ALBERT

Description: 〈p〉Publication date: Available online 28 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Marc Diederich〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Natural compounds are known to display therapeutic potential against a variety of chronic conditions, including cancer and inflammation. The efficacy of these natural substances can be associated with numerous molecular scaffolds present in extracts of living organisms, both terrestrial and marine. Recently, investigators have identified the ability of natural compounds to trigger immunogenic cell death and subsequent activation of the adaptive immune system. Such findings indicate that the full therapeutic potential of natural products has yet to be defined, and further investigations on such agents will continue to yield novel drug candidates.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 28 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Fang Liu, Shaohong Fang, Xinxin Liu, Ji Li, Xuedong Wang, Jinjin Cui, Tao Chen, Zhaoying Li, Fan Yang, Jiangtian Tian, Hulun Li, Li Yin, Bo Yu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉High glucose-induced endothelial dysfunction is a critical initiating factor in the development of diabetic vascular complications. Omentin-1 has been regarded as a novel biomarker of endothelial function in subjects with type-2 diabetes (T2D); however, it is unclear whether omentin-1 has any direct effect in ameliorating high glucose-induced endothelial dysfunction. In the present study, we analyzed the effect of omentin-1 on high glucose-induced endothelial dysfunction in isolated mouse aortas and mouse aortic endothelial cells (MAECs). Vascular reactivity in aortas was measured using wire myography. The expression levels of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor δ (PPARδ), Akt, endothelial nitric-oxide synthase (eNOS), and endoplasmic reticulum (ER)-stress markers in MAECs were determined by Western blotting. The production of reactive oxygen species (ROS) and nitric oxide (NO) was assessed by diluted fluoroprobe, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM DA), respectively. We found that 〈em〉ex vivo〈/em〉 treatment with omentin-1 reversed impaired endothelial-dependent relaxations (EDR) in mouse aortas after high-glucose insult. Elevated ER-stress markers, oxidative stress, and reduction of NO production induced by high glucose in MAECs were reversed by omentin-1 treatment. Omentin-1 also effectively reversed tunicamycin-induced ER stress responses in MAECs, as well as ameliorated impairment of endothelial-dependent relaxation in mouse aortas. Moreover, omentin-1 increased AMPK phosphorylation with a subsequent increase in PPARδ expression, while also restoring the decreased phosphorylation of Akt and eNOS. The effects of omentin-1 were abolished by cotreatment of compound C (AMPK inhibitor) and GSK0660 (PPARδ antagonist). These data indicate that omentin-1 protects against high glucose-induced vascular-endothelial dysfunction through inhibiting ER stress and oxidative stress and increasing NO production via activation of AMPK/PPARδ pathway.〈/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-S000629522030040X-ga1.jpg" width="490" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 28 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Sumathy Mathialagan, Yi-an Bi, Chester Costales, Amit S. Kalgutkar, A. David Rodrigues, Manthena V.S. Varma〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nicotinic acid (NA) and nicotinamide (NAM) are biosynthetic precursors of nicotinamide adenine dinucleotide (NAD〈sup〉+〈/sup〉) – a physiologically important coenzyme that maintains the redox state of cells. Mechanisms driving their entry into cells are not well understood. Here we evaluated the hepatic uptake mechanism(s) of NA and NAM using transporter-transfected cell systems and primary human hepatocytes. NA showed robust organic anion transporter (OAT)2-mediated transport with an uptake ratio (i.e., ratio of accumulation in transfect cells to wild-type cells) of 9.7±0.3, and a Michaelis-Menten constant (K〈sub〉m〈/sub〉) of 13.5±3.3 µM. However, no transport was apparent via other major hepatic uptake and renal secretory transporters, including OAT1/3/4, organic anion transporting polypeptide (OATP)1B1/1B3/2B1, sodium-taurocholate co-transporting polypeptide, organ cation transporter 1/2/3. OAT2-specific transport of NA was inhibited by ketoprofen and indomethacin (known OAT2 inhibitors) in a concentration-dependent manner. Similarly, NA uptake into primary human hepatocytes showed pH- and concentration-dependence and was subject to inhibition by specific OAT2 inhibitors. Unlike NA, NAM was not transported by the hepatic and renal solute carriers upon assessment in transfected cells, although its uptake into human hepatocytes was significantly inhibited by excess unlabelled NAM and a pan-SLC inhibitor (rifamycin SV 1 mM). In conclusion, these studies demonstrate, for the first time, a specific transport mechanism for NA uptake in the human liver and suggest that OAT2 (SLC22A7) has a critical role in its physiological and pharmacological functions.〈/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-S0006295220300393-ga1.jpg" width="489" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Pei Yang, Mingfei Zhang, Xiang Wang, A-Lan Xu, Meiyu Shen, Baoping Jiang, Xueping Zhou, LingLing Zhou〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease with complicated pathogenesis. IL-17-producing T helper cells (Th17) are important players in the RA process. Despite numerous researches have proven that microRNAs (miRNAs) were crucial regulators of autoimmune diseases including RA, the effect of miRNAs on the development and function of Th17 cells in the RA progress is not clear. Here, our results showed that the expression of miRNA let-7g-5p was substantially lower in RA patients and CIA mice compared with healthy controls. Furthermore, let-7g-5p could notably suppress the differentiation of Th17 cells 〈em〉in vitro〈/em〉. And the disease severity in CIA mice was significantly alleviated after the treatment of let-7g-5p mimics, accompanied by the deficiency of Th17 cells. These findings indicated that the let-7g-5p could markedly block the differentiation of Th17 cells in RA, which provided a promising target for the clinical therapy of RA.〈/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-S0006295220300320-ga1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Ryota Yamagata, Wataru Nemoto, Osamu Nakagawasai, Kohei Takahashi, Koichi Tan-No〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉We have previously reported that the spinal angiotensin (Ang) system is involved in the modulation of streptozotocin (STZ)-induced diabetic neuropathic pain in mice. An important drawback of this model however is the fact that the neuropathic pain is independent of hyperglycemia and produced by the direct stimulation of peripheral nerves. Here, using the leptin deficient 〈em〉ob/ob〈/em〉 mouse as a type 2 diabetic model, we examined whether the spinal Ang system was involved in naturally occuring diabetic neuropathic pain. Blood glucose levels were increased in 〈em〉ob/ob〈/em〉 mice at 5-15 weeks of age. Following the hyperglycemia, persistent tactile and thermal hyperalgesia were observed at 11-14 and 9-15 weeks of age, respectively, which was ameliorated by insulin treatment. At 12 weeks of age, the expression of Ang-converting enzyme (ACE) 2 in the spinal plasma membrane fraction was decreased in 〈em〉ob/ob〈/em〉 mice. Spinal ACE2 was expressed in neurons and microglia but the number of NeuN-positive neurons was decreased in 〈em〉ob/ob〈/em〉 mice. In addition, the intrathecal administration of Ang (1-7) and SB203580, a p38 MAPK inhibitor, attenuated hyperalgesia in 〈em〉ob/ob〈/em〉 mice. The phosphorylation of spinal p38 MAPK was also attenuated by Ang (1-7) in 〈em〉ob/ob〈/em〉 mice. These inhibitory effects of Ang (1-7) were prevented by A779, a Mas receptor antagonist. In conclusion, we revealed that the Ang (1-7)-generating system is downregulated in 〈em〉ob/ob〈/em〉 mice and is accompanied by a loss of ACE2-positive neurons. Furthermore, Ang (1-7) decreased the diabetic neuropathic pain through inhibition of p38 MAPK phosphorylation via spinal Mas receptors.〈/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-S0006295220300356-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Joanna Wzorek, Radosław Bednarek, Cezary Watala, Magdalena Boncler〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉Adenosine analogues have high affinity and selectivity for adenosine receptors (AR), and exhibit anti-platelet activity. Plasma proteins play an important role in the regulation of platelet function and may influence the action of anti-platelet compounds. Little is known about the interactions of AR agonists with plasma proteins. This study investigates the interplay between AR agonists and plasma proteins and the consequences of those interactions.〈/p〉 〈p〉Surface plasmon resonance was employed together with molecular docking study to determine the binding kinetics of four selected AR agonists (PSB 0777, Cl-Ado, MRE 0094, UK 432097) to several carrier proteins and to clarify the nature of these interactions. The influence of a whole plasma and of some plasma components on the effectiveness of AR agonists in the inhibition of platelet function was assessed by flow cytometry (platelet activation) and ELISA (platelet adhesion).〈/p〉 〈p〉Plasma proteins remarkably diminished the effectiveness of AR agonists in inhibiting platelet activation and adhesion 〈em〉in vitro〈/em〉. AR agonists were found to strongly bind to human serum albumin (HSA) and the protein components of lipoproteins - apolipoproteins; HSA was essential for the binding of water-soluble PSB 0777, whereas apolipoproteins were needed for interactions with poorly-water soluble compounds such as UK 432097 and MRE 0094. In addition, HSA was shown to significantly reduce the effectiveness of PSB 0777 in inhibiting ADP-induced platelet activation.