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https://www.readbyqxmd.com/read/29775417/targeting-histone-methyltransferase-enhancer-of-zeste-homolog-2-inhibits-renal-epithelial-mesenchymal-transition-and-attenuates-renal-fibrosis
#1
Xiaoxu Zhou, Chongxiang Xiong, Evelyn Tolbert, Ting C Zhao, George Bayliss, Shougang Zhuang
Enhancer of zeste homolog-2 (EZH2) is a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types. Its role in renal epithelial-mesenchymal transition (EMT) remains unknown. In this study, we found that EZH2 and H3K27me3 were highly expressed in mouse kidney with unilateral ureteral obstruction and cultured mouse kidney proximal tubular (TKPT) cells undergoing EMT. Inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) attenuated renal fibrosis, which was associated with preserving E-cadherin expression and inhibiting Vimentin up-regulation in the obstructed kidney...
May 18, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29775416/downregulation-of-the-%C3%AE-1-and-%C3%AE-1-subunit-of-sgc-in-arterial-smooth-muscle-cells-of-opscc-is-hpv-independent
#2
Y Korkmaz, H C Roggendorf, O G Siefer, J Seehawer, T Imhof, M Plomann, W Bloch, A Friebe, C U Huebbers
The nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is a heterodimeric enzyme with an α and β subunit. NO binds to heme of the β1 -subunit of sGC, activates the enzyme in the reduced heme iron state in vascular smooth muscle cells (VSMCs), and generates cGMP-inducing vasodilatation and suppression of VSMC proliferation. In the complex tumor milieu with higher levels of reactive oxygen species (ROS), sGC heme iron may become oxidized and insensitive to NO. To change sGC from an NO-insensitive to NO-sensitive state or NO-independent manner, protein expression of sGC in VSMC is required...
May 1, 2018: Journal of Dental Research
https://www.readbyqxmd.com/read/29775310/fragment-based-discovery-of-a-potent-orally-bioavailable-inhibitor-which-modulates-the-phosphorylation-and-catalytic-activity-of-erk1-2
#3
Tom D Heightman, Valerio Berdini, Hannah Braithwaite, Ildiko Maria Buck, Megan Cassidy, Juan Castro, Aurelie Courtin, James E H Day, Charlotte East, Lynsey Fazal, Brent Graham, Charlotte M Griffiths-Jones, John F Lyons, Vanessa Martins, Sandra Muench, Joanne M Munck, David Norton, Marc O'Reilly, Nick Palmer, Puja Pathuri, Michael Reader, David C Rees, Sharna J Rich, Caroline Richardson, Harpreet Saini, Neil T Thompson, Nicola G Wallis, Hugh Walton, Nicola E Wilsher, Alison J-A Woolford, Michael Cooke, David Cousin, Stuart Onions, Jonathan Shannon, John Watts, Christopher W Murray
Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signalling through ERK1/2. Here we describe the fragment based generation of ERK1/2 inhibitors which block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity...
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29774996/-study-of-gonadotropin-releasing-hormone-on-suppressing-migrationg-and-invationg-of-human-nasopharyngeal-carcinoma-cells-cne2
#4
Y H Sun, T T Kong, T T Wang, H F Zhu, T W Zhuang, D P Wang
Objective: The aim of this study is to investigate the effect of gonadotropin releasing hormone (GnRH) on suppressing cell viability, apoptosis, migrationg and invationg of human nasopharyngeal carcinoma cells CNE2. Method: Nasopharyngeal carcinoma tissues and postnasal catarrh tissues were collected, the expression of GnRH positive cells and GnRH mRNA were detected by immunohistochemical staining and qRT-PCR. The human nasopharyngeal carcinoma CNE2 cells and immortalized nasopharyngeal epithelial cell line NP69 were cultured in vitro, and the expression of GnRH positive cells and GnRH mRNA were detected by immunohistochemical staining and qRT-PCR...
