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https://www.readbyqxmd.com/read/28747667/rna-sequencing-reveals-resistance-of-tlr4-ligand-activated-microglial-cells-to-inflammation-mediated-by-the-selective-jumonji-h3k27-demethylase-inhibitor
#1
Amitabh Das, Sarder Arifuzzaman, Taeho Yoon, Sun Hwa Kim, Jin Choul Chai, Young Seek Lee, Kyoung Hwa Jung, Young Gyu Chai
Persistent microglial activation is associated with the production and secretion of various pro-inflammatory genes, cytokines and chemokines, which may initiate or amplify neurodegenerative diseases. A novel synthetic histone 3 lysine 27 (H3K27) demethylase JMJD3 inhibitor, GSK-J4, was proven to exert immunosuppressive activities in macrophages. However, a genome-wide search for GSK-J4 molecular targets has not been undertaken in microglia. To study the immuno-modulatory effects of GSK-J4 at the transcriptomic level, triplicate RNA sequencing and quantitative real-time PCR analyses were performed with resting, GSK-J4-, LPS- and LPS + GSK-J4-challenged primary microglial (PM) and BV-2 microglial cells...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28747658/a-single-amino-acid-substitution-confers-b-cell-clonogenic-activity-to-the-hiv-1-matrix-protein-p17
#2
Cinzia Giagulli, Pasqualina D'Ursi, Wangxiao He, Simone Zorzan, Francesca Caccuri, Kristen Varney, Alessandro Orro, Stefania Marsico, Benoît Otjacques, Carlo Laudanna, Luciano Milanesi, Riccardo Dolcetti, Simona Fiorentini, Wuyuan Lu, Arnaldo Caruso
Recent data highlight the presence, in HIV-1-seropositive patients with lymphoma, of p17 variants (vp17s) endowed with B-cell clonogenicity, suggesting a role of vp17s in lymphomagenesis. We investigated the mechanisms responsible for the functional disparity on B cells between a wild-type p17 (refp17) and a vp17 named S75X. Here, we show that a single Arginine (R) to Glycine (G) mutation at position 76 in the refp17 backbone (p17R76G), as in the S75X variant, is per se sufficient to confer a B-cell clonogenic potential to the viral protein and modulate, through activation of the PTEN/PI3K/Akt signaling pathway, different molecules involved in apoptosis inhibition (CASP-9, CASP-7, DFF-45, NPM, YWHAZ, Src, PAX2, MAPK8), cell cycle promotion and cancer progression (CDK1, CDK2, CDK8, CHEK1, CHEK2, GSK-3 beta, NPM, PAK1, PP2C-alpha)...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28747563/the-h3k27me3-demethylase-kdm6a-is-suppressed-in-breast-cancer-stem-like-cells-and-enables-the-resolution-of-bivalency-during-the-mesenchymal-epithelial-transition
#3
Joseph H Taube, Nathalie Sphyris, Kelsey S Johnson, Keighley N Reisenauer, Taylor A Nesbit, Robiya Joseph, Geraldine V Vijay, Tapasree R Sarkar, Neeraja A Bhangre, Joon Jin Song, Jeffrey T Chang, Min Gyu Lee, Rama Soundararajan, Sendurai A Mani
The deposition of the activating H3K4me3 and repressive H3K27me3 histone modifications within the same promoter, forming a so-called bivalent domain, maintains gene expression in a repressed but transcription-ready state. We recently reported a significantly increased incidence of bivalency following an epithelial-mesenchymal transition (EMT), a process associated with the initiation of the metastatic cascade. The reverse process, known as the mesenchymal-epithelial transition (MET), is necessary for efficient colonization...
July 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28742189/novel-endogenous-negative-modulators-of-platelet-function-as-potential-anti-thrombotic-targets
#4
Y-J Li, H-X Zhu, D Zhang, H-C Li, P Ma, L-Y Huang
Platelets are megakaryocyte-derived nuclear-free fragments that participate in cardiovascular diseases including acute myocardial infarction, ischemic stroke, hypertension, and atherosclerosis. At the endothelium damage site, platelets interact with sub-endothelial matrix proteins such as glycoprotein VI/Fc receptor γ-chain (GPVI/FcRγ), G protein-coupled receptor/phospholipase Cγ(β) (GPCR/PLCγ(β)), Rho/RhoK and integrin. The activation of these signaling pathways triggers intracellular calcium increase and causes platelet adhesion, aggregation, granule release and finally thrombus formation...
