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Heather N Carter, Marion Pauly, Liam D Tryon, David A Hood
Mitochondrial impairments are often noted in aged skeletal muscle. The transcriptional coactivator PGC-1α is integral to maintaining mitochondria, and its expression declines in aged muscle. It remains unknown whether this is due to a transcriptional deficit during aging. Our study examined PGC-1α transcription in muscle from young and old F344BN rats. Using a rat PGC-1α promoter-reporter construct, we found that PGC-1α transcription was reduced by ~65% in aged TA muscle, accompanied by decreases in PGC-1α mRNA and transcript stability...
March 15, 2018: Journal of Applied Physiology
Tingchao Mao, Chengquan Han, Ruizhi Deng, Biao Wei, Peng Meng, Yan Luo, Yong Zhang
Epigenetic modifications extensively occur in mammalian embryonic development and cell differentiation process. They play an essential role in the reprogramming of nuclei during somatic cell nuclear transfer (SCNT) and subsequent in vitro embryonic development. Recently, SCNT embryos have been verified to contain a subnormal level of histone H3K4 dimethylation (H3K4me2) in contrast to in vitro fertilized embryos. This finding suggested that increasing H3K4me2 levels may ameliorate the aberrant development of cloned embryos...
March 15, 2018: Systems Biology in Reproductive Medicine
Jinbo Huang, Xu Dong, Zhou Gong, Ling-Yun Qin, Shuai Yang, Yue-Ling Zhu, Xiang Wang, Delin Zhang, Tingting Zou, Ping Yin, Chun Tang
N6 -methyladenosine (m6 A), a ubiquitous RNA modification, is installed by METTL3-METTL14 complex. The structure of the heterodimeric complex between the methyltransferase domains (MTDs) of METTL3 and METTL14 has been previously determined. However, the MTDs alone possess no enzymatic activity. Here we present the solution structure for the zinc finger domain (ZFD) of METTL3, the inclusion of which fulfills the methyltransferase activity of METTL3-METTL14. We show that the ZFD specifically binds to an RNA containing 5'-GGACU-3' consensus sequence, but does not to one without...
March 14, 2018: Protein & Cell
Huaijie Shi, Xiaojing Chen, Hao Jiang, Xujie Wang, Hao Yu, Pijiang Sun, Xin Sui
Gastric cancer (GC) is the fourth most common malignant tumor globally. The highest incidence of GC is found in Eastern Asia, particularly in China. It is therefore imperative to further elucidate the molecular pathogenesis of GC in order to identify new biomarkers and targets for effective therapy. In the present study, we determined whether miR-148a was aberrantly downregulated in gastric cancer tissues and significantly correlated with aggressive clinicopathological characteristics in the MGC-803, HGC-27 and GES-1 cell lines using reverse transcription-quantitative PCR and western blot analysis...
April 2018: Oncology Letters
Shuko Hakata, Jun Terashima, Yu Shimoyama, Kouji Okada, Shiho Fujioka, Erika Ito, Wataru Habano, Shogo Ozawa
Irinotecan (CPT-11) is a key therapeutic drug used in the treatment of colorectal cancer, although acquired or constitutive resistance to CPT-11 (and its activated metabolite SN-38) can lead to tumor progression. Since the acquisition of drug resistance can result from DNA hypermethylation, the antitumor activity of CPT-11 and SN-38 was assessed in combination with a known DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, also known as decitabine (DAC). DAC potentiated the antitumor activity of CPT-11 additively, and that of SN-38 synergistically, as measured by colony formation in the human colorectal cancer HCT116 cell line...
April 2018: Oncology Letters
Liang Liang, Ming Zeng, Haixia Pan, Hao Liu, Yangke He
Previous studies have demonstrated that nicotinamide N-methyltransferase (NNMT) is aberrantly expressed in a number of tumors. In the present study, it was demonstrated that the gene and protein levels of NNMT were significantly increased in gastric cancer cells. Furthermore, upregulation of NNMT significantly increased the expression of mesenchymal markers, including α-smooth muscle actin (SMA), vimentin and fibronectin, but decreased the levels of epithelial cadherin. Since transforming growth factor (TGF)-β1 may serve a key function in epithelial-mesenchymal transition (EMT), the effects of NNMT on the expression of TGF-β1 were investigated in BGC-823 cells...