June 5, 2017: Journal of Clinical Otorhinolaryngology, Head, and Neck Surgery
https://www.readbyqxmd.com/read/29774578/the-immunobiology-of-rankl-and-myeloid-derived-suppressor-cell-activation-in-igg4-related-sclerosing-cholangitis
#5
Min Lian, Qixia Wang, Xiang Jiang, Jun Zhang, Yiran Wei, Yanmei Li, Bo Li, Weihua Chen, Haiyan Zhang, Qi Miao, Yanshen Peng, Xiao Xiao, Li Sheng, Weici Zhang, Jingyuan Fang, Ruqi Tang, M Eric Gershwin, Xiong Ma
The primary function of myeloid derived suppressor cells (MDSCs) is reflected in their immune modulatory role in several immune-mediated diseases. In IgG4-related disease (IgG4-RD), it has been hypothesized that there are selective regulatory defects that lead to a Th2 bias immune response. Herein we have taken advantage of a large cohort of patients with IgG4-related sclerosing cholangitis (IgG4-SC), the most common extra-pancreatic involvement of IgG4-RD, as well as controls consisting of primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH) and healthy volunteers, to study MDSC...
May 18, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29774027/clinical-remission-of-sight-threatening-non-infectious-uveitis-is-characterized-by-an-upregulation-of-peripheral-t-regulatory-cell-polarized-towards-t-bet-and-tigit
#6
Rose M Gilbert, Xiaozhe Zhang, Robert D Sampson, Michael R Ehrenstein, Dao X Nguyen, Mahid Chaudhry, Charles Mein, Nadiya Mahmud, Grazyna Galatowicz, Oren Tomkins-Netzer, Virginia L Calder, Sue Lightman
Background: Non-infectious uveitis can cause chronic relapsing and remitting ocular inflammation, which may require high dose systemic immunosuppression to prevent severe sight loss. It has been classically described as an autoimmune disease, mediated by pro-inflammatory Th1 and Th17 T-cell subsets. Studies suggest that natural immunosuppressive CD4+ CD25+ FoxP3+ T-regulatory cells (Tregs) are involved in resolution of inflammation and may be involved in the maintenance of clinical remission...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29774025/co-stimulation-impaired-bone-marrow-derived-dendritic-cells-prevent-dextran-sodium-sulfate-induced-colitis-in-mice
#7
Carl Engman, Yesica Garciafigueroa, Brett Eugene Phillips, Massimo Trucco, Nick Giannoukakis
Dendritic cells (DC) are important in the onset and severity of inflammatory bowel disease (IBD). Tolerogenic DC induce T-cells to become therapeutic Foxp3+ regulatory T-cells (Tregs). We therefore asked if experimental IBD could be prevented by administration of bone marrow-derived DC generated under conventional GM-CSF/IL-4 conditions but in the presence of a mixture of antisense DNA oligonucleotides targeting the primary transcripts of CD40, CD80, and CD86. These cell products (which we call AS-ODN BM-DC) have demonstrated tolerogenic activity in preventing type 1 diabetes and preserving beta cell mass in new-onset type 1 diabetes in the NOD mouse strain, in earlier studies...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29773895/crispr-cas9-system-targeting-regulatory-genes-of-hiv-1-inhibits-viral-replication-in-infected-t-cell-cultures
#8
Youdiil Ophinni, Mari Inoue, Tomohiro Kotaki, Masanori Kameoka
The CRISPR/Cas9 system provides a novel and promising tool for editing the HIV-1 proviral genome. We designed RNA-guided CRISPR/Cas9 targeting the HIV-1 regulatory genes tat and rev with guide RNAs (gRNA) selected from each gene based on CRISPR specificity and sequence conservation across six major HIV-1 subtypes. Each gRNA was cloned into lentiCRISPRv2 before co-transfection to create a lentiviral vector and transduction into target cells. CRISPR/Cas9 transduction into 293 T and HeLa cells stably expressing Tat and Rev proteins successfully abolished the expression of each protein relative to that in non-transduced and gRNA-absent vector-transduced cells...