July 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28741112/investigation-of-naphthofuran-moiety-as-potential-dual-inhibitor-against-bace-1-and-gsk-3%C3%AE-molecular-dynamics-simulations-binding-energy-and-network-analysis-to-identify-first-in-class-dual-inhibitors-against-alzheimer-s-disease
#5
Akhil Kumar, Gaurava Srivastava, Swati Srivastava, Seema Verma, Arvind S Negi, Ashok Sharma
BACE-1 and GSK-3β are potential therapeutic drug targets for Alzheimer's disease. Recently, both the targets received attention for designing dual inhibitors for Alzheimer's disease. Until now, only two-scaffold triazinone and curcumin have been reported as BACE-1 and GSK-3β dual inhibitors. Docking, molecular dynamics, clustering, binding energy, and network analysis of triazinone derivatives with BACE-1 and GSK-3β was performed to get molecular insight into the first reported dual inhibitor. Further, we designed and evaluated a naphthofuran series for its ability to inhibit BACE-1 and GSK-3β with the computational approaches...
August 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28738501/inhibition-of-glycogen-synthase-kinase-3-increased-subventricular-zone-stem-cells-proliferation
#6
Narges Pachenari, Sahar Kiani, Mohammad Javan
The effects of Wnt signaling modifiers on cell proliferation, seem to be cell specific. Enhancing the proliferation of subventricular zone (SVZ) progenitors has been in the focus of research in recent years. Here we investigate the effect of CHIR99021, a Glycogen Synthase Kinase 3 (GSk-3) inhibitor, on SVZ progenitor's proliferation both in vivo and in vitro. Neural stem cells were extracted from the adult C57bl/6 by mincing and trypsin treatment followed by culturing in specific medium. Sphere cells formed within about 7-10days and were characterized by immunostaining...
July 18, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28737627/direct-and-indirect-effectiveness-of-the-ten-valent-pneumococcal-conjugate-vaccine-against-carriage-in-a-cluster-randomized-trial
#7
Arto A Palmu, Maija Toropainen, Tarja Kaijalainen, Lotta Siira, Mika Lahdenkari, Heta Nieminen, Ritva K Syrjänen, Terhi M Kilpi, Jukka Jokinen
Finnish Invasive Pneumococcal disease (FinIP) vaccine trial was designed to evaluate effectiveness of ten-valent pneumococcal conjugate vaccine (PHiD-CV10, GSK). We conducted two satellite studies to evaluate PHiD-CV10 effectiveness against pneumococcal carriage in FinIP-vaccinated children (long-term direct and indirect effectiveness combined) and in their unvaccinated siblings (indirect effectiveness within the family).FinIP was a cluster-randomized trial, where >47000 children <19 months of age were recruited 2009-2010...
July 21, 2017: Pediatric Infectious Disease Journal
https://www.readbyqxmd.com/read/28736149/methylmercury-augments-nrf2-activity-by-downregulation-of-the-src-family-kinase-fyn
#8
Megan Culbreth, Ziyan Zhang, Michael Aschner
Methylmercury (MeHg) is a potent developmental neurotoxicant that induces an oxidative stress response in the brain. It has been demonstrated that MeHg exposure increases nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Nrf2 is a transcription factor that translocates to the nucleus in response to oxidative stress, and upregulates phase II detoxifying enzymes. Although, Nrf2 activity is augmented subsequent to MeHg exposure, it has yet to be established whether Nrf2 moves into the nucleus as a result...
July 20, 2017: Neurotoxicology
https://www.readbyqxmd.com/read/28735965/safety-profile-and-immunologic-responses-of-a-novel-vaccine-against-shigella-sonnei-administered-intramuscularly-intradermally-and-intranasally-results-from-two-parallel-randomized-phase-1-clinical-studies-in-healthy-adult-volunteers-in-europe
#9
Odile Launay, David J M Lewis, Alessandra Anemona, Pierre Loulergue, Jo Leahy, Antonella Silvia Sciré, Anaïs Maugard, Elisa Marchetti, Stefano Zancan, Zhiming Huo, Simona Rondini, Rachid Marhaba, Oretta Finco, Laura B Martin, Jochen Auerbach, Daniel Cohen, Allan Saul, Christiane Gerke, Audino Podda
BACKGROUND: Approximately 164,000 deaths yearly are due to shigellosis, primarily in developing countries. Thus, a safe and affordable Shigella vaccine is an important public health priority. The GSK Vaccines Institute for Global Health (GVGH) developed a candidate Shigella sonnei vaccine (1790GAHB) using the Generalized Modules for Membrane Antigens (GMMA) technology. The paper reports results of 1790GAHB Phase 1 studies in healthy European adults. METHODS: To evaluate the safety and immunogenicity profiles of 1790GAHB, we performed two parallel, phase 1, observer-blind, randomized, placebo-controlled, dose escalation studies in France ("study 1") and the United Kingdom ("study 2") between February 2014 and April 2015 (ClinicalTrials...