〈/p〉 〈p〉In conclusion, HSA and lipoproteins are important carriers for AR agonists, which can affect pharmacodynamics of AR agonists used as platelet 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-S000629522030037X-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Balázs Kelemen, Erika Lisztes, Anita Vladár, Martin Hanyicska, János Almássy, Attila Oláh, Attila Gábor Szöllősi, Zsófia Pénzes, János Posta, Thomas Voets, Tamás Bíró, Balázs István Tóth〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈h6〉Background〈/h6〉 〈p〉Volatile anaesthetics (VAs) are the most widely used compounds to induce reversible loss of consciousness and maintain general anaesthesia during surgical interventions. Although the mechanism of their action is not yet fully understood, it is generally believed, that VAs depress central nervous system functions mainly through modulation of ion channels in the neuronal membrane, including 2-pore-domain K+ channels, GABA and NMDA receptors. Recent research also reported their action on nociceptive and thermosensitive TRP channels expressed in the peripheral nervous system, including TRPV1, TRPA1, and TRPM8. Here, we investigated the effect of VAs on TRPM3, a less characterized member of the thermosensitive TRP channels playing a central role in noxious heat sensation.〈/p〉 〈/div〉 〈div〉 〈h6〉Methods〈/h6〉 〈p〉We investigated the effect of VAs on the activity of recombinant and native TRPM3, by monitoring changes in the intracellular Ca〈sup〉2+〈/sup〉 concentration and measuring TRPM3-mediated transmembrane currents.〈/p〉 〈/div〉 〈div〉 〈h6〉Results〈/h6〉 〈p〉All the investigated VAs (chloroform, halothane, isoflurane, sevoflurane) inhibited both the agonist-induced (pregnenolone sulfate, CIM0216) and heat-activated Ca〈sup〉2+〈/sup〉 signals and transmembrane currents in a concentration dependent way in HEK293T cells overexpressing recombinant TRPM3. Among the tested VAs, halothane was the most potent blocker (IC〈sub〉50〈/sub〉=0.52±0.05 mM). We also investigated the effect of VAs on native TRPM3 channels expressed in sensory neurons of the dorsal root ganglia. While VAs activated certain sensory neurons independently of TRPM3, they strongly and reversibly inhibited the agonist-induced TRPM3 activity.〈/p〉 〈/div〉 〈div〉 〈h6〉Conclusions〈/h6〉 〈p〉These data provide a better insight into the molecular mechanism beyond the analgesic effect of VAs and propose novel strategies to attenuate TRPM3 dependent nociception.〈/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-S0006295220300368-ga1.jpg" width="389" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 24 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Sumit Mukherjee, Juliet N.E. Baidoo, Angela Fried, Probal Banerjee〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Curcumin has been at the center of vigorous research and major debate during the past decade. Inspired by its anti-inflammatory properties, many curcumin-based products are being sold now to manage various forms of arthritis. Parallel preclinical studies have established its role in dissolving beta-amyloid plaques, tau-based neurofibrillary tangles, and also alpha-synuclein-linked protein aggregates typically observed in Parkinson’s disease. In cancer research, most cancer cells in culture are eliminated by curcumin at an IC50 of 15-30 µM, whereas the maximum 〈em〉in vivo〈/em〉 curcumin concentration achieved in humans is only about 6 µM. Additionally, a decade ago, no improvement over the placebo groups was observed in clinical studies using free curcumin as an anticancer agent. The lack of anticancer efficacy was attributed to its low bioavailability, which results from the low water-solubility and high metabolic rate 〈em〉in vivo〈/em〉. Newer lipid-complexed or antibody-targeted forms have been used and these studies have revealed an exciting property of curcumin, which involves repolarization of the tumor-promoting, tumor-associated microglia/macrophages (TAMs) into a tumoricidal form and recruitment of natural killer cells from the periphery. This review will cover some efforts to explore the effect of appropriately-delivered curcumin to dramatically alter the tumor microenvironment, thereby launching an indirect attack on the tumor cells and the tumor stem cells. Reviewing some aspects of immunotherapy, this article will argue for the use of the innate immune cells 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-S0006295220300344-ga1.jpg" width="305" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Ying-Yu Tang, Qiu-Ning Liu, Cheng Wang, Ting-Ting Yang, Bo-Ping Tang, Chun-Lin Zhou, Li-Shang Dai〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈em〉Procambarus clarkii〈/em〉 is one of the most important aquatic invertebrates in China and has high commercial value. However, aquaculture has suffered great economic loss due to outbreaks of infectious diseases in 〈em〉P〈/em〉. 〈em〉clarkii〈/em〉. To identify red swamp crayfish related proteins involved in the response to bacterial infection, we analysed immune-related proteins following lipopolysaccharide (LPS) stimulation by quantitative proteomics. The proteome of the hepatopancreas of 〈em〉P〈/em〉. 〈em〉clarkii〈/em〉 challenged with LPS and phosphate-buffered saline was analysed to evaluate the immune response. Based on liquid chromatography coupled with tandem mass spectrometry, 16 upregulated and 29 downregulated proteins were identified. A Gene Ontology analysis demonstrated 5 biological process, 11 cellular component, and 6 molecular function subcategories. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that the identified proteins were mainly involved in metabolism, phagosome, and ribosome. Real-time quantitative reverse transcription-PCR revealed that eight immune-related genes were upregulated after LPS stimulation compared to the control. Taken together, the data enhance our understanding of the immune response of crayfish to LPS.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Mahmoud A.O. Dawood, Safaa E. Abdo, Mahmoud S. Gewaily, Eman M. Moustafa, Moustafa S. SaadAllah, Marwa F. AbdEl-kader, Awatef H. Hamouda, Amira A. Omar, Rasha A. Alwakeel〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The protective role of β-glucan (BG) on liver function, histopathology, immune and antioxidant related gene expressions in Nile tilapia exposed to subacute deltamethrin (DLM) was investigated for 30 days. Fish (28.18 ± 1.34 g) of the 1st and 2nd groups fed the control diet, while the 3rd and 4th groups fed BG at 0.5 g/kg and the 2nd and 4th groups were exposed to DLM (15 μg/L) in rearing water. DLM-treated fish displayed a considerable increase in blood biochemical parameters (creatinine, urea and bilirubin) as well as hepatic enzymes (ALP, AST and ALT) (〈em〉P〈/em〉 〈 0.05). Blood total protein, globulin, albumin, WBCs, RBCs, Hb, phagocytic index, phagocytic and lysozyme activities were significantly decreased in fish subjected to DLM (〈em〉P〈/em〉 〈 0.05). Fish fed BG showed significantly the lowest cortisol and glucose levels, while fish exposed to DLM without feeding BG showed the highest cortisol and glucose levels (〈em〉P〈/em〉 〈 0.05) after 15 and 30 days. Additionally, DLM toxicity caused downregulation in antioxidant (〈em〉CAT〈/em〉 and 〈em〉GPx〈/em〉) and immune (〈em〉IL-1β〈/em〉 and 〈em〉IL-8〈/em〉) related gene expressions, while and 〈em〉IFN-γ〈/em〉, 〈em〉HSP70〈/em〉 and 〈em〉CASP3〈/em〉 were upregulated. The histopathological examination of Nile tilapia exposed to DLM revealed damage in gills, intestine, spleen and liver which confirmed the toxic effects. Conversely, BG presented protective effects and restored the above-mentioned parameters when fish exposed to DLM and fed BG. Thus, BG supplementation exhibited defensive effects against DLM toxicity in Nile tilapia through improving blood biochemical responses, immune, and antioxidant related gene expressions as well as histopathological effects.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Junjie Nie, Zhixue Yu, Defu Yao, Fan Wang, Chunhua Zhu, Kaihui Sun, Jude Juventus Aweya, Yueling Zhang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The histone deacetylase, sirtuin 6 (SIRT6), plays an essential role in the regulation of oxidative stress, mitochondrial function and inflammation in mammals. However, the specific role of SIRT6 in invertebrate immunity has not been reported. Here, we characterized for the first time, a sirtuin 6 homolog in 〈em〉Litopenaeus vannamei〈/em〉 (〈em〉Lv〈/em〉SIRT6), with full-length cDNA of 2919 bp and 1536 bp open reading frame (ORF) encoding a putative protein of 511 amino acids, which contains a typical SIR2 domain. Sequence and phylogenetic analysis revealed that 〈em〉Lv〈/em〉SIRT6 shares a close evolutionary relationship with SIRT6 from invertebrates. Real-time quantitative PCR analysis of 〈em〉Lv〈/em〉SIRT6 transcripts revealed that they were ubiquitously expressed in shrimp and induced in hepatopancreas and hemocytes upon challenge with 〈em〉Vibrio parahaemolyticus〈/em〉, 〈em〉Streptococcus iniae〈/em〉, lipopolysaccharide (LPS), and white spot syndrome virus (WSSV), suggesting the involvement of 〈em〉Lv〈/em〉SIRT6 in shrimp immune response. Moreover, knockdown of 〈em〉Lv〈/em〉SIRT6 decreased mitochondrial membrane potential and increased total ROS level in hemocytes, especially upon 〈em〉V. parahaemolyticus〈/em〉 challenge. Depletion of 〈em〉Lv〈/em〉SIRT6 also increased hemocytes apoptosis in terms of decreased expression of pro-survival 〈em〉Lv〈/em〉Bcl-2, but increased expression of pro-apoptotic 〈em〉Lv〈/em〉Bax and 〈em〉Lv〈/em〉Cytochrome C, coupled with high 〈em〉Lv〈/em〉Caspase3/7 activity. Shrimp were rendered more susceptible to 〈em〉V. parahaemolyticus〈/em〉 infection upon 〈em〉Lv〈/em〉SIRT6 knockdown. Taken together, our present data suggest that 〈em〉Lv〈/em〉SIRT6 plays an important role in shrimp immune response by modulating hemocytes ROS production and apoptosis during pathogen challenge.