May 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29773813/amelioration-of-experimental-autoimmune-encephalomyelitis-and-dss-induced-colitis-by-ntg-a-009-through-the-inhibition-of-th1-and-th17-cells-differentiation
#9
Suman Acharya, Maheshwor Timilshina, Liyuan Jiang, Sabita Neupane, Dong-Young Choi, Sang Won Park, Sang Yeul Lee, Byeong-Seon Jeong, Jung-Ae Kim, Tae-Gyu Nam, Jae-Hoon Chang
CD4+ T cells are the central for the mammalian adaptive immune system. Naïve CD4+ T cells mainly differentiate in to pro-inflammatory Th1, Th2 and Th17 cells upon antigenic stimulation. IFN-γ secreting Th1 cells and IL-17 secreting Th17 cells are found to play key roles in autoimmune diseases like multiple sclerosis (MS) and ulcerative colitis (UC). In this study we found NTG-A-009, 6-aminopyridin-3-ol, has great inhibitory effect on in vitro differentiation of Th1 and Th17 cells without affecting regulatory T cells...
May 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29773794/calreticulin-and-integrin-alpha-dissociation-induces-anti-inflammatory-programming-in-animal-models-of-inflammatory-bowel-disease
#10
Masayoshi Ohkuro, Jun-Dal Kim, Yoshikazu Kuboi, Yuki Hayashi, Hayase Mizukami, Hiroko Kobayashi-Kuramochi, Kenzo Muramoto, Manabu Shirato, Fumiko Michikawa-Tanaka, Jun Moriya, Teruya Kozaki, Kazuma Takase, Kenichi Chiba, Kishan Lal Agarwala, Takayuki Kimura, Makoto Kotake, Tetsuya Kawahara, Naoki Yoneda, Shinsuke Hirota, Hiroshi Azuma, Nobuko Ozasa-Komura, Yoshiaki Ohashi, Masafumi Muratani, Keiji Kimura, Ieharu Hishinuma, Akiyoshi Fukamizu
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic intestinal inflammatory condition initiated by integrins-mediated leukocyte adhesion to the activated colonic microvascular endothelium. Calreticulin (CRT), a calcium-binding chaperone, is known as a partner in the activation of integrin α subunits (ITGAs). The relationship between their interaction and the pathogenesis of IBD is largely unknown. Here we show that a small molecule, orally active ER-464195-01, inhibits the CRT binding to ITGAs, which suppresses the adhesiveness of both T cells and neutrophils...
May 17, 2018: Nature Communications
https://www.readbyqxmd.com/read/29773655/foxp3-interacts-with-hnrnp-f-to-modulate-pre-mrna-alternative-splicing
#11
Jianguang Du, Qun Wang, Steven F Ziegler, Baohua Zhou
FOXP3 promotes the development and function of regulatory T cells mainly through regulating the transcription of target genes. RNA alternative splicing has been implicated in wide range of physiological and pathophysiological processes. We report here that FOXP3 associates with Heterogeneous Nuclear Ribonucleoprotein (hnRNP) F through the exon 2 encoded region of FOXP3 and the second quasi-RNA recognition motif (qRRM) of hnRNPF. FOXP3 represses the ability of hnRNPF to bind to its target pre-mRNA and thus modulates RNA alternative splicing...
May 17, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29773469/the-effect-of-the-deuterium-depleted-water-on-the-biological-activity-of-the-eukaryotic-cells
#12
A V Syroeshkin, N V Antipova, A V Zlatska, I A Zlatskiy, M D Skylska, T V Grebennikova, V V Goncharuk
Here we show the dependence of the unicellular biosensor S.ambigua lifespan on the water D/H isotopic composition. This dependence is bell-shaped with descents both in case of deficiency or excess of deuterium in water. The influence of the water D/H isotopic composition on the cell culture proliferative potential and colony forming efficiency in vitro was tested on the human dermal fibroblasts. We observed that the deuterium depleted water stimulates cell colony formation at the early passages. The dynamics of the cell doubling index in the deuterium depleted water-based growth medium showed higher proliferation potential compared to the water with normal isotopic composition...
