ALBERT

Description: 〈p〉Publication date: October–December 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Mutation Research/Reviews in Mutation Research, Volume 782〈/p〉 〈p〉Author(s): Yuxiao Liao, Zhao Peng, Liangkai Chen, Liegang Liu, Qinghua Wu, Wei Yang〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mycotoxins, produced by fungi, are secondary metabolites causing adverse, toxic and pathological effects on human and animals. Studies about the association between mycotoxins and microRNAs (miRNAs) were developed since miRNAs have been demonstrated to play a critical role in many developmental processes for regulating messenger RNA (mRNA). As published studies showed, dozens of miRNAs were influenced by mycotoxins, indicating that miRNAs can play important roles in the occurrence and development of mycotoxicosis. Besides, a hypothesis called competing endogenous RNA (ceRNA) was reported to indirectly modulate the expression of mRNA 〈em〉via〈/em〉 miRNA response elements (MREs) to consequently regulate cell functions. As a result, four common miRNAs were focused to predict the corresponding ceRNAs based on their own characteristics and the effects of mycotoxins on them, in hope of providing potential ways or directions of miRNAs regulation for mycotoxicosis, and expanding the research field about mycotoxicosis from ceRNA.〈/p〉〈/div〉

Description: 〈p〉Publication date: October–December 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Mutation Research/Reviews in Mutation Research, Volume 782〈/p〉 〈p〉Author(s): Yanan Xu, Qian Zhang, Liang Tan, Xubiao Xie, Yong Zhao〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Niemann–Pick C disease (NPC) is a rare autosomal recessive disorder characterized by severe neurodegeneration of central nervous system. Linkage studies in multiplex NPC families and genetic complementation research revealed two disease genes, 〈em〉NPC1 and NPC2,〈/em〉 both of which are important transporters for cholesterol trafficking. NPC2 executes cholesterol-transport function through protein-protein interaction with NPC1 as well as through protein-membrane interaction directly with membrane of late endosome and lysosome. In addition, NPC2 may play many other roles as indicated by its widely expressing pattern in different cells and presenting in numerous secretory fluids, although it biological significance is less studied today. About 50 clinical cases have been reported documenting over twenty different mutations of 〈em〉NPC2〈/em〉 in NPC patients so far. In this review, we will mainly summarize the molecular characteristics and biological significance of NPC2, highlighting its vital roles in NPC disease.〈/p〉〈/div〉

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〉 Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Volume 1867, Issue 9〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: Available online 8 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Biomembranes〈/p〉 〈p〉Author(s): Deo R. Singh, Christopher King, Matt Salotto, Kalina Hristova〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉EGFR is a receptor tyrosine kinase that plays a critical role in cell proliferation, differentiation, survival and migration. Its activating ligand, EGF, has long been believed to stabilize the EGFR dimer. Two research studies aimed at quantitative measurements of EGFR dimerization, however, have led to contradicting conclusions and have questioned this view. Given the controversy, here we sought to measure the dimerization of EGFR in the absence and in the presence of saturating EGF concentrations, and to tease out the effect of ligand on dimer stability, using a FRET-based quantitative method. Our measurements show that the dissociation constant is decreased ~150 times due to ligand binding, indicative of significant dimer stabilization. In addition, our measurements demonstrate that EGF binding induces a conformational change in the EGFR dimer.〈/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-S0005273619301476-ga1.jpg" width="265" alt="Unlabelled Image" title="Unlabelled Image"〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 8 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics〈/p〉 〈p〉Author(s): Martina Paumann-Page, Rupert Tscheliessnig, Benjamin Sevcnikar, Romy-Sophie Katz, Irene Schwartz, Stefan Hofbauer, Vera Pfanzagl, Paul G. Furtmüller, Christian Obinger〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Human peroxidasin 1 is a multidomain peroxidase situated in the basement membrane. The iron enzyme with covalently bound heme oxidizes bromide to hypobromous acid which facilitates the formation of distinct sulfilimine cross-links in the collagen IV network and therefore contributes to its mechanical stability. Additional to the catalytically active peroxidase domain peroxidasin comprises a leucine rich repeat domain, four Ig domains and a C-terminal von Willebrand factor type C module (VWC). Peroxidasin has been shown to form homotrimers involving two redox-sensitive cysteine residues and to undergo posttranslational C-terminal proteolytic cleavage. The present study on several recombinantly produced truncated peroxidasin variants showed that the VWC is not required for trimer formation whereas the alpha-helical linker region located between the peroxidase domain and the VWC is crucial for trimerization. Our data furthermore implies that peroxidasin oligomerization occurs intracellularly before C-terminal cleavage. For the first time we present overall solution structures of monomeric and trimeric truncated peroxidasin variants which were determined by rotary shadowing combined with transmission electron microscopy and by small-angle X-ray scattering (SAXS). A triangular arrangement of the peroxidase domains to each other within the homotrimer was revealed and this structure was confirmed by a model of trimeric peroxidase domains. Our SAXS data showed that the Ig domains are highly flexible and interact with the peroxidase domain and that within the homotrimer each alpha-helical linker region interacts with the respective adjacent peroxidase domain. The implications of our findings on the structure-function relationship of peroxidasin are 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-S1570963919301219-ga1.jpg" width="240" alt="Unlabelled Image" title="Unlabelled Image"〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 The International Journal of Biochemistry & Cell Biology, Volume 114〈/p〉 〈p〉Author(s): Deep Pooja, Anusha Gunukula, Nitin Gupta, David J. Adams, Hitesh Kulhari〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The biggest challenge in delivering anticancer agents is the ability to direct these molecules specifically to cancer cells. With this in mind, modern research is focussing on improving the precision of cancer drug delivery by incorporating a ligand that has the ability to specifically recognize cancer cells. Peptides are emerging as a new tool in drug and gene delivery. Peptide-drug conjugates, peptide-modified drug delivery systems, and peptide-coupled imaging agents have been shown to increase on-site delivery. This has allowed better tumor mass contouring in imaging and increased therapeutic efficacy of chemotherapies, reducing adverse effects. Benefits of peptide ligands include their small size, easy and affordable production, high specificity and remarkable flexibility regarding their sequence and conjugation possibilities. Bombesin (Bn) receptors have shown great promise for tumor targeting due to their increased expression in a variety of human cancers, including prostate, breast, small cell lung, and pancreatic cells. This review discusses the overexpression of Bn receptors in different cancers and various approaches to target these receptors for therapeutic and diagnostic interventions in human malignancies.〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 8 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Journal of Computational Physics〈/p〉 〈p〉Author(s): Maxim Rakhuba, Alexander Novikov, Ivan Oseledets〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Such problems as computation of spectra of spin chains and vibrational spectra of molecules can be written as 〈em〉high-dimensional eigenvalue problems〈/em〉, i.e., when the eigenvector can be naturally represented as a multidimensional tensor. Tensor methods have proven to be an efficient tool for the approximation of solutions of high-dimensional eigenvalue problems, however, their performance deteriorates quickly when the number of eigenstates to be computed increases. We address this issue by designing a new algorithm motivated by the ideas of 〈em〉Riemannian optimization〈/em〉 (optimization on smooth manifolds) for the approximation of multiple eigenstates in the 〈em〉tensor-train format〈/em〉, which is also known as matrix product state representation. The proposed algorithm is implemented in TensorFlow, which allows for both CPU and GPU parallelization.〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 8 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Journal of Computational Physics〈/p〉 〈p〉Author(s): Chen Liu, Florian Frank, Faruk O. Alpak, Béatrice Rivière〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Permeability estimation of porous media from directly solving the Navier–Stokes equations has a wide spectrum of applications in petroleum industry. In this paper, we utilize a pressure-correction projection algorithm in conjunction with the interior penalty discontinuous Galerkin scheme for space discretization to build an incompressible Navier–Stokes simulator and to use this simulator to calculate permeability of real rock samples. The proposed method is accurate, numerically robust, and exhibits the potential for tackling realistic problems.〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 8 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Journal of Computational Physics〈/p〉 〈p〉Author(s): Mustapha Malek, Nouh Izem, M. Shadi Mohamed, Mohammed Seaid, Omar Laghrouche〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉An efficient partition of unity finite element method for three-dimensional transient diffusion problems is presented. A class of multiple exponential functions independent of time variable is proposed to enrich the finite element approximations. As a consequence of this procedure, the associated matrix for the linear system is evaluated once at the first time step and the solution is obtained at subsequent time step by only updating the right-hand side of the linear system. This results in an efficient numerical solver for transient diffusion equations in three space dimensions. Compared to the conventional finite element methods with 〈em〉h〈/em〉-refinement, the proposed approach is simple, more efficient and more accurate. The performance of the proposed method is assessed using several test examples for transient diffusion in three space dimensions. We present numerical results for a transient diffusion equation with known analytical solution to quantify errors for the new method. We also solve time-dependent diffusion problems in complex geometries. We compare the results obtained using the partition of unity finite element method to those obtained using the standard finite element method. It is shown that the proposed method strongly reduces the necessary number of degrees of freedom to achieve a prescribed accuracy.〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 8 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Journal of Computational Physics〈/p〉 〈p〉Author(s): Lahbib Bourhrara〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉This document presents a new numerical scheme dealing with the Boltzmann transport equation. This scheme is based on the expansion of the angular flux in a truncated spherical harmonics function and the discontinuous finite element method for the spatial variable. The advantage of this scheme lies in the fact that we can deal with unstructured, non-conformal and curved meshes. Indeed, it is possible to deal with distorted regions whose boundary is constituted by edges that can be either line segments or circular arcs or circles. In this document, we detail the derivation of the method for 2D geometries. However, the generalization to 2D extruded geometries is trivial.〈/p〉〈/div〉

Description: 〈p〉Publication date: November 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Computers & Geosciences, Volume 132〈/p〉 〈p〉Author(s): T. Carlotto, P.L.B. Chaffe〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Streamflow recession analysis is crucial for understanding how catchments release water in periods of drought and therefore is important for water resources planning and management. Despite there being several theories on how to model recession curves, few studies compare the different approaches to that problem. In this work, we developed the Master Recession Curve Parameterization tool (MRCPtool), which brings together a set of automated methods for the analysis of recession periods based only on streamflow data. The methods include: (i) hydrograph separation using numerical filters; (ii) automatic extraction of recession periods; (iii) creation of the MRC with the matching strip method; (iv) creation of the MRC for different flow classes defined from the flow duration curve; (v) analysis of flow recession rates 〈math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" altimg="si1.svg"〉〈mrow〉〈mo〉(〈/mo〉〈mo linebreak="goodbreak" linebreakstyle="after"〉−〈/mo〉〈mi〉d〈/mi〉〈mi〉Q〈/mi〉〈mo〉∕〈/mo〉〈mi〉d〈/mi〉〈mi〉t〈/mi〉〈mo〉)〈/mo〉〈/mrow〉〈/math〉 as a function of flow 〈math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" altimg="si2.svg"〉〈mrow〉〈mo〉(〈/mo〉〈mi〉Q〈/mi〉〈mo〉)〈/mo〉〈/mrow〉〈/math〉 and (vi) creation of the MRC from simulated recession curves with different analytical approaches, including linear and nonlinear models. The MRCPtool contains a graphical user interface developed in MATLAB software that facilitates the analysis of streamflow datasets. Finally, we present an example application of the MRCPtool using a streamflow dataset of 44 years. The MRCPtool is an open source tool that can be downloaded from the site: 〈a href="http://www.labhidro.ufsc.br/static/software/MRCPtool.rar" target="_blank"〉http://www.labhidro.ufsc.br/static/software/MRCPtool.rar〈/a〉.