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Alice Pasini, Oliver J Brand, Gisli Jenkins, Alan J Knox, Linhua Pang
Cyclooxygenase-2 (COX-2), with its main antifibrotic metabolite PGE2 , is regarded as an antifibrotic gene. Repressed COX-2 expression and deficient PGE2 have been shown to contribute to the activation of lung fibroblasts and excessive deposition of collagen in pulmonary fibrosis. We have previously demonstrated that COX-2 expression in lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) is epigenetically silenced and can be restored by epigenetic inhibitors. This study aimed to investigate whether COX-2 downregulation induced by the profibrotic cytokine transforming growth factor-β1 (TGF-β1) in normal lung fibroblasts could be prevented by epigenetic inhibitors...
March 16, 2018: Biochimica et Biophysica Acta
Airi Ohsaki, Yuki Miyano, Rei Tanaka, Sei-Ichi Tanuma, Shuji Kojima, Mitsutoshi Tsukimoto
Skin inflammation is caused by excessive production of cytokines and chemokines in response to an external stimulus, such as radiation, but the mechanisms involved are not completely understood. Here, we report a novel mechanism of γ-irradiation-induced IL-6 production mediated by P2Y11 receptors in epidermal cells. After irradiation of HaCaT cells derived from human epidermal keratinocytes with 5 Gy of γ-rays (137 Cs : 0.78 Gy/min), IL-6 production was unchanged at 24 h after γ-irradiation, but was increased at 48 h...
March 16, 2018: Biological & Pharmaceutical Bulletin
Seon Min Woo, Seung Un Seo, Kyoung-Jin Min, Taeg Kyu Kwon
BIX-01294 (BIX), a G9a histone methyltransferase inhibitor, has been reported for its anti-proliferative and anticancer activities against various cancer cell lines. In this study, we investigated whether BIX could sensitize TRAIL-mediated apoptosis in various cancer cells. Combined treatment with BIX and TRAIL markedly induced apoptosis in human renal carcinoma (Caki, ACHN, and A498), breast carcinoma (MCF-7), and lung carcinoma (A549) cells. In contrast, BIX and TRAIL co-treatment did not induce apoptosis in normal cells, specifically mouse kidney cell (TCMK-1) and human skin fibroblast (HSF)...
December 2018: Cell Death Discovery
Shunsuke Kuroki, Yuji Nakai, Ryo Maeda, Naoki Okashita, Mika Akiyoshi, Yutaro Yamaguchi, Satsuki Kitano, Hitoshi Miyachi, Ryuichiro Nakato, Kenji Ichiyanagi, Katsuhiko Shirahige, Hiroshi Kimura, Yoichi Shinkai, Makoto Tachibana
Histone H3 lysine 9 (H3K9) methylation is unevenly distributed in mammalian chromosomes. However, the molecular mechanism controlling the uneven distribution and its biological significance remain to be elucidated. Here, we show that JMJD1A and JMJD1B preferentially target H3K9 demethylation of gene-dense regions of chromosomes, thereby establishing an H3K9 hypomethylation state in euchromatin. JMJD1A/JMJD1B-deficient embryos died soon after implantation accompanying epiblast cell death. Furthermore, combined loss of JMJD1A and JMJD1B caused perturbed expression of metabolic genes and rapid cell death in embryonic stem cells (ESCs)...
February 27, 2018: Stem Cell Reports
Saori Kataoka, Toshio Norikura, Shin Sato
Maternal malnutrition is known to increase the risk of obesity in offspring. We investigated whether green tea extract (GTE) intake during lactation affects obesity-related fibrosis and inflammation in the kidney of high-fat-diet-fed adult offspring of protein-restricted-diet-fed dams during pregnancy and lactation. Pregnant Wistar rats received diets containing 20% (normal-protein, NP) or 8% (low-protein, LP) casein, and they received 0%-, 0.12%- or 0.24%-GTE-containing LP diets (LP/LP, LP/LGT and LP/HGT, respectively) during lactation...
February 9, 2018: Journal of Nutritional Biochemistry
Danny C Lenstra, Abbas H K Al Temimi, Jasmin Mecinović
Histone lysine methyltransferases G9a and GLP are validated targets for the development of new epigenetic drugs. Most, if not all, inhibitors of G9a and GLP target the histone substrate binding site or/and the S-adenosylmethionine cosubstrate binding site. Here, we report an alternative approach for inhibiting the methyltransferase activity of G9a and GLP. For proper folding and enzymatic activity, G9a and GLP contain structural zinc fingers, one of them being adjacent to the S-adenosylmethionine binding site...
February 24, 2018: Bioorganic & Medicinal Chemistry Letters
Xian Wang, Shaolei Ma, Haibo Wu, Xiaofeng Shen, Shiqin Xu, Xirong Guo, Maria L Bolick, Shizheng Wu, Fuzhou Wang
Our previous works disclosed the contributing role of macrophage migration inhibitory factor (MIF) and dopaminergic inhibition by lysine dimethyltransferase G9a/Glp complex in peripheral nerve injury-induced hypersensitivity. We herein propose that the proinflammatory cytokine MIF participates in the regulation of neuropathic hypersensitivity by interacting with and suppressing the descending dopaminergic system. The lumbar spinal cord (L-SC) and ventral tegmental area (VTA) are two major locations with significant upregulation of MIF after chronic constriction injury (CCI) of the sciatic nerve, and they display time-dependent changes, along with a behavioral trajectory...