May 14, 2018: Journal of Trace Elements in Medicine and Biology
https://www.readbyqxmd.com/read/29773224/early-env-specific-ctls-effectively-suppress-viral-replication-in-shiv-controller-macaques
#13
Jin Fan, Hua Liang, Tao Shen, Shuo Wang, Xiaolin Ji, Cassian Yee, Fengmin Lu, Yiming Shao
Early immunological events in acute HIV infection are thought to fundamentally influence long-term disease outcomes. Though the contribution of Gag-specific CD8 T cell responses to early viral control is well established, little is known about the role of Env-specific CD8 T cell responses in controlling viral replication during acute infection. In a macaque simian-human immunodeficiency virus (SHIV) model, some macaques who were able to control SHIV replication after ART interruption showed expansion of Env-specific CD8 T cell responses during acute infection, compared to macaques who progressed to viral rebound...
May 5, 2018: Cellular Immunology
https://www.readbyqxmd.com/read/29772429/long-non-coding-rna-nron-is-downregulated-in-hcc-and-suppresses-tumour-cell-proliferation-and-metastasis
#14
Zhicheng Yao, Zhiyong Xiong, Ruixi Li, Hao Liang, Changchang Jia, Meihai Deng
Dysregulation of long non-coding RNAs is a newly identified mechanism for tumour progression. Previous studies have suggested that the nuclear factor of activated T cells (NFAT) gene plays a very important role in cancer growth and metastasis. However, lncNRON is a newly identified repressor of NFAT, and its function is largely unknown, especially in hepatocellular carcinoma (HCC). Therefore, the expression levels of lncNRON in 215 pairs of HCC tissue were evaluated by qRT-PCR, and its relationship to clinicopathological parameters, recurrence, and survival was analysed...
May 14, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29772005/atrophy-of-skin-draining-lymph-nodes-predisposes-for-impaired-immune-responses-to-secondary-infection-in-mice-with-chronic-intestinal-nematode-infection
#15
Xiaogang Feng, Cajsa Classon, Graciela Terán, Yunlong Yang, Lei Li, Sherwin Chan, Ulf Ribacke, Antonio Gigliotti Rothfuchs, Jonathan M Coquet, Susanne Nylén
Intestinal nematodes suppress immune responses in the context of allergy, gut inflammation, secondary infection and vaccination. Several mechanisms have been proposed for this suppression including alterations in Th2 cell differentiation and increased Treg cell suppressive function. In this study, we show that chronic nematode infection leads to reduced peripheral responses to vaccination because of a generalized reduction in the available responsive lymphocyte pool. We found that superficial skin-draining lymph nodes (LNs) in mice that are chronically infected with the intestinal nematode Heligmosomides polygyrus, do not reach the same cellularity as worm-free mice upon subsequent BCG infection in the skin...
May 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29771780/biomarkers-of-aging-in-hiv-infected-children-on-suppressive-antiretroviral-therapy
#16
Stephanie Shiau, Renate Strehlau, Jing Shen, Avy Violari, Faeezah Patel, Afaaf Liberty, Marc Foca, Shuang Wang, Mary Beth Terry, Michael T Yin, Ashraf Coovadia, Elaine J Abrams, Stephen M Arpadi, Louise Kuhn
BACKGROUND: Data on accelerated aging in HIV-infected children are limited. In this study we assess two biomarkers of aging - telomere length and DNA methylation (DNAm) age - in a cohort of early-treated HIV-infected children and compare these aging biomarkers to HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) children. SETTING: Cross-sectional study of 120 HIV-infected, 33 HEU, and 25 HUU children enrolled in a cohort study in Johannesburg, South Africa...