〈/p〉〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Free Radical Biology and Medicine, Volume 141〈/p〉 〈p〉Author(s): Chao Wang, Yuan Yuan, Jie Wu, Yuanlin Zhao, Xing Gao, Yihua Chen, Chao Sun, Liming Xiao, Pengfei Zheng, Peizhen Hu, Zengshan Li, Zhe Wang, Jing Ye, Lijun Zhang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉While cardiac hypertrophy and heart failure are accompanied by significant alterations in energy metabolism, more than 50–70% of energy is obtained from fatty acid β-oxidation (FAO) in adult hearts under physiological conditions. Plin5 is involved in the metabolism of lipid droplets (LDs) and is highly abundant in oxidative tissues including heart, liver and skeletal muscle. Plin5 protects the storage of triglyceride (TG) in LDs by inhibiting lipolysis, thereby suppressing excess FAO and preventing excessive oxidative stress in the heart. In this study, we investigated the roles of Plin5 in cardiac hypertrophy and heart failure in mice treated with transverse aortic constriction (TAC). The results indicated that Plin5 deficiency aggravated myocardial hypertrophy in the TAC-treated mice and exacerbated the TAC-induced heart failure. We also found that Plin5 deficiency reduced the cardiac lipid accumulation and upregulated the levels of PPARα and PGC-1α, which stimulate mitochondrial proliferation. Moreover, Plin5 deficiency aggravated the TAC-induced oxidative stress. We consistently found that Plin5 knockdown disrupted TG storage and elevated FAO and lipolysis in H9C2 rat cardiomyocytes. In addition, Plin5 knockdown also provoked mitochondrial proliferation and lipotoxic injury in H9C2 cells. In conclusion, Plin5 deficiency increases myocardial lipolysis, elevates FAO and oxidative burden, and thereby exacerbates cardiac hypertrophy and heart failure in TAC-treated mice.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S089158491930471X-fx1.jpg" width="336" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 7 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Experimental Cell Research〈/p〉 〈p〉Author(s): Rong Jiang, Yan Liao, Fuhuang Yang, Yusi Cheng, Xiaoniu Dai, Jie Chao〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Endothelial-mesenchymal transition (EndoMT) is a key step during lung fibrosis. Studies have shown that bone marrow mesenchymal stem cells (BMSCs) may act as therapeutic candidates for lung fibrosis. However, the effects of BMSCs on EndoMT induced by SiO〈sub〉2〈/sub〉 have not been elucidated, and means to label and track grafted cells have been lacking. The current study explored whether BMSCs prevented pulmonary fibrosis by targeting EndoMT, as well as analyzed the distribution of BMSCs labeled with superparamagnetic iron oxide (SPIO) nanoparticles during treatment. TIE2-GFP mice, human umbilical vein endothelial cells (HUVECs), and BMSCs labeled with SPIO nanoparticles were used to explore the distributions and therapeutic effects of BMSCs in vivo and in vitro. We found that BMSCs reversed lung fibrosis by targeting EndoMT in vivo. Furthermore, we show that BMSCs labeled with SPIO nanoparticles could be used to track stem cells reliably in the lungs for 14 days. Conditioned medium from BMSCs attenuated the increased functional changes and reversed the SiO〈sub〉2〈/sub〉-induced upregulation of ER stress and autophagy markers irrespective of whether they were nanoparticle labeled or not. Our findings identify novel methods to track labeled BMSCs with therapeutic potential.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1862, Issue 8〈/p〉 〈p〉Author(s): Ruifan Wu, Guanqun Guo, Zhen Bi, Youhua Liu, Yuanling Zhao, Nana Chen, Fengqin Wang, Yizhen Wang, Xinxia Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈em〉N〈/em〉〈sup〉6〈/sup〉-methyladenosine (m〈sup〉6〈/sup〉A), the most abundant internal mRNA modification in eukaryotes, plays a vital role in regulating adipogenesis. However, its underlying mechanism remains largely unknown. Here, we reveal that deletion of m〈sup〉6〈/sup〉A demethylase FTO in porcine and mouse preadipocytes inhibits adipogenesis through JAK2-STAT3-C/EBPβ signaling. Mechanistically, FTO deficiency suppresses JAK2 expression and STAT3 phosphorylation, leading to attenuated transcription of C/EBPβ, which is essential for the early stage of adipocyte differentiation. Using dual-luciferase assay, we validate that knockdown of FTO reduces expression of JAK2 in an m〈sup〉6〈/sup〉A-dependent manner. Furthermore, we find that m〈sup〉6〈/sup〉A “reader” protein YTHDF2 directly targets m〈sup〉6〈/sup〉A-modified transcripts of JAK2 and accelerates mRNA decay, which results in decreased JAK2 expression and inactivated JAK2-STAT3-C/EBPβ signaling, thereby inhibiting adipogenesis. Collectively, our results provide a novel insight into the molecular mechanism of m〈sup〉6〈/sup〉A methylation in post-transcriptional regulation of JAK2-STAT3-C/EBPβ signaling axis and highlight the crucial role of m〈sup〉6〈/sup〉A modification and its modulators in adipogenesis.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1861, Issue 8〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 1 October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1865, Issue 10〈/p〉 〈p〉Author(s): Tomonaga Ichikawa, Shingo Nakahata, Masahiro Fujii, Hidekatsu Iha, Kazuya Shimoda, Kazuhiro Morishita〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉N-myc downstream-regulated gene 2 (NDRG2) is a candidate tumor suppressor that is frequently downregulated in adult T-cell leukemia/lymphoma (ATLL) and functions to negatively regulate several cellular signaling pathways as PP2A recruiter. To clarify the molecular mechanisms of suppression of NDRG2 expression, we initially determined the expression pattern of NDRG2 in various types of T-cells and ATLL cells. NDRG2 expression was significantly upregulated in HTLV-1/Tax-immortalized T-cells, which was mediated by NF-κB activation through Tax expression. On the other hand, NDRG2 expression was suppressed in HTLV-1-infected cell lines and various types of ATLL cells, which was dependent on the DNA methylation of the NDRG2 promoter. We found that the expression of enhancer of zeste homolog 2 (EZH2), a member of the polycomb family, is increased in ATLL, and that EZH2 directly binds to the NDRG2 promoter and induces DNA methylation of the NDRG2 promoter. Since the expression of EZH2 were anti-parallelly regulated with the NDRG2 expression, EZH2 might be one of the most important regulators of the downregulation of NDRG2, contributing to enhanced activation of signaling pathways during ATLL development.