dryocrassin 〈strong〉ABBA〈/strong〉 and its analogues. As a result, total synthesis of the compound was achieved in nine steps with an over-all yield of 4.6%. Neuraminidases (NAs) inhibitory activities of the synthesized product and its analogues were evaluated afterward. Comparing with the positive control, OSV (9.6 μM), it was very exciting that dryocrassin 〈strong〉ABBA〈/strong〉 and its analogues (〈strong〉b5〈/strong〉 and 〈strong〉e2〈/strong〉) showed better NAs inhibitory activity against Anhui H7N9 with IC〈sub〉50〈/sub〉 values of 3.6 μM, 2.5 μM and 1.6 μM. For the highly resistant Shanghai N9, these compounds can also show medium inhibitory activities. Docking results indicated the direct interaction of synthesized 3 hits with the key K294 by hydrogen bonds, but no direct interaction of OSV with the key K294 was observed in Shanghai N9. This study suggested that dryocrassin 〈strong〉ABBA〈/strong〉 and its analogues especially 〈strong〉AB〈/strong〉, which consisted of polyphenol groups may have beneficial effects on treating avian influenza H7N9 virus.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉Total synthesis of dryocrassin ABBA and analogue structures with potential inhibitory activity against drug-resistant neuraminidases.〈/p〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619308879-ga1.jpg" width="278" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Yang Hu, Wei-Chao Chen, Yu-Feng Shen, Bin Zhu, Gao-Xue Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Viral diseases in aquaculture were challenging because there are few preventative measures and/or treatments. Our previous study indicated that imidazole arctigenin derivatives possessed antiviral activities against infectious hematopoietic necrosis virus (IHNV). Based on the structure-activity relationship in that study, a new imidazole arctigenin derivative, 4-(8-(2-ethylimidazole)octyloxy)-arctigenin (EOA), was designed, synthesized and its anti-IHNV activity was evaluated. By comparing inhibitory concentration at half-maximal activity (IC〈sub〉50〈/sub〉), we found that EOA (IC〈sub〉50〈/sub〉 = 0.56 mg/L) possessed a higher antiviral activity than those imidazole arctigenin derivatives in our previous study. Besides, EOA could significantly decrease cytopathic effect (CPE) and viral titer induced by IHNV in epithelioma papulosum cyprinid (EPC) cells. In addition, EOA significantly inhibited apoptosis induced by IHNV in EPC cells. Further data verified that EOA inhibited IHNV replication in rainbow trout, with reducing 32.0% mortality of IHNV-infected fish. The results suggested that EOA was more stable with a prolonged inhibitory half-life in the early stage of virus infection (1–4 days). Consistent with above results, EOA repressed IHNV glycoprotein gene expression in virus sensitive tissues (kidney and spleen) in the early stage of virus infection. Moreover, histopathological evaluation showed that tissues from the spleen and kidney of fish infected with IHNV exhibited pathological changes. But there were no lesions in any of the tissues from the control group and EOA-treaten group. In accordance with the histopathological assay, EOA could elicited anti-inflammation response in non-viral infected rainbow trout by down-regulating the expression of cytokine genes (〈em〉IL-8〈/em〉, 〈em〉IL-12p40〈/em〉, and 〈em〉TNF-α〈/em〉). Altogether, EOA was expected to be a therapeutic agent against IHNV infection in the field of aquaculture.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Junjun He, Haiying Liang, Jiaping Zhu, Xiaochen Fang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Antibacterial peptides (AMPs) constitute an important part of the body's innate immune system and are responsible for a wide range of inhibitory effects against pathogens such as bacteria, fungi, and viruses. In this study, multi-step high performance liquid chromatography (HPLC), combined with Mass Spectrometry (MS), was used to isolate and identify proteins with antibacterial activity from the serum of 〈em〉Pinctada fucata martensii〈/em〉 (〈em〉P.f. Martensii〈/em〉) and obtain a component named 〈em〉P.f. Martensii〈/em〉 antimicrobial peptide-1 (PmAMP-1). 〈em〉PmAMP-1〈/em〉 cDNA was cloned and sequenced by rapid amplification of cDNA ends (RACE) and mRNA expression of was analyzed by quantitative real-time PCR (qRT-PCR). From the results of this study, full-length 〈em〉PmAMP-1 c〈/em〉DNA was shown to be 700 base pairs (bp) long with an open reading frame (ORF) of 294 bp, encoding 97 amino acids with a predicted structure that is mostly α-helices. 〈em〉PmAMP-〈/em〉1 mRNA was constitutively expressed in all tested tissues including the adductor muscle, mantle, hepatopancreas, gill, gonads and hemocytes. The highest level of 〈em〉PmAMP-〈/em〉1 transcription was observed at 8 h and 2 h after bacterial challenge in hemocytes and adductor muscle (p 〈 0.01), respectively. Furthermore, PmAMP-1 caused significant morphological alterations in 〈em〉E. coli,〈/em〉 as shown by transmission electron microscopy (TEM). The results from this study provide a valuable base for further exploration of molluscan innate immunity and immune response.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Miriam Rossi, Francesco Caruso, Ilaria Costanzini, Carmen Kloer, Aron Sulovari, Elena Monti, Marzia Gariboldi, Emanuela Marras, Neduri V. Balaji, Modukuri V. Ramani, Gottumukkala V. Subbaraju〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The antiproliferative action of hispolon derivatives is stronger than that of related curcumin against several tumor cell lines. Hispolon size, smaller than curcumin, fits better than curcumin into the active site of HDAC6, an enzyme involved in deacetylation of lysine residues. HDACs are considered potential targets for tumor drug discovery and hydroxamates are known inhibitors of HDACs. One of them, SAHA (Vorinostat) is used in clinical studies. Investigations into possible mechanisms for hispolon derivatives active against the HCT116 colon tumor cell line are done after examining the structural results obtained from hispolon X-ray crystal structures as well as performing associated computational docking and Density Functional Theory techniques on HDAC6. These studies show preference for the HDAC6 active site by chelating the Zn center, in contrast with other ineffective hispolon derivatives, that establish only a single bond to the metal center. Structure activity relationships make clear that hydrogenation of the hispolon bridge also leads to single bond (non chelate) hispolon-Zn binding, and consistently nullifies the antiproliferative action against HCT116 tumor.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619301907-ga1.jpg" width="366" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 16〈/p〉 〈p〉Author(s): Zahra Mojallal-Tabatabaei, Parham Foroumadi, Mahsa Toolabi, Fereshteh Goli, Setareh Moghimi, Sussan Kaboudanian-Ardestani, Alireza Foroumadi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The development of novel leishmanicidal agents that are capable of being replaced by the available therapeutic options has become a priority. In the present study, the synthesis and leishmanicidal activity of a series of 5-(nitroheteroaryl-2-yl)-1,3,4-thiadiazole derivatives are described. All compounds appeared to be potent anti-leishmanial agents against both promastigote and amastigote forms of 〈em〉Leishmania major〈/em〉 (〈em〉L. major)〈/em〉. Amongst the synthesized compounds, 2-([1,4′-bipiperidin]-1′-yl)-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole (〈strong〉IIa〈/strong〉) and 1-(5-(1-methyl-5-nitro-1〈em〉H〈/em〉-imidazole-2-yl)-1,3,4-thiadiazol-2-yl)-4-(piperidine-1-yl) piperidine (〈strong〉IIc〈/strong〉) are the most effective. Infection index was statistically declined in the presence of all compounds. The analysis of redox-related factors revealed that exposure of 〈em〉L. major〈/em〉 cells to 〈strong〉IIa〈/strong〉 and 〈strong〉IIc〈/strong〉 led to an increase in reactive oxygen species (ROS). Furthermore, two compounds were able to increase ROS and NO levels in infected macrophages in a dose-independent manner. In addition, we showed that these compounds induced cell death in promastigotes. Altogether, our results indicated the anti-leishmanial potential of 〈strong〉IIa〈/strong〉 and 〈strong〉IIc〈/strong〉 is mediated by apoptosis through an imbalance in the redox system resulting in the elevation of ROS. This new class of compound seems to hold great promise for the development of new and useful anti-leishmanial agents.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619303700-ga1.jpg" width="335" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Shweta Sinha, Mukesh Doble, S.L. Manju〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The most common inflammatory disease of the airways is asthma among children affecting around 235 million people worldwide. 5-Lipoxygenase (5-LOX) is a crucial enzyme which helps in the conversion of arachidonic acid (AA) to leukotrienes (LTs), the lipid mediators. It is associated with several inflammation related disorders such as asthma, allergy, and atherosclerosis. Therefore, it is considered as a promising target against inflammation and asthma. Currently, the only drug against 5-LOX which is available is Zileuton, while a few inhibitors are in clinical trial stages such as Atreleuton and Setileuton. So, there is a dire requirement in the area of progress of novel 5-LOX inhibitors which necessitates an understanding of their structure activity relationship and mode of action. In this review, novel 5-LOX inhibitors reported so far, their structural design, SAR and developmental strategies along with clinical updates are discussed over the last two decades.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619306777-ga1.jpg" width="412" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Fa-Qian Shen, Lu Shi, Ze-Feng Wang, Chen-Ru Wang, Jin-Jin Chen, Yi Liu, Han-Yue Qiu, Hai-Liang Zhu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉For the purpose of synthesizing drug candidates with desirable bioactivity, a class of benzoyl amide containing nitrogen heterocyclic ring derivatives targeting VEGFR-2 was designed and screened out using Discovery Studio. Eighteen target compounds were synthesized and then selected by some biological trials sequentially including inhibition of VEGFR-2, anti-proliferation in vitro, flow cytometry. Among them, compound 〈strong〉8h〈/strong〉 showed the best inhibitory activity (IC〈sub〉50〈/sub〉 = 0.34 ± 0.02 μM against VEGFR-2, IC〈sub〉50〈/sub〉 = 1.08 ± 0.06 μM and 2.44 ± 0.15 μM against MCF-7 and HepG-2, respectively, which were at the same inhibitory level with the commercially antitumor drug: vandetanib). In addition, flow cytometry demonstrated that compound 〈strong〉8h〈/strong〉 induced MCF-7 cell apoptosis through a cell membrane-mediated pathway. This research highlights the therapeutic potential of novel VEGFR-2 inhibitors in treating cancers and provides a promising strategy for drug discovery.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619304043-ga1.jpg" width="353" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉 〈p〉Binding mode of compound 〈strong〉8h〈/strong〉 with VEGFR-2 (PDB code: 〈strong〉4ASD〈/strong〉). The 3D diagram of the interaction between compound 〈strong〉8h〈/strong〉 and key amino acid residues.〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 16〈/p〉 〈p〉Author(s): George Amato, Robert Wiethe, Amruta Manke, Vineetha Vasukuttan, Rodney Snyder, Scott Runyon, Rangan Maitra〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Antagonists of type 1 cannabinoid receptors (CB1) may be useful in treating diabetes, hepatic disorders, and fibrosis. Otenabant (〈strong〉1〈/strong〉) is a potent and selective CB1 inverse agonist that was under investigation as an anti-obesity agent, but its development was halted once adverse effects associated with another marketed inverse agonist rimonabant (〈strong〉2〈/strong〉) became known. Non-tissue selective antagonists of CB1 that have high levels of brain penetration produce adverse effects in a small subset of patients including anxiety, depression and suicidal ideation. Currently, efforts are underway to produce compounds that have limited brain penetration. In this report, novel analogs of 〈strong〉1〈/strong〉 are explored to develop and test strategies for peripheralization. The piperidine of 〈strong〉1〈/strong〉 is studied as a linker, which is functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a connector in the form of an amine, amide, sulfonamide, sulfamide, carbamate, oxime, amidine, or guanidine. We also report more polar replacements for the 4-chlorophenyl group in the 9-position of the purine core, which improve calculated physical properties of the molecules. These studies resulted in compounds such as 〈strong〉75〈/strong〉 that are potent inverse agonists of hCB1 with exceptional selectivity for hCB1 over hCB2. SAR studies revealed ways to adjust physical properties to limit brain exposure.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619306431-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Pedro Silvino Pereira, Maria do Carmo Alves de Lima, Pedro Paulo Marcelino Neto, Cícera Datiane de Morais Oliveira-Tintino, Saulo Relison Tintino, Irwin Rose de Alencar Menezes, Jamerson Ferreira de Oliveira, Pascal Marchand, Henrique Douglas Melo Coutinho, Maria do Desterro Rodrigues, Teresinha Gonçalves da Silva〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Thiazol and thiazolidinedione derivatives are known in the literature for presenting several biological activities, such as anti-diabetic, anti-inflammatory, antiparasitic, antifungal and antimicrobial activity. With this in mind, this study reports on the synthesis and antibacterial activity of thiazole (NJ) and thiazolidinedione (NW) derivatives, as well as their effects in association with norfloxacin, against NorA efflux pumps in the 〈em〉Staphylococcus aureus〈/em〉 1199B (SA-1199B) strain. Among the 14 compounds evaluated, 9 were found to potentiate norfloxacin activity, with 4 compounds from the NJ series promoting a threefold norfloxacin MIC reduction. Molecular docking assays were used to confirm the binding mode of most active compounds. In the 〈em〉in silico〈/em〉 study, the efficiency of the interaction of NJ series compounds with the NorA pump were evaluated. Derivatives from both series did not show considerable intrinsic antibacterial activity (MIC 〉 1024 μg/mL) against any of the tested strains. However, the NJ16 and NJ17 compounds, when associated with norfloxacin, reduced the MIC of this drug threefold and inhibited NorA pumps in the 1199B strain. Moreover, some NW (05, 10, 18, 19 and 21) and NJ compounds (16, 17, 18 and 20) presented low to moderate cytotoxicity against normal cells. Molecular docking studies supported the potent 〈em〉in vitro〈/em〉 inhibitory activity of NJ16 and NJ17, which showed NJ16 and NJ17 possessed more favorable binding energies of −9.03 Kcal/mol and −9.34 Kcal/mol, respectively. In addition, NJ16 showed different types of interactions involved in complex stabilization. In conclusion, NJ16 and NJ17, in combination with norfloxacin, were able to completely restore the antibacterial activity of norfloxacin against 〈em〉S. aureus〈/em〉 SA-1199B, the norA-overexpressing strain, with low cytotoxicity in normal cells.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961930481X-ga1.jpg" width="267" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 16〈/p〉 〈p〉Author(s): Tamila Galaka, Bruno N. Falcone, Catherine Li, Sergio H. Szajnman, Silvia N.J. Moreno, Roberto Docampo, Juan B. Rodriguez〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉As an extension of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically evaluated against 〈em〉Trypanosoma cruzi〈/em〉 and 〈em〉Toxoplasma gondii〈/em〉, the etiologic agents of these diseases, respectively. In particular, and based on the antiparasitic activity exhibited by 2-alkylaminoethyl-1,1-bisphosphonates targeting farnesyl diphosphate synthase, a series of linear 2-alkylaminomethyl-1,1-bisphosphonic acids (compounds 〈strong〉21〈/strong〉–〈strong〉33〈/strong〉), that is, the position of the amino group was one carbon closer to the 〈em〉gem〈/em〉-phosphonate moiety, were evaluated as growth inhibitors against the clinically more relevant dividing form (amastigotes) of 〈em〉T. cruzi〈/em〉. Although all of these compounds resulted to be devoid of antiparasitic activity, these results were valuable for a rigorous SAR study. In addition, unexpectedly, the synthetic designed 2-cycloalkylaminoethyl-1,1-bisphosphonic acids 〈strong〉47〈/strong〉–〈strong〉49〈/strong〉 were free of antiparasitic activity. Moreover, long chain sulfur-containing 1,1-bisphosphonic acids, such as compounds 〈strong〉54〈/strong〉–〈strong〉56〈/strong〉, 〈strong〉59〈/strong〉, turned out to be nanomolar growth inhibitors of tachyzoites of 〈em〉T. gondii〈/em〉. As many bisphosphonate-containing molecules are FDA-approved drugs for the treatment of bone resorption disorders, their potential nontoxicity makes them good candidates to control American trypanosomiasis and toxoplasmosis.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619307400-ga1.jpg" width="413" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Bin Zhong, Zeyin Jiang, Zhenhuang Chen, Kazue Ishihara, Huilin Mao, Shanghong Wang, Gang Lin, Chengyu Hu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Recently, studies have shown that IκB kinase β (IKKβ), a critical kinase in the nucleus factor kappa-B (NF-κB) pathway, participates in inflammatory responses associated with unfolded protein response (UPR) and plays an important role in ER stress-induced cell death. The unfolded protein response (UPR), which is a regulatory system to restore cellular homeostasis in the endoplasmic reticulum (ER), such as oxidative stress, bacterial infection, and virus invasion. The UPR pathways have been reported to be involved in immune responses in mammals, including the classical NF-κB pathway. However, the molecular mechanism of their crosstalk remains to be elucidated. Previously, we demonstrated that IKKβ also has some conserved functions between fish and human, as grass carp (〈em〉Ctenopharyngodon idella〈/em〉) IKKβ (CiIKKβ) can activate NF-κB pathway. In this study, we found that CiIKKβ level in nucleus was elevated under ER stress and CiIKKβ can interact with grass carp X-box-binding protein 1 (CiXBP1S), a key transcription factor in UPR. Consistently, fluorescent histochemical analysis of grass carp kidney (CIK) cells indicated that CiIKKβ and CiXBP1S colocalized under ER stress. Furthermore, overexpression of CiIKKβ in CIK cells enhanced ER stress tolerance by regulating UPR signaling and resulted in the significant increase of cell viability.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Lu-Yun Ni, Qing Han, Hong-Ping Chen, Xiao-Chun Luo, An-Xing Li, Xue-Ming Dan, Yan-Wei Li〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Macrophage expressed gene 1 (Mpeg1) is a molecule that can form pores and destroy the cell membrane of invading pathogens. In this study, we identified two Mpeg1 isoforms from the orange-spotted grouper (〈em〉Epinephelus coioides〈/em〉) and named them EcMpeg1a and EcMpeg1b. Predicted proteins of the two EcMpeg1s contained a signal peptide, a conserved membrane attack complex/perforin (MACPF) domain, a transmembrane segment, and an intracellular region. Sequence alignment demonstrated that two EcMpeg1 proteins share a high sequence identity with that of other teleosts. Tissue distribution analysis showed that EcMpeg1s were expressed in all tissues tested in healthy grouper, with the highest expression in the head kidney and spleen. After infection with the ciliate parasite 〈em〉Cryptocaryon irritans〈/em〉, expression of the two EcMpeg1s was significantly upregulated in the spleen and gills. Furthermore, the recombinant EcMpeg1a showed antiparasitic and antibacterial activity against Gram-negative and -positive bacteria, whereas EcMpeg1b had an inhibitory effect only against Gram-positive bacteria. These results indicated that EcMpeg1s play an important role in the host response against invading pathogens.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Pengfei Chu, Libo He, Cheng Yang, Wencheng Zeng, Rong Huang, Lanjie Liao, Yongming Li, Zuoyan Zhu, Yaping Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Autophagy is an essential and conserved process that plays an important role in physiological homeostasis, adaptive response to stress and the immune response. Autophagy-related proteins (ATGs) are key components of the autophagic machinery. In the study, grass carp (〈em〉Ctenopharyngodon idella〈/em〉) autophagy-related gene 5 (〈em〉ATG5〈/em〉) and 12 (〈em〉ATG12〈/em〉) were identified. In the gill and intestine, 〈em〉ATG5〈/em〉 and 〈em〉ATG12〈/em〉 were highly expressed, but after grass carp reovirus (GCRV) infection, they were decreased significantly. In 〈em〉Ctenopharyngodon idella〈/em〉 kidney (CIK) cells, the sharp variation of 〈em〉ATG5〈/em〉 and 〈em〉ATG12〈/em〉 expression was observed after poly(I:C) infection. Subcellular localisation showed that ATG5 and ATG12 were evenly distributed in the cytoplasm and nucleus. However, the interaction between ATG5 and ATG12 was only found in cytoplasm in both 293T cells and CIK cells. In addition, the overexpression of ATG5 or ATG12 in 293T cells showed enhanced autophagy, and autophagic process was facilitated when ATG5 and ATG12 were simultaneously overexpressed. Dual-luciferase activity assay indicated that both ATG5 and ATG12 remarkably suppressed the promoter activity of 〈em〉IRF3〈/em〉, 〈em〉IRF7〈/em〉, and 〈em〉IFN-I〈/em〉. Further, ATG5 and ATG12 conjugate showed far stronger inhibitory affection on the expression of 〈em〉IFN-I〈/em〉 than either ATG5 or ATG12 in response to poly(I:C) or GCRV infection. Taken together, the results demonstrate that grass carp ATG5 and ATG12 play an important role in innate immunity and autophagy.