April 2018: Oncology Letters
Muhammad Shahid, Nicole Gull, Austin Yeon, Eunho Cho, Jooeun Bae, Hyun Seok Yoon, Sungyong You, Hana Yoon, Minjung Kim, Benjamin P Berman, Jayoung Kim
Interstitial cystitis (IC) is a chronic urinary tract disease that is characterized by unpleasant sensations, such as persistent pelvic pain, in the absence of infection or other identifiable causes. We previously performed comprehensive metabolomics profiling of urine samples from IC patients using nuclear magnetic resonance and gas-chromatography/mass spectrometry and found that urinary α-oxoglutarate (α-OG), was significantly elevated. α-OG, a tricarboxylic acid (TCA) cycle intermediate, reportedly functions to suppress the proliferation of immortalized normal human bladder epithelial cells...
March 14, 2018: Scientific Reports
Gamze Kuser-Abali, Lu Gong, Jiawei Yan, Qingqing Liu, Weiqi Zeng, Amanda Williamson, Chuan Bian Lim, Mary Ellen Molloy, John B Little, Lei Huang, Zhi-Min Yuan
Renewable tissues exhibit heightened sensitivity to DNA damage, which is thought to result from a high level of p53. However, cell proliferation in renewable tissues requires p53 down-regulation, creating an apparent discrepancy between the p53 level and elevated sensitivity to DNA damage. Using a combination of genetic mouse models and pharmacologic inhibitors, we demonstrate that it is p53-regulated MDM2 that functions together with MDMX to regulate DNA damage sensitivity by targeting EZH2 (enhancer of zeste homolog 2) for ubiquitination/degradation...
March 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Cheng-Han Yu, Chi-Chi Chou, Der-Yen Lee, Kay-Hooi Khoo, Geen-Dong Chang
Phenyl vinyl sulfone (PVS) and phenyl vinyl sulfonate (PVSN) inactivate protein tyrosine phosphatases (PTPs) by mimicking the phosphotyrosine structure and providing a Michael addition acceptor for the active-site cysteine residue of PTPs, thus forming covalent adducts between PVS (or PVSN) and PTPs. We developed a specific antiserum against PVS. This antiserum can be used in general antibody-based assays such as immunoblotting, immunofluorescence staining, and immunoprecipitation. Target identification through immunoprecipitation and mass spectrometry analysis reveals potential targets of PVS, mostly proteins with reactive cysteine residues or low-pKa cysteine residues that are prone to reversible redox modifications...
March 14, 2018: Bioscience Reports
Sigrun Schmähling, Arno Meiler, Yoonjung Lee, Arif Mohammed, Katja Finkl, Katharina Tauscher, Lars Israel, Marc Borath, Julia Philippou-Massier, Helmut Blum, Bianca Habermann, Axel Imhof, Ji-Joon Song, Jürg Müller
The Drosophila Ash1 protein is a trithorax-group (trxG) regulator that antagonizes Polycomb repression at HOX genes. Ash1 di-methylates lysine 36 in histone H3 (H3K36me2) but how this activity is controlled and at which genes it functions is not well understood. We show that Ash1 protein purified from Drosophila exists in a complex with MRG15 and Caf1 that we named AMC. In Drosophila and human AMC, MRG15 binds a conserved FxLP motif near the Ash1 SET domain and stimulates H3K36 di-methylation on nucleosomes...
March 14, 2018: Development
Mei Mei, Haojun Song, Lina Chen, Bin Hu, Ru Bai, Diandou Xu, Ying Liu, Yuliang Zhao, Chunying Chen
BACKGROUND: Epidemiological studies have suggested that elevated levels of air pollution contribute to an increased incidence or severity of asthma. Although late-onset adult asthma seems to be more attributable to environmental risk factors, limited data is available on the impact of early-life exposure to size-fractionated ambient particulate matter (PM) on asthma in adults. We aimed to determine the effect on the development and exacerbation of asthma in the adult after the mice were exposed as juveniles to three size-fractionated ambient particulates collected from Beijing...