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Elisa Zuccarello, Erica Acquarone, Elisa Calcagno, Elentina K. Argyrousi, Shi-Xian Deng, Donald W. Landry, Ottavio Arancio, Jole Fiorito〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nitric oxide (NO) is a gaseous molecule that plays a multifactorial role in several cellular processes. In the central nervous system, the NO dual nature in neuroprotection and neurotoxicity has been explored to unveil its involvement in Alzheimer’s disease (AD). A growing body of research shows that the activation of the NO signaling pathway leading to the phosphorylation of the transcription factor cyclic adenine monophosphate responsive element binding protein (CREB) (so-called NO/cGMP/PKG/CREB signaling pathway) ameliorates altered neuroplasticity and memory deficits in AD animal models. In addition to NO donors, several other pharmacological agents, such as phosphodiesterase 5 (PDE5) inhibitors have been used to activate the pathway and rescue memory disorders. PDE5 inhibitors, including sildenafil, tadalafil and vardenafil, are marketed for the treatment of erectile dysfunction and arterial pulmonary hypertension due to their vasodilatory properties. The ability of PDE5 inhibitors to interfere with the NO/cGMP/PKG/CREB signaling pathway by increasing the levels of cGMP has prompted the hypothesis that PDE5 inhibition might be used as an effective therapeutic strategy for the treatment of AD. To this end, newly designed PDE5 inhibitors belonging to different chemical classes with improved pharmacologic profile (e.g. higher potency, improved selectivity, and blood-brain barrier penetration) have been synthesized and evaluated in several animal models of AD. In addition, recent medicinal chemistry effort has led to the development of agents concurrently acting on the PDE5 enzyme and a second target involved in AD. Both marketed and investigational PDE5 inhibitors have shown to reverse cognitive defects in young and aged wild type mice as well as transgenic mouse models of AD and tauopathy using a variety of behavioral tasks. These studies confirmed the therapeutic potential of PDE5 inhibitors as cognitive enhancers. However, clinical studies assessing cognitive functions using marketed PDE5 inhibitors have not been conclusive. Drug discovery efforts by our group and others are currently directed towards the development of novel PDE5 inhibitors tailored to AD with improved pharmacodynamic and pharmacokinetic properties. In summary, the present perspective reports an overview of the correlation between the NO signaling and AD, as well as an outline of the PDE5 inhibitors used as an alternative approach in altering the NO pathway leading to an improvement of learning and memory. The last two sections describe the preclinical and clinical evaluation of PDE5 inhibitors for the treatment of AD, providing a comprehensive analysis of the current status of the AD drug discovery efforts involving PDE5 as a new therapeutic target.〈/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-S0006295220300289-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Dewi Safitri, Matthew Harris, Harriet Potter, Ho Yan Yeung, Ian Winfield, Liliya Kopanitsa, Fredrik Svensson, Taufiq Rahman, Matthew T Harper, David Bailey, Graham Ladds〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Supressed levels of intracellular cAMP have been associated with malignancy. Thus, elevating cAMP through activation of adenylyl cyclase (AC) or by inhibition of phosphodiesterase (PDE) may be therapeutically beneficial. Here, we demonstrate that elevated cAMP levels suppress growth in C6 cells (a model of glioma) through treatment with forskolin, an AC activator, or a range of small molecule PDE inhibitors with differing selectivity profiles. Forskolin suppressed cell growth in a PKA-dependent manner by inducing a G〈sub〉2〈/sub〉/M phase cell cycle arrest. In contrast, trequinsin (a non-selective PDE2/3/7 inhibitor), not only inhibited cell growth via PKA, but also stimulated (independent of PKA) caspase-3/-7 and induced an aneuploidy phenotype. Interestingly, a cocktail of individual PDE 2,3,7 inhibitors suppressed cell growth in a manner analogous to forskolin but not trequinsin. Finally, we demonstrate that concomitant targeting of both AC and PDEs synergistically elevated intracellular cAMP levels thereby potentiating their antiproliferative actions.〈/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-S0006295220300332-ga1.jpg" width="495" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 16 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Zhe Pei, Kuo-Chieh Lee, Amber Khan, Gabriell Erisnor, Hoau-Yan Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉Brain tumors, particularly high-grade glioblastomas, are a crucial public health issue due to poor prognosis and an extremely low survival rate. The glioblastoma multiforme (GBM) grows rapidly within its unique microenvironment that is characterized by active neural communications. Therefore, diverse neurotransmitters not only maintain normal brain functions but also influence glioma progression. To fully appreciate the relationship between neurotransmitters and glioma progression, we reviewed potential neurotransmitter contributors in human GBM and the much less aggressive Low-grade glioma (LGG) by combining previously published data from gene-mutation/mRNA sequencing databases together with protein–protein interaction (PPI) network analysis results. The summarized results indicate that glutamatergic and calcium signaling may provide positive feedback to promote glioma formation through 1) metabolic reprogramming and genetic switching to accelerate glioma duplication and progression; 2) upregulation of cytoskeleton proteins and elevation of intracellular Ca〈sup〉2+〈/sup〉 levels to increase glutamate release and facilitate formation of synaptic-like connections with surrounding cells in their microenvironment. The upregulated glutamatergic neuronal activities in turn stimulate glioma growth and signaling. Importantly, the enhanced electrical and molecular signals from both neurons and glia propagate out to enable glioma symptoms such as epilepsy and migraine. The elevated intracellular Ca〈sup〉2+〈/sup〉 also activates nitric oxide synthase to produce nitric oxide (NO) that can either promote or inhibit tumorigenesis.〈/p〉 〈p〉By analyzing the network effects for complex interaction among neurotransmitters such as glutamate, Ca〈sup〉2+〈/sup〉 and NO in brain tumor progression, especially GBM, we identified the glutamatergic signaling as the potential therapeutic targets and suggest manipulation of glutamatergic signaling may be an effective treatment strategy for this aggressive brain cancer.〈/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-S0006295220300241-ga1.jpg" width="251" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Chang-Fang Chiu, Jing-Ru Weng, Shou-Lun Lee, Chia-Yung Wu, Po-Chen Chu, Yan-Shen Shan, Horng-Ren Yang, Li-Yuan Bai〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Pyruvate kinase M2 (PKM2) is a key enzyme responsible for the final step of glycolysis. It is still unclear whether PKM2 is involved in reactive oxygen species (ROS)-mediated cytotoxicity in gastrointestinal cancer, and what mechanisms are involved. One duodenal (AZ521) and two gastric (NUGC and SCM-1) cancer cell lines were treated with an indole-3-carbinol derivative OSU-A9, which caused cytotoxicity in acute myeloid leukemia through ROS generation. OSU-A9 caused a dose- and time-dependent cytotoxicity and induced apoptosis in duodenal and gastric cancer cells through ROS generation. Pretreatment with ROS scavengers rescued cancer cells from apoptosis and concomitant poly (ADP-ribose) polymerase cleavage, implying a key role of ROS in OSU-A9-induced cell death. Moreover, OSU-A9-induced ROS generation decreased protein levels of p〈sup〉Tyr105〈/sup〉-PKM2, and this effect was rescued by pretreatment with ROS scavengers. Interestingly, p〈sup〉Tyr105〈/sup〉-PKM2 protein levels decreased in the cell nucleus rather than in the cytoplasm. PKM2 overexpression partially rescued the survival of duodenal and gastric cancer cells treated with OSU-A9. Furthermore, the anticancer activity of OSU-A9 extended 〈em〉in vivo〈/em〉, as OSU-A9 administered by oral gavage suppressed the growth of AZ521 xenograft tumors in nude mice without obvious toxicity. In conclusion, OSU-A9 inhibited duodenal and gastric cancer cell proliferation through ROS generation and caused a subsequent decrease in nuclear p〈sup〉Tyr105〈/sup〉-PKM2 protein. These findings provide evidence for the non-canonical activity of PKM2 in cancer cell survival. Furthermore, they highlight the potential role of PKM2 as a future therapeutic target for duodenal and gastric cancer.〈/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-S0006295220300216-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 172〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Lang Lang, Minnan Bao, Weixin Jing, Wei Chen, Lan Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉Toll is essential in innate immune system which is important for defense against bacterial, fungal and viral infections in invertebrates. Our previous study showed that cadmium (Cd) could change the expression pattern of ShToll3 in the epithelium (gills and midgut from the freshwater crab 〈em〉Sinopotamon henanense〈/em〉) infected by 〈em〉Aeromonas hydrophila〈/em〉. To investigate the diverse innate immune roles of crustacean homolog Tolls, in this study, we cloned 〈em〉Shtoll1〈/em〉 from 〈em〉S. henanense〈/em〉. The full-length cDNA of 〈em〉Shtoll1〈/em〉 was 4746 bp, with an ORF of 3033 bp encoding a putative protein of 111 amino acids, a 5′-untranslated region of 255 bp and a 3′-untranslated region of 1713 bp. Phylogenetic analysis showed that ShToll1 was clustered into the group of DmToll1, DmToll 4 and DmToll 5. In addition, the tissue distribution results showed that 〈em〉Shtoll1〈/em〉 was expressed widely in different tissues, with the highest expression in heamocytes. Besides, 〈em〉Shtoll1〈/em〉 expressions were upregulated in heamocytes and hepatopancreas after 〈em〉A. hydrophila〈/em〉 infection. At the same time, the increase of 〈em〉Shtoll1〈/em〉 expressions were examined in heamocytes in response to Cd exposure and 〈em〉A. hydrophila〈/em〉 infection in combination. Through western blotting and immunohistochemical analysis, the ShToll1 expressions in heamocytes were increased in response to 〈em〉A. hydrophila〈/em〉 and Cd independently as well as in combination. Moreover, the mRNA level of three antimicrobial peptides (AMPs) 〈em〉alf5, alf6,〈/em〉 and 〈em〉c-lys〈/em〉, which possibly responded to Cd and 〈em〉A. hydrophila〈/em〉 stimulation through 〈em〉Shtoll1,〈/em〉 were analyzed.