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Chao Xu, Wen-Bin Liu, Sofie Charlotte Remø, Bing-Ke Wang, Hua-Juan Shi, Li Zhang, Jia-Dai Liu, Xiang-Fei Li〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉This study investigated the effects of restricted feeding on the growth performance, oxidative stress and inflammation of 〈em〉Megalobrama amblycephala〈/em〉 fed high-carbohydrate (HC) diets. Fish (46.94 ± 0.04 g) were randomly assigned to four groups containing the satiation of a control diet (30% carbohydrate) and three satiate levels (100% (HC1), 80% (HC2) and 60% (HC3)) of the HC diets (43% carbohydrate) for 8 weeks. Results showed that HC1 diet remarkably decreased final weight (FW), weight gain rate (WGR), specific growth rate (SGR), feed conversion ratio (FCR), hepatic activities of total anti-oxidation capacity (T-AOC), superoxide dismutase (SOD) and catalase (CAT), the AMP/ATP ratio, the p-AMPKα/t-AMPKα ratio, sirtuin-1 (SIRT1) protein expression and hepatic transcriptions of AMPKα2, SIRT1, nuclear factor erythroid 2-related factor 2 (Nrf2), catalase (CAT), manganese superoxide dismutase (Mn-SOD), glutathione peroxidase 1 (GPx1) and interleukin10 (IL 10) compared to the control group, whereas the opposite was true for protein efficiency ratio (PER), nitrogen retention efficiency (NRE), energy retention efficiency (ERE), plasma glucose levels, alanine transaminase (AST) and aspartate aminotransferase (ALT) activities, hepatic contents of malondialdehyde (MDA), tumour necrosis factor α (TNF α) and interleukin 1β (IL 1β), ATP and AMP contents and hepatic transcriptions of kelch-like ECH associating protein 1 (Keap1), IkB kinase α (IKK α), nuclear factor kappa B (NF-κB), TNF α, IL 1β, interleukin 6 (IL 6) and transforming growth factor β (TGF β). As for the HC groups, fish fed the HC2 diet obtained relatively high values of SGR, PER, NRE, ERE, hepatic activities of T-AOC, SOD and CAT, the AMP/ATP ratio, the p-AMPKα/t-AMPKα ratio, SIRT1 protein expression and hepatic transcriptions of AMPKα2, Nrf2, CAT, copper/zinc superoxide dismutase (Cu/Zn-SOD), Mn-SOD, GPx1, glutathione S-transferase (GST) and interleukin10 (IL 10), while the opposite was true for hepatic content of IL 6 and transcription of IKK α. Overall, an 80% satiation improved the growth performance and alleviated the oxidative stress and inflammation of blunt snout bream fed HC diets via the activation of the AMPK-SIRT1 pathway and the up-regulation of the activities and transcriptions of Nrf2-modulated antioxidant enzymes coupled with the depression of the levels and transcriptions of the NF-κB-mediated pro-inflammatory cytokines.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): Jiangfan Zhang, Chuanju Dong, Junchang Feng, Junpeng Li, Shengjie Li, Jianxin Feng, Xiaodi Duan, Gaigai Sun, Peng Xu, Xuejun Li〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈em〉HIFs〈/em〉 (Hypoxia inducible factors) are the main regulators of the expression change of oxygen-dependent genes, in addition, they also play important roles in immune regulation. 〈em〉HIFs〈/em〉 participate in infectious diseases and inflammatory responses, providing us a new therapeutic target for the treatment of diseases. In this study, 16 〈em〉HIFs〈/em〉 were identified in common carp genome database. Comparative genomics analysis showed large expansion of 〈em〉HIF〈/em〉 gene family and approved the four round whole genome duplication (WGD) event in common carp. To further understand the function of 〈em〉HIFs〈/em〉, the domain architectures were predicted. All HIF proteins had the conserved HLH-PAS domain, which were essential for them to form dimer and bind to the downstream targets. The differences in domain of HIFα and HIFβ might result in their different functions. Phylogenetic analysis revealed that all 〈em〉HIFs〈/em〉 were divided into two subfamilies and the 〈em〉HIFs〈/em〉 in common carp were clustered with their teleost counterparts indicating they are highly conservative during evolution. In addition, the tissue distribution was examined by RT-PCR showed that most of 〈em〉HIF〈/em〉 genes had a wide range of tissue distribution but exhibited tissue-specific expression patterns. The expression divergences were observed between the copy genes, for example, 〈em〉HIF1A-1〈/em〉, 〈em〉HIF2A-1〈/em〉, 〈em〉ARNT-〈/em〉2 had wide tissue distribution while their copies had limited tissue distribution, proving the function divergence of copies post the WGD event. In order to find an effective activation of 〈em〉HIFs〈/em〉 and apply to treatment of aquatic diseases, we investigate the dietary supplementation effects of different strains of 〈em〉Lactococcus lactis〈/em〉 on the expression of 〈em〉HIFα〈/em〉 subfamily members in kidney of common carp infected with 〈em〉A. hydrophila〈/em〉. In addition, all of the 〈em〉HIF〈/em〉 genes have a high expression in the early stages of infection, and decreased in the treatment time point of 48 h in common carp. This phenomenon confirms that as a switch, the main function of 〈em〉HIFs〈/em〉 is to regulate the production of immune response factors in early infection. So activation of the switch may be an effective method for infectious disease treatment. As expected, the treatment groups improved the expression of 〈em〉HIFs〈/em〉 compared with the control group, and the effects of the three strains are different. The strain1 of 〈em〉L. lactis〈/em〉 had a stronger induction on 〈em〉HIF〈/em〉 genes than strain2 and strain3, and it might be applied as a potential activation of 〈em〉HIF〈/em〉 genes for disease treatment. So, adding befitting 〈em〉L. lactis〈/em〉 maybe a well method to activate the 〈em〉HIF〈/em〉 genes to protect them from mycobacterial infection.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 92〈/p〉 〈p〉Author(s): K.A.S.N. Shanaka, M.D. Neranjan Tharuka, Thanthrige Thiunuwan Priyathilaka, Jehee Lee〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Viperin, also known as RSAD2 (Radical S-adenosyl methionine domain containing 2), is an interferon-induced endoplasmic reticulum-associated antiviral protein. Previous studies have shown that viperin levels are elevated in the presence of viral RNA, but it has rarely been characterized in marine organisms. This study was designed to functionally characterize rockfish viperin (〈em〉SsVip〈/em〉), to examine the effects of different immune stimulants on its expression, and to determine its subcellular localization. SsVip is a 349 amino acid protein with a predicted molecular mass of 40.24 kDa. It contains an S-adenosyl 〈span〉l〈/span〉-methionine binding conserved domain with a CNYKCGFC sequence. Unchallenged tissue expression analysis using quantitative real time PCR (qPCR) revealed 〈em〉SsVip〈/em〉 expression to be the highest in the blood, followed by the spleen. When challenged with poly I:C, 〈em〉SsVip〈/em〉 was upregulated by approximately 60-fold in the blood after 24 h, and approximately 50-fold in the spleen after 12 h. Notable upregulation was detected throughout the poly I:C challenge experiment in both tissues. Significant expression of 〈em〉SsVip〈/em〉 was detected in the blood following 〈em〉Streptococcus iniae〈/em〉 and lipopolysaccharide challenge, and viral hemorrhagic septicemia virus (VHSV) gene transcription was significantly downregulated during SsVip overexpression. Furthermore, cell viability assay and virus titer quantification with the presence of SsVip revealed a significant reduction in virus replication. As with previously identified viperin counterparts, SsVip was localized in the endoplasmic reticulum. Our findings show that SsVip is an antiviral protein crucial to innate immune defense.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Jing Li, Zhi-Bin Wu, Zhao Zhang, Ji-Wei Zha, Shen-Ye Qu, Xiao-Zhou Qi, Gao-Xue Wang, Fei Ling〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nowadays, there is no suitable treatment for vibriosis in groupers. So an eco-efficient and environmentally friendly treatment is necessary for the grouper industry. Probiotic-feeding has been a promising strategy to control the bacterial pathogens in aquaculture. A new 〈em〉Bacillus velezensis〈/em〉 strain named K2 was isolated from the intestinal tract of healthy grouper, and exhibited wide antimicrobial spectrum of against fish pathogens, including 〈em〉Vibrio harveyi〈/em〉, 〈em〉Vibrio alginolyticus〈/em〉, 〈em〉Aeromonas hydrophila〈/em〉, 〈em〉Aeromonas veronii〈/em〉, 〈em〉Aeromonas caviae〈/em〉, 〈em〉Enterococcus casseliflavus〈/em〉 and 〈em〉Lactococcus garvieae〈/em〉. Moreover, results of the safety of 〈em〉B. velezensis〈/em〉 K2 showed that intraperitoneal injection of K2 in healthy grouper did not cause any pathological abnormality or death, indicating this bacteria could be considered as a candidate probiotic in aquaculture. Groupers were fed with the diets containing 1 × 10〈sup〉7〈/sup〉 cfu/g of 〈em〉B. velezensis〈/em〉 K2 for 4 weeks. Various immune parameters were examined at 1, 2, 3, and 4 weeks of post-feeding. Results showed that diets supplemented with K2 significantly increased serum acid phosphatase (ACP) activity (〈em〉P〈/em〉 〈 0.05). Results of the mRNA expression of immune-related genes in the head kidney of hybrid grouper showed that the expression of lysozyme gene was significantly upregulated after 1 and 2 weeks of feeding (〈em〉P〈/em〉 〈 0.05). A significant up-regulation of the expression of piscidin, IgM and MyD88 were detected at day 21, whereas the TLR3 and TLR5 showed lower expression compared to the controls during 21 days, and a significant decrease of TLR3 gene was found at day 28 (〈em〉P〈/em〉 〈 0.05). After challenge with 〈em〉V. harveyi〈/em〉, the survival rate of fish administrated with the strain K2 for 28 days was signifiacantly higher than the controls without this strain (〈em〉P〈/em〉 〈 0.05). These results collectively suggest that 〈em〉B. velezensis〈/em〉 K2 is a potential probiotic species to improve health status and disease resistance and can be developed as a probiotic agent in grouper industry.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Phennapa Promthale, Pattira Pongtippatee, Boonsirm Withyachumnarnkul, Kanokpan Wongprasert〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Fishmeal is the main source of protein in the shrimp feed industry and is normally derived from trash fish. As such, the production of fishmeal has an adverse effect on the marine environment by taking away small and juvenile fish, leading to depletion of marine species. There is a need for alternative sources of protein which will substitute fishmeal in the aquaculture industry. This study evaluated the components and nutritional efficacy of bioflocs, which were used to substitute fishmeal protein. The effect of bioflocs diets on growth performance, survival rate, and immune response in shrimp compared to normal fishmeal feed were determined. Bioflocs were harvested from the shrimp ponds (C:N ratio 〉12:1) at Shrimp Village, Chaiya district, Surat Thani, Thailand. The total protein in bioflocs was about 48% and the total lipid was about 5% (dried weight) and the percentages of essential amino acids (EAA) and fatty acids (EFA) in bioflocs were similar to those of fishmeal feed. Shrimp fed with the different dietary bioflocs feed regimens [% to replace fishmeal; 0% (B0), 25% (B25), 50% (B50), 75% (B75), and 100% (B100)] for 42 days revealed that all growth parameters were almost similar to those of the control shrimp (shrimp fed with normal fishmeal, B0) including final body weight, weight gain, specific growth rate, and feed conversion ratio. Remarkably, the survival rates, the levels of immune parameters, and expression of immune genes (proPO-I, PEN-4 and dicer) were significantly higher in bioflocs fed shrimp, especially in B25 and B50 shrimp. Moreover, B25 and B50 bioflocs fed shrimp showed notably increased survival rates following 〈em〉Vibrio parahaemolyticus (V. parahaemolyticus)〈/em〉 infection. In conclusion, the present study demonstrates that shrimp survival and immunity are enhanced by biofiocs substituted fishmeal. Significantly, the bioflocs diets activated the immune response to prevent 〈em〉V. parahaemolyticus〈/em〉 infection.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Sarah J. Poynter, Shanee Herrington-Krause, Stephanie J. DeWitte-Orr〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In mammals, the multifunctional DExH/D-box helicases, DDX3 and DHX9, are nucleic acid sensors with a role in antiviral immunity; their role in innate immunity in fish is not yet understood. In the present study, full-length DDX3 and DHX9 coding sequences were identified in rainbow trout (〈em〉Oncorhynchus mykiss)〈/em〉. Bioinformatic analysis demonstrated both deduced proteins were similar to those of other species, with ~80% identity to other fish species and ~70–75% identity to mammals, and both protein sequences had conserved domains found amongst all species. Phylogenetic analysis revealed clustering of DDX3 and DHX9 with corresponding proteins from other fish. Cellular localization of overexpressed DDX3 and DHX9 was performed using GFP-tagged proteins, and endogenous DDX3 localization was measured using immunocytochemistry. In the rainbow trout gonadal cell line, RTG-2, DHX9 localized mostly to the nucleus, while DDX3 was found mainly in the cytoplasm. Tissue distribution from healthy juvenile rainbow trout revealed ubiquitous constitutive expression, highest levels of DDX3 expression were seen in the liver and DHX9 levels were fairly consistent among all tissues tested. Stimulation of RTG-2 cells revealed that DDX3 and DHX9 transcripts were both significantly upregulated by treatment with the dsRNA molecule, poly I:C. A pull-down assay suggested both proteins were able to bind dsRNA. In addition to their roles in RNA metabolism, the conserved common domains found between the rainbow trout proteins and other species having defined antiviral roles, combined with the ability for the proteins to bind to dsRNA, suggest these proteins may play an important role in fish innate antiviral immunity. Future studies on both DDX3 and DHX9 function will contribute to a better understanding of teleost immunity.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: November 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 94〈/p〉 〈p〉Author(s): Ke-Cheng Zhu, Hua-Yang Guo, Nan Zhang, Bao-Suo Liu, Liang Guo, Shi-Gui Jiang, Dian-Chang Zhang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Interferon regulatory factor 8 (IRF8) increases type I IFN transcription levels by binding to IFN promoters, thereby playing a role in innate immunity. Nevertheless, the detailed mechanism through which IRF8 regulates type II IFN in fish remains ambiguous. In the present study, two genes from the golden pompano (〈em〉Trachinotus ovatus〈/em〉), 〈em〉IRF8〈/em〉 (〈em〉ToIRF8〈/em〉) and 〈em〉IFN gamma〈/em〉 (〈em〉ToIFNγ〈/em〉), were identified in the IFN/IRF-based signalling pathway. The full-length 〈em〉ToIRF8〈/em〉 cDNA was composed of 2,141 bp and encoded a 421 amino acid polypeptide; the genomic DNA was 2,917 bp in length and consisted of 8 exons and 7 introns. The putative protein showed the highest sequence identity (90–92%) with fish IRF8 and possessed a DNA-binding domain (DBD), an IRF-association domain (IAD) and a nuclear localization signal (NLS) motif consistent with those of IRF8 in other vertebrates. Furthermore, the 〈em〉ToIRF8〈/em〉 transcripts were expressed in all examined tissues of healthy fish, with higher levels observed in the central nervous and immune relevant tissues. They were upregulated by polyinosinic acid: polycytidylic acid [poly (I: C)], lipopolysaccharide (LPS) and flagellin treatments in the blood, liver, intestine and kidney. The results from assays of subcellular localization showed that 〈em〉ToIRF8〈/em〉 was localized to the cytoplasm. Moreover, to investigate whether ToIRF8 was a regulator of 〈em〉ToIFNγ〈/em〉, a promoter analysis was performed using progressive deletion mutations of 〈em〉ToIFNγ〈/em〉. The results indicated that the region from −601 bp to −468 bp includes the core promoter. Mutation analyses indicated that the activity of the 〈em〉ToIFNγ〈/em〉 promoter significantly decreased after the targeted mutation of the M1-M3 binding sites. Additionally, overexpressed 〈em〉ToIRF8〈/em〉 in vitro notably increased the expression of several IFN/IRF-based signalling pathway genes. These results suggest that 〈em〉IRF8〈/em〉 is vital in the defence of 〈em〉T. ovatus〈/em〉 against bacterial infection and contributes to a better understanding of the transcriptional mechanisms of ToIRF8 on type II IFN in fish.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 28 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Hong Chen, Jingxiao Zhang, Peixin Hu, Yuna Qian, Jing Li, Jianliang Shen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Prostate cancer (PCa) is a major cause of cancer-related male death in worldwide. To develop of potential anti-prostate cancer agents, 22 kinds of 4-Amino-2H-benzo[h]chromen-2-one analogs were designed and synthesized as potent androgen receptor (AR) antagonist through rational drug modification leading to the discovery of a series of novel antiproliferative compounds. Analogs (〈strong〉3〈/strong〉, 〈strong〉4〈/strong〉, 〈strong〉5〈/strong〉, 〈strong〉7〈/strong〉, 〈strong〉8〈/strong〉, 〈strong〉10〈/strong〉, 〈strong〉11〈/strong〉, 〈strong〉12〈/strong〉, 〈strong〉16〈/strong〉, 〈strong〉18〈/strong〉, 〈strong〉21〈/strong〉, 〈strong〉23〈/strong〉, and 〈strong〉24〈/strong〉) exhibited potent antagonistic potency against AR (inhibition 〉50%), and exhibited potent AR binding affinities as well as displayed the higher activities than finasteride toward LNCaP cells (AR-rich) 〈em〉versus〈/em〉 PC-3 cells (AR-deficient). Moreover, the docking study suggested that the most potent antagonist 〈strong〉23〈/strong〉 mainly bind to AR ligand binding pocket (LBP) site through Van der Waals' force interactions. The structure-activity relationship (SAR) of these designed 4-Amino-2H-benzo[h]chromen-2-one analogs was rationally explored and discussed. Collectively, this work provides a potential lead compound for anticancer agent development related to prostate cancer therapy, and took a step forward towards the development of novel and improved AR antagonists.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619311836-ga1.jpg" width="320" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Tetsuro Ikuta, Akihiro Tame, Masaki Saito, Yui Aoki, Yukiko Nagai, Makoto Sugimura, Koji Inoue, Katsunori Fujikura, Kazue Ohishi, Tadashi Maruyama, Takao Yoshida〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In symbiotic systems in which symbionts are transmitted horizontally, hosts must accept symbionts from the environment while defending themselves against invading pathogenic microorganisms. How they distinguish pathogens from symbionts and how the latter evade host immune defences are not clearly understood. Recognition of foreign materials is one of the most critical steps in stimulating immune responses, and pattern recognition receptors (PRRs) play vital roles in this process. In this study, we focused on a group of highly conserved PRRs, peptidoglycan recognition proteins (PGRPs), in the deep-sea mussel, 〈em〉Bathymodiolus septemdierum〈/em〉, which harbours chemosynthetic bacteria in their gill epithelial cells. We isolated 〈em〉B. septemdierum〈/em〉 PGRP genes 〈em〉BsPGRP-S〈/em〉 and 〈em〉BsPGRP-L〈/em〉, which encode a short- and a long-type PGRP, respectively. The short-type PGRP has a signal peptide and was expressed in the asymbiotic goblet mucous cells in the gill epithelium, whereas the long-type PGRP was predicted to include a transmembrane domain and was expressed in gill bacteriocytes. Based on these findings, we hypothesize that the secreted and transmembrane PGRPs are engaged in host defence against pathogenic bacteria and/or in the regulation of symbiosis via different cellular localizations and mechanisms.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Guilherme Rabelo Coelho, Pedro Prezotto Neto, Fernanda Cortinhas Barbosa, Rafael Silva Dos Santos, Patrícia Brigatte, Patrick Jack Spencer, Sandra Coccuzzo Sampaio, Fernanda D’Amélio, Daniel Carvalho Pimenta, Juliana Mozer Sciani〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Stingrays skin secretions are largely studied due to the human envenoming medical relevance of the sting puncture that evolves to inflammatory events, including necrosis. Such toxic effects can be correlated to the biochemical composition of the sting mucus, according to the literature. Fish skin plays important biological roles, such as the control of the osmotic pressure gradient, protection against mechanical forces and microorganism infections. The mucus, on the other hand, is a rich and complex fluid, acting on swimming, nutrition and the innate immune system. The elasmobranch's epidermis is a tissue composed mainly by mucus secretory cells, and marine stingrays have already been described to present secretory glands spread throughout the body. Little is known about the biochemical composition of the stingray mucus, but recent studies have corroborated the importance of mucus in the envenomation process. Aiming to assess the mucus composition, a new non-invasive mucus collection method was developed that focused on peptides and proteins, and biological assays were performed to analyze the toxic and immune activities of the 〈em〉Hypanus americanus〈/em〉 mucus. Pathophysiological characterization showed the presence of peptidases on the mucus, as well as the induction of edema and leukocyte recruitment in mice. The fractionated mucus improved phagocytosis on macrophages and showed antimicrobial activity against 〈em〉T. rubrumç. neoformans〈/em〉 and 〈em〉C. albicans in vitro〈/em〉. The proteomic analyses showed the presence of immune-related proteins like actin, histones, hemoglobin, and ribosomal proteins. This protein pattern is similar to those reported for other fish mucus and stingray venoms. This is the first report depicting the 〈em〉Hypanus〈/em〉 stingray mucus composition, highlighting its biochemical composition and importance for the stingray immune system and the possible role on the envenomation process.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Mariana Maluli Marinho de Mello, Camila de Fátima Pereira de Faria, Fábio Sabbadin Zanuzzo, Elisabeth Criscuolo Urbinati〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In this study, we show that β-glucan can modulate cortisol release in fish. We simulated a common situation in aquaculture: the transport of fish followed by contact with an opportunistic pathogen and observed what effect glucan had on the immune and stress response in these conditions. Pacu (〈em〉Piaractus mesopotamicus〈/em〉) were fed with a diet containing β-glucan (0.1%) for 15 days prior to transport followed by an injection with heat-killed 〈em〉Aeromonas hydrophila.〈/em〉 We sampled fish before transport, at arrival and at 3 and 24 h after bacterial injection. β-Glucans are used in aquaculture and have a known immunostimulatory effect, which was observed in this study. The results showed that β-glucan modulated the plasma cortisol levels differently by increasing these levels up to 24 h after transport and preventing the increase caused by bacterial inoculum injection. In addition, β-glucan enhanced the activity of the complement system at 24 h and reduced the monocytes and lymphocytes number in peripheral blood at 3 and 24 h after bacterial inoculation. Our results suggest that β-glucan modulated a bidirectional interaction between the stress and the immune responses. The modulation of cortisol levels and the immunostimulation by β-glucan at different moments in our study suggest the compound has a protective effect by avoiding higher levels of the hormone and improving resistance against bacterial infection in pacu. These results add evidence to support the use of β-glucan as an immunomodulator in the aquaculture industry.