March 14, 2018: Particle and Fibre Toxicology
Qingbo Chen, Lei Huang, Dongning Pan, Lihua J Zhu, Yong-Xu Wang
Transcriptional co-activator Prdm16 controls brown fat development and white fat browning, but how this thermogenic function is modulated post-translationally is poorly understood. Here, we report that Cbx4, a Polycomb group protein, is a SUMO E3 ligase for Prdm16 and that Cbx4-mediated sumoylation of Prdm16 is required for thermogenic gene expression. Cbx4 expression is enriched in brown fat and is induced in adipose tissue by acute cold exposure. Sumoylation of Prdm16 at lysine 917 by Cbx4 blocks its ubiquitination-mediated degradation, thereby augmenting its stability and thermogenic function...
March 13, 2018: Cell Reports
Kun Qian, Hao Hu, Hui Xu, Y George Zheng
Protein arginine methyltransferases (PRMTs) are crucial epigenetic regulators in eukaryotic organisms that serve as histone writers for chromatin remodeling. PRMTs also methylate a variety of non-histone protein substrates to modulate their function and activity. The development of potent PRMT inhibitors has become an emerging and imperative research area in the drug discovery field to provide novel therapeutic agents for treating diseases and as tools to investigate the biological functions of PRMTs. PRMT1 is the major type I enzyme that catalyzes the formation of asymmetric dimethyl arginine, and PRMT1 plays important regulatory roles in signal transduction, transcriptional activation, RNA splicing, and DNA repair...
2018: Signal Transduction and Targeted Therapy
Lisa B Caruso, Kayla A Martin, Elisabetta Lauretti, Michael Hulse, Micheal Siciliano, Lena N Lupey-Green, Aaron Abraham, Tomasz Skorski, Italo Tempera
The enzyme Poly(ADP-ribose) polymerase 1 (PARP1) plays a very important role in the DNA damage response, but its role in numerous aspects is not fully understood. We recently showed that in the absence of DNA damage, PARP1 regulates the expression of the chromatin-modifying enzyme EZH2. Work from other groups has shown that EZH2 participates in the DNA damage response. These combined data suggest that EZH2 could be a target of PARP1 in both untreated and genotoxic agent-treated conditions. In this work we tested the hypothesis that, in response to DNA damage, PARP1 regulates EZH2 activity...
February 13, 2018: Oncotarget
Shuyi Wang, Cong Wang, Subat Turdi, Kacy L Richmond, Yingmei Zhang, Jun Ren
BACKGROUND AND AIMS: Uncorrected obesity contributes to cardiac remodeling and contractile dysfunction although the underlying mechanism remains poorly understood. Mitochondrial aldehyde dehydrogenase (ALDH2) is a mitochondrial enzyme with some promises in a number of cardiovascular diseases. This study was designed to evaluate the impact of ALDH2 on cardiac remodeling and contractile property in high fat diet-induced obesity. METHODS: Wild-type (WT) and ALDH2 transgenic mice were fed low (10% calorie from fat) or high (45% calorie from fat) fat diet for 5 months prior to the assessment of cardiac geometry and function using echocardiography, IonOptix system, Lectin, and Masson Trichrome staining...
March 13, 2018: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Philip Knuckles, Tina Lence, Irmgard U Haussmann, Dominik Jacob, Nastasja Kreim, Sarah H Carl, Irene Masiello, Tina Hares, Rodrigo Villaseñor, Daniel Hess, Miguel A Andrade-Navarro, Marco Biggiogera, Mark Helm, Matthias Soller, Marc Bühler, Jean-Yves Roignant
N 6 -methyladenosine (m6 A) is the most abundant mRNA modification in eukaryotes, playing crucial roles in multiple biological processes. m6 A is catalyzed by the activity of methyltransferase-like 3 (Mettl3), which depends on additional proteins whose precise functions remain poorly understood. Here we identified Zc3h13 (zinc finger CCCH domain-containing protein 13)/Flacc [Fl(2)d-associated complex component] as a novel interactor of m6 A methyltransferase complex components in Drosophila and mice. Like other components of this complex, Flacc controls m6 A levels and is involved in sex determination in Drosophila We demonstrate that Flacc promotes m6 A deposition by bridging Fl(2)d to the mRNA-binding factor Nito...