〈/p〉 〈p〉Thus, we conclude that Cd expand the susceptibility of ShToll1 to 〈em〉A. hydrophila〈/em〉 infection in heamocytes. This suggest that ShToll1 may contribute to the innate immune defense of 〈em〉S. henanense〈/em〉 against 〈em〉A. hydrophila〈/em〉 and Cd in heamocytes.〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 13 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology〈/p〉 〈p〉Author(s): A. Panigrahi, R.R. Das, M.R. Sivakumar, A. Saravanan, C. Saranya, N.S. Sudheer, K.P. Kumaraguru Vasagam, P. Mahalakshmi, S. Kannappan, G. Gopikrishna〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Effect of bio-augmentation of 〈em〉Bacillus spp〈/em〉 in biofloc on growth, survival and immunity in Indian white shrimp 〈em〉Penaeus indicus〈/em〉 was evaluated. Nine 〈em〉Bacillus〈/em〉 strains were isolated and screened individually as well as in the form of a consortia. To maintain a C:N ratio of 12:1 a blend of carbohydrate sources was used. Bio-augmentation with bacterial consortium and 〈em〉Virgibacillus sp.〈/em〉 produced improved growth and immunity. Shrimp survival ranged from 80 to 95% among treatments. Production was higher (35%) in the biofloc tanks with an average body weight (ABW) of 10.89 ± 1.2 g. On evaluating the immune responses, it was found that trypsin significantly (P 〈 0.05) enhanced Prophenoloxidase (PO) activity in 〈em〉Lysinibacillus〈/em〉, 〈em〉Bacillus cereus〈/em〉, 〈em〉Bacillus licheniformis〈/em〉 and 〈em〉Bacillus subtilis〈/em〉 bio-augmented groups. Laminarin induced PO activity was observed in groups supplemented with 〈em〉Oceanobacillus sp.〈/em〉, 〈em〉Bacillus sp.〈/em〉and 〈em〉Bacillus megaterium〈/em〉. The lysozyme (LZ) activity was significantly (P 〈 0.05) higher in 〈em〉B. cereus〈/em〉 and Microbial Consortia (MC), while other treatments were less effective. Total hemocyte count (THC) significantly (P 〈 0.05) increased in all treatment groups compared to the control. Hyaline hemocyte (HH) count was significantly (P 〈 0.05) higher in the control group (14.43%). Semi granular hemocytes (SGH) was higher in groups treated with 〈em〉Lysinibacillus, Bacillus sp., B. licheniformis〈/em〉 and 〈em〉B. subtilis.〈/em〉 The granular hemocyte (GH) count was significantly (P 〈 0.05) higher in 〈em〉Virgibacillus sp.〈/em〉, 〈em〉B. cereus〈/em〉, 〈em〉B.megaterium〈/em〉 and 〈em〉Oceanobacillus sp.〈/em〉 The biofloc alone (BF), treated and augmented with 〈em〉B. megaterium〈/em〉 significantly (P 〈 0.05) increased phagocytic activity. Highly significant phagocytic index (PI) was observed in bio-augmented groups, BF and MC. The relative expression levels of immune genes were found to be significantly up-regulated in shrimps grown in bio-augmented groups. Enhanced immunological parameters implies that bio-augmentation of biofloc with 〈em〉Bacillus spp.〈/em〉 improved immunity in shrimps. Hence, bio-augmentation of probiotics in biofloc may be useful in improving culture conditions to produce 〈em〉P. indicus.〈/em〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Jessica L. Piesz, Sarah E. Barker, Ian R. Bricknell〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The ectoparasite, 〈em〉Lepeophtheirus salmonis〈/em〉 (Kroyer 1837)〈em〉,〈/em〉 is effective at avoiding elimination from its host, Atlantic salmon, 〈em〉Salmo salar〈/em〉 L., by inhibiting the recruitment of immune cells to the site of attachment. In other ectoparasitic arthropods, numerous factors have been identified that bind or neutralize chemokines preventing their interaction with receptors on the surfaces of immune cells. To determine if 〈em〉L. salmonis〈/em〉 is utilizing a similar mechanism of immune modulation, the chemotactic activity of peripheral blood leukocytes (PBL) to leukotriene B4 (LTB4) and the secreted/excreted products (SEPs) of the sea louse were investigated 〈em〉in vitro〈/em〉. The results showed that incubation of LTB4 with SEPs reduced leukocyte migration compared to LTB4 immune stimulation alone. Data suggests that one of the mechanisms 〈em〉L. salmonis〈/em〉 may be using to regulate immune cell recruitment in Atlantic salmon is by inhibiting or neutralizing the activity of chemokines.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Li-Jie Huo, Ming-Chong Yang, Jin-Xing Wang, Xiu-Zhen Shi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉ATPase Inhibitory Factor 1 (IF1) is a mitochondrial protein that functions as a physiological inhibitor of F〈sub〉1〈/sub〉F〈sub〉0〈/sub〉-ATP synthase. In the present study, a mitochondrial ATPase inhibitor factor 1 (〈em〉Mj〈/em〉ATPIF1) was identified from kuruma shrimp (〈em〉Marsupenaeus japonicus〈/em〉), which was demonstrated to participate in the viral immune reaction of white spot syndrome virus (WSSV). 〈em〉Mj〈/em〉ATPIF1 contained a mitochondrial ATPase inhibitor (IATP) domain, and was widely distributed in hemocytes, heart, hepatopancreas, gills, stomach, and intestine of shrimp. 〈em〉MjATPIF1〈/em〉 transcription was upregulated in hemocytes and intestines by WSSV. WSSV replication decreased after 〈em〉MjATPIF1〈/em〉 knockdown by RNA interference and increased following recombinant 〈em〉Mj〈/em〉ATPIF1 protein injection. Further study found that 〈em〉Mj〈/em〉ATPIF1 promoted the production of superoxide and activated the transcription factor nuclear factor kappa B (NF-κB, Dorsal) to induce the transcription of WSSV RNAs. These results demonstrate that 〈em〉Mj〈/em〉ATPIF1 benefits WSSV replication in kuruma shrimp by inducing superoxide production and NF-κB activation.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Muting Yan, Zhihao Liu, Kaihang Xu, Wenjing Wang, Lanfen Fan, Han Gong〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Previous studies have indicated that white spot syndrome virus (WSSV) infection induces apoptosis in many shrimp organs. However, the mechanism by which WSSV causes host apoptosis remains largely unknown. In this study, we demonstrated the function of wsv152, the first mitochondrial protein identified as encoded by WSSV. Glutathione S-transferase pulldown and co-immunoprecipitation analysis revealed that wsv152 interacts with the shrimp mitochondrial protein cytochrome 〈em〉c〈/em〉 oxidase 5a (COX5a), a subunit of the COX complex. We also found that wsv152 expression significantly increased the rate of apoptosis, suggesting a role of wsv152 in WSSV-induced apoptosis in shrimp. Knockdown of wsv152 〈em〉in vivo〈/em〉 led to downregulation of several apoptosis-related shrimp genes, including cytochrome 〈em〉c〈/em〉, apoptosis-inducing factor and caspase-3. Suppression of wsv152 also resulted in significant reductions in the number of WSSV genome copies in tissues and in the mortality of WSSV-infected shrimp. Together, these results suggest that wsv152 targets host COX5a and is associated with the expression profiles of apoptosis-related shrimp genes. Wsv152 is likely also involved in WSSV-induced apoptosis, thereby facilitating virus infection and playing a complex role in WSSV pathogenesis.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Sen Xu, Ming Jing, Wen-Ying Liu, He Dong, De-Min Kong, Ya-Ru Wang, Han-Han Zhang, Zhen Yue, You-Jie Li, Fei Jiao, Shu-Yang Xie〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉L-type lectins (LTLs) belong to the lectin family and are characterized by a conserved structural motif in their carbohydrate recognition domain. LTLs are homologous to leguminous lectins. In this study, we identified and functionally characterized an LTL from kuruma shrimp 〈em〉Marsupenaeus japonicus〈/em〉. We designated this LTL as 〈em〉Mj〈/em〉LTL2. 〈em〉Mj〈/em〉LTL2 contains a signal peptide, a Lectin_leg domain, a coiled coil, and transmembrane domain. 〈em〉Mj〈/em〉LTL2 is distributed in hemocytes, heart, hepatopancreas, gill, stomach, and intestine; higher expression levels are seen in hemocytes and the hepatopancreas than in other tissues. 〈em〉Mj〈/em〉LTL2 was upregulated following challenge of shrimp with 〈em〉Vibrio anguillarum〈/em〉 and white spot syndrome virus (WSSV). 〈em〉Mj〈/em〉LTL2 can agglutinate several bacteria without Ca〈sup〉2+〈/sup〉. In addition, 〈em〉Mj〈/em〉LTL2 could bind to several Gram-positive and -negative bacteria by binding to their lipopolysaccharide and peptidoglycan. However, 〈em〉Mj〈/em〉LTL2 could not enhance the clearance of 〈em〉V. anguillarum〈/em〉 in vivo. In the presence of WSSV infection, 〈em〉Mj〈/em〉LTL2 knockdown by RNA interference resulted in a 7-day lower cumulative mortality of 〈em〉M. japonicus〈/em〉. Moreover, less 〈em〉VP19, VP24, VP26,〈/em〉 and 〈em〉VP2〈/em〉8 mRNAs were extracted from the hemocytes of 〈em〉Mj〈/em〉LTL2 knockdown shrimp than from the control. These results suggest that 〈em〉Mj〈/em〉LTL2 is involved in immune responses in shrimp.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Vanessa P. Cedron, Andrea M.J. Weiner, Manuel Vera, Laura Sanchez〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In spite of its toxic effects, N-acetyl-p-aminophenol (APAP), also commonly known as acetaminophen or paracetamol, is one of the most widely used analgesic and antipyretic agents. It can be obtained without a medical prescription. To test the effect over the zebrafish embryonic development, a Fish Embryo acute Toxicity (FET) test was carried out with acetaminophen to establish the range of concentrations that cause a harmful effect on the zebrafish development. Diminished pigmentation (in embryos treated from 0 h post-fertilization) and blockage of melanin synthesis (in larvae treated from 72 h post-fertilization) were detected, suggesting the involvement of this compound in the development of black pigment cells as described recently for human epidermal melanocytes. Morphological abnormalities such as aberrant craniofacial structures, pericardial edemas, and blood accumulation were also found. All these effects could be due to higher levels of apoptotic cells detected in treated embryos. Therefore, teratogenic effects of acetaminophen cannot be ruled out, and its wide use should be taken with caution.