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Min Sun Kim, Ki Hong Kim〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Although the type I interferon-mediated increase of Mx1 and ISG15 gene expression in Epithelioma papulosum cyprini (EPC) cells has been reported, the antiviral role of Mx1 and ISG15 in EPC cells has not been investigated. In this study, to know the anti-viral hemorrhagic septicemia virus (VHSV) role of Mx1 and ISG15 of EPC cells, either Mx1 or ISG15 gene was knocked-out using a CRISPR/Cas9 system, and the progression of cytopathic effects (CPE) and viral growth were analyzed. Mx1 gene and ISG15 gene knockout EPC cells were successfully produced via CRISPR/Cas9 coupled with a single-cell cloning. Through the sequence analysis, one clone showing two heterozygous indel patterns in Mx1 gene and a clone showing three heterozygous indel patterns in ISG15 gene were selected for further analyses. Mx1 knockout EPC cells did not show any differences in VHSV-mediated CPE progression, even when pre-treated with polyinosinic:polycytidylic acid (poly I:C), compared to control EPC cells. These results suggest that Mx1 in EPC cells may be unfunctional to cytoplasmic RNA viruses. In contrast to Mx1, ISG15 knockout cells showed clearly hampered anti-VHSV activity even when pre-treated with poly I:C, indicating that ISG15 plays an important role in type I interferon-mediated anti-viral activity in EPC cells, which allowed VHSV to replicate more efficiently in ISG15 knockout cells than Mx1 knockout and control cells.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: November 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 94〈/p〉 〈p〉Author(s): José Luis Sánchez-Salgado, Mohamed Alí Pereyra, Concepción Agundis, Montserrat Calzada-Ruiz, Erika Kantun-Briceño, Edgar Zenteno〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In crustaceans, it has been suggested that specific protection against pathogens could be triggered by vaccines and biological response modifiers; although the specific mechanisms of this protection have not been clarified yet. In the crayfish 〈em〉Cherax quadricarinatus〈/em〉, a humoral lectin (CqL) binds its own granular hemocytes through a specific receptor (CqLR) and increases the production of reactive oxygen species (ROS). In the present study, we challenged 〈em〉in vivo〈/em〉 crayfishes with immunostimulants, β-glucan (200 μg/kg) or LPS (20 μg/kg), and identified the participation of cellular and humoral mechanisms. The stimulants generated a complex modification in the total hemocytes count (THC), as well as in the proportion of hemocyte subsets. At 2 h after the challenge, the largest value in THC was observed in either challenged crayfishes. Furthermore, at the same time, hyaline hemocytes were the most abundant subset in the hemolymph; after 6 h, granular hemocytes (GH) were the most abundant hemocyte subset. It has been observed that a specific subset of GH possesses a CqLR that has been related to ROS production. After 2 and 6 h of the β-glucan challenge, a significant increase in CqLR expression was observed in the three circulating hemocyte subsets; also, an increased expression of CqL was detected in a granular hemocytes sub-population. After 2 and 6 h of stimulation, the specific activity of the serum lectin challenged with β-glucan was 250% and 160% higher than in the LPS-treated-group, respectively (〈em〉P〈/em〉 〈 0.05). Hemocytes from challenged crayfishes were stimulated 〈em〉ex vivo〈/em〉 with CqL, ROS production was 180% higher in hemocytes treated with β-glucan + CqL than in hemocytes treated with LPS + CqL (〈em〉P〈/em〉 〈 0.05). The results evidence the effectivity of immune stimulators to activate specific crayfish defense mechanisms, the participation of CqL and its receptor (CqLR) could play an important role in the regulation of immune cellular functions, like ROS production, in 〈em〉Cherax quadricarinatus〈/em〉.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Nikolai Mugue, Nadezhda Terekhanova, Sergey Afanasyev, Aleksei Krasnov〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Sturgeons represent a substantial scientific interest due to their high economic value, endangered status and also as the most primitive group of ray-finned fishes. Rapid progress in knowledge of sturgeon immunity was achieved recently with use of RNA sequencing. We report transcriptome sequencing of gill, head kidney, and spleen of bester sturgeon (a hybrid of beluga 〈em〉Huso huso〈/em〉 and sterlet 〈em〉Acipen〈/em〉s〈em〉er ruthenus〈/em〉) injected with synthetic double-stranded RNA (polyI:C). The composition of transcriptome and responses to treatment were examined in the context of comparative genomics with focus on immune genes. Sturgeon transcripts matched to 21.5 k different proteins (blastx). With reference to Atlantic salmon, the functional groups and pathways of the immune system were uniformly represented: at average 36.5 ± 0.8% genes were found. Immune genes comprise a significant fraction of transcriptome. Among twenty genes with highest transcription levels, five are specialized immune genes and two encode heme and iron binding proteins (〈em〉serotransferrin〈/em〉 and 〈em〉hemopexin〈/em〉) also known as acute phase proteins. Challenge induced multiple functional groups including apoptosis, cell cycle and a number of metabolic pathways. Treatment stimulated innate antiviral immunity, which is well conserved between sturgeon and salmon, the most responsive genes were 〈em〉mx, rsad2 (viperin)〈/em〉, 〈em〉interferon induced protein 44〈/em〉 and 〈em〉protein with tetratricopeptide repeats 5〈/em〉, 〈em〉cd87〈/em〉 and 〈em〉receptor transporting protein 3〈/em〉. Results added to knowledge of immune phylogeny. Gain and loss of genes was assessed by comparison with genomes from different phylogenetic groups. Among differentially expressed genes, percentage of acquired and lost genes was much lower in comparison with genes present in all vertebrates. Innate antiviral immunity was subject to the greatest changes in evolution of jawed vertebrates. A significant fraction of genes (15%) was lost in mammals and only half of genes is annotated in public databases as involved in antiviral responses. Change of function may have an important role in evolution of immunity together with gain and loss of genes.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Malene Soleng, Lill-Heidi Johansen, Hanne Johnsen, Gunhild S. Johansson, Mette W. Breiland, Lisbeth Rørmark, Karin Pittman, Lars-Flemming Pedersen, Carlo C. Lazado〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Peracetic acid (PAA), a strong organic peroxide, is considered a relatively sustainable disinfectant in aquaculture because of its broad effectivity against many pathogens at low concentrations and because it degrades spontaneously to harmless residues. The impacts of PAA on fish health must be determined before its use as either a routine disinfectant or chemotherapeutant. Here we investigated the systemic and mucosal stress responses of Atlantic salmon (〈em〉Salmo salar〈/em〉) to PAA. In experiment 1, salmon were exposed to different nominal concentrations (0, 0.6, and 2.4 ppm) of PAA for 5 min, followed by a re-exposure to the same concentrations for 30 min 2 weeks later. Sampling was performed before exposure to PAA and at 2 h, 48 h, and 2 w after exposures. In experiment 2, fish were subjected to crowding stress prior to PAA exposure at 4.8 ppm for 30 min. The fish were sampled before exposure and 1 h, 4 h, and 2 w after. The two trials were performed in a recirculation system. Both systemic (i.e., plasma cortisol, glucose, lactate, total antioxidant capacity) and mucosal (i.e., expression of antioxidant coding genes in the skin and gills) stress indicators were affected by the treatments at varying levels, and it was apparent that the fish were able to mount a robust response to the physiological demands of PAA exposure. The cortisol levels increased in the early hours after exposure and returned to basal level afterwards. Prior exposure history to PAA did not markedly affect the levels of plasma lactate and glucose when fish were re-exposed to PAA. Crowding stress before PAA treatment, however, did alter some of the stress indicators (i.e., lactate, glucose and expression of antioxidant genes in the gills), suggesting that stress history serves as both a confounding and compounding factor on how stress responses to PAA are mobilised. Nonetheless, the changes were not substantial. Gene expression profile analyses revealed that the antioxidant system was more responsive to PAA in the gills than in the skin. The increased antioxidant capacity in the plasma, particularly at 2.4 ppm and higher, indicates that antioxidants were produced to neutralise the internal redox imbalance resulting from PAA exposure. In conclusion, the results show that salmon were able to mount a robust adaptive response to different PAA doses and exposure times, and a combined exposure to stress and PAA. These results underscore the potential of PAA as a chemotherapeutant for salmon at PAA concentrations commonly applied to control parasitic infestations.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Zhiwei Cao, Sijia Liu, Hao Nan, Kaixia Zhao, Xiaodong Xu, Gaoxue Wang, Hong Ji, Hongying Chen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Cyprinid herpesvirus 2 (CyHV-2) is the causative pathogen of herpesviral haematopoietic necrosis disease, which has caused huge economic losses to aquaculture industry in China. In this study, nine truncated CyHV-2 membrane glycoproteins (ORF25, ORF25C, ORF25D, ORF30, ORF124, ORF131, ORF136, ORF142A, ORF146) and a GFP reporter protein were respectively expressed using baculovirus surface displaying system. Western blot showed that the proteins were successfully packaged in the recombinant virus particles. In baculovirus transduced gibel carp kidney cells, the target proteins were expressed and displayed on the fish cell surface. Healthy gibel carp were immunized by immersion with the recombinant baculoviruses and the fish treated with phosphate-buffered saline (PBS) were served as mock group. The expression of 〈em〉interleukin-11〈/em〉 (〈em〉IL-11〈/em〉), 〈em〉interferon α〈/em〉 (〈em〉IFNα〈/em〉) and a complement component gene 〈em〉C3〈/em〉 were significantly up-regulated in most experimental groups, and 〈em〉interferon γ〈/em〉 (〈em〉IFNγ〈/em〉) expression in some groups were also induced after immunization. Subsequently, the immunized gibel carp were challenged by intraperitoneal injection of CyHV-2 virus. All the immunized groups exhibited reduced mortality after CyHV-2 challenge. In the groups immunized with baculoviruses displaying and expressing ORF25, ORF25C and ORF146, the relative percentage survival values reached 83.3%, 87.5% and 70.8%, respectively. Our data suggested that baculovirus-displayed ORF25, ORF25C and ORF146 could be potential vaccine candidates for the prevention of CyHV-2 infection in gibel carp.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Armando Vega-López, Nataraj S. Pagadala, Brenda P. López-Tapia, Ruth L. Madera-Sandoval, Erika Rosales-Cruz, Minerva Nájera-Martínez, Elba Reyes-Maldonado〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The signaling mediated by small non-proteinogenic molecules, which probably have the capacity to serve as a bridge amongst complex systems is one of the most exiting challenges for the study. In the current report, stem cells differentiation of the immune system in Nile tilapia treated with sub-basal doses of GABA evaluated as c-kit〈sup〉+〈/sup〉 and Sca-1〈sup〉+〈/sup〉 cells disappearance on pronephros, thymus, spleen and peripheral blood mononuclear cells by flow cytometry was assessed. Explanation of biological response was performed by molecular docking approach and multiparametric analysis. Stem cell differentiation depends on a delicate balance of negative and positive interactions of this neurotransmitter with receptors and transcription factors involved in this process. This in turn depends on the type of interaction with hematopoietic niche to differentiate into primordial, early or late hematopoiesis as well as from the dose delivery. In fish treated with the low doses of GABA (0.1% over basal value) primordial hematopoiesis is regulated by interaction of glutamate (Glu) with the Ly-6 antigen. Early hematopoiesis was influenced by the bond of GABA near or adjacent to turns of FLTR3-Ig-IV domain. During late hematopoiesis, negative regulation by structural modifications on PU.1/IRF-4 complex, IL-7Rα and GM-CSFR mainly prevails. Results of molecular docking were in agreement with the percentages of the main blood cells lineages estimated in pronephros by flow cytometry. Current study provides the first evidences about the role of inhibitory and excitatory neurotransmitters such as GABA and Glu, respectively with the most transcriptional factors and receptors involved on hematopoiesis in adult Nile tilapia.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S1050464819308320-fx1.jpg" width="266" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Xianyun Ren, Yunbin Zhang, Ping Liu, Jian Li〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉This study aimed to use isobaric tags (IBTs) to investigate the immune response of the hepatopancreas of 〈em〉Marsupenaeus japonicas〈/em〉 infected with 〈em〉Vibrio parahaemolyticus〈/em〉 or white spot syndrome virus (WSSV). Liquid chromatography-tandem mass spectrometry and protein sequencing identified 1005 proteins. Among them, 109 proteins were upregulated and 94 were downregulated after 〈em〉V. parahaemolyticus〈/em〉 infection. After WSSV infection, 130 proteins were identified as differentially abundant, including 88 that were upregulated and 42 were downregulated. Fifty-four proteins were identified as differentially abundant after both 〈em〉V. parahaemolyticus〈/em〉 and WSSV infection. A number of proteins related to cytoskeletal processes, including actin and myosin, and apoptosis-related proteins were upregulated in shrimp after 〈em〉V. parahaemolyticus〈/em〉 and WSSV infection, indicating that phagocytosis and apoptosis may be involved in the response to in 〈em〉V. parahaemolyticus〈/em〉 or WSSV infection. Quantitative real-time PCR was carried out to verify the reliability of the proteomic data. These data provide a basis to characterize the immunity-related processes of shrimp in response to infection with WSSV or 〈em〉V. parahaemolyticus〈/em〉.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Rostislav Kuskovsky, Dina Lloyd, Kriti Arora, Balbina J. Plotkin, Jacalyn M. Green, Helena I. Boshoff, Clifton Barry, Jeffrey Deschamps, Monika I. Konaklieva〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉C4-phenylthio β-lactams are a new family of antibacterial agents that have activity against two phylogenetically distant bacteria – 〈em〉Mycobacterium tuberculosis〈/em〉 (Mtb) and 〈em〉Moraxella catarrhalis〈/em〉 (M. cat). These compounds are effective against β-lactamase producing Mtb and M. cat unlike the clinically relevant β-lactam antibiotics. The structure-activity relationship for the C4 phenylthio β-lactams has not yet been completely defined. Earlier efforts in our laboratories established that the C4-phenylthio substituent is essential for antimicrobial activity, while the N1 carbamyl substituent plays a more subtle role. In this present study, we investigated the role that the stereochemistry at C4 plays in these compounds’ antibacterial activity. This was achieved by synthesizing and testing the antimicrobial activity of diastereomers with a chiral carbamyl group at N1. Our findings indicate that a strict stereochemistry for the C4-phenylthio β-lactams is not required to obtain optimal anti-Mtb and anti-M. cat activity. Furthermore, the structure–bioactivity profiles more closely relate to the electronic requirement of the phenylthiogroup. In addition, the MICs of Mtb are sensitive to growth medium composition. Select compounds showed activity against non-replicating and multi-drug resistant Mtb.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619307539-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 21 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Hongrui Lei, Fang Jia, Meng Cao, Jie Wang, Ming Guo, Minglin Zhu, Daiying Zuo, Xin Zhai〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The pyrimidine-2,4-diamine analogs exerted excellent activities in down-regulation of ALK phosphorylation. However, the prevalent drug-resistant site-mutation has gradually prevented the agents from being widely used. Herein, we conducted an exploration of high affinity moiety that bound to the solvent-front region (G1202R located) within the ATP binding site of ALK leading to the synthesis of thirty-five pyrimidine-2,4-diamine derivatives. Among these compounds, urea group was extensively derivatized which finally resulted in the identification of the ‘semi-free urea’ compound 〈strong〉39〈/strong〉. All compounds were assayed cytotoxicity and enzymatic activities and 〈strong〉39〈/strong〉 turned out to be the most potent one with IC〈sub〉50〈/sub〉 values of 2.1, 0.91, 4.3 and 0.73 nM towards ALK〈sup〉wt〈/sup〉, ALK〈sup〉L1196M〈/sup〉, ALK〈sup〉G1202R〈/sup〉 and ROS1, respectively. The performances of 〈strong〉39〈/strong〉 on ALK- & ROS1-dependent cell lines were in good accordance with enzymatic activities with IC〈sub〉50〈/sub〉 values below 0.06 µM. Besides, 〈strong〉39〈/strong〉 induced cell apoptosis in a dose-dependent manner in H2228 cells. Finally, the binding models of 〈strong〉39〈/strong〉 with ALK〈sup〉wt〈/sup〉, ROS1, ALK〈sup〉L1196M〈/sup〉 and ALK〈sup〉G1202R〈/sup〉 were ideally established which further clearly elucidated their mode of action within the active site.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619311228-ga1.jpg" width="401" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: November 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 94〈/p〉 〈p〉Author(s): Jiajia Yu, Hongxia Wang, Xin Yue, Baozhong Liu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈em〉Meretrix petechialis〈/em〉 is an important commercial aquaculture species in China. During the clam culture period, mass mortality events often occurred due to the 〈em〉Vibrio〈/em〉 infection. In this paper, 〈em〉M. petechialis〈/em〉 were challenged with 〈em〉Vibrio parahaemolyticus〈/em〉 immersion to simulate a natural infection, and the infection process were divided into four phases including latency, prodrome, onset and recovery phases based on the clam mortality data. Then, the dynamic response of clams to 〈em〉Vibrio〈/em〉 infection at different infection phases were investigated by transcriptome analysis. A total of 38,067 differentially expressed genes (DEGs) were identified at different infection phases. DEG annotations showed that immune-related and metabolism-related signaling pathways were enriched, indicating that immune defense and metabolism process play key roles during bacterial infection. Three kinds of expression pattern were classified by cluster analysis, including U-shape, L-shape and inverted V-shape. Anabolism and cellular growth proliferation related signaling pathways were repressed (long-lasting or transient) during bacterial infection. However, the immune related signaling pathways with different immune functions showed induction expression or repression expression against bacterial infection, which indicated that immune system take different strategies against bacterial infection. Furthermore, some signaling pathways such as PI3K-Akt signaling pathway both involved in immune defense and cell metabolism. This study provides a sight that the dynamic immunity and metabolic responses may be integrated to improve the host survival and shift more energy for immune defense.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 28 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Juliana C. Gomes, Lorenzo Cianni, Jean Ribeiro, Fernanda dos Reis Rocho, Samelyn da Costa Martins Silva, Pedro Henrique Jatai Batista, Carolina Borsoi Moraes, Caio Haddad Franco, Lucio H.G. Freitas-Junior, Peter W. Kenny, Andrei Leitão, Antonio C.B. Burtoloso, Daniela de Vita, Carlos A. Montanari〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly non-additive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the non-additivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619310041-ga1.jpg" width="369" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Guang-hua Wang, Zhao-xia Li, En-mian Guo, Jing-jing Wang, Min Zhang, Yong-hua Hu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Calreticulin (CRT) is a highly conserved and multi-functional protein with diverse localizations. CRT has lectin-like properties and possesses important immunological activities in mammalian. In teleost, very limited studies on CRT immunologic function have been documented. In the present study, a CRT homologue (SsCRT) was cloned, identified and characterized from black rockfish, 〈em〉Sebastes schlegeli〈/em〉, an important aquaculture species in East Asia. The full length of 〈em〉SsCRT〈/em〉 cDNA is 2180 bp and encoded a polypeptide of 425 amino acids. SsCRT contains a signal peptide, three distinct structural and functional domains (N-, P- and C-domains), and an endoplasmic reticulum (ER) retrieval signal sequence (KDEL). The deduced amino acid sequence of SsCRT shares 89–92% overall sequence identities with the CRT proteins of several fish species. 〈em〉SsCRT〈/em〉 was distributed ubiquitously in all the detected tissues and was highly expressed in the spleen, muscle and liver. After the infection of fish extracellular bacterial pathogen 〈em〉Vibrio anguillarum〈/em〉 and intracellular bacterial pathogen 〈em〉Edwardsiella tarda〈/em〉, the mRNA transcripts of 〈em〉SsCRT〈/em〉 in spleen, liver, and head kidney were significantly up-regulated. The expression patterns were time-dependent and tissue-dependent. Recombinant SsCRT (rSsCRT) exhibited apparent binding activities against different bacteria and PAMPs. 〈em〉In vivo〈/em〉 studies showed that the expressions of multiple immune-related genes such as TNF13B, IL-1β, IL-8, SAA, Hsp70, and ISG15 in head kidney were significantly enhanced when black rockfish were treated with rSsCRT. Furthermore, rSsCRT reduced pathogen dissemination and replication in fish kidney and spleen. These results indicated that SsCRT served as an immune receptor to recognize and eliminate the invading pathogens, which played a vital role in the immune response of 〈em〉Sebastes schlegeli〈/em〉. These findings provide new insights into understanding the roles of CRT proteins in immune response and pathogen infection in teleost.