February 16, 2018: Experimental & Molecular Medicine
Hong Ding, Wen Chao Lu, Jun Chi Hu, Yu-Chih Liu, Chen Hua Zhang, Fu Lin Lian, Nai Xia Zhang, Fan Wang Meng, Cheng Luo, Kai Xian Chen
SET7, serving as the only histone methyltransferase that monomethylates 'Lys-4' of histone H3, has been proved to function as a key regulator in diverse biological processes, such as cell proliferation, transcriptional network regulation in embryonic stem cell, cell cycle control, protein stability, heart morphogenesis and development. What's more, SET7 is involved inthe pathogenesis of alopecia aerate, breast cancer, tumor and cancer progression, atherosclerosis in human carotid plaques, chronic renal diseases, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis...
March 2, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Isai Pratha Karthik, Pavitra Desai, Sudarkodi Sukumar, Aleksandra Dimitrijevic, Krishnaraj Rajalingam, Sundarasamy Mahalingam
Ras proteins are major human oncogenes and most of the studies are focussed on enzymatic RAS effectors. Recently, non-enzymatic Ras effectors (RASSF-Ras association domain family) have garnered special attention because of their tumor suppressive properties in contrast to the oncogenic potential of the classical enzymatic Ras effectors. While most members of RASSF family are deregulated by promoter hypermethylation, RASSF8 promoter remains unmethylated in many cancers but the mechanism(s) of its downregulation remains unknown...
February 21, 2018: Journal of Biological Chemistry
Ayumi Yamada, Chikako Shimura, Yoichi Shinkai
Kleefstra syndrome (KS) (9q34 deletion syndrome) is a rare autosomal dominant disorder characterized by intellectual disability, frequently coupled with a spectrum of complex physical and clinical manifestations. As the euchromatic histone methyltransferase-1 gene (EHMT1, GLP, or KMT1D) within the 9q34 region is deleted or mutated in most of the individuals with KS, its absence or defect in one allele is speculated to cause the major symptoms of the syndrome. Most of the EHMT1 mutations are frameshift or nonsense mutations, but two individuals with KS were reported to possess EHMT1 missense mutations...
February 19, 2018: Journal of Human Genetics
Lei Hu, Ming-de Zang, He-Xiao Wang, Bao-Gui Zhang, Zhen-Qiang Wang, Zhi-Yuan Fan, Huo Wu, Jian-Fang Li, Li-Ping Su, Min Yan, Zhi-Qiang Zhu, Qiu-Meng Yang, Qiang Huang, Bing-Ya Liu, Zheng-Gang Zhu
Tumor metastasis is the leading cause of death in patients with advanced gastric cancer (GC). Limited therapeutic regimens are available for this condition, which is associated with a poor prognosis, and the mechanisms underlying tumor metastasis remain unclear. In the present study, increased histone methyltransferase G9A expression in GC tissues correlated with advanced stage and shorter overall survival, and in vitro and in vivo experiments revealed that G9A promoted tumor invasion and metastasis. Moreover, we observed that Reg IV induced G9A via the p-ERK/p-SP1 pathway...
February 15, 2018: Cell Death & Disease
Guang-Hui Zhao, Ai-Yu Gong, Yang Wang, Xin-Tian Zhang, Min Li, Nicholas W Mathy, Xian-Ming Chen
Intestinal infection by the zoonotic protozoan, Cryptosporidium parvum, causes significant alterations in the gene expression profile in host epithelial cells. The molecular mechanisms of how C. parvum may modulate host cell gene transcription and the pathological significance of such alterations are largely unclear. Previous studies demonstrate that a panel of parasite RNA transcripts are delivered into infected host cells and may modulate host gene transcription. Using in vitro models of intestinal cryptosporidiosis, in this study, we analyzed the impact of host delivery of C...
February 15, 2018: Veterinary Parasitology
Dong-Yao Wang, Joel Kosowan, James Samsom, Laura Leung, Kai-Lai Zhang, Ying-Xiang Li, Yan Xiong, Jian Jin, Arturas Petronis, Gabriel Oh, Albert H C Wong
Epigenetic gene-regulation abnormalities have been implicated in various neuropsychiatric disorders including schizophrenia and depression, as well as in the regulation of mood and anxiety. In addition, epigenetic mechanisms are involved in the actions of psychiatric drugs. Current anxiolytic drugs have significant shortcomings, and development of new medications is warranted. Two proteins, G9a (also known as EHMT2 or KMT1C) and GLP (G9a-like protein, also known as EHMT1 or KMT1D), which methylate lysine 9 of histone H3 (H3K9), could be promising anxiolytic targets...