〈/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-S0006295220300265-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 20 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Ashwini Gore, Alex G. Gauthier, Mosi Lin, Vivek Patel, Douglas D. Thomas, Charles R. Ashb, Lin L. Mantell〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mechanical ventilation (MV) with supraphysiological levels of oxygen (hyperoxia) is a life-saving therapy for the management of patients with respiratory distress. However, a significant number of patients on MV develop ventilator-associated pneumonia (VAP). Previously, we have reported that prolonged exposure to hyperoxia impairs the capacity of macrophages to phagocytize 〈em〉Pseudomonas aeruginosa〈/em〉 (PA), which can contribute to the compromised innate immunity in VAP. In this study, we show that the high mortality rate in mice subjected to hyperoxia and PA infection was accompanied by a significant decrease in the airway levels of nitric oxide (NO). Decreased NO levels were found to be, in part, due to a significant reduction in NO release by macrophages upon exposure to PA lipopolysaccharide (LPS). Based on these findings, we postulated that NO supplementation should restore hyperoxia-compromised innate immunity and decrease mortality by increasing the clearance of PA under hyperoxic conditions. To test this hypothesis, cultured macrophages were exposed to hyperoxia (95% O〈sub〉2〈/sub〉) in the presence or absence of the NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO). Interestingly, D-NO (up to 37.5 µM) significantly attenuated hyperoxia-compromised macrophage migratory, phagocytic, and bactericidal function. To determine whether the administration of exogenous NO enhances the host defense in bacteria clearance, C57BL/6 mice were exposed to hyperoxia (99% O〈sub〉2〈/sub〉) and intranasally inoculated with PA in the presence or absence of D-NO. D-NO (300 µM - 800 µM) significantly increased the survival of mice inoculated with PA under hyperoxic conditions, and significantly decreased bacterial loads in the lung and attenuated lung injury. These results suggest the NO donor, D-NO, can improve the clinical outcomes in VAP by augmenting the innate immunity in bacterial clearance. Thus, provided these results can be extrapolated to humans, NO supplementation may represent a potential therapeutic strategy for preventing and treating patients with VAP.〈/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-S0006295220300277-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Young Shin Ko, Hana Jin, Sang Won Park, Hye Jung Kim〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Diabetes is related to alterations in glucose and lipid metabolism, which are linked to endothelial cell (EC) dysfunction. Salvianolic acid B (Sal B), one of the major ingredient of Danshen (〈em〉Salvia miltiorrhiza〈/em〉), possesses many of the biological activities. However, protective effect of Sal B against oxLDL induced ECs dysfunction under high glucose condition (high Glu) is not well known. Thus, in this study, we investigated the protective effects of Sal B against EC dysfunction induced by oxLDL and high Glu and examined the associated mechanisms. Our results showed that Sal B significantly and dose-dependently decreased oxLDL- and high Glu–mediated induction of lectin-like oxLDL receptor-1 and significantly decreased oxLDL- and high Glu–induced mitochondrial ROS (mtROS) production and mitochondrial DNA (mtDNA) expression. In addition, oxLDL stimulation under high-Glu conditions activated the intrinsic apoptosis pathway in ECs. These effects were abolished by Sal B through reductions in mtROS and mtDNA. Furthermore, Sal B inhibited oxLDL- and high Glu–induced increases in fission protein (p-DRP 1 and FIS 1) levels. OxLDL and high Glu activated the ROCK1 pathway, which is involved in apoptosis and mitophagy, while Sal B significantly reduced ROCK1 protein levels. The protective effects of Sal B against oxLDL- and high Glu–induced endothelial dysfunction may be mediated by reductions in apoptosis-related proteins and fission proteins through suppression of the ROCK1-mediated pathway.〈/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-S0006295220300253-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Sevda Gheibi, Alan P. Samsonov, Shahsanam Gheibi, Alexandra B. Vazquez, Khosrow Kashfi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nitric oxide (NO) and hydrogen sulfide (H〈sub〉2〈/sub〉S) are two gasotransmitters that are produced in the human body and have a key role in many of the physiological activities of the various organ systems. Decreased NO bioavailability and deficiency of H〈sub〉2〈/sub〉S are involved in the pathophysiology of type 2 diabetes and its complications. Restoration of NO levels have favorable metabolic effects in diabetes. The role of H〈sub〉2〈/sub〉S in pathophysiology of diabetes is however controversial; H〈sub〉2〈/sub〉S production is decreased during development of obesity, diabetes, and its complications, suggesting the potential therapeutic effects of H〈sub〉2〈/sub〉S. On the other hand, increased H〈sub〉2〈/sub〉S levels disturb the pancreatic β-cell function and decrease insulin secretion. In addition, there appear to be important interactions between NO and H〈sub〉2〈/sub〉S at the levels of both biosynthesis and signaling pathways, yet clear an insight into this relationship is lacking. H〈sub〉2〈/sub〉S potentiates the effects of NO in the cardiovascular system as well as NO release from its storage pools. Likewise, NO increases the activity and the expression of H〈sub〉2〈/sub〉S-generating enzymes. Inhibition of NO production leads to elimination/attenuation of the cardioprotective effects of H〈sub〉2〈/sub〉S. Regarding the increasing interest in the therapeutic applications of NO or H〈sub〉2〈/sub〉S-releasing molecules in a variety of diseases, particularly in the cardiovascular disorders, much is to be learned about their function in glucose/insulin metabolism, especially in diabetes. The aim of this review is to provide a better understanding of the individual and the interactive roles of NO and H〈sub〉2〈/sub〉S in carbohydrate metabolism.〈/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-S0006295220300290-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Yiyi Yan, Xingchen Huo, Taoshan Ai, Jianguo Su〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉As one of the most important fish in freshwater aquaculture, gibel carp (〈em〉Carassius auratus gibelio〈/em〉) is easily susceptible to Cyprinid herpesvirus 2 (CyHV-2). Immersion vaccination has attracted many researchers due to its simple operation in preventing infectious diseases. However, the unavoidable disadvantage is that the immersion vaccine must be used with adjuvants to get a better performance. In this study, gibel carps were vaccinated by a 60 min bath in a β-propiolactone-inactivated Cyprinid herpesvirus 2, mixed with DTT, β-glucan, anisodamine and scopolamine, respectively. After immunization, the fishs were challenged by CyHV-2 in 2 weeks. By analyzing pathological section, we found that β-glucan, anisodamine and scopolamine groups protected the gibel carp compared to the control group, which was consistent with the trend of survival rate. Specifically, β-glucan group in serum appeared best on lysozyme, TSOD and complement C3. Real time quantitative RT-PCR results demonstrated that in both spleen and head kidney tissues, mRNA expressions of typical Th1 immune response cytokines IL-2 and IFN-γ2 in β-glucan group and anisodamine group were significantly higher than other groups and the level of immunoglobulins related to systemic immunity (IgM) and mucosal immunity (IgZ) were also enhanced in the immune period. DTT group slightly affected immune gene and serum enzyme activity, while did not show an adjuvant effect on survival rate. In addition, four adjuvant groups could obviously inhibit CyHV-2 replication. This study explored and proved the good efficiency of β-glucan or anisodamine as immersion immune adjuvant and also provided reference for improving the efficiency of immersion immunity.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Jing Wang, Wenjing Hong, Fei Zhu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Astakine is a crucial factor in the proliferation and differentiation of hematopoietic stem cells and is directly involved in hematopoiesis in crustaceans. To assess the role of Astakine in the innate immune system of 〈em〉Scylla paramamosain〈/em〉, the immune responses in healthy and Astakine-inhibited 〈em〉S. paramamosain〈/em〉 were investigated in the present study. The RNA transcripts of 〈em〉Astakine〈/em〉 were widely distributed in all examined tissues, with significantly higher levels of expression in hemocytes of both healthy and challenged 〈em〉S. paramamosain〈/em〉 with 〈em〉Vibrio alginolyticus〈/em〉 and WSSV. When 〈em〉Astakine〈/em〉 was knocked down by RNA interference technology, immune-related genes, including 〈em〉Janus kinase〈/em〉, 〈em〉prophenoloxidase〈/em〉, 〈em〉hemocyanin〈/em〉, 〈em〉β-actin〈/em〉, 〈em〉myosin II essential light chain-like protein〈/em〉, 〈em〉signal transducer and activator of transcription〈/em〉, 〈em〉Relish〈/em〉, and 〈em〉C-type-lectin〈/em〉, were significantly down-regulated in hemocytes. The levels of phenoloxidaseactivity (PO), total hemocyte counts (THC) and hemocyte proliferation decreased significantly in hemocytes of Astakine-dsRNA treated 〈em〉S. paramamosain〈/em〉. After being challenged with 〈em〉V. alginolyticus〈/em〉 and WSSV, the THC decreased significantly and the levels of hemocyte apoptosis increased significantly in Astakine-dsRNA treated 〈em〉S. paramamosain〈/em〉 in comparison with those in infected groups without Astakine-dsRNA treatment. After being challenged with WSSV, the WSSV copies were significantly lower in Astakine-dsRNA treated groups than those in the WSSV infection group, which suggested that knockdown of 〈em〉Astakine〈/em〉 was not conductive to WSSV replication and this might be associated with the decreasing THC. The results of survival analysis showed that the survival rate of 〈em〉V. alginolyticus〈/em〉 or WSSV infected 〈em〉S. paramamosain〈/em〉 decreased significantly following 〈em〉Astakine〈/em〉 knockdown. These results suggested that RNA interference of 〈em〉Astakine〈/em〉 might weaken the resistance of 〈em〉S. paramamosain〈/em〉 to 〈em〉V. alginolyticus〈/em〉 or WSSV infection. The weaken resistivity after knockdown 〈em〉Astakine〈/em〉 might be related to the changes of important immune-related gene expression, THC, PO activity, proliferation and apoptosis of hemocytes.