April 27, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/29771602/irisin-promotes-proliferation-but-inhibits-differentiation-in-osteoclast-precursor-cells
#17
Yaxian Ma, Xiaoyong Qiao, Rujun Zeng, Ran Cheng, Jun Zhang, Yunyao Luo, Ying Nie, Ying Hu, Zhilan Yang, Jing Zhang, Lin Liu, Wenming Xu, Charles C Xu, Liangzhi Xu
The receptor activator of NF-κB ligand-induced osteoclast differentiation has a critical role in the process of bone metabolism. Overactivation of osteoclastogenesis may result in a series of diseases. Irisin, a novel myokine, which was first reported in 2012, has been proposed to mediate the beneficial metabolic effects of exercise. Studies have demonstrated that irisin targets osteoblasts by promoting osteoblast proliferation and differentiation; however, the underlying mechanism regarding the effect of irisin on osteoclasts remains elusive...
May 17, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29771386/immunotherapy-in-cns-cancers-the-role-of-immune-cell-trafficking
#18
Nivedita M Ratnam, Mark R Gilbert, Amber J Giles
Glioblastoma (GBM) is a highly malignant CNS tumor with very poor survival despite intervention with conventional therapeutic strategies. Although the CNS is separated from the immune system by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), emerging evidence of immune surveillance and the selective infiltration of GBMs by immune suppressive cells indicates that there is breakdown or compromise of these physical barriers. This in turn offers hope that immunotherapy can be applied to specifically target and reduce tumor burden...
May 15, 2018: Neuro-oncology
https://www.readbyqxmd.com/read/29770132/differing-outcome-of-experimental-autoimmune-encephalitis-in-macrophage-neutrophil-and-t-cell-specific-gp130-deficient-mice
#19
Kristian Holz, Marco Prinz, Stefanie M Brendecke, Alexandra Hölscher, Fengyuan Deng, Hans-Willi Mitrücker, Stefan Rose-John, Christoph Hölscher
gp130 cytokines are differentially involved in regulating the T helper (H) 17-driven pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model of human multiple sclerosis. Interleukin (IL)-6 directly promotes the development of TH17 cells through the gp130/IL-6R complex. By contrast, IL-27 has been shown to suppress a TH17 immune response by gp130/IL-27R-alpha (α) receptor ligation. The IL-27-dependent regulation of a TH17 development could be mediated on the level of CD4 T cells. However, because IL-27 also suppresses the secretion of the TH17-driving cytokines IL-6 and IL-12/23p40 in accessory cells, TH17 immune responses may also be controlled by IL-27 on the level of macrophages and/or neutrophils...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29769573/discovery-of-a-novel-il-15-based-protein-with-improved-developability-and-efficacy-for-cancer-immunotherapy
#20
Qiyue Hu, Xin Ye, Xiangdong Qu, Dongbing Cui, Lei Zhang, Zhibin Xu, Hong Wan, Lianshan Zhang, Weikang Tao
Interleukin-15 (IL-15) can promote both innate and adaptive immune reactions by stimulating CD8+ /CD4+ T cells and natural killer cells (NK) while showing no effect in activating T-regulatory (Treg) cells or inducing activation-associated death among effector T cells and NK cells. Thus, IL-15 is considered as one of the most promising molecules for antitumor immune therapy. To improve the drug-like properties of natural IL-15, we create an IL-15-based molecule, named P22339, with the following characteristics: 1) building a complex of IL-15 and the Sushi domain of IL-15 receptor α chain to enhance the agonist activity of IL-15 via transpresentation; 2) through a rational structure-based design, creating a disulfide bond linking the IL-15/Sushi domain complex with an IgG1 Fc to augment its half-life...
May 16, 2018: Scientific Reports
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