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Ying Wu, Yongcan Zhou, Zhenjie Cao, Yun Sun, Yang Chen, Yajing Xiang, Lu Wang, Shengnan Zhang, Weiliang Guo〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Interleukins (ILs) are a subgroup of cytokines, which are molecules involved in the intercellular regulation of the immune system. These cytokines have been extensively studied in mammalian models, but systematic analyses of fish are limited. In the current study, 3 IL genes from golden pompano (〈em〉Trachinotus ovatus〈/em〉) were characterized. The IL-1β protein contains IL-1 family signature motif, and four long helices (αA - αD) in IL-11 and IL-34, which were well conserved. All 3 ILs clustered phylogenetically with their respective IL relatives in mammalian and other teleost species. Under normal physiological conditions, the expression of IL-1β, IL-11, and IL-34 were detected at varied levels in the 11 tissues examined. Most of the 3 ILs examined were highly expressed in liver, spleen, kidney, gill, or skin. Following pathogenic bacterial, viral, or parasitic challenge, IL-1β, IL-11, and IL-34 exhibited distinctly different expression profiles in a time-, tissue-, and pathogen-dependent manner. In general, IL-1β was expressed at higher levels following challenge with all pathogens examined than was observed for IL-11 and IL-34. Furthermore, 〈em〉Streptococcus agalactiae〈/em〉 and 〈em〉Cryptocaryon irritans〈/em〉 caused higher levels of IL-1β and IL-11 expression than 〈em〉Vibrio harveyi〈/em〉 and viral nervous necrosis virus (VNNV). The increased expression of IL-34 caused by VNNV and 〈em〉C. irritans〈/em〉 were higher than that caused by 〈em〉V. harveyi〈/em〉 and 〈em〉S. agalactiae〈/em〉. These results suggest that these 3 ILs in 〈em〉T. ovatus〈/em〉 may play different effect pathogen type specific responses.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Dinglong Yang, Yijing Han, Lizhu Chen, Ruiwen Cao, Qing Wang, Zhijun Dong, Hui Liu, Xiaoli Zhang, Qianqian Zhang, Jianmin Zhao〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Bactericidal permeability-increasing protein (BPI) is an antimicrobial protein with potent endotoxin-neutralising activity and plays a crucial role in innate immunity against bacterial infection. In the present study, a 〈em〉bpi〈/em〉 (designed as 〈em〉rpbpi〈/em〉) was identified and characterized from manila clam 〈em〉Ruditapes philippinarum〈/em〉. Multiple alignments and phylogenetic analysis suggested that 〈em〉rpbpi〈/em〉 was a new member of the 〈em〉bpis〈/em〉 family. In non-stimulated clams, 〈em〉rpbpi〈/em〉 transcripts were ubiquitously expressed in all tested tissues with the highest expression level in hemocytes. After 〈em〉Vibrio anguillarum〈/em〉 challenge, the expression levels of 〈em〉rpbpi〈/em〉 mRNA in hemocytes were up-regulated significantly at 3 h and 48 h compared with that in the control, which were 4.01- and 19.10-fold (〈em〉P〈/em〉 〈 0.05), respectively. The recombinant RpBPI (rRpBPI) showed high antibacterial activities against Gram-negative bacteria 〈em〉Escherichia coli〈/em〉 and 〈em〉V. anguillarum〈/em〉, but not 〈em〉Staphylococcus aureus〈/em〉. Moreover, membrane integrity analysis revealed that rRpBPI increased the membrane permeability of Gram-negative bacteria, and then resulted in cell death. Overall, our results suggested that RpBPI played an important role in the elimination of invaded bacteria through membrane-disruptive activity.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Wenlin Wu, Congjie Dai, Xunwei Duan, Cuifang Wang, Xiaosi Lin, Jiaying Ke, Yixuan Wang, Xiaobo Zhang, Haipeng Liu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉White shrimp 〈em〉Litopenaeus vannamei〈/em〉 are widely cultured in the world and white spot syndrome virus (WSSV) led to huge economic losses in the shrimp industry every year. In the present study, miRNAs involved in the response of shrimp 〈em〉L. vannamei〈/em〉 to WSSV infection were obtained through the Illumina HiSeq 2500 high-throughput next-generation sequencing technique. A total number of 7 known miRNAs and 54 putative novel miRNAs were obtained. Among them, 14 DEMs were identified in the shrimp infected with WSSV. The putative target genes of these DEMs were related to host immune response or signaling pathways, indicating the importance of miRNAs in shrimp against WSSV infection. The results will provide information for further research on shrimp response to virus infection and contribute to the development of new strategies for effective protection against WSSV infections.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Rahul Krishnan, Syed Shariq Nazir Qadiri, Myung-Joo Oh〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nectin-4/PVRL4 belonging to the family of immunoglobulin-like cell adhesion molecules was identified as a potential cellular receptor for several animal viruses. Here we show that nervous necrosis virus that causes viral nervous necrosis in teleosts uses the same receptor in its life cycle. Transfection of SSN-1 cell lines with an expression vector encoding Nectin-4 rendered them to be more susceptible to NNV. Immunofluorescence microscopy on Nectin-4 expressing cells revealed that the protein interacted with NNV specifically. A virus binding assay indicated that Nectin-4 was a bonafide receptor that supported virus attachment to the host cell whereas siRNA directed against Nectin-4 blocked NNV infections in grouper primary brain cells. Results of the present study will improve our understanding of the pathogenesis of NNV infection and provide a target for the development of novel antiviral interventions in marine finfish aquaculture.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Jun Di, Zhipeng Chu, Shuhuan Zhang, Jun Huang, Hao Du, Qiwei Wei〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In the present study, we aimed to screen the potential probiotic 〈em〉Bacillus subtilis〈/em〉 isolated from the gut of healthy fish using 〈em〉in vitro〈/em〉 assays and to evaluate its effect on Dabry's sturgeon (〈em〉Acipenser dabryanus〈/em〉) using 〈em〉in vivo〈/em〉 feeding experiments. Among the isolates, 〈em〉B. subtilis〈/em〉 BSth-5 and BSth-19 exhibited antimicrobial effect against four sturgeon-pathogenic bacteria, including 〈em〉Aeromonas hydrophila〈/em〉, 〈em〉A. veronii〈/em〉, 〈em〉A. media〈/em〉, and 〈em〉Streptococcus iniae〈/em〉. The cell number of 〈em〉B. subtilis〈/em〉 BSth-5 and BSth-19 changed little after 2 h of exposure to pH 3.0 or fresh Dabry's sturgeon bile at 2.5% and 5.0%. Meanwhile, 〈em〉B. subtilis〈/em〉 BSth-5 and BSth-19 produced extracellular protease, cellulose, and lipase. And it was proved that 〈em〉B. subtilis〈/em〉 BSth-5 and BSth-19 were harmless after injection of Dabry's sturgeon. One group of Dabry's sturgeon was fed a control diet and two groups were fed experimental diets containing 2.0 × 10〈sup〉8〈/sup〉 CFU/g BSth-5 (T1 group) or BSth-19 (T2 group) for 8 weeks. No significant differences in final weight, weight gain rate, and special growth rate were observed in the T1 and T2 groups compared to the control group (〈em〉P〈/em〉 〉 0.05), but a significant improvement in survival rate was detected after 4 and 8 weeks of feeding (〈em〉P〈/em〉 〈 0.05). After 8 weeks, serum total antioxidant capacity, total superoxide dismutase activity, and IgM levels were significantly higher in the T1 and T2 groups compared to the control group (〈em〉P〈/em〉 〈 0.05). Moreover, serum lysozyme activity was significantly higher in the T1 group relative to the control group during the whole experiment period (〈em〉P〈/em〉 〈 0.05); however, the differences were not significant between the T2 and control groups (〈em〉P〈/em〉 〉 0.05). Serum malondialdehyde levels in the T1 and T2 groups were significantly lower than those in the control group after 4 weeks (〈em〉P〈/em〉 〈 0.05). Sturgeons in the T1 and T2 groups showed a higher survival rate after 〈em〉Aeromonas hydrophila〈/em〉 infection. To summarize, dietary supplementation with BSth-5 and BSth-19 could enhance the survival rate, antioxidant activity, serum immunity, and disease resistance in 〈em〉A. dabryanus〈/em〉.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S1050464819308204-fx1.jpg" width="388" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Håvard Bjørgen, Oskar Mongstad Løken, Ida Bergva Aas, Per Gunnar Fjelldal, Tom Hansen, Lars Austbø, Erling Olaf Koppang〈/p〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Pan Wu, Weiguang Yang, Yuying Dong, Yanling Wang, Ying Zhang, Xuejun Zou, Hui Ge, Dongxue Hu, Yubo Cui, Zhaobo Chen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Application of traditional bait in aquaculture caused environment pollution and disease frequent occurrence. Residual coconut could be re-utilized to culture Spinibarbus sinensis as dietary supplement. Therefore, a novel integrated system of the improvement of yield, antioxidant and nonspecific immunity of Spinibarbus sinensis by dietary residual coconut was proposed and investigated. Spinibarbus sinensis could grow well in all supplement residual coconut groups. Survival rate, yield, whole fish body composition under 15–45% groups were increased compared with control group (CK). Bioactive substances (polyphenols and vitamin) in residual coconut enhanced AKP, ACP, phagocytic, SOD, CAT activities through up-regulating 〈em〉AKP, ACP, SOD, CAT〈/em〉 genes expression levels. Theoretical analysis showed bioactive substances regulated these genes expressions and enzyme activities as stimulus signal, component, active center. Moreover, residual coconut improved mTOR and NF-kB signaling pathway. Furthermore, residual coconut inhibited 〈em〉Aeromonas hydrophila〈/em〉 that increased resistance to diseases. This technology completed the solid waste recovery and the Spinibarbus sinensis culture simultaneously.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Jianting Lu, Xianyong Bu, Shusheng Xiao, Zhideng Lin, Xinyue Wang, Yongyi Jia, Xiaodan Wang, Jian G. Qin, Liqiao Chen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉This study evaluates the effect of dietary supplementation of immunostimulants on the Chinese mitten crab (〈em〉Eriocheir sinensis〈/em〉) with a single administration of mannan oligosaccharide (MOS), or its combination with either β-glucan or with inulin for 8 weeks. Four diets included an untreated control diet (C), MOS alone (3 g kg〈sup〉−1〈/sup〉, M), MOS with β-glucan (3 g kg 〈sup〉−1〈/sup〉 MOS + 1.5 g kg 〈sup〉−1〈/sup〉 β-glucan, MB), and MOS with inulin (3 g kg 〈sup〉−1〈/sup〉 MOS + 10 g kg 〈sup〉−1〈/sup〉 inulin, MI). The weight gain and specific growth rate of the crabs fed M, MB, and MI diets were improved by lowing feed conversion ratio. The growth and feed utilization of the crabs fed the MB diet were improved compared with the other three groups. The crabs fed the M, MB and MI diets showed a higher intestinal trypsin activity than that in the M and control groups. The highest trypsin activity in the hepatopancreas was observed in the MB group. Crabs fed M, MB and MI diets increased antioxidant system-related enzyme activities, but reduced malondialdehyde. The highest activities of alkaline phosphatase, acid phosphatase, lysozyme and phenol oxidase in the gut and the respiratory burst of the crabs were found in the MB group. The MB diet promoted the mRNA expression of 〈em〉E. sinensis〈/em〉 immune genes (ES-PT, ES-Relish, ES-LITAF, p38MAPK and Crustin) compared with the control. After 3 days of infection with 〈em〉Aeromonas hydrophila〈/em〉, the highest survival of crabs was also found in the MB group. This study indicates that the combination of MOS with β-glucan or with inulin can improve growth, antioxidant capacity, non-specific immunity and disease resistance in 〈em〉E. sinensis〈/em〉.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Marco Rozas-Serri, Andrea Peña, Lucerina Maldonado〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Piscirickettsiosis is the most challenging disease present in the Chilean salmon industry. The aim of this study was to describe the expression of genes associated with immune response of Atlantic salmon intraperitoneally infected with LF-89 and EM-90 〈em〉Piscirickettsia salmonis〈/em〉 and vaccinated with inactivated whole-cell bacterin of 〈em〉P. salmonis〈/em〉. The fish infected with PS-LF-89 showed an anti-inflammatory response, whereas this finding was not observed in the PS-EM-90-infected fish and vaccinated fish. Fish infected with both 〈em〉P. salmonis〈/em〉 isolates showed 〈em〉mhc1-mhc2〈/em〉, 〈em〉cd4-cd8b〈/em〉 and 〈em〉igm〈/em〉 overexpression, suggesting that 〈em〉P. salmonis〈/em〉 promotes a T CD4〈sup〉+〈/sup〉 and T CD8〈sup〉+〈/sup〉 cell response and a humoral immune response. The vaccinated-fish exhibited 〈em〉mhc1〈/em〉, 〈em〉mhc2〈/em〉 and 〈em〉cd4〈/em〉 overexpression but a significant downregulation of 〈em〉cd8b〈/em〉 and 〈em〉igm〈/em〉, suggesting that the vaccine supported the CD4〈sup〉+〈/sup〉 T-cell response but did not induce an immune response mediated by CD8〈sup〉+〈/sup〉 T cells or a humoral response. In conclusion, the expression pattern of genes related to the humoral and cell-mediated adaptive immune response showed upregulation in fish infected with 〈em〉P. salmonis〈/em〉 and down-regulation in vaccinated fish. The results of this study contribute to our understanding of the immune response against 〈em〉P. salmonis〈/em〉 and can be used in the optimization of SRS prevention and control measures.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Wen-rui Li, Yong-hua Hu, Shuai Jiang, Li Sun〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Japanese flounder (〈em〉Paralichthys olivaceus〈/em〉) is an important economic fish species farmed in China and other countries. It is susceptible to infection by 〈em〉Edwardsiella tarda〈/em〉, a severe fish pathogen with a broad host range. In this study, we employed high-throughput deep sequencing technology to identify, in a global scale, flounder kidney microRNAs (miRNAs) induced by 〈em〉E. tarda〈/em〉 at different stages of infection. Differentially expressed miRNAs (DEmiRNAs) and mRNAs (DEmRNAs) exhibiting significantly altered expression levels before and after 〈em〉E. tarda〈/em〉 infection were examined. A total of 96 DEmiRNAs were identified, for which 2779 target genes were predicted. Eighty-seven miRNA–mRNA pairs, involving 29 DEmiRNAs and 86 DEmRNAs, showed negative correlations in their expression patterns. GO and KEGG enrichment analysis revealed that the putative target genes of the DEmiRNAs were associated with diverse biological processes, cellular components, and molecular functions. One of the DEmiRNAs, pol-miR-182-5p, was demonstrated to regulate sphingosine-1-phosphate receptor 1 (PoS1PR1) negatively in a manner that depended on the specific interaction between the seed sequence of pol-miR-182-5p and the 3'-UTR of PoS1PR1. Overexpression of pol-miR-182-5p in flounder cells promoted apoptosis and inhibited cellular viability. Knockdown of PoS1PR1 in flounder enhanced 〈em〉E. tarda〈/em〉 invasion and dissemination in fish tissues. These results provide new insights into miRNA-mediated anti-bacterial immunity in flounder.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Hongli Xia, Yuan Li, Zhiwen Wang, Wenjie Chen, Jun Cheng, Dapeng Yu, Yishan Lu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nile tilapia (〈em〉Oreochromis niloticus〈/em〉) is a pivotal economic fish that has been plagued by Streptococcus infections. Tumor necrosis factor receptor-associated factor 5 (TRAF5) is a crucial adaptor molecule, which can trigger downstream signaling cascades involved in immune pathway. In this study, Nile tilapia TRAF5 coding sequence (named OnTRAF5) was obtained, which contained typical functional domains, such as RING, zinc finger, coiled-coil and MATH domain. Different from other TRAF molecules, OnTRAF5 had shown relatively low identify with its homolog, and it was clustered into other teleost TRAF5 proteins. qRT-PCR was used to analysis the expression level of OnTRAF5 in gill, skin, muscle, head kidney, heart, intestine, thymus, liver, spleen and brain, In healthy Nile tilapia, the expression level of OnTRAF5 in intestine, gill and spleen were significantly higher than other tissues. While under 〈em〉Streptococcus agalactiae〈/em〉 infection, the expression level of OnTRAF5 was improved significantly in all detected organs. Additionally, over-expression WT OnTRAF5 activated NF-κB, deletion of RING or zinc finger caused the activity impaired. In conclusion, OnTRAF5 participate in anti-bacteria immune response and is crucial for the signaling transduction.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Tianjian Hu, Ran Chen, Lingzhi Zhang, Zhuang Wang, Dahai Yang, Yuanxing Zhang, Xiaohong Liu, Qin Liu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈em〉Edwardsiella piscicida〈/em〉 is an important pathogen that infects a wide range of hosts, from fish to human. Its infection leads to extensive losses in a diverse array of commercially important fish, like Japanese flounder, turbot, and tilapia. During the infection, type III secretion system (T3SS) and type VI secretion system (T6SS) of 〈em〉E. piscicida〈/em〉 play significant roles, but how T3SS and T6SS cooperatively contribute to its virulence is still unknown. In this study, we first examined the roles of T3SS and T6SS in different processes during 〈em〉E. piscicida〈/em〉 infection of host cells, and revealed that T3SS of 〈em〉E. piscicida〈/em〉 is responsible for promoting bacterial invasion, the following intracellular replication and inducing cell death in host cells, while T6SS restrains 〈em〉E. piscicida〈/em〉 intracellular replication and cell death in J774A.1 cells, which suggested that T3SS and T6SS antagonistically concert 〈em〉E. piscicida〈/em〉 infection. Furthermore, we found an significant decrease in transcription level of IL-1β in zebrafish kidney infected with T3SS mutant and an drastically increase in transcription level of TNF- α infected with T6SS mutant when compared with the wild-type. Interestingly, both T3SS and T6SS mutants showed significant attenuated virulence in the zebrafish infection model when compared with the wild-type. Finally, considering the cooperative role of T3SS and T6SS, we generated a mutant strain WEDΔT6SS based on the existing live attenuated vaccine (LAV) WED which showed improved vaccine safety and comparable immune protection. Therefore, WEDΔT6SS could be used as an optimized LAV in the future. Taken together, this work suggested a bilateral role of T3SS and T6SS which respectively act as spear and shield during 〈em〉E. piscicida〈/em〉 infection, together contribute to 〈em〉E. piscicida〈/em〉 virulence.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Damian A. Madrigal, Carlos H. Escalante, Gabriel A. Gutiérrez-Rebolledo, José M. Cristobal-Luna, Omar Gómez-García, Roberto I. Hernández-Benitez, Ana L. Esquivel-Campos, Salud Pérez-Gutiérrez, Germán A. Chamorro-Cevallos, Francisco Delgado, Joaquín Tamariz〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Since NSAIDs are commonly used anti-inflammatory agents that produce adverse effects, there have been ongoing efforts to develop more effective and less toxic compounds. Based on the structure of the anti-inflammatory pyrrolizines licofelone and ketorolac, a series of 1-arylpyrrolizin-3-ones was synthesized. Also prepared was a series of substituted pyrroles, mimicking similar known anti-inflammatory agents. The anti-inflammatory activity of the test compounds was determined with a phorbol ester (TPA)-induced murine ear edema protocol. For the most active derivatives, 〈strong〉19b〈/strong〉–〈strong〉c〈/strong〉/〈strong〉20b〈/strong〉–〈strong〉c〈/strong〉, the anti-inflammatory effect was the same as that of the reference compound (indomethacin) and was dose-dependent. These compounds have an aryl ring at the C-1 position and a methoxycarbonyl group at the C-2 position of the pyrrolizine framework, which represent plausible pharmacophore groups with anti-inflammatory activity. The anti-inflammatory activity of 1-substituted analogs containing a five- or six-membered heterocycles was lower but still good, while that of the pyrroles was only moderate. Although the docking studies suggests that the effect of analogs 〈strong〉19a〈/strong〉–〈strong〉c〈/strong〉/〈strong〉20a〈/strong〉–〈strong〉c〈/strong〉 is associated with the inhibition of cyclooxygenase-2, experimental assays did not corroborate this idea. Indeed, a significant inhibition of NO was found experimentally as a plausible mechanism of action.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619305036-ga1.jpg" width="400" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Yuanxia Cheng〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉This study aims to investigate the effects of 〈em〉Rhodiola rosea〈/em〉 polysaccharide (RRP) on the growth performance and nonspecific immunity of red swamp crayfish 〈em〉Procambarus clarkia〈/em〉. RRP was prepared by hot water extraction and partly characterised by high-performance liquid chromatography and sugar composition analyses. Three diets supplemented with three different levels of RRP (0.2, 0.6 and 1 g kg diet〈sup〉−1〈/sup〉) were formulated and tested for growth performance and nonspecific immunity of red swamp crayfish 〈em〉Procambarus clarkii,〈/em〉 while a diet without any RRP supplementation served as control. After 8 weeks of feeding, body weight gain, feed efficiency, survival rate, phenoloxidase activity, superoxide dismutase activity, glutathione peroxidase level, total haemocyte count and number of hyaline cells, semigranular cells and granular cells and resistance to 〈em〉Aeromonas hydrophila〈/em〉 were higher than those of the control. Moreover, based on the efficiency of RRP on the growth performance and nonspecific immunity of crayfish, the optimum dose of RRP was found to be 0.6 g kg diet〈sup〉−1〈/sup〉. Hence, intake of diets containing RRP could enhance the growth performance, immune responses and improve resistance of crayfish to infection by 〈em〉A. hydrophila.