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1861, Issue 9〈/p〉 〈p〉Author(s): Mariafrancesca Scalise, Michele Galluccio, Lorena Pochini, Jessica Cosco, Miriam Trotta, Manuele Rebsamen, Giulio Superti-Furga, Cesare Indiveri〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The lysosomal amino acid transporter SLC38A9 is referred to as transceptor, i.e. a transporter with a receptor function. The protein is responsible for coupling amino acid transport across the lysosomal membrane according to the substrate availability to mTORC1 signal transduction. This process allows cells to sense amino acid level responding to growth stimuli in physiological and pathological conditions triggering mTOR regulation. The main substrates underlying this function are glutamine and arginine. The functional and kinetic characterization of glutamine and arginine transport was performed using human SLC38A9 produced in 〈em〉E. coli〈/em〉, purified by affinity chromatography and reconstituted in liposomes. A cooperative behaviour for the wild type protein was revealed for both the substrates. A novel Na〈sup〉+〈/sup〉 binding site, namely T453, was described by combined approaches of bioinformatics, site-directed mutagenesis and transport assay. Stimulation by cholesterol of glutamine and arginine transport was observed. The biological function of SLC38A9 relies on the interaction between its N-terminus and components of the mTOR complex; a deletion mutant of the N-terminus tail was produced and transport of glutamine was assayed revealing that this portion does not play any role in the intrinsic transport function of the human SLC38A9. Different features for glutamine and arginine transport were revealed: human SLC38A9 is competent for glutamine efflux, while that of arginine is negligible. In line with these results, imposed ∆pH stimulated glutamine, not arginine transport. Arginine plays, on the contrary, a modulatory function and is able to stimulate glutamine efflux. Interestingly, reciprocal inhibition experiments also supported by bioinformatics, suggested that glutamine and arginine may bind to different sites in the human SLC38A9 transporter.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉Proteoliposome reconstitution of hSLC38A9 WT and mutants.〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0005273619301567-ga1.jpg" width="301" alt="Unlabelled Image" title="Unlabelled Image"〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 8 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Computer Methods and Programs in Biomedicine〈/p〉 〈p〉Author(s): Alae Ammour, Ibtissame Aouraghe, Ghizlane Khaissidi, Mostapha Mrabti, Ghita Aboulem, Faouzi Belhacen〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Parkinson's disease (PD) is the second most common neurodegenerative disease affecting significant portion of elderly population. One of the most frequent hallmarks and the first manifestation of PD is deterioration of handwriting. Since the diagnosis of Parkinson's disease is difficult, researchers have worked to develop a support tool based on algorithms to separate healthy controls from PD patients. On-line handwriting analysis is one of the methods that can be used to diagnose PD. In this study, we aimed to analyze the Arabic Handwriting of 28 Parkinson's disease patients and 28 healthy controls (HCs) who were the same age and have the same intellectual level. We focused on copying an Arabic text task. For each participant we have calculated 1482 features. Based on the most relevant features selected by the Pearson's coefficient correlation, the Hierarchical Ascendant Classification (HAC) was applied and generated 3 clusters of writers. The characterization of these clusters was carried out by using the quantitative and qualitative parameters. The obtained results show that the combination of these two aspects can discriminate at best PD patients from HCs.〈/p〉〈/div〉

Description: 〈p〉Publication date: September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1863, Issue 9〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1861, Issue 9〈/p〉 〈p〉Author(s): Oumaima Et-Thakafy, Fanny Guyomarc'h, Christelle Lopez〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The biological membrane surrounding milk fat globules (MFGM) exhibits lateral phase separation of lipids, interpreted as gel or liquid-ordered phase sphingomyelin-rich (milk SM) domains dispersed in a fluid continuous lipid phase. The objective of this study was to investigate whether changes in the phase state of milk SM-rich domains induced by temperature (T 〈 Tm or T 〉 Tm) or cholesterol affected the Young modulus of the lipid membrane. Supported lipid bilayers composed of MFGM polar lipids, milk SM or milk SM/cholesterol (50:50 mol) were investigated at 20 °C and 50 °C using atomic force microscopy (AFM) and force spectroscopy. At 20 °C, gel-phase SM-rich domains and the surrounding fluid phase of the MFGM polar lipids exhibited Young modulus values of 10–20 MPa and 4–6 MPa, respectively. Upon heating at 50 °C, the milk SM-rich domains in MFGM bilayers as well as pure milk SM bilayers melted, leading to the formation of a homogeneous membrane with similar Young modulus values to that of a fluid phase (0–5 MPa). Upon addition of cholesterol to the milk SM to reach 50:50 mol%, membranes in the liquid-ordered phase exhibited Young modulus values of a few MPa, at either 20 or 50 °C. This indicated that the presence of cholesterol fluidized milk SM membranes and that the Young modulus was weakly affected by the temperature. These results open perspectives for the development of milk polar lipid based vesicles with modulated mechanical 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-S0005273619301555-ga1.jpg" width="317" alt="Unlabelled Image" title="Unlabelled Image"〉〈/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: August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Journal of Magnetic Resonance, Volume 305〈/p〉 〈p〉Author(s): A. Gallo, W.T. Franks, J.R. Lewandowski〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉We present a suite of two-receiver solid-state NMR experiments for backbone and side chain resonance assignment. The experiments rely on either dipolar coupling or scalar coupling for polarization transfer and are devised to acquire a 〈sup〉1〈/sup〉H–detected 3D experiment AND a nested 〈sup〉13〈/sup〉C–detected 2D from a shared excitation pulse. In order to compensate for the lower sensitivity of detection on 〈sup〉13〈/sup〉C nucleus, 2D rows are signal averaged during 3D planes. The 3D dual receiver experiments do not suffer from any appreciable signal loss compared to their single receiver versions and require no extra optimization. The resulting data is higher in information content with no additional experiment time. The approach is expected to become widespread as multiple receivers become standard for new NMR spectrometers.〈/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-S1090780719301302-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Journal of Magnetic Resonance, Volume 305〈/p〉 〈p〉Author(s): Ibrahim A. Elabyad, M. Terekhov, M.R. Stefanescu, D. Lohr, M. Fischer, L.M. Schreiber〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The design, simulation, assembly and testing of a novel dedicated antisymmetric transmit/receive (Tx/Rx) coil array to demonstrate the feasibility of cardiac magnetic resonance imaging (cMRI) in pigs at 7 T was described. The novel antisymmetric array is composed of eight elements based on mirrored and reversed loop orientations to generate varying 〈math xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si1.svg"〉〈mrow〉〈msubsup〉〈mi〉B〈/mi〉〈mrow〉〈mn〉1〈/mn〉〈/mrow〉〈mo〉+〈/mo〉〈/msubsup〉〈/mrow〉〈/math〉 field harmonics for RF shimming. The central four loop elements formed together a pair of antisymmetric L-shaped channels to allow good decoupling between all neighboring elements of the entire array. The antisymmetric array was compared to a standard symmetric rectilinear loop array with an identical housing dimension. Both arrays were driven in the parallel transmit (pTx) mode forming an 8-channel transmit and 16-channel receive (8Tx/16Rx) coil array, where the same posterior array was combined with both anterior arrays. The hardware and imaging performance of the dedicated cardiac arrays were validated and compared by means of electromagnetic (EM) simulations, bench-top measurements, phantom, and 〈em〉ex-vivo〈/em〉 MRI experiments with 46 kg female pig. Combined signal-to-noise ratio (SNR), geometry factor (g-factor), noise correlation maps, and high resolution 〈em〉ex-vivo〈/em〉 cardiac images were acquired with an in-plane resolution of 0.3 mm × 0.3 mm using both arrays. The novel antisymmetric array enhanced the SNR within the heart by about two times and demonstrated good decoupling and improved control of the 〈math xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si1.svg"〉〈mrow〉〈msubsup〉〈mi〉B〈/mi〉〈mrow〉〈mn〉1〈/mn〉〈/mrow〉〈mo〉+〈/mo〉〈/msubsup〉〈/mrow〉〈/math〉 field distributions for RF shimming compared to the standard coil array. Parallel imaging with acceleration factor (R) up to 4 was possible using the novel antisymmetric coil array while maintaining the mean g-factor within the heart region of 1.13.