February 8, 2018: Acta Pharmacologica Sinica
Yong Li, Cai Cheng
Osteosarcoma (OS) is the most common histological form of primary bone cancer. Long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1) functions as an oncogene in some cancers. However, the functional role of NEAT1 in OS metastasis remains elusive. In the present study, we found that NEAT1 expression was significantly increased in OS tissues and cell lines. Overexpression of NEAT1 in OS tissues was correlated with higher clinical stage, distant metastasis and poorer prognosis. Loss- and gain-of-function assays showed that NEAT1 positively regulated metastasis in vitro and in vivo ...
2018: American Journal of Cancer Research
Raluca Ștefănescu, Loredana Lupu, Marilena Manea, Roxana E Iacob, Michael Przybylski
Alzheimer disease is a neurodegenerative disease affecting an increasing number of patients worldwide. Current therapeutic strategies are directed to molecules capable to block the aggregation of the β-amyloid(1-42) (Aβ) peptide and its shorter naturally occurring peptide fragments into toxic oligomers and amyloid fibrils. Aβ-specific antibodies have been recently developed as powerful antiaggregation tools. The identification and functional characterization of the epitope structures of Aβ antibodies contributes to the elucidation of their mechanism of action in the human organism...
January 2018: Journal of Peptide Science: An Official Publication of the European Peptide Society
Sandeep Sundriyal, Patty B Chen, Alexandra S Lubin, Gregor A Lueg, Fengling Li, Andrew J P White, Nicholas A Malmquist, Masoud Vedadi, Artur Scherf, Matthew J Fuchter
Plasmodium falciparum HKMTs (PfHKMTs) play a key role in controlling Plasmodium gene expression and represent exciting new anti-malarial epigenetic targets. Using an inhibitor series derived from the diaminoquinazoline HKMT inhibitory chemotype, we have previously identified compounds with highly promising antimalarial activity, including irreversible asexual cycle blood stage-independent cytotoxic activity at nM concentrations, oral efficacy in in vivo models of disease, and the unprecedented ability to reactivate dormant liver stage parasites (hypnozoites)...
May 1, 2017: MedChemComm
Hani Choudhry, Mazin A Zamzami, Ziad Omran, Wei Wu, Marc Mousli, Christian Bronner, Mahmoud Alhosin
Ubiquitin-like containing plant homeodomain and RING finger domains 1 (UHRF1) is an anti-apoptotic protein involved in the silencing of several tumor suppressor genes (TSGs) through epigenetic modifications including DNA methylation and histone post-translational alterations, and also epigenetic-independent mechanisms. UHRF1 overexpression is observed in a number of solid tumors and hematological malignancies, and is considered a primary mechanism in inhibiting apoptosis. UHRF1 exerts its inhibitory activity on TSGs by binding to functional domains and therefore influences several epigenetic actors including DNA methyltransferase, histone deacetylase 1, histone acetyltransferase Tat-interacting protein 60 and histone methyltransferases G9a and Suv39H1...
January 2018: Oncology Letters
Juan Roberto Rodriguez-Madoz, Edurne San Jose-Eneriz, Obdulia Rabal, Natalia Zapata-Linares, Estibaliz Miranda, Saray Rodriguez, Angelo Porciuncula, Amaia Vilas-Zornoza, Leire Garate, Victor Segura, Elizabeth Guruceaga, Xabier Agirre, Julen Oyarzabal, Felipe Prosper
The combination of defined factors with small molecules targeting epigenetic factors is a strategy that has been shown to enhance optimal derivation of iPSCs and could be used for disease modelling, high throughput screenings and/or regenerative medicine applications. In this study, we showed that a new first-in-class reversible dual G9a/DNMT1 inhibitor compound (CM272) improves the efficiency of human cell reprogramming and iPSC generation from primary cells of healthy donors and patient samples, using both integrative and non-integrative methods...
2017: PloS One
Jengmin Kang, Seung-Hyun Shin, Haejin Yoon, June Huh, Hyun-Woo Shin, Yang-Sook Chun, Jong-Wan Park
The prolyl hydroxlyases PHD1-3 and the asparaginly hydroxlyase FIH are oxygen sensors for HIF-driven transcription of hypoxia-induced genes, but whether these sensors affect oxygen-dependent epigenetic regulation more broadly is not known. Here we show that FIH exerts an additional role as an oxygen sensor in epigenetic control by the histone lysine methyltransferases G9a and GLP. FIH hydroxylated and inhibited G9a and GLP under normoxia. When the FIH reaction was limited under hypoxia, G9a and GLP were activated and repressed metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts...
December 19, 2017: Cancer Research
Ethan M Anderson, Erin B Larson, Daniel Guzman, Anne Marie Wissman, Rachael L Neve, Eric J Nestler, David W Self
Repeated exposure to cocaine induces lasting epigenetic changes in neurons that promote the development and persistence of addiction. One epigenetic alteration involves reductions in levels of the histone dimethyltransferase G9a in nucleus accumbens (NAc) after chronic cocaine administration. This reduction in G9a may enhance cocaine reward because overexpressing G9a in the NAc decreases cocaine-conditioned place preference. Therefore, we hypothesized that HSV-mediated G9a overexpression in the NAc shell (NAcSh) would attenuate cocaine self-administration (SA) and cocaine-seeking behavior...
January 24, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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