〈/em〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Xiujuan Zhou, Jing Xing, Xiaoqian Tang, Xiuzhen Sheng, Wenbin Zhan〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Interleukin-2 receptor subunit beta of flounder (〈em〉Paralichthys olivace〈/em〉, fIL-2Rβ) was annotated on the NCBI, its gene was cloned and characterized functionally in this study. And then the amino acids sequences and tertiary structure of fIL-2Rβ were analyzed, respectively. RT-PCR and ImageJ analyzed showed that fIL-2Rβ mRNA were expressed in the gill, spleen, kidney, intestines, liver, blood, muscle and skin, which showed high signals in spleen and blood. And then the recombinant protein of fIL-2Rβ extracellular region and its polyclonal antibodies were produced, native fIL-2Rβ molecules in flounder peripheral blood leukocytes (PBLs) were identified at 60.7 kDa by Mass spectrometry, which were in accordance with the molecular mass of full fIL-2Rβ protein calculated on the predicted protein sequence. Then the IL-2Rβ+ cell in T/B lymphocytes were characterized by Flow cytometry and indirect immunofluorescence assay, respectively. The results showed that the percentages of IL-2Rβ+ leukocytes, IL-2Rβ+/CD4+, IL-2Rβ+/IgM+ lymphocytes were 18.4 ± 2.7%, 4.5 ± 0.8%, 4.3% ± 0.5 in PBLs, and were 13.6 ± 0.9%, 4.6 ± 1.1%, 6.1% ± 0.4 in spleen, similarly, the percentages of IL-2Rβ+ leukocytes, IL-2Rβ+/CD4+, IL-2Rβ+/IgM+ lymphocytes were 9.4 ± 0.3%, 4.0 ± 0.5%, 5.7 ± 0.1% in head kidney, respectively. After KLH injection, compared with control group, the gene expression of IL-2, IL-2Rβ, CD3, TCR, CD79b and IgM in spleen of flounder were up-regulated, respectively (〈em〉p〈/em〉 〈 0.05). And the FCM results showed that the percentages of IL-2Rβ+ leukocytes in PBLs were significantly increased post Keyhole limpet hemocyanin (KLH) injection, which peaked 23.9 ± 0.9% at 9〈sup〉th〈/sup〉 day (〈em〉p〈/em〉 〈 0.05). To our knowledge, those results first reported that the characteristics of IL-2R and IL-2R + molecules were expressed on both B and T lymphocytes in fish. At the same time, this study lays a foundation for further exploring the interaction between IL-2 and IL-2R to promote cell proliferation and carrying out biological functions.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Ebru Yilmaz〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The present study investigated the effects of dietary anthocyanin on the growth performance, haematological, non-specific immune, and spleen gene expression responses of Nile tilapia, 〈em〉Oreochromis niloticus〈/em〉. Five experimental groups of fish with mean weights of 8.24 ± 0.64 g were used in the study; four of these were fed with diets incorporating anthocyanin (20 mg kg -〈sup〉1〈/sup〉, 40 mg kg〈sup〉−1〈/sup〉, 80 mg kg〈sup〉−1〈/sup〉 and 160 mg kg〈sup〉−1〈/sup〉), while the fifth was a control group without dietary anthocyanin. Growth performance and haematological parameters of tilapia were not affected by anthocyanin-supplemented diets (p 〉 0.05). Dietary anthocyanin significantly increased respiratory burst activity, phagocytic activity, phagocytic index, lysozyme activity, myeloperoxidase activity, serum total superoxide dismutase (T.SOD) activity, and serum catalase (CAT) activity (p 〈 0.05). The total immunoglobulin level was highest in the 80 mg kg〈sup〉−1〈/sup〉 group compared with the other groups (p 〈 0.05). In addition, with the anthocyanin-containing diets, the gene levels of interleukin 1, beta (〈em〉IL-1β〈/em〉), interleukin 8 (〈em〉IL-8〈/em〉), tumor necrosis factor (〈em〉TNF-α〈/em〉), heat shock protein 70 (〈em〉HSP70〈/em〉), and interferon gamma (〈em〉IFN-γ〈/em〉) were increased in the fish spleen, and the gene levels of 〈em〉CAT〈/em〉, 〈em〉GPx〈/em〉, and 〈em〉SOD〈/em〉 were also increased in fish liver (p 〈 0.05). At the end of the experiment, the fish were subjected to ammonia stress. The groups fed with 20 and 40 mg kg〈sup〉−1〈/sup〉 anthocyanin exhibited higher survival rates than the other groups. In summary, feeding Nile tilapia with anthocyanin-containing diets caused increases in the innate immune parameters, gene expression responses, and the survival rate of the fish subjected to ammonia stress.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Yan-Lin Guo, Lin Feng, Wei-Dan Jiang, Pei Wu, Yang Liu, Sheng-Yao Kuang, Ling Tang, Wu-Neng Tang, Xiao-Qiu Zhou〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Iron is an important mineral element for fish. In this study, we investigated the influences of dietary iron deficiency on intestinal immune function as well as underlying signaling of on-growing grass carp (〈em〉Ctenopharyngodon idella〈/em〉). Fish were fed with six graded level of dietary iron for sixty days, and a fourteen days’ challenge test under infection of 〈em〉Aeromonas hydrophila〈/em〉 thereafter. Results showed that compared with optimal iron level, iron deficiency increased enteritis morbidity, decreased lysozyme (LZ) and acid phosphatase (ACP) activities, complement 3 (C3), C4 and immunoglobulin M (IgM) concentrations and down-regulated mRNA levels of hepcidin, liver expressed antimicrobial peptide 2A (LEAP-2A), LEAP-2B, Mucin2, β-defensin-1, anti-inflammatory cytokines transforming growth factor β1 (TGF-β1), TGF-β2, interleukin 4/13A (IL-4/13A), IL-4/13B, IL-10, IL-11 and IL-15, inhibitor of κBα (IκBα), target of rapamycin (TOR) and ribosomal protein S6 kinase 1 (S6K1), whereas up-regulated mRNA levels of pro-inflammatory cytokines IL-1β, interferon γ2 (IFN-γ2), IL-8, IL-12p35, IL-12p40 and IL-17D, nuclear factor kappa B (NF-κB) p65, IκB kinases α (IKKα), IKKβ and eIF4E-binding protein (4E-BP) in intestine of on-growing grass carp, indicating that iron deficiency impaired intestinal immune function of fish under infection of 〈em〉A. hydrophila〈/em〉. Besides, iron excess also increased enteritis morbidity and impaired immune function of fish under infection of 〈em〉A. hydrophila〈/em〉. In addition, the effect of ferrous fumarate on intestinal immune function of on-growing grass carp is more efficient than ferrous sulfate. Finally, based on ability against enteritis, LZ activities in mid intestine and distal intestine, we recommended adding 83.37, 86.71 and 85.39 mg iron/kg into diet, respectively.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Luqing Pan, Xin Zhang, Liubing Yang, Shanshan Pan〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Hemocyanin, a multifunctional oxygen-carrying protein, has critical effects on immune defense in crustaceans. To explore the role of hemocyanin in anti-pathogen mechanism, effects of 〈em〉Vibrio harveyi〈/em〉 (〈em〉V. harvey〈/em〉) and 〈em〉Staphyloccocus aureus〈/em〉 (〈em〉S. aureus〈/em〉) on hemocyanin synthesis and innate immune responses were investigated in 〈em〉Litopenaeus vannamei〈/em〉 (〈em〉L. vannamei〈/em〉) during infection 〈em〉in vivo〈/em〉. Results showed that 10〈sup〉5〈/sup〉 and 10〈sup〉6〈/sup〉 cells mL〈sup〉−1〈/sup〉 〈em〉V. harveyi〈/em〉 and 10〈sup〉6〈/sup〉 cells mL〈sup〉−1〈/sup〉 〈em〉S. aureus〈/em〉 significantly affected plasma hemocyanin concentration, hepatopancreas hemocyanin mRNA and subunits expressions, plasma phenol oxidase (PO), hemocyanin-derived PO (Hd-PO), antibacterial, and bacteriolytic activities during the experiment under bacterial stress, while these parameters did not change remarkably in control group. The concentration of hemocyanin in plasma fluctuated, with a minimum at 12 h and a maximum at 24 h. Moreover, the expression of hemocyanin mRNA peaked at 12 h, while the level of hemocyanin p75 and p77 subunits reached maximum at 24 h. Besides, plasma PO and Hd-PO activities peaked at 24 h, and antimicrobial and bacteriolytic activities peaked at 12 h and 24 h, respectively. In addition, 10〈sup〉5〈/sup〉 cells mL〈sup〉−1〈/sup〉 〈em〉S. aureus〈/em〉 had no significant effect on the synthesis of hemocyanin and prophenoloxidase activating (pro-PO) system, but significantly increased antimicrobial activity at 12 h and bacteriolytic activity at 24 h. Therefore, these results suggest that the hemocyanin synthesis was initiated after invasion of pathogen, and the newly synthesized hemocyanin, acted as an immune molecule, can exerts PO activity to regulate the immune defense in 〈em〉L. vannamei in vivo〈/em〉.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Jana Deitersen, Dina H. El-Kashef, Peter Proksch, Björn Stork〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In order to overcome therapy resistance in cancer, scientists search in nature for novel lead structures for the development of improved chemotherapeutics. Anthraquinones belong to a class of tricyclic organic natural compounds with promising anti-cancer effects. Anthraquinone derivatives are rich in structural diversity, and exhibit pleiotropic properties, among which the modulation of autophagy seems promising in the context of overcoming cancer-therapy resistance. Among the most promising derivatives in this regard are emodin, aloe emodin, rhein, physcion, chrysophanol and altersolanol A. On the molecular level, these compounds target autophagy via different upstream pathways including the AKT/mTOR-axis and transcription of autophagy-related proteins. The role of autophagy is pro-survival as well as cell death-promoting, depending on derivatives and their cell type specificity. This review summarizes observed effects of anthraquinone derivatives on autophagy and discusses targeted pathways and crosstalks. A cumulative knowledge about this topic paves the way for further research on modes of action, and aids to find a therapeutic window of anthraquinones in cancer-therapy.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619305292-ga1.jpg" width="186" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 5 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Rick Raudszus, Robert Nowotny, Christoph G.W. Gertzen, Andrea Schöler, Andor Krizsan, Ines Gockel, Hermann Kalwa, Holger Gohlke, René Thieme, Finn K. Hansen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Fluorescent tagging of bioactive molecules is a powerful tool to study cellular uptake kinetics and is considered as an attractive alternative to radioligands. In this study, we developed fluorescent histone deacetylase (HDAC) inhibitors and investigated their biological activity and cellular uptake kinetics. Our approach was to introduce a dansyl group as a fluorophore in the solvent-exposed cap region of the HDAC inhibitor pharmacophore model. Three novel fluorescent HDAC inhibitors were synthesized utilizing efficient submonomer protocols followed by the introduction of a hydroxamic acid or 2-aminoanilide moiety as zinc-binding group. All compounds were tested for their inhibition of selected HDAC isoforms, and docking studies were subsequently performed to rationalize the observed selectivity profiles. All HDAC inhibitors were further screened in proliferation assays in the esophageal adenocarcinoma cell lines OE33 and OE19. Compound 〈strong〉2〈/strong〉, 6-((〈em〉N〈/em〉-(2-(benzylamino)-2-oxoethyl)-5-(dimethylamino)naphthalene)-1-sulfonamido)-〈em〉N〈/em〉-hydroxyhexanamide, displayed the highest HDAC inhibitory capacity as well as the strongest anti-proliferative activity. Fluorescence microscopy studies revealed that compound 〈strong〉2〈/strong〉 showed the fastest uptake kinetic and reached the highest absolute fluorescence intensity of all compounds. Hence, the rapid and increased cellular uptake of 〈strong〉2〈/strong〉 might contribute to its potent anti-proliferative properties.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619304778-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 3 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Ronnakorn Leechaisit, Ratchanok Pingaew, Veda Prachayasittikul, Apilak Worachartcheewan, Supaluk Prachayasittikul, Somsak Ruchirawat, Virapong Prachayasittikul〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A library of bis-sulfonamides (〈strong〉9〈/strong〉–〈strong〉26〈/strong〉) were synthesized and tested for their aromatase inhibitory activities. Interestingly, all bis-sulfonamide derivatives inhibited the aromatase with IC〈sub〉50〈/sub〉 range of 0.05–11.6 μM except for compound 〈strong〉23〈/strong〉. The analogs 〈strong〉15〈/strong〉 and 〈strong〉16〈/strong〉 bearing hydrophobic chloro and bromo groups exhibited the potent aromatase inhibitory activity in sub-micromolar IC〈sub〉50〈/sub〉 values (i.e., 50 and 60 nM, respectively) with high safety index. Molecular docking revealed that the chloro and bromo benzenesulfonamides (〈strong〉15〈/strong〉 and 〈strong〉16〈/strong〉) may play role in the hydrophobic interaction with Leu477 of the aromatase to mimic steroidal backbone of the natural substrate, androstenedione. QSAR study also revealed that the most potent activity of compounds was governed by van der Waals volume (GATS6v) and mass (Mor03m) descriptors. Finally, the two compounds (〈strong〉15〈/strong〉 and 〈strong〉16〈/strong〉) were highlighted as promising compounds to be further developed as novel aromatase inhibitors.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619310028-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Fangyi Chen, Kejian Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mud crabs, 〈em〉Scylla paramamosain〈/em〉, are one of the most economical and nutritious crab species in China and South Asia. Inconsistent with the high development of commercial mud crab aquaculture, effective immunological methods to prevent frequently-occurring diseases have not yet been developed. Thus, high mortalities often occur throughout the different developmental stages of this species resulting in large economic losses. In recent years, numerous attempts have been made to use various advanced biological technologies to understand the innate immunity of 〈em〉S. paramamosain〈/em〉 as well as to characterize specific immune components. This review summarizes these research advances regarding cellular and humoral responses of the mud crab during pathogen infection, highlighting hemocytes and gills defense, pattern recognition, immune-related signaling pathways (Toll, IMD, JAK/STAT, and prophenoloxidase (proPO) cascades), immune effectors (antimicrobial peptides), production of reactive oxygen species and the antioxidant system. Diseases affecting the development of mud crab aquaculture and potential disease control strategies are discussed.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S1050464819307867-fx1.jpg" width="354" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Ai-Guo Huang, Xiao-Ping Tan, Shen-Ye Qu, Gao-Xue Wang, Bin Zhu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉White spot syndrome virus (WSSV) is a serious epidemic pathogen of crustaceans and cause severe economic losses to aquaculture. However, no commercial drugs presently available to control WSSV infection. Genipin (GN) is a bioactive compound extracted from the fruit of 〈em〉Gardenia jasminoides〈/em〉 and exhibits potential antiviral activity. In the study, the antiviral activity of GN against WSSV was investigated in crayfish 〈em〉Procambarus clarkii〈/em〉 and in shrimp 〈em〉Litopenaeus vannamei〈/em〉. 〈em〉In vitro〈/em〉 antiviral test showed that GN could inhibit WSSV replication in crayfish and in shrimp, and the highest inhibition on WSSV was over 99% when treatment with 50 mg/kg of GN for 24 h. 〈em〉In vivo〈/em〉 antiviral test proved that GN could be used to treat and prevent WSSV infection. GN could also effectively protect crayfish from WSSV infection by reducing the mortality rate of WSSV-infected crayfish. Moreover, GN attenuated the WSSV-induced oxidative stress and inflammatory by upregulation the expression of antioxidant-related genes and downregulation the expression of inflammatory-related genes, respectively. Mechanically, GN inhibited WSSV replication at least via decreasing 〈em〉STAT〈/em〉 (〈em〉signal transducer and activator of transcription〈/em〉) gene expression to block WSSV immediate-early gene 〈em〉ie1〈/em〉 transcription. Additionally, the inhibition of 〈em〉BI-1〈/em〉 (〈em〉Bax inhibitor-1〈/em〉) gene expression also played an important role in the suppression of WSSV infection. In conclusion, GN represented a potential therapeutic and preventive agent to block WSSV infection.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Zhiying He, Fan Mao, Yue Lin, Jun Li, Xiangyu Zhang, Yuehuan Zhang, Zhiming Xiang, Zohaib Noor, Yang Zhang, Ziniu Yu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Phagocytosis is one of the fundamental cellular immune defense parameter that helps in the elimination of the invading pathogens in both vertebrates and invertebrates, which require plenty of energy for functioning. In the present study, we identified the critical energy regulator AMP-activated protein kinase (AMPK) in 〈em〉Crassostrea hongkongensis〈/em〉 which is composed of three subunits, named 〈em〉Ch〈/em〉AMPK-α, 〈em〉Ch〈/em〉AMPK-β, and 〈em〉Ch〈/em〉AMPK-γ, and then analyzed the function of AMPK in regulating hemocyte phagocytosis. All the three 〈em〉Ch〈/em〉AMPK subunits mRNA were detected to be expressed at various embryological stages, and also constitutively expressed in multiple tissues with high expression in gill and mantle. The phylogenetic tree showed that the three subunits of AMPK were correspondingly clustered with its orthologue branches. Furthermore Western Blot analysis revealed that the AMPK pharmacological inhibitors Compound C could effectively down-regulate the Thr〈sup〉172〈/sup〉 phosphorylation level of AMPK-α, and the hemocyte phagocytosis was inhibited by Compound C (CC), which indicate its existence in the oyster. Our results showed that treatment of AMPK inhibitors significantly attenuated the capacity of hemocytes phagocytosis. Moreover, Compound C could also change the organization of actin cytoskeleton in the oyster hemocytes, demonstrating the crucial role of AMPK signaling in control of phagocytosis.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Jian He, Tao-Lin Xie, Xiao Li, Yang Yu, Zhi-Peng Zhan, Shao-Ping Weng, Chang-Jun Guo, Jian-Guo He〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mandarin fish (〈em〉Siniperca chuatsi〈/em〉) is a universally farmed fish species in China and has a large farming scale and economic value. With the high-density cultural mode in mandarin fish, viral diseases, such as infectious spleen and kidney necrosis virus (ISKNV) and 〈em〉Siniperca chuatsi〈/em〉 rhabdovirus (SCRV), have increased loss, which has seriously restricted the development of aquaculture. Y-Box binding protein 1 (YB-1) is a member of cold shock protein family that regulates multiple cellular processes. The roles of mammalian YB-1 protein in environmental stress and innate immunity have been studied well, but its roles in teleost fishes remain unknown. In the present study, the characteristic of 〈em〉S. chuatsi〈/em〉 YB-1 (〈em〉sc〈/em〉YB-1) and its roles in cold stress and virus infection were investigated. The 〈em〉sc〈/em〉YB-1 obtained an 1541 bp cDNA that contains a 903 bp open reading frame encoding a protein of 300 amino acids. Tissue distribution results showed that the 〈em〉sc〈/em〉YB-1 is a ubiquitously expressed gene found among tissues from mandarin fish. Overexpression of 〈em〉sc〈/em〉YB-1 can increase the expression levels of cold shock-responsive genes, such as 〈em〉scHsc70a〈/em〉, 〈em〉scHsc70b〈/em〉, and 〈em〉scp53〈/em〉. Furthermore, the role of 〈em〉sc〈/em〉YB-1 in innate immunity was also investigated in mandarin fish fry (MFF-1) cells. The expression level of 〈em〉sc〈/em〉YB-1 was significant change in response to poly (I:C), poly (dG:dC), PMA, ISKNV, or SCRV stimulation. The overexpression of 〈em〉sc〈/em〉YB-1 can significantly increase the expression levels of NF-κB-responsive genes, including 〈em〉scIL-8, scTNF-α〈/em〉, and 〈em〉scIFN-h.〈/em〉 The NF-κB-luciferase report assay results showed that the relative expression of luciferin was significantly increased in the cells overexpressed with 〈em〉sc〈/em〉YB-1 compared with those in cells overexpressed with control plasmid. These results indicate that 〈em〉sc〈/em〉YB-1 can induce the NF-κB signaling pathway in MFF-1 cells. Overexpressed 〈em〉sc〈/em〉YB-1 can downregulate the expression of ISKNV viral major capsid protein (〈em〉mcp〈/em〉) gene but upregulates the expression of SCRV 〈em〉mcp〈/em〉 gene. Moreover, knockdown of 〈em〉sc〈/em〉YB-1 using siRNA can upregulate the expression of ISKNV 〈em〉mcp〈/em〉 gene but downregulates the expression of SCRV 〈em〉mcp〈/em〉 gene. These results indicate that 〈em〉sc〈/em〉YB-1 suppresses ISKNV infection while enhancing SCRV infection. The above observations suggest that 〈em〉sc〈/em〉YB-1 is involved in cold stress and virus infection. Our study will provide an insight into the roles of teleost fish YB-1 protein in stress response and innate immunity.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Hien Van Doan, Seyed Hossein Hoseinifar, Korawan Sringarm, Sanchai Jaturasitha, Bundit Yuangsoi, Mahmoud A.O. Dawood, Maria Ángeles Esteban, Einar Ringø, Caterina Faggio〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The present study aimed to assess the possible effects of Assam tea (〈em〉Camellia sinensis〈/em〉) extract (ATE) on growth performances, immune responses, and disease resistance of Nile tilapia, 〈em〉Oreochromis niloticus〈/em〉 against 〈em〉Streptococcus agalactiae〈/em〉. Five levels of ATE were supplemented into the based diet at 0, 1, 2, 4, and 8 g kg〈sup〉−1〈/sup〉 feed of Nile tilapia fingerlings (10.9 ± 0.04 g initial weight) in triplicate. After four and eight weeks of feeding, fish were sampled to determine the effects of the tea supplements upon their growth performance, as well as serum and mucosal immune responses. A disease challenge using 〈em〉S. agalactiae〈/em〉 was conducted at the end of the feeding trial. Fish fed ATE revealed significantly improved serum lysozyme, peroxidase, alternative complement (ACH50), phagocytosis, and respiratory burst activities compared to the basal control fed fish (〈em〉P〈/em〉 〈 0.05). The mucus lysozyme and peroxidase activities were ameliorated through ATE supplementation in the tilapia diets. Supplementation of ATE significantly (〈em〉P〈/em〉 〈 0.05) enhanced final body weight, weight gain, and specific growth rate; while a decreased feed conversion ratio was revealed at 2 g kg〈sup〉−1〈/sup〉 inclusion level, after four and eight weeks. Challenge test showed that the relative percent survival (RSP) of fish in each treatment was 33.33%, 60.00%, 83.33%, 76.68%, and 66.68% in groups fed 0, 1, 2, 4, and 8 g kg〈sup〉−1〈/sup〉, respectively. In summary, diets supplemented with ATE especially at 2 g kg〈sup〉−1〈/sup〉 increased the humoral and mucosal immunity, enhanced growth performance, and offered higher resistance against 〈em〉S. agalactiae〈/em〉 infection in Nile tilapia.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Jiquan Zhang, Yujie Liu, Yongzhao Zhou, Wenzheng Wang, Naike Su, Yuying Sun〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Trehalose, a nonreducing disaccharide, is present in a wide variety of organisms and plays a key role in many organisms under different stress conditions. In the study, the full-length cDNA sequence encoding trehalose-6-phosphate synthase (EcTPS) was obtained from 〈em〉Exopalaemon carinicauda〈/em〉. The complete nucleotide sequence of 〈em〉EcTPS〈/em〉 contained a 2532 bp open reading frame (ORF) encoding a putative protein of 843 amino acids. The domain architecture of the deduced EcTPS contained a glycol_transf_20 domain and a trehalose_PPase domain. 