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Neural Regeneration Research 2018年第12期13卷 2160-2163页

作者： Viviane Rostirola Elsner Laura Reck Cechinel Louisiana Carolina Ferreira de Meireles Karine Bertoldi Ionara Rodrigues Siqueira Programa de Pós-Graduacao em Ciências Biológicas:Fisiologia Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul Programa de Pós-Graduacao em Biociências e Reabilitacao Centro Universitário Metodista-IPA Curso de Fisioterapia Centro Universitário Metodista-IPA

Although the involvement of gender in epigenetic machinery in peripheral tissues during the neonatal period has been suggested, the gender-related epigenetic profile of brain areas during the adolescent period is rarely exploited. Furthermore, the influence of time of day on hippocampal acetylation marks has been demonstrated in young adult and aged rats; however, there are no studies reporting epigenetic changes in the adolescent period. Therefore, this study aimed to investigate the effects of gender on hippocampal DNA methyltransferase 1 content and histone deacetylase（HDAC） activity of adolescent rats at different time points, specifically early morning and afternoon. Both epigenetic markers increased significantly in the hippocampi of female rats compared to the male group, an indicator of reduced transcriptional activity. In addition, HDAC activity during the early morning was higher compared to afternoon groups in both male and female rats, while DNA methyltransferase 1 content was not altered by the time of day. Our findings demonstrate that hippocampal DNA methylation and histone acetylation status can be influenced by gender during the adolescent period, while the time of the day impacts HDAC activity.

关键词： adolescent rats DNA methyltransferase 1 histone deacetylase hippocampus time of the day gender epigenetic marks

Design, Synthesis, Inhibiting HDACs Ability and Antitumor Activity of Pyrimidin-4（3H）-one Hydroxamate Derivatives

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Chemical Research in Chinese Universities 2016年第4期32卷 576-580页

作者： LU Haibin JIN Xiangqun JIN Yang HUANG Bangrui WANG Cheng WANG Chunhe MA Fangyuan CHEN Yuting LI Jiarui CONG Yu WANG Wenlong SONG Yuming MU Xupeng College of Pharmacy Jilin University Changchun 130021 P. R. China China-Japan Union Hospital of Jilin University Changchun 130033 P. R. China

A series of novel pyrimidin-4（3H）-one hydroxamate derivatives was designed, synthesized and studied for their activities against histone deacetylases（HDACs）. The results indicate that all the compounds show HDACs inhibitiory activity. The antiproliferative activities of the compounds against HeLa and A549 cells were also investigated. The pharmacological results show compound 9g has potent activity in the enzymatic inhibition assay and cell-based assay.

关键词： histone deacetylase Antitumor acitivty Pyrimidin-4(3H)-one hydroxamate derivative

组蛋白去乙酰化酶在子宫颈癌靶向治疗中的作用研究

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组蛋白去乙酰化酶在子宫颈癌靶向治疗中的作用研究

作者：吴群英延边大学

学位级别：硕士

目的:探讨组蛋白去乙酰化酶(histone deacetylase,HDAC)基因及其蛋白表达检测在宫颈癌及其癌前病变中的临床病理学意义以及HDAC抑制剂曲古抑菌素A(Trichostatin A,TSA)在宫颈癌分子靶向治疗中的作用。材料与方法:8例正常宫颈鳞状上皮,5... 详细信息

目的:探讨组蛋白去乙酰化酶(histone deacetylase,HDAC)基因及其蛋白表达检测在宫颈癌及其癌前病变中的临床病理学意义以及HDAC抑制剂曲古抑菌素A(Trichostatin A,TSA)在宫颈癌分子靶向治疗中的作用。材料与方法:8例正常宫颈鳞状上皮,52例宫颈上皮内瘤变(Cervicalintraepithelial neoplasia,CIN),141例宫颈鳞状上皮细胞癌(Squamous cellcarcinomas,SCC)和24例宫颈腺癌(Adenocarcinomas,AC)共225例宫颈病变的存档蜡块标本选自延边大学医院、延边妇幼保健院和韩国高丽大学医科大学医疗中心病理科。同时,选取HeLa和CaSki两种宫颈癌细胞系作为TSA体外治疗效应的XTT检测对象。应用免疫组织化学、免疫荧光染色和Western Blot等实验方法检测5种HDAC基因蛋白在正常宫颈上皮、CIN和宫颈癌中的表达变化,并应用小分子RNA干扰、XTT和流式细胞仪检测方法测定HDACs抑制剂TSA对于宫颈癌细胞的杀伤作用和机制。结果:HDAC1、3和HDAC5蛋白主要表现为细胞核阳性,在正常宫颈上皮中的表达率分别为0(0/8)、12.5%(1/8)和25%(2/8),而且阳性细胞位于上皮的基底细胞层,但在CIN、宫颈鳞癌和腺癌中的表达率明显升高。HDAC1在CIN、宫颈鳞癌和腺癌中阳性率分别为82.7%(43/50)、83%(117/141)和91.7%(22/24);HDAC3在CIN、宫颈鳞癌和腺癌中的阳性率分别为58.7%(27/46)、62.4%(87/141)和70.8%(17/24);HDAC5在CIN、宫颈鳞癌和腺癌中的阳性率分别为66%(33/50)、63.1%(89/141)和75%(18/24)。HDAC6则表现为胞浆阳性,在正常宫颈上皮中的阳性表达率为0(0/8),而且弱阳性染色细胞分布在上皮的基底部细胞层;在CIN、SCC和腺癌中的表达率也明显升高,分别达到84.6%(44/52)、83.0%(117/141)和91.7%(22/24)。HDAC2蛋白在宫颈正常上皮组织中表达为阴性,而且在宫颈癌及其癌前病变中的表达也较弱,只有少数病例表现为HDAC2蛋白阳性。TSA对于HeLaCaSki宫颈癌细胞具有明显的杀伤作用,但正常的皮肤鳞状上皮细胞对TSA则不敏感。而且,TSA处理组的HeLa细胞凋亡和死亡率明显较未经处理的HeLa对照组高,Acetylated Tubulin(乙酰化微管蛋白)的表达水平也明显上调。结论:HDAC1、3、5和HDAC6蛋白检测对于宫颈癌的诊断具有重要的辅助意义,而且可以作为宫颈癌治疗的新靶点。同时,HDAC抑制剂TSA对于宫颈癌具有明显的杀伤作用,其机制主要是通过上调Acetylated tubulin和诱导凋亡而实现的。