July 15, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28734998/oxidative-stress-with-tau-hyperphosphorylation-in-memory-impaired-1-2-diacetylbenzene-treated-mice
#10
Sin-Woo Kang, Sung Jin Kim, Min-Sun Kim
Long-term exposure to organic solvent may be related to the incidence of neuronal diseases, such as, Alzheimer's disease, depression, multiple sclerosis, dementia, Parkinson's disease. Previously, the authors reported 1,2-diacetylbenzene (DAB; a neurotoxic metabolite of 1,2-diethylbenzene) causes central and peripheral neuropathies that lead to motor neuronal deficits. Furthermore, it is known DAB increases oxidative stress and protein adduct levels and impairs hippocampal neurogenesis in mice. The authors examined the relevance of oxidative stress and tau hyperphosphorylation in the hippocampus...
July 19, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28732518/impact-of-the-change-of-copay-policy-in-medicare-part-d-on-zoster-vaccine-uptake-among-medicare-beneficiaries-in-a-managed-care-organization
#11
Rulin C Hechter, Lei Qian, Songkai Yan, Yi Luo, Girishanthy Krishnarajah, Hung-Fu Tseng
BACKGROUND: Kaiser Permanente Southern California (KPSC) adopted the Medicare Part D Tier-6 with zero patient copay for zoster vaccination in 2012. We assessed the impact of the implementation on zoster vaccination rate (GSK study identifier: HO-13-14,182). METHODS: Zoster vaccination rate was examined among an open cohort of ≥65-year-old Medicare Part D beneficiaries during 01/01/2008-06/30/2014, compared to ≥65-year-old commercial health plan members and 60-64-year-old members...
July 21, 2017: BMC Health Services Research
https://www.readbyqxmd.com/read/28732374/the-protective-effect-of-pft%C3%AE-on-alcohol-induced-osteonecrosis-of-the-femoral-head
#12
Yi-Xuan Chen, Dao-Yu Zhu, Jun-Hui Yin, Wen-Jing Yin, Yue-Lei Zhang, Hao Ding, Xiao-Wei Yu, Jiong Mei, You-Shui Gao, Chang-Qing Zhang
Epidemiologic studies have shown alcohol plays a pivotal role in the development of osteonecrosis of the femoral head (ONFH). The aim of this study was to explore the underlying mechanism of alcohol-induced ONFH and the protective effect of pifithrin-α (PFTα). In vitro, we found ethanol treatment significantly activated p53, suppressed Wnt/β-catenin signaling and inhibited osteogenic-related proteins. Furthermore, by separating the cytoplasmic and nuclear proteins, we found ethanol inhibited osteogenesis by impairing the accumulation of β-catenin in both the cytoplasm and nucleus in human bone mesenchymal stem cells (hBMSCs), which resulted from activating glycogen synthase kinase-3β (GSK-3β)...
July 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28731198/gsk-3%C3%AE-inhibition-suppresses-instability-induced-osteolysis-by-a-dual-action-on-osteoblast-and-osteoclast-differentiation
#13
Mehdi Amirhosseini, Rune Vinther Madsen, K Jane Escott, Mathias Bostrom, F Patrick Ross, Anna Fahlgren
Currently, there are no medications available to treat aseptic loosening of orthopedic implants. Using osteoprotegerin fusion protein (OPG-Fc), we previously blocked instability-induced osteoclast differentiation and peri-prosthetic osteolysis. Wnt/β-catenin signaling, which regulates OPG secretion from osteoblasts, also modulates the bone tissue response to mechanical loading. We hypothesized that activating Wnt/β-catenin signaling by inhibiting glycogen synthase kinase-3β (GSK-3β) would reduce instability-induced bone loss through regulation of both osteoblast and osteoclast differentiation...
July 21, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28726275/cpkc%C3%AE-mediated-down-regulation-of-uchl1-alleviates-ischaemic-neuronal-injuries-by-decreasing-autophagy-via-erk-mtor-pathway
#14
Dan Zhang, Song Han, Shizun Wang, Yanlin Luo, Li Zhao, Junfa Li
Stroke is one of the leading causes of death in the world, but its underlying mechanisms remain unclear. Both conventional protein kinase C (cPKC)γ and ubiquitin C-terminal hydrolase L1 (UCHL1) are neuron-specific proteins. In the models of 1-hr middle cerebral artery occlusion (MCAO)/24-hr reperfusion in mice and 1-hr oxygen-glucose deprivation (OGD)/24-hr reoxygenation in cortical neurons, we found that cPKCγ gene knockout remarkably aggravated ischaemic injuries and simultaneously increased the levels of cleaved (Cl)-caspase-3 and LC3-I proteolysis product LC3-II, and the ratio of TUNEL-positive cells to total neurons...