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Yunkun Li, Jiabei Han, Jiayu Wu, Dong Li, Xixi Yang, Anqi Huang, Guixian Bu, Fengyan Meng, Fanli Kong, Xiaohan Cao, Xingfa Han, Xiaofu Pan, Shiyong Yang, Xianyin Zeng, Xiaogang Du〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Quantification real-time PCR (qRT-PCR) is a common method in analysis of gene expression, but the stable reference genes for the normalization analysis have not been appreciated before identifying expression pattern of genes in teleost fishes. In this study, we selected eight candidate reference genes (〈em〉18S〈/em〉, 〈em〉Actin〈/em〉, 〈em〉EF-1α〈/em〉, 〈em〉40S〈/em〉, 〈em〉B2M〈/em〉, 〈em〉TUBA〈/em〉, 〈em〉UBCE〈/em〉 and 〈em〉GAPDH〈/em〉) basing on transcriptome analysis and the traditional housekeeping genes, and analyzed the stability of the reference genes in spleen, head kidney and head kidney leukocytes (HKL) after pathogen challenge in 〈em〉Schizothorax prenanti〈/em〉 (〈em〉S. prenanti〈/em〉). Three common programs (geNorm, NormFinder and Bestkeeper) were used to evaluate the stability of the candidate reference genes. Two reference genes, 〈em〉Actin〈/em〉 and 〈em〉EF-1α〈/em〉 presented higher stability, while 〈em〉18S〈/em〉 and 〈em〉GAPDH〈/em〉 were the lower stable genes, both in 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉. An important immune gene, 〈em〉toll-like receptor 22a〈/em〉 (〈em〉TLR22a〈/em〉), was selected to validate the stability of the proposed reference genes (〈em〉Actin〈/em〉 and 〈em〉EF-1α〈/em〉) across different experiment treatments. The results reveal that 〈em〉Actin〈/em〉 and 〈em〉EF-1α〈/em〉 are quite suitable reference genes for the normalization analysis. Otherwise, using the most stable gene 〈em〉Actin〈/em〉 to validate the reliable of transcriptome data showed the high correlation between the fold change of transcriptome data and qRT-PCR data. In conclusion, our study not only acquired the suitable reference gene for the qRT-PCR assay under specific experiment condition, but also provided a comprehensive method to evaluate and validate the reference gene based on transcriptome analysis in teleost fishes.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Christian Bailly, Gérard Vergoten〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have emerged as efficient cancer biotherapeutics. In parallel, small molecules targeting PD-L1 are actively searched to offer novel therapeutic opportunities and to reduce treatment costs. Thus far, all PD-L1 small molecule inhibitors identified present the unique property to induce and to stabilize the formation of PD-L1 protein homodimers. PD-L1 itself can form heterodimers with B7-1 (CD80) but it is essentially monomeric in solution, although the homolog viral protein vOX2 is known to dimerize. Drug-induced sequestration of PD-L1 homodimers prevents binding of PD-L1 to PD-1, thus blocking the downstream signaling. We have analyzed this phenomenon of drug-induced protein dimerization to show that PD-L1 is not an isolated case. Several examples of drug-mediated protein homodimer stabilization are presented here. In particular, a similar phenomenon has been observed with small molecules, such as NSC13728 and KI-MS2-008, which stabilize Max-Max protein homodimers, to block the formation of Myc-Max heterodimers and the ensuing signalization. PD-L1, Max and ten other examples of drug-stabilized protein homodimers point to a general mechanism of protein regulation by small molecules. Nevertheless, the extent and functions of drug-induced PD-L1 homodimers await validation in vivo.〈/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-S0006295220300319-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 20 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Jun-Wan Shin, Kyung-Soo Chun, Do-Hee Kim, Su-Jung Kim, Seong Hoon Kim, Nam-Chul Cho, Hye-Kyung Na, Young-Joon Surh〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The present study was aimed to investigate the effects of curcumin, a representative chemopreventive phytochemical with pronounced antioxidant and anti-inflammatory properties, on activation of Nrf2 and its target protein heme oxygenase-1 (HO-1) in mouse skin 〈em〉in vivo〈/em〉 and in cultured murine epidermal cells. Treatment of mouse epidermal JB-6 cells with curcumin resulted in the induction of HO-1 expression, and this was abrogated in cells transiently transfected with Nrf2 siRNA. While curcumin treatment increased protein expression of Nrf2, it failed to did not alter the steady-state level of the Nrf2 mRNA transcript. Treatment of cells with curcumin stabilized Nrf2 by inhibiting ubiquitination and subsequent 26S proteasomal degradation of this transcription factor. Tetrahydrocurcumin, a non-electrophilic analogue of curcumin that lacks the α,β-unsaturated carbonyl group, failed to induce HO-1 expression as well as Nrf2 nuclear translocation of Nrf2 and its binding to the antioxidant/electrophile response elements. Cells transfected with a mutant Keap1 protein in which cysteine 151 is replaced by serine exhibited marked reduction in curcumin-induced Nrf2 transactivation. Mass spectrometric analysis revealed that curcumin binds to Keap1 Cys151, supporting that this amino acid is a critical target for curcumin modification of Keap1, which facilitates the liberation of Nrf2. Thus, it is likely that the α,β-unsaturated carbonyl moiety of curcumin is critical essential for its binding to Keap1 and stabilization of Nrf2 by hampering ubiquitination and proteasomal degradation.〈/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-S0006295220300307-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Xiang Sun, Peng Jin, Qin Liu, Qiyao Wang, Yuanxing Zhang, Xiaohong Liu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Inactivated vaccines are often applied with adjuvants in commercial fish farming. Although some mineral or non-mineral oil adjuvants show efficient improvement with inactivated vaccines, but sometimes bring side effects such as tissue adhesion and granulomatous lesion at the injection site. CpG ODN is a novel type of soluble adjuvant which has been proved to possess excellent advantages in fish vaccine development. In this study, we designed a tandem sequence of CpG ODN synthesized in plasmid pcDNA 3.1, and an inactivated 〈em〉Vibrio anguillarum〈/em〉 vaccine developed in our previous work was chosen for determining the efficiency of the CpG-riched plasmids (pCpG) as an adjuvant. Results showed that pCpG we designed can offer higher immunoprotection with the vaccine. Interestingly, even below the minimum immune dosage of the vaccine, a high RPS of 84% was observed once the vaccine was administrated with the pCpG. Serum specific antibody titer, superoxide dismutase and total protein were enhanced and some immune genes related to both innate and adaptive immune response were upregulated, implying an effective auxiliary function of the pCpG. Totally, our study suggested that the pCpG is a potential and available adjuvant for turbot vaccine development.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Amit S. Kalgutkar, James P. Driscoll〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Basic amine substituents provide several pharmacokinetic benefits relative to acidic and neutral functional groups, and have been extensively utilized as substituents of choice in drug design. On occasions, basic amines have been associated with off-target pharmacology via interactions with aminergic G-protein coupled receptors, ion-channels, kinases, etc. Structural features associated with the promiscuous nature of basic amines have been well-studied, and can be mitigated in a preclinical drug discovery environment. In addition to the undesirable secondary pharmacology, α-carbon oxidation of certain secondary or tertiary cycloalkyl amines can generate electrophilic iminium and aldehyde metabolites, potentially capable of covalent adduction to proteins or DNA. Consequently, cycloalkyl amines have been viewed as structural alerts (SAs), analogous to functional groups such as anilines, furans, thiophenes, etc., which are oxidized to reactive metabolites that generate immunogenic haptens by covalently binding to host proteins. Detailed survey of the literature, however, suggests that cases where preclinical or clinical toxicity has been explicitly linked to the metabolic activation of a cycloalkyl amine group are extremely rare. Moreover, there is a distinct possibility for the formation of electrophilic iminium/amino-aldehyde metabolites with numerous cycloalkyl amine-containing marketed drugs, since stable ring cleavage products have been characterized as metabolites in human mass balance studies. In the present work, a critical analysis of the evidence for and against the role of iminium ions/aldehydes as mediators of toxicity is discussed with a special emphasis on often time overlooked detoxication pathways of these reactive species to innocuous metabolites.〈/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-S000629522030006X-ga1.jpg" width="391" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Tao Yu, Zhibin Wang, Wang Jie, Xiuxiu Fu, Bing Li, Hong Xu, Yan Liu, Min Li, Eunji Kim, Yanyan Yang, Jae Youl Cho〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉BX795, a small molecule with an aminopyrimidine backbone, is a potent ATP-competitive inhibitor of phosphoinositide-dependent kinase 1 (PDK1) and TANK-binding kinase 1 (TBK1). BX795 has significant functions in various immune responses and cancer. Few reports on the anti-inflammatory effect of BX795 are available, and its molecular mechanisms have not been fully elucidated. In this study, lipopolysaccharide (LPS)-treated macrophages (RAW264.7 cells), luciferase reporter gene assay, knock-down and overexpression strategies, kinase assay, protein chip, immunoprecipitation, and immunoblotting analyses were employed to clarify the anti-inflammatory mechanism of BX795. BX795 was found to dose-dependently inhibit the production of pro-inflammatory mediators without exhibiting cytotoxicity. Luciferase assay and immunoblotting analysis with nuclear fractions showed that activator protein-1 (AP-1), signal transducer and activator of transcription 1 (STAT1), and interferon regulatory factor 3 (IRF3) are targeted by BX795 rather than nuclear factor (NF)-κB. Moreover, TBK1 and AKT, transforming growth factor activated kinase (TAK)-1/c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase kinase 4 (MKK4) for AP-1 activation, and Janus kinase 2 (JAK2)/STAT1 were inhibited by BX795. Consistent with these findings, BX795 strongly ameliorated inflammatory symptoms in colitis models. These results suggest that BX795 can suppress inflammatory responses triggered by Gram-positive bacteria by suppressing multiple pathways.