〈/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-S1090780719301284-ga1.jpg" width="356" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 6 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Experimental Cell Research〈/p〉 〈p〉Author(s): Yan Zhang, Hongyan Wang, Tao Yin, Yue Liu, Wenchao Zhou, Xinbin Fan, Liang Wu, Chao Song, Jin Shao, Tieyi Yang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Transmembrane protein 18 (〈em〉Tmem18〈/em〉) is an obesity-associated gene essential for adipogenesis; however, its function in the osteogenic differentiation of bone marrow–derived mesenchymal stem cells (BMSCs) is still unclear. In this study, we found that 〈em〉Tmem18〈/em〉 was significantly downregulated in rat BMSCs after osteogenic induction. TMEM18 overexpression remarkably downregulated osteo-specific genes including alkaline phosphatase (〈em〉Alp〈/em〉), Runt˗related transcription factor 2 (〈em〉Runx2〈/em〉), osteocalcin (〈em〉Ocn〈/em〉), and osteopontin (〈em〉Opn〈/em〉), and reduced the number of mineral deposits and ALP activity 〈em〉in vitro〈/em〉, whereas knockdown of 〈em〉Tmem18〈/em〉 yielded the opposite results. 〈em〉In vivo〈/em〉 assays also indicated that TMEM18 knockdown BMSCs have an increased bone formation potential in a rat model of calvarial defects. Analyses of the mechanism suggested that TMEM18 overexpression decreased β-catenin expression, whereas the TMEM18 knockdown enhanced β-catenin expression and promoted its nuclear translocation. The positive effects on osteogenic differentiation of rat BMSCs owing to the TMEM18 knockdown were attenuated by β-catenin downregulation. Taken together, these results indicate that TMEM18 plays an inhibitory role in osteogenic differentiation of BMSCs via inactivation of β-catenin.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Experimental Cell Research〈/p〉 〈p〉Author(s): Olaf Strømme, Katarzyna M. Psonka-Antonczyk, Bjørn Torger Stokke, Anders Sundan, Carl-Jørgen Arum, Gaute Brede〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Multiple myeloma is an incurable cancer of antibody-producing plasma cells. Hepatocyte growth factor (HGF), a cytokine aberrantly expressed in half of myeloma patients, is involved in myeloma pathogenesis by enhancing myeloma growth and invasiveness, and may play a role in myeloma bone disease by inhibiting osteoblastogenesis. In this study, we investigated whether extracellular vesicles (EVs) may play a role in HGF signaling between myeloma cells and osteoblast-like target cells. EVs from the HGF-positive cell line JJN-3 and the HGF-negative cell line INA-6, and from bone marrow plasma and primary human myeloma cells, were isolated using sequential centrifugation techniques and the presence of HGF on the EV-surface was investigated with ELISA. EVs from both cell lines were added to an established bioassay where HGF is known to induce interleukin-11 secretion in osteoblast-like cells. Our results show that HGF was bound to the surface of JJN-3-derived EVs, while INA-6-derived EVs were negative for HGF. Only JJN-3-derived EVs induced IL-11 secretion in osteoblast-like recipient cells. When osteoblast-like cells were preincubated with a specific HGF-receptor (c-Met) inhibitor, no induction of interleukin-11 was observed. Downstream c-Met phosphorylation was demonstrated by immunoblotting. EVs isolated from bone marrow plasma and primary myeloma cells were HGF-positive for a subset of myeloma patients. Taken together, this work shows for the first time that HGF bound on the surface of myeloma-derived EVs can effectuate HGF/c-Met signaling in osteoblast-like cells. Myeloma-derived EVs may play a role in myeloma bone disease by induction of the osteoclast-activating cytokine interleukin-11 in osteoblasts.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0014482719303313-fx1.jpg" width="280" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Experimental Cell Research〈/p〉 〈p〉Author(s): Kepeng Ou, Sonja Mertsch, Sofia Theodoropoulou, Jiahui Wu, Jian Liu, David A. Copland, Stefan Schrader, Lei Liu, Andrew D. Dick〈/p〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 218〈/p〉 〈p〉Author(s): Yuwei Liu, Biao Kuang, Benjamin B. Rothrauff, Rocky S. Tuan, Hang Lin〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mesenchymal stem cells (MSCs) embedded in their secreted extracellular matrix (mECM) constitute an exogenous scaffold-free construct capable of generating different types of tissues. Whether MSC-mECM constructs can recapitulate endochondral ossification (ECO), a developmental process during 〈em〉in vivo〈/em〉 skeletogenesis, remains unknown. In this study, MSC-mECM constructs are shown to result in robust bone formation both 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉 through the process of endochondral ossification when sequentially exposed to chondrogenic and osteogenic cues. Of interest, a novel trypsin pre-treatment was introduced to change cell morphology, which allowed MSC-mECM constructs to undergo the N-cadherin-mediated developmental condensation process and subsequent chondrogenesis. Furthermore, bone formation by MSC-mECM constructs were significantly enhanced by the ECO protocol, as compared to conventional 〈em〉in vitro〈/em〉 culture in osteogenic medium alone. This was designed to promote direct bone formation as seen in intramembranous ossification (IMO). The developmentally informed method reported in this study represents a robust and efficacious approach for stem-cell based bone generation, which is superior to the conventional osteogenic induction procedure.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Gyeong Han Jeong, Jae-Hyeon Cho, Tae Hoon Kim〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Convenient structure modification of (+)-catechin (〈strong〉1〈/strong〉) induced by nonthermal dielectric barrier discharge (DBD) plasma treatment afforded three novel methylene-linked flavan-3-ol oligomers, methylenetetracatechin (〈strong〉2〈/strong〉), methylenetricatechin (〈strong〉3〈/strong〉), and methylenedicatechin (〈strong〉4〈/strong〉), together with two known catechin dimers, 〈em〉bis〈/em〉 8,8′-catechinylmethane (〈strong〉5〈/strong〉) and 〈em〉bis〈/em〉 6,8′-catechinylmethane (〈strong〉6〈/strong〉). The structures of the three new catechin oligomers 〈strong〉2〈/strong〉–〈strong〉4〈/strong〉 with methylene bridges were elucidated by detailed 1D- and 2D-NMR analysis, and the absolute configurations were established by the observation of circular dichroism (CD). The novel products 〈strong〉2〈/strong〉 and 〈strong〉3〈/strong〉 showed significantly enhanced anti-adipogenic capacities against both pancreatic lipase and differentiation of 3T3-L1 preadipocytes compared to the parent (+)-catechin.