〈em〉EcTPS〈/em〉 mRNA was predominantly expressed in the hepatopancreas. The expression of 〈em〉EcTPS〈/em〉 in the prawns challenged with 〈em〉Vibrio parahaemolyticus〈/em〉 and 〈em〉Aeromonas hydrophila〈/em〉 changed in a time-dependent manner. The function of 〈em〉EcTPS〈/em〉 was also studied by double-strand RNA interference. The results showed that the knock-down of 〈em〉EcTPS〈/em〉 increased the mortality of the 〈em〉Vibrio〈/em〉-challenged group and 〈em〉Aeromonas〈/em〉-challenged group compared with the control group. The present study provides some new insight into the immune function of the trehalose-6-phosphate synthase in prawns.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Rui Jia, Zhengyan Gu, Qin He, Jinliang Du, Liping Cao, Galina Jeney, Pao Xu, Guojun Yin〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Radix Bupleuri extract (RBE) is one of the most popular oriental herbal medicines, which has anti-oxidative and anti-inflammatory properties. However, its protective effects and underlying molecular mechanisms on oxidative damage in tilapia are still unclear. The aims of the study were to explore the anti-oxidative, anti-inflammatory and hepatoprotective effects of RBE against oxidative damage, and to elucidate underlying molecular mechanisms in fish. Tilapia received diet containing three doses of RBE (0, 1 and 3 g/kg diet) for 60 days, and then were given an intraperitoneal injection of H〈sub〉2〈/sub〉O〈sub〉2〈/sub〉 or saline. Before injection, RBE treatments improved growth performance and partial anti-oxidative capacity in tilapia. After oxidative damage, RBE pretreatments were able to signally reduce the higher serum aminotransferases, alkaline phosphatase (AKP) and liver necrosis. In serum and liver, the abnormal lipid peroxidation level and antioxidant status induced by H〈sub〉2〈/sub〉O〈sub〉2〈/sub〉 injection were restored by RBE treatments. Furthermore, RBE treatments activated erythroid 2-related factor 2 (Nrf2) signaling pathway, which promoted the gene expression of heme oxygenase 1 (HO-1), NAD(P) H:quinone oxidoreductase 1 (NQO-1), glutathione-S-transferase (GST) and catalase (CAT). Meanwhile, RBE treatments reduced inflammatory response by inhibiting TLRs-MyD88-NF-κB signaling pathway, accompanied by the lower interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and IL-8 mRNA levels. In addition, RBE treatments upregulated complement (C3) gene expression and downregulated heat shock protein (HSP70) gene expression. In conclusion, the current study suggested that RBE pretreatments protected against H〈sub〉2〈/sub〉O〈sub〉2〈/sub〉-induced oxidative damage in tilapia. The beneficial activity of RBE may be due to the modulation of Nrf2/ARE and TLRs-Myd88-NF-κB signaling pathway.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Ye Zhao, Hui Liu, Qing Wang, Bingjun Li, Hongxia Zhang, Yongrui Pi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The gut microbiota is essential for health and physiological functions in the host organism. However, the toxicological evaluation of environmental pollutants on the gut microbiota is still insufficient. In the present study, the juvenile sea cucumber 〈em〉Apostichopus japonicus〈/em〉 was exposed for 14 days to Benzo[〈em〉a〈/em〉]pyrene (BaP), which is a model polycyclic aromatic hydrocarbon (PAH), at four different concentrations (0, 0.5, 5, and 25 μg/L). We analyzed the intestinal microbial community of 〈em〉A. japonicas〈/em〉 using 16S rRNA gene amplicon sequencing. Our results demonstrate that BaP exposure caused alterations to the microbiome community composition in sea cucumbers. At the phylum level, 〈em〉Planctomycetes〈/em〉 were significantly more abundant in BaP exposure groups at 14 d compared with the control group, and the abundance of 〈em〉Proteobacteria〈/em〉 and 〈em〉Bacteroidetes〈/em〉 increased while the abundance of 〈em〉Firmicutes〈/em〉 decreased following BaP exposure. At the genus level, multiple beneficial and autochthonous genera declined in the BaP treatment groups compared to the control, including 〈em〉Lactococcus〈/em〉, 〈em〉Bacillus〈/em〉, 〈em〉Lactobacillus〈/em〉, 〈em〉Enterococcus〈/em〉, 〈em〉Leuconostoc〈/em〉 and 〈em〉Weissella〈/em〉; however, a bloom of alkane-degrading bacteria was found in BaP-exposed guts and included 〈em〉Lutibacter〈/em〉, 〈em〉Pseudoalteromonas〈/em〉, 〈em〉Polaribacter〈/em〉, 〈em〉Rhodopirellula〈/em〉 and 〈em〉Blastopirellula〈/em〉. Furthermore, histological morphology, enzymatic activity and gene expression analysis revealed that BaP exposure also negatively impacted gut structure and function and presented as inflammation or atrophy, oxidative stress and immune suppression in sea cucumber intestines. Collectively, these findings provide insights into the toxic effects of BaP exposure on 〈em〉A. japonicas〈/em〉 associated with intestinal microbiota and health.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Mengting Luo, Linwei Yang, Zi-ang Wang, Hongliang Zuo, Shaoping Weng, Jianguo He, Xiaopeng Xu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉C-type lectins (CTLs) are a group of lectins with at least one carbohydrate recognition domain (CRD), the binding of which to carbohydrates requires the presence of calcium ions. CTLs generally function as pattern recognition receptors (PRRs), essentially participating in innate immunity. In the current study, a novel CTL termed LvCTL5 was identified from Pacific white shrimp 〈em〉Litopenaeus vannamei〈/em〉, which shared sequence identities with other crustacean CTLs. LvCTL5 was highly expressed in hepatopancreas and could be activated by infection with bacteria, virus and fungi. The recombinant LvCTL5 protein purified from 〈em〉E. coli〈/em〉 showed microbiostatic and agglutination activities against bacteria and fungi 〈em〉in vitro〈/em〉. Silencing of LvCTL5 〈em〉in vivo〈/em〉 could significantly affect expression of a series of immune effector genes and down-regulate the phagocytic activity of hemocytes. Compared with controls, the LvCTL5-silenced shrimp were highly susceptible to 〈em〉Vibrio parahaemolyticus〈/em〉 and white spot syndrome virus (WSSV) infections. These suggest that LvCTL5 has microbiostatic and immune regulatory activities and is implicated in antiviral and antibacterial responses.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Yi Tang, Yujia Sun, Lingmin Zhao, Xiaojin Xu, Lixing Huang, Yingxue Qin, Yongquan Su, Ganfeng Yi, Qingpi Yan〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Large yellow croaker (〈em〉Larimichthys crocea〈/em〉) is an economical important farmed fish in China. “Visceral White Spot Disease” caused by 〈em〉Pseudomonas plecoglossicida〈/em〉 is a disease with a high mortality rate in cage-cultured 〈em〉L. crocea〈/em〉 in recent years and resulted in heavy economy lossess. The dual RNA-seq results of previous study showed that the expression of 〈em〉clpV〈/em〉 gene in 〈em〉P. plecoglossicida〈/em〉 was significantly up-regulated during infection. RNAi significantly reduced the expression of 〈em〉clpV〈/em〉 in 〈em〉P. plecoglossicida〈/em〉 with maximum silencing efficiency of 96.1%. Compared with the wild type strain, infection of 〈em〉clpV〈/em〉-RNAi strain resulted in a delayed onset time and a 25% reduction in mortality of 〈em〉L. crocea〈/em〉, as well as lessening the symptoms of the spleen. The results of dual RNA-seq of 〈em〉L. crocea〈/em〉 infected by 〈em〉clpV〈/em〉-RNAi strain of 〈em〉P. plecoglossicida〈/em〉 changed considerably, compared with the counterpart infected with the wild strain. The KEGG enrichment analysis showed that Cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, C-type lectin receptor signaling pathway and MAPK signaling pathway of 〈em〉L. crocea〈/em〉 were most affected by the silence of 〈em〉clpV〈/em〉 in 〈em〉P. plecoglossicida〈/em〉. RNAi of 〈em〉clpV〈/em〉 resulted in the downregulation of genes in flagella assembly pathway and a weaker immune response of host.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Hao Chen, Minxiao Wang, Huan Zhang, Hao Wang, Zhao Lv, Li Zhou, Zhaoshan Zhong, Chao Lian, Lei Cao, Chaolun Li〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉As domain species in seep and vent ecosystem, Bathymodioline mussels has been regarded as a model organism in investigating deep sea chemosymbiosis. However, mechanisms underlying their symbiosis with chemosynthetic bacteria, especially how the host recognizes symbionts, have remained largely unsolved. In the present study, a modified pull-down assay was conducted using enriched symbiotic methane-oxidation bacteria as bait and gill proteins of 〈em〉Bathymodiolus platifrons〈/em〉 as a target to isolate pattern recognition receptors involved in the immune recognition of symbionts. As a result, a total of 47 proteins including BpLRR-1 were identified from the pull-down assay. It was found that complete cDNA sequence of BpLRR-1 contained an open reading frame of 1479 bp and could encode a protein of 492 amino acid residues with no signal peptide or transmembrane region but eight LRR motif and two EFh motif. The binding patterns of BpLRR-1 against microbial associated molecular patterns were subsequently investigated by surface plasmon resonance analysis and LPS pull-down assay. Consequently, BpLRR-1 was found with high binding affinity with LPS and suggested as a key molecule in recognizing symbionts. Besides, transcripts of BpLRR-1 were found decreased significantly during symbiont depletion assay yet increased rigorously during symbionts or nonsymbiotic 〈em〉Vibrio alginolyticus〈/em〉 challenge, further demonstrating its participation in the chemosynthetic symbiosis. Collectively, these results suggest that BpLRR-1 could serve as an intracellular recognition receptor for the endosymbionts, providing new hints for understanding the immune recognition in symbiosis of 〈em〉B. platifrons〈/em〉.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: November 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 94〈/p〉 〈p〉Author(s): Yuan Luo, Yun-Ni Zhang, Han Zhang, Hong-Bo Lv, Mei-Ling Zhang, Li-Qiao Chen, Zhen-Yu Du〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Peroxisome proliferator-activated receptor α (PPARα) plays critical physiological roles in energy metabolism, antioxidation and immunity of mammals, however, these functions have not been fully understood in fish. In the present study, Nile tilapia (〈em〉Oreochromis niloticus〈/em〉) were fed with fenofibrate, an agonist of PPARα, for six weeks, and subsequently challenged with 〈em〉Aeromonas hydrophila〈/em〉. The results showed that PPARα was efficiently activated by fenofibrate through increasing mRNA and protein expressions and protein dephosphorylation. PPARα activation increased significantly mitochondrial fatty acid β-oxidation efficiency, the copy number of mitochondrial DNA and expression of monoamine oxidase (MAO), a marker gene of mitochondria. Meanwhile, PPARα activation also increased significantly the expression of NADH dehydrogenase [ubiquinone] 1α subcomplex subunit 9 (NDUFA9, complex I) and mitochondrial cytochrome 〈em〉c〈/em〉 oxidase 1 (MTCO1, complex IV). The fenofibrate-fed fish had higher survival rate when exposed to 〈em〉A. hydrophila〈/em〉. Moreover, the fenofibrate-fed fish also had higher activities of immune and antioxidative enzymes, and gene expressions of anti-inflammatory cytokines, while had lower expressions of pro-inflammatory cytokine genes. Taken together, PPARα activation improved the ability of Nile tilapia to resist 〈em〉A. hydrophila〈/em〉, mainly through enhancing mitochondrial fatty acids β-oxidation, immune and antioxidant capacities, as well as inhibiting inflammation. This is the first study showing the regulatory effects of PPARα activation on immune functions through increasing mitochondria-mediated energy supply in fish.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: November 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 94〈/p〉 〈p〉Author(s): Ivon F. Maha, Xiao Xie, Suming Zhou, Youbin Yu, Xiao Liu, Aysha Zahid, Yuhua Lei, Rongrong Ma, Fei Yin, Dong Qian〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉The yellow drum 〈em〉Nibea albiflora〈/em〉 is less susceptible to 〈em〉Cryptocaryon irritans〈/em〉 infection than is the case with other marine fishes such as 〈em〉Larimichthys crocea〈/em〉, 〈em〉Lateolabrax japonicus,〈/em〉 and 〈em〉Pagrus major〈/em〉. To investigate further their resistance mechanism, we infected the 〈em〉N. albiflora〈/em〉 with the 〈em〉C. irritans〈/em〉 at a median lethal concentration of 2050 theronts/g fish. The skins of the infected and the uninfected fishes were sampled at 24 h and 72 h followed by an extensive analysis of metabolism. The study results revealed that there were 2694 potential metabolites. At 24 h post-infection, 12 metabolites were up-regulated and 17 were down-regulated whereas at 72 h post-infection, 22 metabolites were up-regulated and 26 were down-regulated. Pathway enrichment analysis shows that the differential enriched pathways were higher at 24 h with 22 categories and 58 subcategories (49 up, 9 down) than at 72 h whereby the differential enriched pathways were 6 categories and 8 subcategories (4 up, 4 down). In addition, the principal component analysis (PCA) plot shows that at 24 h the metabolites composition of infected group were separately clustered to uninfected group while at 72 h the metabolites composition in infected group were much closer to uninfected group. This indicated that 〈em〉C. irritans〈/em〉 caused strong metabolic stress on the 〈em〉N. albiflora〈/em〉 at 24 h and restoration of the dysregulated metabolic state took place at 72 h of infection. Also, at 72 h post infection a total of 17 compounds were identified as potential biomarkers.〈/p〉 〈p〉Furthermore, out of 2694 primary metabolites detected, 23 metabolites could be clearly identified and semi quantified with a known identification number and assigned into 66 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Most of the enriched KEGG pathways were mainly from metabolic pathway classes, including the metabolic pathway, biosynthesis of secondary metabolites, taurine and hypotaurine metabolism, purine metabolism, linoleic acid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis. Others were glyoxylate and dicarboxylate metabolism, glutathione metabolism, and alanine, aspartate, and glutamate metabolism. Moreover, out of the identified metabolites, only 6 metabolites were statistically differentially expressed, namely, L -glutamate (up-regulated) at 24 h was important for energy and precursor for other glutathiones and instruments of preventing oxidative injury; 15-hydroxy- eicosatetraenoic acid (15-HETE), (S)-(−)-2-Hydroxyisocaproic acid, and adenine (up-regulated) at 72 h were important for anti-inflammatory and immune responses during infection; others were delta-valerolactam and betaine which were down-regulated compared to uninfected group at 72 h, might be related to immure responses including stimulation of immune system such as production of antibodies.〈/p〉 〈p〉Our results therefore further advance our understanding on the immunological regulation of 〈em〉N. albiflora〈/em〉 during immune response against infections as they indicated a strong relationship between skin metabolome and 〈em〉C. irritans〈/em〉 infection.〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 19 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Yinda Qiu, Zhongxiang Xiao, Yanyan Wang, Dingfang Zhang, Wenxin Zhang, Guangbao Wang, Wenbin Chen, Guang Liang, Xiaokun Li, Yali Zhang, Zhiguo Liu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Myeloid differentiation protein 2 (MD2) is a co-receptor of toll-like receptor 4 (TLR4) responsible for the recognition of lipopolysaccharide (LPS) and mediates a series of TLR4-dependent inflammatory responses in inflammatory lung diseases including acute lung injury (ALI). Targeting MD2 thus may provide a therapeutic strategy against these lung diseases. In this study, we identified a novel compound 〈strong〉4k〈/strong〉 with the potent anti-inflammatory activity among 39 methyl gallate derivatives (MGDs). MGD 〈strong〉4k〈/strong〉 exhibited a high binding affinity to MD2, which in turn prevented the formation of the LPS/MD2/TLR4 complex. In addition, MGD 〈strong〉4k〈/strong〉 significantly reversed the upregulation of LPS-induced inflammatory mediators such as tumor necrosis factor-α, interleukin-6, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉. Mechanistically, MGD 〈strong〉4k〈/strong〉 performed anti-inflammatory function by inactivating JNK, ERK and p38 signaling pathways. Taken together, our study identified MGD 〈strong〉4k〈/strong〉 as a novel potential therapeutic agent for ALI through inhibiting MD2, inflammatory responses, and major inflammation-associated signaling pathways.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉Novel methyl gallate derivatives were synthesized, and evaluated their anti-inflammatory activities for the treatment of ALI as MD2 inhibitors.〈/p〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619306297-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Hye-Jin Go, Chan-Hee Kim, Ji Been Park, Tae Young Kim, Tae Kwan Lee, Hye Young Oh, Nam Gyu Park〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Fish skin mucus is considered to act as the first line of defense against waterborne pathogens and to be potential source of novel antimicrobial components. Here we report the purification and characterization of a novel hepcidin type 2-like antimicrobial peptide (〈em〉Tp〈/em〉HAMP2) from the skin mucus of the pufferfish 〈em〉Takifugu pardalis〈/em〉. The purified 〈em〉Tp〈/em〉HAMP2 comprised of 23 amino acids (AAs) with eight Cys residues that form four intramolecular disulfide bonds. The 〈em〉Tp〈/em〉HAMP2 gene shared overall structural characteristics with all known hepcidins, which have a tripartite exon-intron gene organization and three structural signatures in the precursor protein. Phylogenetically, 〈em〉Tp〈/em〉HAMP2 was classified as HAMP2 class in acanthopterygian fish. Interestingly, the AA sequence of 〈em〉Tp〈/em〉HAMP2 did not contain a proprotein cleavage site (RXXR motif) that conserved in most hepcidins and showed a highly positive charged (RKR-) short N-terminus and Val〈sup〉18〈/sup〉 and Gly〈sup〉22〈/sup〉 residues, which are distinctive structures compared to other known active hepcidins. Recombinant 〈em〉Tp〈/em〉HAMP2 identical to the native form exhibited a broad spectrum and potent antimicrobial activity against tested gram-positive and -negative bacteria. Expression of 〈em〉Tp〈/em〉HAMP2 mRNA was predominant in the liver and was upregulated in the liver, the spleen, the intestine, and the skin of 〈em〉T. pardalis〈/em〉 post immune challenge. Thus, our findings suggests that 〈em〉Tp〈/em〉HAMP2 might be of importance in the framework of discovering the fish hepcidins, especially type 2s, and provide noteworthy insight into its gene structure and expression and in the innate immunity as well as the mucosal immunity in regard to hepcidins’ evolutionary history in fish species.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Chen Li, Yepin Yu, Xin Zhang, Jingguang Wei, Qiwei Qin〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Autophagy is an evolutionarily conserved, multi-step lysosomal degradation process used to maintain cell survival and homeostasis. A series of autophagy-related genes (Atgs) are involved in the autophagic pathway. In mammals, a growing number of studies have attributed functions to some Atgs that are distinct from their classical role in autophagosome biogenesis, such as resistance to pathogens. However, little is known about the functions of fish Atgs. In this study, we cloned and characterized an 〈em〉atg12〈/em〉 homolog from orange spotted grouper (〈em〉Epinephelus coioides〈/em〉) (〈em〉Ecatg12〈/em〉). 〈em〉Ecatg12〈/em〉 encodes a 117 amino acid protein that shares 94.0% and 76.8% identity with gourami (〈em〉Anabas_testudineus〈/em〉) and humans (〈em〉Homo sapiens〈/em〉), respectively. The transcription level of 〈em〉Ecatg12〈/em〉 was lower in cells infected with Singapore grouper iridovirus (SGIV) than in non-infected cells. Fluorescence microscopy revealed that EcAtg12 localized in the cytoplasm and nucleus in grouper spleen cells. Overexpression of EcAtg12 significantly increased the replication of SGIV, as evidenced by increased severity of the cytopathic effect, transcription levels of viral genes, levels of viral proteins, and progeny virus yield. Further studies showed that EcAtg12 overexpression decreased the expression levels of interferon (IFN) related molecules and pro-inflammatory factors and inhibited the promoter activity of IFN-3, interferon-stimulated response element, and nuclear factor-κB. Together, these results demonstrate that EcAtg12 plays crucial roles in SGIV replication by downregulating antiviral immune responses.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 14 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Ravi P. Singh, Marian N. Aziz, Delphine Gout, Walid Fayad, May A. El-Manawaty, Carl J. Lovely〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of N-substituted (〈em〉Z〈/em〉)-2-imino-(5〈em〉Z〈/em〉)-ylidene thiazolidines/thiazolidin-4-ones were synthesized and their antiproliferative activities against colon (HCT-116) and breast (MCF7) cancer cell lines were evaluated utilizing an MTT growth assay. A 2D-QSAR investigation was conducted to probe and validate the obtained antiproliferative properties for the thiazolidine derivatives. The majority of the thiazolidines exhibit higher potency against a colon cancer cell line relative to the standard reference. The 〈em〉p〈/em〉-halophenylimino 〈em〉p〈/em〉-anisylidene derivatives exhibited the highest anti-proliferative activity against HCT116 relative to control (IC〈sub〉50〈/sub〉 = 8.9–10.0 μM compared to 20.4 μM observed for 5-fluorouracil as positive control). An X-ray study confirmed the 〈em〉Z〈/em〉, 〈em〉Z〈/em〉′-configurations for two examples of the synthesized compounds.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619306030-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 9 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Annalisa Reale, Simone Brogi, Alessia Chelini, Marco Paolino, Angela Di Capua, Germano Giuliani, Andrea Cappelli, Gianluca Giorgi, Giulia Chemi, Alessandro Grillo, Massimo Valoti, Lidia Sautebin, Antonietta Rossi, Simona Pace, Concettina La Motta, Lorenzo Di Cesare Mannelli, Elena Lucarini, Carla Ghelardini, Maurizio Anzini〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉A novel series of 1,5-diarylpyrrol-3-sulfur derivatives (〈strong〉10〈/strong〉–〈strong〉12〈/strong〉) was synthesized and characterized by NMR and mass spectroscopy and x-ray diffraction. The biological activity of these compounds was evaluated in 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉 tests to assess their COX-2 inhibitory activity along with anti-inflammatory and antinociceptive effect.