〈/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-S0006295220300071-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 10 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Rana Gbyli, Yuanbin Song, Stephanie Halene〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Humanized mice have proven to be invaluable for human hematological translational research since they offer essential tools to dissect disease biology and to bridge the gap between pre-clinical testing of novel therapeutics and their clinical applications. Many efforts have been placed to advance and optimize humanized mice to support the engraftment, differentiation, and maintenance of hematopoietic stem cells (HSCs) and the human hematological system in order to broaden the scope of applications of such models. This review covers the background of humanized mice, how they are used as platforms to model myeloid malignancies, and the various current and potential approaches to further enhance their utilization in biomedical research.〈/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-S0006295220300046-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 9 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Nadire Özenver, Thomas Efferth〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nitric oxide synthases (NOS) are a family of isoforms, which generate nitric oxide (NO). NO is one of the smallest molecules in nature and acts mainly as a potent vasodilator. It participates in various biological processes ranging from physiological to pathological conditions. Inducible NOS (iNOS, NOS2) is a calcium-independent and inducible isoform. Despite high iNOS expression in many tumors, the role of iNOS is still unclear and complex with both enhancing and prohibiting actions in tumorigenesis. Nature presents a broad variety of natural stimulators and inhibitors, which may either promote or inhibit iNOS response. In the present review, we give an overview of iNOS-modulating agents with a special focus on both natural and synthetic molecules and their effects in related biological processes. The role of iNOS in physiological and pathological conditions is also discussed.〈/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-S0006295220300022-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Guangben Wei, Shuanghu Cai, Yuanzhi Wu, Shaohong Ma, Yucong Huang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈em〉Vibrio harveyi〈/em〉 is the pathogen causing vibriosis in marine-cultured animals, leading to massive deaths in farmed grouper around the world. It is urgent to develop an effective vaccine to prevent vibriosis. In the previous study, we developed a 〈em〉V. harveyi〈/em〉 formalin-killed cells vaccine (FKC), and sought an effective adjuvant for enhancing the immune efficacy of vaccine. In this study, we aimed to evaluate the immune responses and protective effect of FKC combined with chitosan oligosaccharide (COS) or 〈em〉Astragalus〈/em〉 polysaccharides (APS) in the pearl gentian grouper〈em〉♀Epinephelus fuscoguttatus × ♂E. lanceolatus〈/em〉. The results indicated the vaccine triggered a remarkably higher expression levels of IL-1β, IL-16, TNF-α, MHC-Iα and IgM in the kidney and spleen of groupers post-vaccination. Antibody titers, lysozyme, catalase, superoxide dismutase and total protein were significantly elevated in the vaccinated fish compared with those in the control. The experimental groupers were challenged intraperitoneally by 〈em〉V. harveyi〈/em〉 at 35 d post-vaccination, and the relative percentage of survival (RPS) of group FKC + COS, FKC + APS, COS, APS and FKC were 80%, 72%, 52%, 47% and 55%, respectively. These results demonstrated COS and APS was the potential adjuvants for FKC against 〈em〉V. harveyi〈/em〉 in aquaculture.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Chin-Cheng Chien, Tzu-Yung Lin, Chia-Chun Chi, Chun-Hung Liu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The purpose of this study was to profile the mechanisms of action of probiotic, 〈em〉Bacillus subtilis〈/em〉 E20 in activating the immunity of white shrimp, 〈em〉Litopenaeus vannamei〈/em〉. Two groups of shrimp were studied. One group was fed a control diet without probiotic supplementation and the other was fed a probiotic-containing diet at a level of 10〈sup〉9〈/sup〉 cfu kg diet〈sup〉−1〈/sup〉. After the 8-week feeding regimen, the metabolite composition in the hepatopancreas of shrimp were investigated using 〈sup〉1〈/sup〉H nuclear magnetic resonance (〈sup〉1〈/sup〉H NMR) based metabolomic analysis. Results from the 〈sup〉1〈/sup〉H NMR analysis revealed that 16 hepatopancreatic metabolites were matched and identified among groups, of which 2 metabolites, creatinine and glutamine were significantly higher in probiotic group than in the control group. This result was confirmed by the reverse-phase high-performance liquid chromatography (RP-HPLC) and spectrophotometric analysis. Transcriptome analysis indicated the expressions of 10 genes associated with antioxidant enzymes, pattern recognition proteins and antimicrobial molecules, more active expression in the shrimp fed a diet supplemented with probiotic as compared to that of shrimp in control. In addition, the expressions of 4 genes involved with hexosamine biosynthesis pathway (HBP) and UDP-N-acetylglucosamine-peptide N-acetylglucosaminyltransferase for protein 〈em〉O-〈/em〉glycosylation were also higher in hepatopancreas of probiotic-treated shrimp than in shrimp fed a control diet. Western blot and enzyme-linked immunosorbent assay showed that heat shock factor 1, heat shock protein 70, and protein 〈em〉O〈/em〉-glycosylation in hepatopancreas were higher in probiotic group than the control group. These findings suggest that probiotic, 〈em〉B. subtilis〈/em〉 E20 promotes the digestibility of glutamine in the diet, and that the increased glutamine in shrimp can be used as fuel for immune cells or may be used to regulate immune molecule expressions and protein 〈em〉O〈/em〉-glycosylation via the HBP to increase protein 〈em〉O〈/em〉-glycosylation, thereby improving the health of shrimp.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Hourong Liu, Chengwen Song, Junhao Ning, Yuan Liu, Zhaoxia Cui〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Variable lymphocyte receptors (VLRs) play an important role via their antigen-special reorganization in jawless vertebrates (agnathans) adaptive immune response. In the present study, the open reading frame (ORF) of 〈em〉Eriocheir sinensis〈/em〉 VLRA (designated as EsVLRA) was identified. EsVLRA comprised a 799-amino-acid polypeptide with one LRR_NT domain, thirteen LRR domains and one LRR_CT domain, which showed a high domain consistency of the VLR genes in lamprey (〈em〉Petromyzon marinus〈/em〉). The transcript of EsVLRA was detected in all examined tissues with the highest level detected in hepatopancreas. Notably, the expression of EsVLRA in hepatopancreas, gonads, gill and intestine of male crabs was significantly higher than that in females. The recombinant EsVLRA exhibited strong bacteria-binding activity rather than antibacterial activity, suggesting its crucial role in immune recognition. Furthermore, 6 h earlier response and a significantly higher peak of EsVLRA mRNA expression was observed after challenge with live 〈em〉Vibrio parahaemolyticus〈/em〉 (240.6-fold, 〈em〉P〈/em〉 〈 0.01, crabs receive secondary challenge after 〈em〉V. parahaemolyticus〈/em〉 vaccine to the carbs only receive twice PBS injection, N = 6), compared with those only received first injection with formalin-inactivated 〈em〉V. parahaemolyticus〈/em〉 (39.7-fold, 〈em〉P〈/em〉 〈 0.01, challenge 6 h to vaccination 12 h). The findings of this study together demonstrated that EsVLRA plays an important role in the immune system of 〈em〉E. sinensis〈/em〉, serving as a pattern recognition receptor and involving in the immune priming.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Iris Barjhoux, Damien Rioult, Alain Geffard, Melissa Palos Ladeiro〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Immunotoxicity analysis receives a strong interest in environmental 〈em〉a priori〈/em〉 and 〈em〉a posteriori〈/em〉 risk assessment procedures considering the direct involvement of the immune system in the health status of organisms, populations and thus ecosystems. The freshwater mussel 〈em〉Dreissena polymorpha〈/em〉 is an invasive species widely used in ecotoxicology studies and biomonitoring surveys to evaluate the impacts of contaminants on aquatic fauna. Bivalve hemocytes are the immunocompetent cells circulating in the open circulatory system of the organism. However, there is nowadays no consensus on a protocol to evaluate the immunocompetent state of this particular cell type using flow cytometry. Wild species such as 〈em〉D. polymorpha〈/em〉 present several technical barriers complicating their analyze including (i) the quality and the purity of the hemolymph sample, (ii) the controversial characterization of hemocyte subpopulations and their diversity, (iii) the quantity of biological material, and (iv) the high inter-individual variability of hemocyte responses. The present work proposes several technical and analytical improvements to control the above-mentioned issues. The inclusion of sedimentation and cell detachment steps in the pre-analytical phase of the protocol substantially ameliorate the quality of the hemolymph sample as well as the accuracy of the cytometric measurements, by selecting the analyzed cells on their adhesion ability and by increasing the concentration of the analyzed events. The development of an effective triple-labeling procedure including the cellular probe Hoechst® 33342, the membrane impermeant dye propidium iodide and yellow-green fluorescent microspheres allowed the simultaneous analysis of cytotoxicity and phagocytosis activity in hemocytes. It also significantly enhanced the accuracy of hemocyte endpoint measurements by eliminating non-target events from the analysis and allowing relevant gating strategies. Finally, the use of pooled samples of hemolymph noticeably reduced inter-sample variability while providing more plasticity in the experimental design and improving the discriminating potency between treatments. The developed protocol is suitable for 〈em〉ex vivo〈/em〉 exposure of hemocyte in a chemical/environmental toxicity assessment as well as for 〈em〉in vivo〈/em〉 exposure in the laboratory or 〈em〉in situ〈/em〉 biomonitoring surveys with few adaptations.