〈/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-S0960894X19304536-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): 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: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Yasushi Ogasawara, Yo Nakagawa, Chitose Maruyama, Yoshimitsu Hamano, Tohru Dairi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mitomycins, produced by several 〈em〉Streptomyces〈/em〉 strains, are potent anticancer antibiotics that comprise an aziridine ring fused to a tricyclic mitosane core. Mitomycins have remarkable ability to crosslink DNA with high efficiency. Despite long clinical history of mitomycin C, the biosynthesis of mitomycins, especially mitosane core formation, remains unknown. Here, we report 〈em〉in vitro〈/em〉 characterization of three proteins, MmcB (acyl carrier protein), MitE (acyl AMP ligase), and MitB (glycosyltransferase) involved in mitosane core formation. We show that 3-amino-5-hydroxybenzoic acid (AHBA) is first loaded onto MmcB by MitE at the expense of ATP. MitB then catalyzes glycosylation of AHBA-MmcB with uridine diphosphate-〈em〉N〈/em〉-acetylglucosamine (UDP-GlcNAc) to generate a key intermediate, GlcNAc-AHBA-MmcB, which contains all carbon and nitrogen atoms of the mitosane core. These results provide important insight into mitomycin biosynthesis.〈/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-S0960894X19304548-ga1.jpg" width="490" 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〉 Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1861, Issue 9〈/p〉 〈p〉Author(s): Anargyros Doukas, Ekaterini Karena, Maria Botou, Konstantinos Papakostas, Amalia Papadaki, Olympia Tziouvara, Evaggelia Xingi, Stathis Frillingos, Haralabia Boleti〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Recombinant expression systems for mammalian membrane transport proteins are often limited by insufficient yields to support structural studies, inadequate post-translational processing and problems related with improper membrane targeting or cytotoxicity. Use of alternative expression systems and optimization of expression/purification protocols are constantly needed. In this work, we explore the applicability of the laboratory strain LEXSY of the ancient eukaryotic microorganism 〈em〉Leishmania tarentolae〈/em〉 as a new expression system for mammalian nucleobase permeases of the NAT/NCS2 (Nucleobase-Ascorbate Transporter/Nucleobase-Cation Symporter-2) family. We achieved the heterologous expression of the purine-pyrimidine permease rSNBT1 from 〈em〉Rattus norvegicus〈/em〉 (tagged at C-terminus with a red fluorescent protein), as confirmed by confocal microscopy and biochemical analysis of the subcellular fractions enriched in membrane proteins. The cDNA of rSNBT1 has been subcloned in a pLEXSY-〈em〉sat-mrfp1〈/em〉vector and used to generate transgenic 〈em〉L〈/em〉. 〈em〉tarentolae-rsnbt1-mrfp1〈/em〉 strains carrying the pLEXSY-sat-〈em〉rsnbt1-mrfp1〈/em〉 plasmid either episomally or integrated in the chromosomal DNA. The chimeric transporter rSNBT1-mRFP1 is targeted to the ER and the plasma membrane of the 〈em〉L〈/em〉. 〈em〉tarentolae〈/em〉 promastigotes. The transgenic strains are capable of transporting nucleobases that are substrates of rSNBT1 but also of the endogenous 〈em〉L〈/em〉. 〈em〉tarentolae〈/em〉 nucleoside/nucleobase transporters. A dipyridamole-resistant Na〈sup〉+〈/sup〉-dependent fraction of uptake is attributed to the exogenously expressed rSNBT1.〈/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-S0005273619301452-ga1.jpg" width="500" alt="Unlabelled Image" title="Unlabelled Image"〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: October 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 168〈/p〉 〈p〉Author(s): Daniel Lavall, Nadine Jacobs, Felix Mahfoud, Peter Kolkhof, Michael Böhm, Ulrich Laufs〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mineralocorticoid receptor (MR) overactivation promotes cardiac fibrosis. We studied the ability of the non-steroidal MR antagonist finerenone to prevent fibrotic remodeling. In neonatal rat cardiac fibroblasts, finerenone prevented aldosterone-induced nuclear MR translocation. Treatment with finerenone decreased the expression of connective tissue growth factor (CTGF) (74 ± 15% of control, p = 0.005) and prevented aldosterone-induced upregulation of CTGF and lysyl oxidase (LOX) completely. Finerenone attenuated the upregulation of transforming growth factor ß (TGF-ß), which was induced by the Rac1 GTPase activator 〈span〉l〈/span〉-buthionine sulfoximine. Transgenic mice with cardiac-specific overexpression of Rac1 (RacET) showed increased left ventricular (LV) end-diastolic (63.7 ± 8.0 vs. 93.8 ± 25.6 µl, p = 0.027) and end-systolic (28.0 ± 4.0 vs. 49.5 ± 16.7 µl, p = 0.014) volumes compared to wild-type FVBN control mice. Treatment of RacET mice with 100 ppm finerenone over 5 months prevented LV dilatation. Systolic and diastolic LV function did not differ between the three groups. RacET mice exhibited overactivation of MR and 11ß hydroxysteroid dehydrogenase type 2. Both effects were reduced by finerenone (reduction about 36%, p = 0.030, and 40%, p = 0.032, respectively). RacET mice demonstrated overexpression of TGF-ß, CTGF, LOX, osteopontin as well as collagen and myocardial fibrosis in the left ventricle. In contrast, expression of these parameters did not differ between finerenone-treated RacET and control mice. Finerenone prevented left atrial dilatation (6.4 ± 1.5 vs. 4.7 ± 1.4 mg, p = 0.004) and left atrial fibrosis (17.8 ± 3.1 vs. 12.8 ± 3.1%, p = 0.046) compared to vehicle-treated RacET mice. In summary, finerenone prevented from MR-mediated structural remodeling in cardiac fibroblasts and in RacET mice. These data demonstrate anti-fibrotic myocardial effects of finerenone.〈/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-S0006295219302564-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〉 Cellular Signalling, Volume 62〈/p〉 〈p〉Author(s): Vitor de Miranda Ramos, Juciano Gasparotto, Fabrício Figueiró, Amanda de Fraga Dias, Diana Carolina Rostirolla, Nauana Somensi, Helen Tais da Rosa, Lucas Kich Grun, Florencia María Barbé-Tuana, Daniel Pens Gelain, José Cláudio Fonseca Moreira〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Recent studies have investigated the use of retinoic acid (RA) molecule in combined chemotherapies to cancer cells as an attempt to increase treatment efficiency and circumvent cell resistance. Positive results were obtained in clinical trials from lung cancer patients treated with RA and cisplatin. Meanwhile, the signalling process that results from the interaction of both molecules remains unclear. One of the pathways that RA is able to modulate is the activity of NRF2 transcription factor, which is highly associated with tumour progression and resistance. Therefore, the aim of this work was to investigate molecular mechanism of RA and cisplatin co-treatment in A549 cells, focusing in NRF2 pathway. To this end, we investigated NRF2 and NRF2-target genes expression, cellular redox status, cisplatin-induced apoptosis, autophagy and DNA repair through homologous recombination. RA demonstrated to have an inhibitory effect over NRF2 activation, which regulates the expression of thiol antioxidants enzymes. Moreover, RA increased reactive species production associated with increased oxidation of thiol groups within the cells. The expression of proteins associated with DNA repair through homologous recombination was also suppressed by RA pre-treatment. All combined, these effects appear to create a more sensitive cellular environment to cisplatin treatment, increasing apoptosis frequency. Interestingly, autophagy was also increased by combination therapy, suggesting a resistance mechanism by A549 cells. In conclusion, these results provided new information about molecular mechanisms of RA and cisplatin treatment contributing to chemotherapy optimization.