July 20, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28726150/inhibition-mechanism-of-cdk-2-and-gsk-3%C3%AE-by-a-sulfamoylphenyl-derivative-of-indoline-a-molecular-dynamics-study
#15
Przemysław Czeleń
A good understanding of the inhibition mechanism of enzymes exhibiting high levels of similarity is the first step to the discovery of new drugs with selective potential. Examples of such proteins include glycogen synthase kinase-3 (GSK-3β) and cyclin-dependent kinase 2 (CDK-2). This article reports the mechanism of such enzyme inhibition as analyzed by an indoline sulfamylophenyl derivative (CHEMBL410072). Previous work has shown that such compounds exhibit selective properties towards their biological targets...
August 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28724942/physiological-oxygen-tension-reduces-hepatocyte-dedifferentiation-in-in-vitro-culture
#16
Ren Guo, Xinxiu Xu, Yuting Lu, Xin Xie
Primary hepatocytes cultured in vitro are a powerful tool to study the functions of hepatocytes and to evaluate the metabolism and toxicity of new drugs. However, in vitro culture of hepatocytes has proven to be very difficult. Ordinary culture conditions lead to dedifferentiation of hepatocytes, resulting in rapid change in cell morphology and significant reduction in specific cell functions. In the current study, we show that hepatocyte dedifferentiation is a rapid process under 21% O2 conditions. Hepatocytes cultured in 21% O2 undergo epithelial-to-mesenchymal transition (EMT), obtain fibroblast-like morphology, and show decreased hepatic functions...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28723656/inhibitor-of-h3k27-demethylase-jmjd3-utx-gsk-j4-is-a-potential-therapeutic-option-for-castration-resistant-prostate-cancer
#17
Viacheslav M Morozov, Ying Li, Matthew M Clowers, Alexander M Ishov
Androgen receptor (AR) mediates initiation and progression of prostate cancer (PCa); AR-driven transcription is activated by binding of androgens to the ligand-binding domain (LBD) of AR. Androgen ablation therapy offers only a temporary relief of locally advanced and metastatic PCa, and the disease eventually recurs as a lethal castration-resistant PCa (CRPC) as there is no effective treatment for CRPC patients. Thus, it is critical to identify novel targeted and combinatorial regimens for clinical management of CRPC...
July 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28722477/advances-toward-lsd1-inhibitors-for-cancer-therapy
#18
Xiaoli Fu, Peng Zhang, Bin Yu
LSD1 has become an important biologically validated epigenetic target for cancer therapy since its identification in 2004. LSD1 mediates many cellular signaling pathways and is involved in the initiation and development of cancers. Aberrant overexpression of LSD1 has been observed in different types of cancers, and inactivation by small molecules suppresses cancer cell differentiation, proliferation, invasion and migration. To date, a large number of LSD1 inhibitors have been reported, RG6016, GSK-2879552, INCB059872, IMG-7289 and CC-90011 are currently undergoing clinical assessment for the treatment of acute myeloid leukemia, small-cell lung cancer, etc...
July 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28720858/gsk-3%C3%AE-deletion-in-dentate-gyrus-excitatory-neuron-impairs-synaptic-plasticity-and-memory
#19
Enjie Liu, Ao-Ji Xie, Qiuzhi Zhou, Mengzhu Li, Shujuan Zhang, Shihong Li, Weijin Wang, Xiaochuan Wang, Qun Wang, Jian-Zhi Wang
Increasing evidence suggests that glycogen synthase kinase-3β (GSK-3β) plays a crucial role in neurodegenerative/psychiatric disorders, while pan-neural knockout of GSK-3β also shows detrimental effects. Currently, the function of GSK-3β in specific type of neurons is elusive. Here, we infused AAV-CaMKII-Cre-2A-eGFP into GSK-3β(lox/lox) mice to selectively delete the kinase in excitatory neurons of hippocampal dentate gyrus (DG), and studied the effects on cognitive/psychiatric behaviors and the molecular mechanisms...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28720775/metformin-ameliorates-the-phenotype-transition-of-peritoneal-mesothelial-cells-and-peritoneal-fibrosis-via-a-modulation-of-oxidative-stress
#20
Hyun-Soo Shin, Jiyeon Ko, Dal-Ah Kim, Eun-Sun Ryu, Hye-Myung Ryu, Sun-Hee Park, Yong-Lim Kim, Eok-Soo Oh, Duk-Hee Kang
Phenotype transition of peritoneum is an early mechanism of peritoneal fibrosis. Metformin, 5'-adenosine monophosphate-activated protein kinase (AMPK) activator, has recently received a new attention due to its preventive effect on organ fibrosis and cancer metastasis by inhibiting epithelial-to-mesenchymal transition (EMT). We investigated the effect of metformin on EMT of human peritoneal mesothelial cells (HPMC) and animal model of peritoneal dialysis (PD). TGF-β1-induced EMT in HPMC was ameliorated by metformin...
July 18, 2017: Scientific Reports
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