March 13, 2018: Genes & Development
Yakai Song, Linjuan Li, Yantao Chen, Jingqiu Liu, Senhao Xiao, Fulin Lian, Naixia Zhang, Hong Ding, Yuanyuan Zhang, Kaixian Chen, Hualiang Jiang, Chenhua Zhang, Yu-Chih Liu, Shijie Chen, Cheng Luo
DOT1L (the disruptor of telomeric silencing 1-like), through its methyltransferase activity of H3K79, plays essential roles in transcriptional regulation, cell cycle regulation, and DNA damage response. In addition, DOT1L is believed to be involved in the development of MLL-rearranged leukemia driven by the MLL (mixed-lineage leukemia) fusion proteins, which thus to be a crucial target for leukemia therapy. Hence, discovering of novel DOT1L inhibitors has been in a great demand. In this study, we initiated the discovering process from setting up the AlphaLISA based High Throughput Screening (HTS) assay of DOT1L...
February 24, 2018: Bioorganic & Medicinal Chemistry
Xiaoqing Gong, Shenghui Mei, Xindi Li, Xingang Li, Heng Zhou, Yonghong Liu, Anna Zhou, Li Yang, Zhigang Zhao, Xinghu Zhang
Thiopurines (TPRs) are effective drugs in treating neuromyelitis optica spectrum disorders (NMOSD) and other diseases. TPRs' toxicity is mainly imputed to thiopurine S-methyltransferase (TPMT) activity. In Chinese population, the most common and important variation of TPMT is TPMT*3C (rs1142345). This study aims to reveal the association between TPMT activity and genetic polymorphisms of TPMT in patients with NMOSD in China. An LC-MS/MS method was used to evaluate the TPMT activity by using 6-mercapthioprine as substrate in human erythrocyte hemolysate via 1 h incubation at 37 °C to form its methylated product 6-methylmercaptopurine (6-MMP)...
March 10, 2018: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Zhi-Mei Li, Xiao Zhang, Ru-Ping Liang, Xiang-Juan Zheng, Jian-Ding Qiu
In this work, a newly developed surface plasma resonance (SPR) system for the sensitive detection of M.SssI activity has been designed based on double signal amplification with DNA chain cyclic reactions and AuNPs. In the absence of M.SssI, hairpin DNA 1 (HP1) can be cleaved into s1 fragments catalyzed by HpaII. The s1 fragments can then trigger a recycling process of hairpin DNA 2 (HP2) hybridization and subsequently release massive s2 and s3 in the solution of Nt.AlwI and HPII. AuNPs-DNA can be captured on gold film by the released s2 and s3 to produce a strong SPR signal...
August 3, 2018: Analytica Chimica Acta
Luděk Eyer, Radim Nencka, Erik de Clercq, Katherine Seley-Radtke, Daniel Růžek
Nucleoside analogs represent the largest class of small molecule-based antivirals, which currently form the backbone of chemotherapy of chronic infections caused by HIV, hepatitis B or C viruses, and herpes viruses. High antiviral potency and favorable pharmacokinetics parameters make some nucleoside analogs suitable also for the treatment of acute infections caused by other medically important RNA and DNA viruses. This review summarizes available information on antiviral research of nucleoside analogs against arthropod-borne members of the genus Flavivirus within the family Flaviviridae, being primarily focused on description of nucleoside inhibitors of flaviviral RNA-dependent RNA polymerase, methyltransferase, and helicase/NTPase...
January 2018: Antiviral Chemistry & Chemotherapy
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