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S1050464819312318-fx1.jpg" width="500" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Limei Qiu, Hao Chen, Zhi Zhou, Huan Zhang, Rui Liu, Qilin Yi, Chuanyan Yang, Lei Gao, Lingling Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Oyster 〈em〉Crassostrea gigas〈/em〉, is considered as a useful environmental indicator since it is widely distributed along the intertidal zone whereby it tends to accumulate cadmium and is always exposed to various pathogen agents. However, its molecular responses to both cadmium and pathogen stimulation remain unclear. In the present study, transcriptome data of hemocytes from oysters were analyzed to reveal specific molecular responses of oyster to cadmium or cadmium/bacteria stimulation. A total of 21591, 22872 and 20107 genes were detected in the BLANK, Cd24h and Cd/Bac24h group, respectively. Among them, there were 685 differentially expressed genes collected in the comparison of Cd24h versus BLANK. GO analysis of these genes found that sixteen terms into the Molecular Function category displayed transporter activities, and were all over-enrichment by cadmium exposure, whereas twelve terms into Biological Process category involved mainly in metabolic process of the various cellular components and two terms into Cellular Component category were all under-enrichment. The 330 immune responsive genes were shared by two gene lists of CdBac24h versus BLANK and CdBac24h versus Cd24h, and seven out of thirty terms in GO analysis were related to the immune process. Further annotation of these genes from the KEGG database revealed fourteen pathways, including two nervous system related pathways, arachidonic acid pathway, four immune pathways, MAPK cascade and other four cell signaling pathways, and two energy related pathways. Twenty-two differentially expressed genes were identified to responsive to both cadmium exposure and bacteria stimulation, but in different expression patterns, suggesting that bilateral responsive genes, such as alkaline phosphatase and sodium and chloride-dependent glycine transporter gene, could be candidate biomarkers for early warning of cadmium pollution. The present results collectively indicated that a profound neuro-endocrine-immune regulatory network was activated in response to cadmium and bacteria stimulation in oyster 〈em〉C. gigas〈/em〉, and the expression pattern of some cadmium responsive genes may be either reversed or strengthened by bacteria stimulation. The results provide knowledge on the transcriptomic response profile of oyster after short-term cadmium exposure and bacteria stimulation, which would be useful for future studies on stress response mechanism of mollusc, and some cadmium-bacteria responsive genes may be explored as potential biomarkers for monitoring marine pollution.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Samir Jana, B. Madhu Krishna, Jyotsana Singhal, David Horne, Sanjay Awasthi, Ravi Salgia, Sharad S. Singhal〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉SRY-related high-mobility group box 9 (SOX9) is an indispensable transcription factor that regulates multiple developmental pathways related to stemness, differentiation, and progenitor development. Previous studies have demonstrated that the SOX9 protein directs pathways involved in tumor initiation, proliferation, migration, chemoresistance, and stem cell maintenance, thereby regulating tumorigenesis as an oncogene. SOX9 overexpression is a frequent event in breast cancer (BC) subtypes. Of note, the molecular mechanisms and functional regulation underlying SOX9 upregulation during BC progression are still being uncovered. The focus of this review is to appraise recent advances regarding the involvement of SOX9 in BC pathogenesis. First, we provide a general overview of SOX9 structure and function, as well as its involvement in various kinds of cancer. Next, we discuss pathways of SOX9 regulation, particularly its miRNA-mediated regulation, in BC. Finally, we describe the involvement of SOX9 in BC pathogenesis via its regulation of pathways involved in regulating cancer hallmarks, as well as its clinical and therapeutic importance. In general, this review article aims to serve as an ample source of knowledge on the involvement of SOX9 in BC progression. Targeting SOX9 activity may improve therapeutic strategies to treat BC, but precisely inhibiting SOX9 using drugs and/or small peptides remains a huge challenge for forthcoming cancer research.〈/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-S0006295219304885-ga1.jpg" width="305" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Lei Liu, Yunfei Dang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mannose-binding lectin (MBL) is a crucial pattern recognition receptor in the host innate immune system. Previously, we reported the biological function of 〈em〉Ctenopharyngodon idella〈/em〉 MBL (CiMBL) in initiating the lectin pathway of the complement system. In the present study, we further explored its biological function including the agglutinating ability, binding capacity and protective role 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉. After 〈em〉Aeromonas hydrophila〈/em〉 infection, western blot analysis revealed that the CiMBL were fluctuated and expressed in the serum and major immune-related tissues. The result of quantitative PCR (qPCR) showed that the recombinant CiMBL (rCiMBL) significantly inhibited the mRNA expression of interleukin-1β (〈em〉IL-1β〈/em〉) and tumor necrosis factor-α (〈em〉TNF-α〈/em〉) in liver, spleen and hepatic cells. Due to rCiMBL bound to 〈span〉d〈/span〉-mannose, 〈span〉d〈/span〉-galactose, 〈span〉d〈/span〉-glucose, N-acetyl-〈span〉d〈/span〉-glucosamine (GlcNAc), lipopolysaccharide (LPS), peptidoglycan (PGN) and Agar in the presence of Ca〈sup〉2+〈/sup〉, herein gram-positive (〈em〉Staphylococcus aureus〈/em〉 and 〈em〉Micrococcus luteus〈/em〉) and gram-negative (〈em〉A. hydrophila〈/em〉 and 〈em〉Vibrio anguillarum〈/em〉) bacteria were agglutinated by rCiMBL in a Ca〈sup〉2+〈/sup〉-dependent manner. More importantly, rCiMBL enhanced the survival rate of grass carp following bacterial infection. Overall, the results provide an evidence that CiMBL can protect grass carp against 〈em〉A. hydrophila〈/em〉 infection in aquaculture.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 98〈/p〉 〈p〉Author(s): Chao Zhang, Xueying Cao, Kaiqiang Wang, Xiaoling Dai, Ruidong Zhang, Zhuoxing Zhang, Xin Huang, Qian Ren〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Transcription factor activator protein 1 (AP1) plays an irreplaceable role in the response to a variety of external stimulants, such as cellar stress, bacterial and viral infections, and inflammatory cytokines. In this study, we identified a novel 〈em〉AP1〈/em〉 gene from 〈em〉Macrobrachium nipponense〈/em〉 and named it 〈em〉MnAP1〈/em〉, which has a full length of 1747 bp contains an 882 bp open reading frame, and encodes a protein with 293 amino acids. The MnAP1 protein contains Pfam and bZIP domains. 〈em〉MnAP1〈/em〉 is widely distributed in hemocytes, heart, hepatopancreas, gill, stomach, and intestinal tissues. The expression levels of 〈em〉MnAP1〈/em〉 in the gills and stomach were significantly upregulated after 〈em〉Vibrio parahaemolyticus〈/em〉 and 〈em〉Staphylococcus aureus〈/em〉 attacks. We studied the relationship between 〈em〉MnAP1〈/em〉 and the transcripts of antimicrobial peptides (AMPs) in gills through RNA interference. Interestingly, the regulatory effects of 〈em〉MnAP1〈/em〉 on the expression of different AMPs were different. We found that the expression levels of crustins, including 〈em〉Cru1〈/em〉, 〈em〉Cru3,〈/em〉 and 〈em〉Cru4〈/em〉 in the gills were evidently decreased, whereas the synthesis of 〈em〉Cru5〈/em〉 and anti-lipopolysaccharide factors (〈em〉ALF〈/em〉3 and 〈em〉ALF4〈/em〉) were obviously increased. We further explored the effect of 〈em〉MnAP1〈/em〉 on the expression of transcription factor relish from 〈em〉M. nipponense〈/em〉. The result showed that the knockdown of 〈em〉MnAP1〈/em〉 can remarkably upregulate the expression of 〈em〉MnRelish〈/em〉. Relish as a member of the nuclear factor κB family that regulates the expression of AMPs in the innate immunity of crustacean. Hence, we also detected the expression levels of 〈em〉Cru5〈/em〉, 〈em〉ALF3〈/em〉, and 〈em〉ALF4〈/em〉 in the gills of 〈em〉MnRelish〈/em〉-silenced prawns. The Data showed that the expression levels of these three AMPs were evidently reduced after 〈em〉MnRelish〈/em〉 silencing. Our results indicated that 〈em〉MnAP1〈/em〉 plays a positive role in regulating the expression of AMPs, promotes the JNK/AP1 signaling pathway, and exerts a negative regulatory effect on the synthesis of AMPs by inhibiting the transcription of NF-κB factor in the innate immunity of 〈em〉M. nipponense〈/em〉.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 99〈/p〉 〈p〉Author(s): Shuo Li, Gaixiang Hao, Yu Feng, Jiafang Li, Nan Wang, Jinsheng Sun〈/p〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Fish & Shellfish Immunology, Volume 99〈/p〉 〈p〉Author(s): Chang-Sheng Zhao, Di-An Fang, Dong-Po Xu〈/p〉

Description: 〈p〉Publication date: Available online 27 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Zhenzhu Sun, Wenqiang Lu, Na Lin, Hui Lin, Jie Zhang, Tingjuan Ni, Liping Meng, Chuanjing Zhang, Hangyuan Guo〈/p〉

Description: 〈p〉Publication date: Available online 27 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Xunzhen Zheng, Veani Fernando, Vandana Sharma, Yashna Walia, Joshua Letson, Saori Furuta〈/p〉