〈/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-S0898656819301524-ga1.jpg" width="487" alt="Unlabelled Image" title="Unlabelled Image"〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Methods〈/p〉 〈p〉Author(s): Athanasia Mizi, Eduardo Gade Gusmao, Argyris Papantonis〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Genome organization is now understood to be tightly linked to all genomic functions. Thus, the high-resolution mapping of higher-order chromosomal structures via 3C-based approaches has become an integral tool for studying transcriptional and cell cycle regulation, signaling effects or disease onset. Nonetheless, 3C-based protocols are not without caveats, like dependencies on fixation conditions, restriction enzyme pervasiveness in crosslinked chromatin and ligation efficiency. To address some of these caveats, we describe here the streamlined iHi-C 2.0 protocol that allows for the genome-wide interrogation of native spatial chromatin contacts without a need for chemical fixation. This approach improves ligation efficiency and presents minimal material losses, and is thus suitable for analysing samples with limiting cell numbers. Following high throughput sequencing, iHi-C 2.0 generates high signal-to-noise and focal maps of the interactions within and between mammalian chromosomes under native conditions.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: November 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Computers & Geosciences, Volume 132〈/p〉 〈p〉Author(s): Hongxing Zhang, Mingliang Zhang, Yongpeng Ji, Yini Wang, Tianping Xu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Vegetation exerts a significant damping effect on tsunami wave run-up on coastal beaches, thus effectively mitigating the tsunami hazard. A depth-integrated two-dimensional numerical model (HydroSed2D, Liu et al., 2008; Liu et al., 2010) is developed to investigate tsunami wave run-up and land inundation on coastal beaches covered with 〈em〉Pandanus odoratissimus〈/em〉 (〈em〉P. odoratissimus〈/em〉). The present model is based on a finite volume Roe-type scheme, that solves the non-linear shallow water equations with the capacity of treating the wet or dry boundary at the wave front. The momentum equations in this model are modified by adding a drag force term, thus considering the resistance effects of vegetation on tsunami waves. The accuracy of the numerical scheme and the vegetation drag force are validated by three experimental cases of dam-break flow propagation in a dry channel, solitary wave propagation in a vegetated flume, and tsunami run-up over an uneven bed. Subsequently, a numerical model is applied to simulate tsunami run-up and land inundation on actual-scale vegetated beaches and a series of sensitive analyses are conducted by comparing numerical results. The obtained numerical results suggest that 〈em〉P. odoratissimus〈/em〉 can effectively attenuate tsunami run-up and land inundation distance on coastal beaches, and a higher attenuation rate for tsunami wave can be achieved by increasing both vegetation width and vegetation density. The tsunami wave height is also an important factor that impacts the tsunami wave run-up and land inundation on vegetated beaches.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: July–December 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 SoftwareX, Volume 10〈/p〉 〈p〉Author(s): R.D. Martin, Q. Cai, T. Garrow, C. Kapahi〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉QExpy is an open source python-3 module that was developed in order to simplify the analysis of data in undergraduate physics laboratories. Through the use of this module, students can focus their time on understanding the science and the data from their experiments, rather than on processing their data. In particular, the module allows users to easily propagate uncertainties from measured quantities using a variety of techniques (derivatives, Monte Carlo), as well as to plot and fit functions to data. The interface is designed to be pedagogical so that students with no prior programming experience can be eased into using python in their introductory physics laboratories.〈/p〉〈/div〉

Description: 〈p〉Publication date: July–December 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 SoftwareX, Volume 10〈/p〉 〈p〉Author(s): Simon Behrendt, Thomas Dimpfl, Franziska J. Peter, David J. Zimmermann〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉This paper shows how to quantify and test for the information flow between two time series with Shannon transfer entropy and Rényi transfer entropy using the 〈math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" altimg="si1.svg"〉〈mi〉R〈/mi〉〈/math〉 package 〈em〉RTransferEntropy〈/em〉. We discuss the methodology, the bias correction applied to calculate effective transfer entropy and outline how to conduct statistical inference. Furthermore, we describe the package in detail and demonstrate its functionality by means of several simulated processes and present an application to financial time series.〈/p〉〈/div〉

Description: 〈p〉Publication date: July–December 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 SoftwareX, Volume 10〈/p〉 〈p〉Author(s): Jacob L. Moore, Nathaniel R. Morgan, Mark F. Horstemeyer〈/p〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉We discuss the creation and implementation of a generalized library, named ELEMENTS, of mathematical functions for supporting a very broad range of element types including: linear, quadratic, and cubic serendipity elements in 2D and 3D; high-order spectral elements; and a linear 4D element. The ELEMENTS library can be used for research and development of both continuous and discontinuous finite element methods for solving a diverse range of partial differential equations. The library has functions for calculating quantities that are commonly used in finite element methods such as the gradient of a basis function, the Jacobi matrix, the inverse Jacobi matrix, the determinant of the Jacobi matrix, and a physical position inside the element, to name a few examples. The library also supports both Gauss–Legendre and Gauss–Lobatto quadrature rules up to 8 quadrature points in each coordinate direction. The examples and discussions in this paper will focus on Lagrangian solid mechanics and dynamics, but ELEMENTS can be used for many other applications.〈/p〉〈/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: Clinical Pharmacology &Therapeutics, EarlyView.