〈/p〉 〈p〉Results showed that the bioisosteric transformation of previously reported alkoxyethyl ethers (〈strong〉9a-c)〈/strong〉 into the corresponding alkyl thioethers (〈strong〉10a-c〈/strong〉) still leads to selective and active compounds being the COX-2 inhibitory activity for most of them in the low nanomolar range. The oxidation products of 〈strong〉10a,b〈/strong〉 were also investigated and both couple of sulfoxides (〈strong〉11a〈/strong〉,〈strong〉b〈/strong〉) and sulfones (〈strong〉12a〈/strong〉,〈strong〉b〈/strong〉) showed an appreciable COX-2 inhibitory activity. Molecular modeling studies were performed to investigate the binding mode of the representative compounds 〈strong〉10b〈/strong〉, 〈strong〉11b〈/strong〉, and 〈strong〉12b〈/strong〉 into COX-2 enzyme and to explore the potential site of metabolism of 〈strong〉10a〈/strong〉 and 〈strong〉10b〈/strong〉 due to the different 〈em〉in vivo〈/em〉 efficacy. Among the developed compounds, compound 〈strong〉10b〈/strong〉 showed a significant 〈em〉in vivo〈/em〉 anti-inflammatory and antinociceptive activity paving the way to develop novel anti-inflammatory drugs.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961931079X-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Lijun Xu, Luqing Pan, Xin Zhang, Cun Wei〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Shrimps like other arthropods rely on innate immune system, and may have some form of adaptive immunity in defending against pathogens. Phagocytosis is one of the oldest cellular processes, serving as a development process, a feeding mechanism and especially as a key defense reaction in innate immunity of all multicellular organisms. It is confirmed that crustacean hyperglycemic hormone (CHH) is one of the most important neuropeptides produced by Neuro-endocrine Immune (NEI) regulatory network, which undertakes important roles in various biological processes, especially in immune function and stress response. In this study, the recombinant 〈em〉Litopenaeus vannamei〈/em〉 CHH (rLvCHH) was obtained from a bacterial expression system and the intracellular signaling pathways involved in the mechanism of phagocytosis after rLvCHH injection was investigated. The results showed that the contents of adenylyl cyclase (AC), phospholipase C (PLC) and calmodulin (CaM) in hemocytes were increased significantly after rLvCHH injection. Furthermore, the mRNA expression levels of NF-kB family members (relish and dorsal) and phagocytosis-related proteins in hemocytes were basically overexpressed after rLvCHH stimulation, while the expression level of NF-kB repressing factor (NKRF) gene was down-regulated significantly. Eventually, the total hemocyte count and phagocytic activity of hemocyte were dramatically enhanced within 3 h. Collectively, these results indicate that shrimps 〈em〉L. vannamei〈/em〉 could carry out a simple but ‘smart’ NEI regulation through the action of neuroendocrine factors, which could couple with their receptors and trigger the downstream signaling pathways during the phagocytic responses of hemocytes.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 9 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Toshinori Suzuki, Yuki Kishida〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉When a neutral solution of thymidine and ascorbic acid was irradiated with UV light of wavelength longer than 300 nm in the presence of salicylic acid as a photosensitizer, six product peaks appeared in an HPLC chromatogram in addition to small amounts of thymidine dimers. The six products were identified as three pairs of diastereomers of 5-(2-deoxy-2-〈span〉l〈/span〉-ascorbyl)-5,6-dihydrothymidine, 5-(2-〈span〉l〈/span〉-ascorbyl)-5,6-dihydrothymidine, and 5,6-dihydrothymidine. These results suggest that novel DNA damage may be generated by ascorbic acid with salicylic acid induced by sunlight.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619311423-ga1.jpg" width="312" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Chenyin Wang, Laura Engelke, David Bickel, Alexandra Hamacher, Marian Frank, Peter Proksch, Holger Gohlke, Matthias U. Kassack〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Platinum compounds are the first-line therapy for many types of cancer. However, drug resistance has frequently been reported for and is a major limitation of platinum-based chemotherapy in the clinic. In the current study, we examined the anti-tumor activity of phomoxanthone A (PXA), a tetrahydroxanthone dimer isolated from the endophytic fungus 〈em〉Phomopsis longicolla〈/em〉, in several solid cancer cell lines and their cisplatin-resistant sub-cell lines. PXA showed strong cytotoxic effects with IC〈sub〉50〈/sub〉 values in the high nanomolar or low micromolar range in MTT assays. IC〈sub〉50〈/sub〉 values of PXA were lower than those of cisplatin. Remarkably, equipotent anti-cancer activity was found in cisplatin-sensitive and respective cisplatin-resistant cells. Anticancer effects of PXA were studied in further detail in ovarian cancer (A2780) and bladder cancer (J82) cell pairs. PXA led to rapid depolarization of the mitochondrial membrane potential and strong activation of caspase 3 and 7, eventually resulting in strong induction of apoptosis. These effects occurred again both in sensitive and resistant cell lines. IC〈sub〉50〈/sub〉 values of PXA from MTT and mitochondrial membrane depolarization assays were in good agreement. Configurational free energy computations indicate that both the neutral and singly negatively charged PXA show membrane partitioning and can penetrate the inner mitochondrial membrane. PXA treatment did not damage the plasma membranes of cancer cells, thus excluding unspecific membrane effects. Further, PXA had neither an effect on intracellular ROS nor on reduction of ROS after hydrogen peroxide treatment. In conclusion, our studies present PXA as a natural compound with strong apoptotic anticancer effects against platinum-resistant solid cancers. This may open new treatment options in clinically resistant malignancies.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619307850-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 7 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Marc Pflieger, Alexandra Hamacher, Taner Öz, Nadine Horstick-Muche, Benedikt Boesen, Christian Schrenk, Matthias U. Kassack, Thomas Kurz〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of α,β-unsaturated hydroxamic acid derivatives as novel HDAC inhibitors (HDACi) with structural modifications of the connecting unit and the CAP group was synthesized. The 〈em〉in vitro〈/em〉 evaluation against the human cancer cell lines A2780 and Cal27 identified 〈strong〉6e〈/strong〉 and 〈strong〉7j〈/strong〉 as the most potent compounds regarding HDAC inhibitory activity and inhibition of proliferation. Isoform profiling against HDAC2, 4, 6 and 8 revealed a preference for HDAC2 and 6 for both compounds in contrast to the pan HDACi panobinostat. 〈strong〉6e〈/strong〉 and 〈strong〉7j〈/strong〉 enhanced significantly cisplatin-induced cytotoxicity in a combination treatment mediated by increased apoptosis induction and caspase-3/7 activation. The interaction between 〈strong〉6e〈/strong〉 or 〈strong〉7j〈/strong〉 and cisplatin was highly synergistic and more pronounced for the cisplatin resistant subline Cal27CisR. IC〈sub〉50〈/sub〉 values of cisplatin were even lower in Cal27CisR pretreated with 〈strong〉6e〈/strong〉 or 〈strong〉7j〈/strong〉 than for the parental cell line Cal27. Based on our findings, the novel dual class I/HDAC6 inhibitors could serve as an option to overcome cisplatin resistance with fewer side effects in comparison to panobinostat.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961930522X-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 7 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Patrick M. Wehrli, Ivana Uzelac, Thomas Olsson, Tomas Jacso, Daniel Tietze, Johan Gottfries〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉High-throughput screening of small-molecule libraries has led to the identification of thiadiazoles as a new class of inhibitors against 〈em〉Staphylococcus aureus〈/em〉 sortase A (SrtA). N-(5-((4-nitrobenzyl)thio)-1,3,4-thiadiazol-2-yl)nicotinamide (IC〈sub〉50〈/sub〉 = 3.8 µM) was identified as a potent inhibitor of SrtA after synthetic modification of hit compounds. Additional ligands developed in this study displayed affinities in the low micromolar range without affecting bacterial growth 〈em〉in vitro〈/em〉. The study also suggest a new mode of action through covalent binding to the active site cysteine.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619303943-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Maxime Boutier, Yuan Gao, Owen Donohoe, Alain Vanderplasschen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Aquaculture is one of the world's most important and fastest growing food production sectors, with an average annual growth of 5.8% during the period 2001–2016. Common carp (〈em〉Cyprinus carpio〈/em〉) is one of the main aquatic species produced for human consumption and is the world's third most produced finfish. Koi carp, on the other hand, are grown as a popular ornamental fish. In the late 1990s, both of these sectors were threatened by the emergence of a deadly disease caused by cyprinid herpesvirus 3 (CyHV-3; initially called koi herpesvirus or KHV). Since then, several research groups have focused their work on developing methods to fight this disease. Despite increasing knowledge about the pathobiology of this virus, there are currently no efficient and cost-effective therapeutic methods available to fight this disease. Facing the lack of efficient treatments, safe and efficacious prophylactic methods such as the use of vaccines represent the most promising approach to the control of this virus. The common carp production sector is not a heavily industrialized production sector and the fish produced have low individual value. Therefore, development of vaccine methods adapted to mass vaccination are more suitable. Multiple vaccine candidates against CyHV-3 have been developed and studied, including DNA, bacterial vector, inactivated, conventional attenuated and recombinant attenuated vaccines. However, there is currently only one vaccine commercially available in limited regions. The present review aims to summarize and evaluate the knowledge acquired from the study of these vaccines against CyHV-3 and provide discussion on future prospects.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Yilong Wang, Baojie Wang, Xuqing Shao, Jianchun Shao, Mei Liu, Mengqiang Wang, Lei Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Rearing density and disease management are considered as pivotal factors determining shrimp farm productivity and profitability. To systematically investigate the potential mechanisms for density-related differences between disease susceptibility and rearing densities, we conducted comparative transcriptome analysis of the molecular differences between hepatopancreas and intestine of 〈em〉Litopenaeus vannamei〈/em〉 under two different rearing densities (800- and 400- shrimp/m〈sup〉3〈/sup〉) for 15 d and further analyzed the differences in immune response to 〈em〉Vibrio parahaemolyticus〈/em〉 E1 (VPE1) raised under two density conditions. Totally 45 different expression genes (DEGs) were identified in the hepatopancreas under two different rearing densities, the DEGs were grouped into four processes or pathways related to animal immune system. Then, exposure to the VPE1 resulted in 639 DEGs, involved into fourteen immune related processes or pathways. In the intestine, seventeen processes or pathways related to the immune system were identified among the 5470 DEGs under two different rearing densities. 279 DEGs were identified post VPE1 challenge, classified into five processes or pathways associated with the immune system. Meanwhile, the results of growth performance, histopathology and the activities of antioxidant enzymes in the hepatopancreas and intestines of shrimp showed that high density decreased weight gain rate (63.20 ± 1.67% and 18.73 ± 3.35% in the high and low rearing density groups, respectively), severely destroyed the histopathology and inhibited the antioxidant enzymes activities. This study demonstrated that rearing density in 〈em〉L. vannamei〈/em〉 significantly impacts susceptibility to the VPE1, via altered transcriptional challenge responses, and thus higher mortality due to disease.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Youliang Rao, Jianfei Ji, Zhiwei Liao, Hang Su, Jianguo Su〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉TANK-binding kinase 1 (TBK1) is an important kinase that regulates the activation of interferon regulatory factor 3/7 (IRF3/7) to induce type I interferon (IFN–I) production in antiviral immune responses. However, in long-term virus-host crosstalk, viruses have evolved elaborate strategies to evade host immune defense mechanisms. In the present study, we found that grass carp (〈em〉Ctenopharyngodon idella〈/em〉) reovirus (GCRV) hijacks TBK1 to escape IRF7-IFN-Is signaling activation. In brief, GCRV inhibited TBK1 activation by restaining K63-linked ubiquitination of TBK1 and promoting its K48-linked ubiquitination. This regulation resulted in that under low titer of GCRV infection, TBK1 overexpression specifically supressed promoter activity and phosphorylation of IRF7 and induction of downstream IFN1and IFN3. qRT-PCR data uncovered that TBK1 negatively regulated IRF7, IFN1 and IFN3 transcription levels under low viral titer infection. Along with enhancement of GCRV titers, TBK1 swiched its function to up-regulate IRF7, IFN1 and IFN3 mRNA levels. Accordingly, TBK1 promoted GCRV replication at low infected titer, but inhibited GCRV replication at high infected titer. All these results revealed a viral evasion strategy that GCRV utilizes TBK1 to block cellular IFN responses at low titers or early stages in fish species, which will lay a foundation for further researching on host-virus interactions and developing novel antiviral strategies in lower vertebrates.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Dongyan Guan, Huiwen Sun, Xiao Meng, Jiting Wang, Wenju Wan, Haojun Han, Zhen Wang, Yang Li〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A feeding trial was conducted to evaluate the effects of different molar mass chitooligosaccharides (1000 Da, 3000 Da and 8000 Da) on growth, antioxidant capacity, non-specific immune response, and resistance to 〈em〉Aeromonas hydrophila〈/em〉 in GIFT tilapia (〈em〉Oreochromis niloticus〈/em〉). A total of 600 fish were divided into four treatments with five replicates of thirty fish per tank. The results showed that the supplementation of 1000 Da and 3000 Da COS significantly improved the growth performance and feed utilization in GIFT tilapia. The trend of decreasing total cholesterol, triglyceride, ALT, and ACP activity was observed in fish fed diet supplemented COS. The supplementation of 1000 Da and 3000 Da COS significantly improved the serum TAC activity, and decreased the serum MDA and catalase activities (〈em〉P〈/em〉 〈 0.05). The lysozyme activity of blood, liver, and gills in fish fed diets supplemented with 1000 Da and 3000 Da COS was significantly higher than that of fish fed control diet after 56 days of feeding (〈em〉P〈/em〉 〈 0.05). The phagocytic activity and phagocytic index of fish fed diets supplemented with 1000 Da and 3000 Da COS were significantly higher than those of fish fed control diet. Post-challenge test showed that fish mortality in 1000 Da, 3000 Da, and 8000 Da COS groups were significantly lower than that of fish in control group (〈em〉P〈/em〉 〈 0.05). In conclusion, the present study indicated that dietary 1000 Da and 3000 Da COS supplementation could enhance more performance and immune response of GIFT tilapia than 8000 Da COS.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Ke Ji, Hualiang Liang, Mingchun Ren, Xianping Ge, Bo Liu, Bingwen Xi, Liangkun Pan, Heng Yu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Dietary administration of tryptophan has been proved improving growth performance of fish. An 8-week feeding trial was conducted to investigate the effects of dietary tryptophan level on antioxidant capacity and immune response through Nrf2 and TOR signaling pathway. The results showed that, 0.08% tryptophan level significantly increased plasma aspartate aminotransferase (AST), while immunoglobulin M (IgM) and alkaline phosphatase (ALP) were strikingly increased by 0.40% level. The level of plasma complement component 3 (C3), alanine aminotransferase (ALT) and albumin (ALB) were independent of tryptophan supplementation. Total superoxide dismutase (T-SOD), catalase (CAT), total antioxidant capacity (T-AOC) and glutathione (GSH) activity were increased with increasing dietary tryptophan level until 0.40% and then decreased, while the level of malondialdehyde (MDA) showed a reverse trend. 0.19% and 0.28% tryptophan level significantly improved the glutathione peroxidase 1 (GPx-1) activity. Compared with 0.08% dietary tryptophan level, 0.40% level significantly improved nuclear factor erythroid 2-related factor 2 (Nrf2), GPx, manganese superoxide dismutase (Mn-SOD), CAT and transforming growth factor-β (TGF-β) mRNA level, while Kelch-like ECH-associated protein 1 (Keap1) and interleukin 1β (IL-1β) mRNA level were significantly decreased. The relative expression of copper zinc superoxide dismutase (Cu/Zn-SOD), heme oxygenase-1 (HO-1), target of rapamycin (TOR), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), protein kinase B (Akt) and interleukin 10 (IL-10) were significantly improved by 0.28% diet, while the mRNA level of tumor necrosis factor-α (TNF-α) and nuclear factor-kappa B (NF-κB) were increased by 0.08% diet. Interleukin 8 (IL-8) mRNA level was not significantly affected by dietary tryptophan. Based on MDA and T-SOD value, the optimal dietary tryptophan level of juvenile blunt snout bream was determined to be 0.33% (1.03% of dietary protein) and 0.36% (1.13% of dietary protein), respectively, using quadratic regression analysis.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 5 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Orit Jacobson, Zhantong Wang, Guocan Yu, Ying Ma, Xiaoyuan Chen, Dale O. Kiesewetter〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉The efficient radiosynthesis of biomolecules utilizing minute quantities of maleimide substrate is important for availability of novel peptide molecular imaging agents. We evaluated both 3-〈sup〉18〈/sup〉F-fluoropropane-1-thiol and 2-(2-(2-(2-〈sup〉18〈/sup〉F-fluoroethoxy)ethoxy)ethoxy)ethane-1-thiol (〈sup〉18〈/sup〉F-fluoro-PEG〈sub〉4〈/sub〉 thiol) as prosthetic groups for radiolabeling under physiological conditions. The precursor employed a benzoate for protection of the thiol and an arylsulfonate leaving group. The radiofluorination was fully automated on an Eckert & Ziegler synthesis system using standard Kryptofix〈sub〉222〈/sub〉/K〈sub〉2〈/sub〉CO〈sub〉3〈/sub〉 conditions. In order to minimize the amount of biological molecule required for subsequent conjugation, the intermediates, S-(3-〈sup〉18〈/sup〉F-fluoropropyl) benzothioate and 〈sup〉18〈/sup〉F-fluoro-PEG〈sub〉4〈/sub〉 benzothioate, were purified by HPLC. The intermediates were isolated from the HPLC in yields of 37–47% and 28–35%, respectively, and retrieved from eluate using solid phase extraction. Treatment of the benzothioates with sodium methoxide followed by acetic acid provided the free thiols. The desired maleimide substrate in acetonitrile or phosphate buffer was then added and incubated at room temperature for 15 min. The final radiolabeled bioconjugate was purified on a separate HPLC or NAP-5 column. Maleimides utilized for the coupling reaction included phenyl maleimide, an Evans Blue maleimide derivative, a dimeric RGDfK maleimide (E[〈em〉c〈/em〉(〈em〉RGDfK〈/em〉)]〈sub〉2〈/sub〉), two aptamer maleimides, and PSMA maleimide derivative. Isolated radiochemical yields (non-decay corrected) of maleimide addition products based on starting 〈sup〉18〈/sup〉F-fluoride ranged from 6 to 22% in a synthesis time of about 90 min.〈/p〉 〈p〉〈sup〉18〈/sup〉F-thiol prosthetic groups were further tested 〈em〉in vivo〈/em〉 by conjugation to E[〈em〉c〈/em〉(〈em〉RGDfK〈/em〉)]〈sub〉2〈/sub〉 maleimide in a U87MG xenograft model. PET studies demonstrated similar tumor accumulation of both prosthetic groups. 〈sup〉18〈/sup〉F-fluoro-PEG〈sub〉4〈/sub〉-S-E[〈em〉c〈/em〉(〈em〉RGDfK〈/em〉)]〈sub〉2〈/sub〉 displayed a somewhat favorable pharmacokinetics compared to 〈sup〉18〈/sup〉F-fluoropropyl-S-E[〈em〉c〈/em〉(〈em〉RGDfK〈/em〉)]〈sub〉2〈/sub〉. Bone uptake was low for both indicating 〈em〉in vivo〈/em〉 stability.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619310661-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Changle Qi, Xiaodan Wang, Fenglu Han, Yongyi Jia, Zhideng Lin, Chunling Wang, Jianting Lu, Lu Yang, Xinyue Wang, Erchao Li, Jian G. Qin, Liqiao Chen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉To investigate the effects of arginine (Arg) on the growth, antioxidant capacity, immunity and disease resistance of juvenile Chinese mitten crab, three diets containing Arg levels at 1.72% (control), 2.73% and 3.72% were formulated and fed to Chinese mitten crab (0.22 ± 0.03 g) for eight weeks. The weight gain, ecdysterone and growth hormone in the serum, relative expression of insulin-like growth factor 2 in the hepatopancreas significantly increased in crabs fed the 2.73% and 3.72% Arg diets. The protein and lipid contents significantly increased in crabs fed the 3.72% Arg diet. The feed conversion ratios in crabs fed the diets with Arg additions were lower than in the control. Arg supplementation also enhanced the antioxidative capacity by increasing the activities of superoxide dismutase, catalase and the relative expression of Kelch-like ECH-associated protein 1 gene in the hepatopancreas, which subsequently decreased malondialdehyde content in the hepatopancreas. Besides, Arg also decreased nitric oxide content in the serum and the activity of nitric oxide synthetase in the hepatopancreas. The relative mRNA levels of crustin, relish, lysozyme and cryptocyanin genes were significantly upregulated by Arg supplementation. The activities of acid phosphatase and alkaline phosphatase in the serum significantly increased in crabs fed the 3.72% Arg diet than those in the control. Similarly, the relative mRNA levels of crustin, cryptocyanin and proPO genes were significantly upregulated in crabs fed the 2.73% Arg diet after lipopolysaccharide challenge, and in crabs fed the 3.72% Arg diet after the Poly (I:C) challenge. The crabs fed the 2.73% and 3.72% Arg diets had higher survival rate after bacterial infection than those fed the control diet. This study indicates that the addition of Arg to the diet at 2.7–3.7% can improve the growth, survival, antioxidant capacity, immunity and disease resistance in juvenile Chinese mitten crab.