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: Available online 4 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Hiroyuki Miyachi, Tomohiro Yuzuriha, Ryotaro Tabata, Syohei Fukuda, Kazuto Nunomura, Bangzhong Lin, Tadayuki Kobayashi, Kenji Ishimoto, Takefumi Doi, Keisuke Tachibana〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉We previously reported that 1〈em〉H〈/em〉-pyrazolo-[3,4-〈em〉b〈/em〉]pyridine-4-carboxylic acid derivative 〈strong〉6〈/strong〉 is an agonist of human peroxisome proliferator-activated receptor alpha (hPPARα). Here, we prepared a series of 1〈em〉H〈/em〉-pyrazolo-[3,4-〈em〉b〈/em〉]pyridine-4-carboxylic acid derivatives in order to examine the structure-activity relationships (SAR). SAR studies clearly indicated that the steric bulkiness of the substituent on 1〈em〉H〈/em〉-pyrazolo-[3,4-〈em〉b〈/em〉]pyridine ring, the position of the distal hydrophobic tail part, and the distance between the distal hydrophobic tail part and the acidic head part are critical for hPPARα agonistic activity. These SAR results are somewhat different from those reported for fibrate-class hPPARα agonists. A representative compound (〈strong〉10f〈/strong〉) was as effective as fenofibrate in reducing the elevated plasma triglyceride levels in a high-fructose-fed rat model.〈/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-S0960894X19304445-ga1.jpg" width="408" 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: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Trends in Neurosciences〈/p〉 〈p〉Author(s): Ruslan Rust, Lisa Grönnert, Rebecca Zoe Weber, Geertje Mulders, Martin E. Schwab〈/p〉 〈div xml:lang="en"〉〈div〉〈p〉Stroke patients have only limited therapeutic options and often remain with considerable disabilities. To promote neurological recovery, angiogenesis in the ischemic peri-infarct region has been recognized as an encouraging therapeutic target. Despite advances in mechanistic understanding of vascular growth and repair, effective and safe angiogenic treatments are currently missing. Besides the most intensively studied angiogenic growth factors, recent research has indicated that the process of vascular sprouting and migration also requires the participation of guidance molecules, many of which were initially identified as regulators of axonal growth. Here, we review the inhibitory and growth-promoting effects of guidance molecules on the vascular system and discuss their potential as novel angiogenic targets for neurovascular diseases.〈/p〉〈/div〉〈/div〉

Description: 〈p〉Publication date: November 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Protein Expression and Purification, Volume 163〈/p〉 〈p〉Author(s): Derrick Afful, Liming Cai, Cory Momany〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The bacterial RNA polymerase (RNAP) is a large, complex molecular machine that is the engine of gene expression. Despite global conservation in their structures and function, RNAPs from different bacteria can have unique features in promoter and transcription factor recognition. Therefore, availability of purified RNAP from different bacteria is key to understanding these species-specific aspects and will be valuable for antibiotic drug discovery. 〈em〉Pseudomonas aeruginosa〈/em〉 is one of the leading causes of hospital and community acquired infections worldwide - making the organism an important public health pathogen. We developed a method for producing high quantities of highly pure and active recombinant 〈em〉P. aeruginosa〈/em〉 str. PAO1 RNAP core and holoenzyme complexes that employed two-vector systems for expressing the core enzyme (α, β, β’, and ω subunits) and for expressing the holoenzyme complex (core + σ〈sup〉70〈/sup〉). Unlike other RNAP expression approaches, we used a low temperature autoinduction system in 〈em〉E. coli〈/em〉 with T7 promoters that produced high cell yields and stable protein expression. The purification strategy comprised of four chromatographic separation steps (metal chelate, heparin, and ion-exchange) with yields of up to 11 mg per 500 mL culture. Purified holoenzyme and reconstituted holoenzyme from core and σ〈sup〉70〈/sup〉 were highly active at transcribing both small and large-sized DNA templates, with a determined elongation rate of ~18 nt/s for the holoenzyme. The successful purification of the 〈em〉P. aeruginosa〈/em〉 RNAP provides a gateway for studies focusing on 〈em〉in vitro〈/em〉 transcriptional regulation in this pathogen.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Journal of Magnetic Resonance, Volume 305〈/p〉 〈p〉Author(s): Michael Mullen, Alexander Gutierrez, Naoharu Kobayashi, Jarvis Haupt, Michael Garwood〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Large magnetic field inhomogeneity can be a significant cause of spatial flip-angle variation when using ordinary, limited-bandwidth RF pulses. Multidimensional RF pulses are particularly sensitive to inhomogeneity due to their extended pulse length, which decreases their bandwidth. Previously, it was shown that, by breaking a 2D pulse into multiple undersampled k-space segments, the excitation bandwidth can be increased at the expense of increased imaging time. The present study shows how this increased imaging time can be offset by undersampling acquisition k-space in a phase-encoded dimension that is in the direction of excitation segmentation. Data from each segment are viewed as originating from “virtual receive coils” rather than multiple physical coils. The undersampled data are reconstructed using parallel imaging techniques (e.g. as in GRAPPA). The method was tested in vivo with brain imaging at both 3 T and 4 T, and used in conjunction with a 32-channel head coil and conventional GRAPPA on the 3 T data. Relationships with existing techniques and future applications are 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-S1090780719301259-ga1.jpg" width="366" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