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 18〈/p〉 〈p〉Author(s): Jaiprakash Sangshetti, Shahebaaz K. Pathan, Rajesh Patil, Siddique Akber Ansari, Santosh Chhajed, Rohidas Arote, Devanand B. Shinde〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Phthalazine, a structurally and pharmacologically versatile nitrogen-containing heterocycle, has gained more attention from medicinal chemists in the design and synthesis of novel drugs owing to its pharmacological potential. In particular, phthalazine scaffold appeared as a pharmacophoric feature numerous drugs exhibiting pharmacological activities, in particular, antidiabetic, anticancer, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant and antimicrobial activities. This review presents a summary of updated and detailed information on phthalazine as illustrated in both patented and non-patented literature. The reported literature have described the optimal pharmacological characteristics of phthalazine derivatives and highlighted the applicability of phthalazine, as potent scaffold in drug discovery.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619310193-ga1.jpg" width="399" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 18〈/p〉 〈p〉Author(s): Daisuke Mori, Hiroyuki Kimura, Hidekazu Kawashima, Yusuke Yagi, Kenji Arimitsu, Masahiro Ono, Hideo Saji〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that have been implicated in higher brain functions. To elucidate the functional mechanisms underlying nAChRs and contribute significantly to development of drugs targeting neurological and neuropsychiatric diseases, non-invasive nuclear medical imaging can be used for evaluation. In addition, technetium-99m (〈sup〉99m〈/sup〉Tc) is a versatile radionuclide used clinically as a tracer in single-photon emission computed tomography. Because A85380 is known as a potent α4β2-nAChR agonist, we prepared A85380 derivatives labeled with 〈sup〉99m〈/sup〉Tc using a bifunctional chelate system. A computational scientific approach was used to design the probe efficiently. We used non-radioactive rhenium (Re) for a 〈sup〉99m〈/sup〉Tc analog and found that one of the derivatives, Re-A-YN-IDA-C4, exhibited high binding affinity at α4β2-nAChR in both the docking simulation (−19.3 kcal/mol) and binding assay (Ki = 0.4 ± 0.04 nM). Further, 〈sup〉99m〈/sup〉Tc-A-YN-IDA-C4 was synthesized using microwaves, and its properties were examined. Consequently, we found that 〈sup〉99m〈/sup〉Tc-A-YN-IDA-C4, with a structure optimized by using computational chemistry techniques, maintained affinity and selectivity for nAChR 〈em〉in vitro〈/em〉 and possessed efficient characteristics as a nuclear medicine molecular imaging probe, demonstrated usefulness of computational scientific approach for molecular improvement strategy.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619304183-ga1.jpg" width="279" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 31 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Yifan Feng, Weiming Duan, Shu Fan, Hao Zhang, San-Qi Zhang, Minhang Xin〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉PI3Kδ is an intriguing target for developing anti-cancer agent. In this study, a new series of 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were synthesized. After biological evaluation, compounds 〈strong〉A5〈/strong〉 and 〈strong〉A8〈/strong〉 were identified as potent PI3Kδ inhibitors, with IC〈sub〉50〈/sub〉 values of 1.3 and 0.7 nM, respectively, which are equivalent to or better than idelalisib (IC〈sub〉50〈/sub〉 = 1.2 nM). Further PI3K isoforms selectivity evaluation showed that compound 〈strong〉A5〈/strong〉 afforded excellent PI3Kδ selectivity over PI3Kα, PI3Kβ and PI3Kγ. 〈strong〉A8〈/strong〉 exhibited superior PI3Kδ/γ selectivity over PI3Kα and PI3Kβ. Moreover, compounds 〈strong〉A5〈/strong〉 and 〈strong〉A8〈/strong〉 selectively exhibited anti-proliferation against SU-DHL-6 〈em〉in vitro〈/em〉 with IC〈sub〉50〈/sub〉 values of 0.16 and 0.12 μM. Western blot analysis indicated that 〈strong〉A8〈/strong〉 could attenuate the AKT〈sup〉S473〈/sup〉 phosphorylation. Molecular docking study suggested that 〈strong〉A8〈/strong〉 formed three key H-bonds action with PI3Kδ, which may account for its potent inhibition of PI3Kδ. These findings indicate that 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were potent PI3Kδ inhibitors with distinctive PI3K-isoforms and anti-proliferation profiles.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619310065-ga1.jpg" width="448" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 18〈/p〉 〈p〉Author(s): Xiaoman Zheng, Zhengfeng Fu, Chunyun Wang, Shengbo Zhang, Min Dai, Enbo Cai, Yan Zhao〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈h6〉Objective〈/h6〉 〈p〉To study the changes of ginsenoside content in different proportion of 〈em〉Panax ginseng-Angelica sinensis〈/em〉 (GA) co-decoction, and to explore the amelioration of hematopoietic function in mice after combined use of the two drugs. The active ingredient profiles in 〈em〉P. ginseng〈/em〉 single decoction and co-decoction of GA were determined by high performance liquid chromatography (HPLC). The experimental pharmacology method was used to explore the effect of GA co-decoction on the hematopoietic function of chemotherapy mice.〈/p〉 〈/div〉 〈div〉 〈h6〉Results〈/h6〉 〈p〉The active ingredient profiles of the co-decoction of GA significantly changed compared with those of the single decoction. Compared with GA1:0 (single decoction of 〈em〉Panax ginseng〈/em〉), the routine ginsenosides of all proportions of GA decreased significantly, but the proportion of rare ginsenosides increased significantly. The changes of contents of rare ginsenosides of GA were basically consistent with the trends of effects on the myelosuppression induced by CY. Compared with the model group, GA significantly increased the number of bone marrow nucleated cells, thymus index, peripheral blood leukocytes and platelets, and significantly reduced the spleen index. Moreover, GA could promote G1 phase bone marrow cells to enter the cell cycle, increase the proportion of S phase cells and G2/M phase cells, and increase the cell proliferation index.〈/p〉 〈/div〉 〈div〉 〈h6〉Conclusion〈/h6〉 〈p〉GA can ameliorate the hematopoietic function of mice after chemotherapy, and GA2:3, GA3:2 were the best, which may be due to the changes of the pharmacodynamic material basis of GA after compatibility. All these results implied that GA may be an ideal drug and food supplement for the treatment of toxic and side effects of chemotherapeutic drugs.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619306844-ga1.jpg" width="367" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 19 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Richa Mishra, Soumendra Rana〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The human complement fragment 5a (〈sup〉h〈/sup〉C5a) is an extremely potent proinflammatory glycoprotein, which upon binding to C5aR triggers a plethora of immune and non-immunological responses in humans. Dysregulation of complement system is associated with the upregulation of 〈sup〉h〈/sup〉C5a, leading to the surge of proinflammatory cytokines, which further exacerbate the chronic inflammation induced pathological conditions. Thus, 〈sup〉h〈/sup〉C5a is considered as a major pharmacological target for developing complement therapeutics that can directly or indirectly modulate the function of 〈sup〉h〈/sup〉C5a. However, the idea of small molecules, directly neutralizing the function of excessive 〈sup〉h〈/sup〉C5a remains unexplored in the literature. By recruiting cheminformatics approach, the avenue of drug repositioning is explored in the current study for discovering novel neutraligands of 〈sup〉h〈/sup〉C5a. The systematic exercise yields a pool of potential neutraligands, from which four FDA approved drugs, such as carprofen, oxaprozin, sulindac and raloxifene have been subjected to a battery of computational and biophysical studies against 〈sup〉h〈/sup〉C5a. The data obtained from docking, molecular dynamics, and molecular mechanics Poisson-Boltzmann surface area studies, strongly correlate with the data obtained from the circular dichroism, steady state fluorescence, and fluorescence quenching studies, involving the recombinant 〈sup〉h〈/sup〉C5a and the selected drugs. The proof of the concept study successfully documents the rational discovery of first generation template neutraligands of 〈sup〉h〈/sup〉C5a through drug repositioning approach and suggests that the selected drugs perhaps bind functionally distinct hot spots on 〈sup〉h〈/sup〉C5a. The identified neutraligands can be subsequently optimized as complement specific therapeutics for strongly modulating the 〈sup〉h〈/sup〉C5a-C5aR signaling axes.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619305541-ga1.jpg" width="317" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Kamila Oliveira Santos, João Costa-Filho, Jade Riet, Kérolin Luana Spagnol, Bruna Félix Nornberg, Mateus Tavares Kütter, Marcelo Borges Tesser, Luis Fernando Marins〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉Although aquaculture is among the fastest growing food production sectors in the world, one of the bottlenecks for the continuity of its expansion is the dependence of animal protein on commercial feed formulations. Vegetable proteins are an alternative due to the low cost and high availability. However, this protein source is accompanied by a series of antinutritional and pro-inflammatory compounds, including phytate. Phytases can be added in feed for phytate degradation and increase nutrient availability. However, the use of purified phytases significantly increases the production costs. An interesting alternative is to use probiotics genetically modified as bioreactors for phytase production. In the present study, a strain of 〈em〉Bacillus subtilis〈/em〉 secreting a fungal phytase was used to evaluate the effect of a feed with high content of soybean meal on zebrafish (〈em〉Danio rerio〈/em〉). We analysed the condition factor (K) of fish, and the expression of genes related to the immune system, inflammatory response and oxidative.〈/p〉 〈p〉stress. The results obtained demonstrate that the transgenic probiotic was efficient in improving the fish condition factor, stimulating the immune system, reducing the inflammatory response and oxidative stress. Thus, probiotics acting as phytase bioreactors can be considered an interesting tool for the adaptation of commercial species to feed of lower cost.〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Kun Yang, Shiyu Feng, Shengnan Zhang, Licheng Yin, Hong Zhou, Anying Zhang, Xinyan Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In this study, a new 〈em〉il-4/13〈/em〉 cDNA was isolated from grass carp 〈em〉(Ctenopharyngodon idella)〈/em〉 using homologous cloning. The phylogenetic tree and sequence alignment of the deduced amino acid (aa) sequence showed that it was closer to grass carp 〈em〉il-4/13b〈/em〉 (〈em〉gcil-4/13b〈/em〉) than other homologues and therefore named 〈em〉gcil-4/13b-like〈/em〉 (〈em〉gcil-4/〈/em〉13bl). It has 399-nt coding sequence (CDS) which is less than 〈em〉gcil-4/13b〈/em〉 (408 nt). In addition, the cloned 〈em〉gcil-4/〈/em〉13bl gene is approximately 1600 bp in length and has a conserved genetic structure consisting of four exons and three introns. Compared to 〈em〉gcil-4/13b〈/em〉 gene, it has a variety of nucleotides variation across the CDS and contains a longer intron 3, suggesting that it is a new 〈em〉gcil-4/13〈/em〉 gene. The 〈em〉gcil-4/〈/em〉13bl transcripts were ubiquitously expressed in almost all selected tissues, and there was almost only 〈em〉gcil-4/〈/em〉13bl detected in brain and head kidney (HK). Recombinant grass carp (rgc) Il-4/13bl was prepared by using 〈em〉Escherichia coli〈/em〉 (〈em〉E. coli〈/em〉) Rosetta-gami 2 (DE3). The functional study demonstrated that rgcIl-4/13bl significantly upregulated 〈em〉arginase-2〈/em〉 gene expression and arginase activity, whilst downregulated nitric oxide (NO) production as well as the transcript levels of inducible nitric oxide synthesase (〈em〉inos〈/em〉) and 〈em〉ifn-γ〈/em〉 in freshly isolated grass carp HK monocytes/macrophages (M0/Mϕ). These data suggested that the newly cloned 〈em〉il-4/〈/em〉13bl had the conserved functions to activate M2-type but antagonize M1-type macrophages. Furthermore, rgcIl-4/13bl was able to drive the proliferation of M0/Mϕ which were pre-treated by rgcM-csf, indicating the involvement of gcIl-4/13bl in the proliferation of macrophages. Here we not only identified a new 〈em〉il-4/13〈/em〉-encoding gene in grass carp, but also for the first time revealed a novel function of fish Il-4/13 combined with M-csf engaging in M0/Mϕ proliferation.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Laura Camacho-Jiménez, Monserrath Felix-Portillo, Dahlia M. Nuñez-Hernandez, Gloria Yepiz-Plascencia〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Hypoxia is a common stressor for aquaculture species. The Pacific white shrimp 〈em〉Litopenaeus vannamei〈/em〉 survives low dissolved oxygen (DO) conditions by adjusting its energy metabolism. In vertebrates, the transcription factor p53 regulates glucose metabolism under stress through diverse target genes like the Tp53-induced glycolysis and apoptotic regulator (TIGAR), a protein similar to fructose-2,6-bisphosphatase that has a pro-survival role in cells participating in the defense against oxidative damage. Until now, TIGAR has been not reported in any invertebrate species, including crustaceans. In this work, we report the molecular cloning of the white shrimp TIGAR. The cDNA sequence is 765 bp encoding a 254 amino acid protein. Bioinformatics analyses predicted that although the overall sequence identities of 〈em〉L. vannamei〈/em〉 TIGAR and vertebrate proteins are not very high (33.61%–35.34%), they have a remarkable predicted structural similarity with full conservation of catalytic residues, secondary and three-dimensional structures. Gene expression analysis by RT-qPCR revealed that the mRNA abundance of TIGAR in white shrimp is tissue-specific under normal oxygen conditions, with higher expression in gills than hepatopancreas and muscle. Also, gene expression in gills and hepatopancreas is modified by environmental hypoxia, suggesting that TIGAR participates in the cellular tolerance of 〈em〉L. vannamei〈/em〉 to this stressor.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 93〈/p〉 〈p〉Author(s): Rajamanthrilage Kasun Madusanka, Thanthrige Thiunuwan Priyathilaka, N.D. Janson, T.D.W. Kasthuriarachchi, Sumi Jung, M.D. Neranjan Tharuka, Jehee Lee〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Galectins are β-galactoside-binding lectins, which are involved in pattern recognition, cell adhesion, and stimulation of the host innate immune responses against microbial pathogens. In spite of several functional studies on different galectins isolated from vertebrates and invertebrates, this is the first report to present functional studies for galectin-8 from the marine teleost tissues. In the present study, we characterized galectin-8 homolog from black rockfish (〈em〉Sebastes schlegelii〈/em〉), in molecular and functional aspects. Rockfish galectin-8 (〈em〉SsGal8〈/em〉) was found to consist of a 969 bp long open reading frame (ORF), encoding a protein of 322 amino acids and the predicted molecular weight was 35.82 kDa. 〈em〉In silico〈/em〉 analysis of 〈em〉SsGal8〈/em〉 revealed the presence of two carbohydrate binding domains (CRDs), at both N and C-termini and a linker peptide of 40 amino acids, in between the two domains. As expected, the phylogenetic tree categorized 〈em〉SsGal8〈/em〉 as a tandem-repeat galectin, and ultimately positioned it in the sub-clade of fish galectin-8. rSsGal8 was able to strongly agglutinate fish erythrocytes and the inhibition of agglutination was successfully exhibited by lactose and 〈span〉d〈/span〉-galactose. Bacterial agglutination assay resulted in agglutination of both Gram (+) and Gram (−) bacteria, including 〈em〉Escherichia coli, Vibrio harveyi, Vibrio parahaemolyticus, Streptococcus parauberis, Lactococcus garvieae, Streptococcus iniae〈/em〉 and 〈em〉Vibrio tapetis.〈/em〉 The tissue distribution analysis based on qPCR assays, revealed a ubiquitous tissue expression of 〈em〉SsGal8〈/em〉 for the examined rockfish tissues, with the most pronounced expression in blood, followed by brain, intestine, head kidney and kidney. Furthermore, the mRNA transcription level of 〈em〉SsGal8〈/em〉 was significantly up-regulated in spleen, liver and head kidney, upon immune challenges with 〈em〉Streptococcus iniae〈/em〉, LPS and poly I:C, in a time dependent manner. Taken together, these findings strongly suggest the contribution of 〈em〉SsGal8〈/em〉 in regulating innate immune responses to protect the rockfish from bacterial infections.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 29 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Kazuma Ogawa, Ryohei Masuda, Kenji Mishiro, Mengfei Wang, Takashi Kozaka, Kazuhiro Shiba, Seigo Kinuya, Akira Odani〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Sigma-1 receptor imaging probes for determining the expression levels are desirable for diagnoses of various diseases and companion diagnoses of therapeutic agents targeting the sigma-1 receptor. In this study, we aimed to develop probes with higher affinity for the sigma-1 receptor. For this purpose, we synthesized and evaluated compounds, namely, vesamicol derivatives, in which alkyl chains of varying chain length were introduced between a piperazine ring and a benzene ring. The binding affinity of the vesamicol derivatives for the sigma-1 receptor tended to increase depending on the length of the alkyl chain between the benzene ring and the piperazine ring. The sigma-1 receptor of 2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol (〈strong〉5〈/strong〉) (K〈sub〉i〈/sub〉 = 5.8 nM) exhibited the highest binding affinity; therefore, we introduced radioiodine into the benzene ring in 〈strong〉5〈/strong〉. The radioiodine labeled probe [〈sup〉125〈/sup〉I]2-(4-(3-(4-iodophenyl)propyl)piperazin-1-yl)cyclohexan-1-ol ([〈sup〉125〈/sup〉I]〈strong〉10〈/strong〉) showed high accumulation in the sigma-1 receptor expressing DU-145 cells both 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉. Co-injection of [〈sup〉125〈/sup〉I]〈strong〉10〈/strong〉 with an excess level of a sigma receptor ligand, haloperidol, resulted in a significant decrease in the tumor accumulation 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉, indicating sigma receptor-mediated tumor uptake. These results provide useful information for developing sigma-1 receptor imaging probes.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618319989-ga1.jpg" width="414" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 30 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Natarajan Arumugam, Abdulrahman I. Almansour, Raju Suresh Kumar, D. Kotresha, R. Saiswaroop, S. Venketesh〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉A small library of new class of dispiropyrrolidinyl-piperidone tethered indono[1,2-〈em〉b〈/em〉]quinoxaline heterocyclic hybrids 7〈strong〉a-j〈/strong〉 were synthesized employing multicomponent 1,3-dipolar cycloaddition strategy in [bmim]Br. The azomenthine ylide employed is first of its kind and generated 〈em〉in situ〈/em〉 from indenoquinoxalinone and 〈em〉L〈/em〉-tryptophan, a combination that has not been employed previously for the 〈em〉in situ〈/em〉 generation of azomethine ylides. The synthesized heterocyclic hybrids 〈strong〉7a-j〈/strong〉 were evaluated for their 〈em〉in vitro〈/em〉 acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, therein compounds 〈strong〉7h〈/strong〉 and 〈strong〉7j〈/strong〉 displayed more potent AChE and BChE enzyme inhibition than the standard drug with IC〈sub〉50〈/sub〉 values of 3.22, 2.01, 12.40 and 10.45 mM, respectively. Molecular docking studies have also been investigated for most active compounds that disclosed interesting binding templates to the active site channel of cholinesterase enzyme.〈/p〉 〈p〉____________________________________________________________________〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619303426-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 29 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology〈/p〉 〈p〉Author(s): Sarithaa Sellaththurai, Thanthrige Thiunuwan Priyathilaka, Jehee Lee〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Organisms possess a cellular antioxidant defense system inclusive of ROS scavengers to maintain the homeostasis of antioxidant levels. Catalase is a major ROS scavenger enzyme that plays a significant role in the antioxidant defense mechanism of organisms by reducing toxic hydrogen peroxide molecules into a nontoxic form of oxygen and water with a high turnover rate. In the present study, we performed molecular and functional characterization of the catalase homolog from 〈em〉Hippocampus abdominalis〈/em〉 (HaCat). The 〈em〉HaCat〈/em〉 cDNA sequence was identified as a 1578 bp ORF (open reading frame) that encodes a polypeptide of 526 amino acids with 59.33 kDa molecular weight. Its estimated pI value is 7.7, and it does not have any signal sequences. HaCat shared a conserved domain arrangement including the catalase proximal active site signature and heme ligand signature domain with the previously identified catalase counterparts. Phylogenetic analysis displayed close evolutionary relationships between HaCat and catalases from other teleost fish. According to our qPCR results, ubiquitous expression of 〈em〉HaCat〈/em〉 transcripts were observed in all the tested tissues with high expression in the kidney followed by liver. Significant modulations of 〈em〉HaCat〈/em〉 transcription were observed in blood, liver, and kidney tissues post-challenge with 〈em〉Streptococcus iniae〈/em〉, 〈em〉Edwardsiella tarda〈/em〉, poly I:C, and LPS. Peroxidase activity of recombinant HaCat (rHaCat) was evaluated using an ABTS assay and the ROS removal effect was further confirmed by oxidative DNA damage protection and cell viability assays. The rHaCat showed more than 97% activity over a temperature and pH range of 10 °C–40 °C and 5 to 6, respectively. The above results suggest that HaCat plays an indispensable role in the oxidative homeostasis of the seahorse during pathogenic attack.〈/p〉〈/div〉 〈/div〉