关键词： histone deacetylase 宫颈癌 Short interfering RNA 免疫组织化学免疫荧光染色 Western Blot

Corticosteroid resistance in chronic obstructive pulmonary disease： new uses of theophylline

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Chinese Medical Journal 2013年第5期126卷 965-970页

作者： WU Jun-ping WU Qi SUN Xin SUN Hong-fen Division of Pulmonary Medicine Tianjin Haihe Hospital TianjinInstitute of Respiratory Disease Tianjin 300350 China Division of Pulmonary and Critical Care Medicine Duke University Medical Centre Durham NC27710 USA

Chronic obstructive pulmonary disease （COPD） is a major global health problem with a rising morbidity and mortality, which is expected to account for about 27% of tobacco related deaths and is anticipated to move from the fifth to the fourth leading cause of death worldwide from 2002 to 2030.1 COPD is characterized by the abnormal and chronic inflammation induced by cigarette smoking and other inflammatory insults in both small airway and lung parenchyma.2＇3 Glucocorticosteroids （also called glucocorticoids, corticosteroids or steroids） are the most effective anti-inflammatory drugs available for the treatment of many chronic inflammatory and immune diseases.

关键词： dimethylxanthine histone deacetylase neutrophil apoptosis chronic obstructive pulmonary disease corticosteroid resistance

Gene expression profile of Sox1,Sox2,p53,Bax and Nestin in neural stem cells and adult mouse brain tissues

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BIOCELL 2019年第2期43卷 59-64页

作者： HAIFENG WANG KAI WANG JUAN GUO TIEQIAO WEN School of Environmental Engineering Central Plains Specialty Food Engineering&Technology Research CenterKaifeng Key Laboratory of Food Composition and Quality AssessmentYellow River Conservancy Technical InstituteDong Jing AvenueKaifeng475004China Laboratory of Molecular Neural Biology School of Life SciencesShanghai University99 Shang Da RoadShanghai200444China

histone deacetylation is a key modulator involved in cell proliferation,apoptosis,and mRNA ***,the effects of histone deacetylation on C17.2 neural stem cells(NSCs)remain ***,the histone deacetylase inhibitors nicotinamide and trichostatin A(TSA)were used to determine the role of histone deacetylation on gene transcription in *** results showed that the mRNA expression of p53,Sox1,Sox2,and Bax were significantly higher in E14.5 NSCs than in C17.2 ***,a marker gene of neuronal differentiation,did not differ significantly between E14.5 NSCs and C17.2 *** transcription levels of p53 and Nestin were significantly higher in C17.2 NSCs than in differentiated brain tissues,and the expression of Bax,Sox1,and Sox2 was higher in the olfactory bulb than in other brain *** and TSA treatment decreased the transcription of Sox2,p53,Nestin,and Bax in C17.2 NSCs,although the difference was statistically significant only for Sox2 and Nestin,Sox1 transcription was not *** results demonstrated that mRNA expression profiles differ between C17.2 NSCs,E14.5 NSCs,and adult mouse brain tissues,and HDAC inhibitors regulate gene expression by modulating histone acetylation.

关键词： histone deacetylase Inhibitors Brain tissues Transcription profile C17.2 neural stem cells

Synergistic Suppressive Effect of PARP-1 Inhibitor PJ34 and HDAC Inhibitor SAHA on Proliferation of Liver Cancer Cells

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2015年第4期35卷 535-540页

作者：梁宾勇熊敏纪桂宝张二雷张尊义董可帅陈孝平黄志勇 Research Laboratory and Hepatic Surgery Center Department of SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and Technology Department of Obstetrics and Gynecology Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology Department of General Surgery Pu’ai HospitalTongji Medical CollegeHuazhong University of Science and Technology

Summary： Poly （ADP-ribose） polymerase-1 （PARP-1） inhibitors and histone deacetylase （HDAC） in- hibitors have recently emerged as promising anticancer drugs. The aim of this study was to investigate the effect of combination treatment with the PARP inhibitor P J34 and HDAC inhibitor SAHA on the proliferation of liver cancer cells. Cell proliferation and apoptosis were assessed in three human liver cancer cell lines （HepG2, Hep3B and HCC-LM3） treated with PJ34 （8 μmol/L） and SAHA （1 panol/L）, alone or combined, by Cell Counting Kit-8 assay and flow cytometry, respectively. The nude mice bear- ing subcutaneous HepG2 tumors were administered different groups of drugs （10 mg/kg PJ34, 25 mg/kg SAHA, 10 mg/kg PJ34＋25 mg/kg SAHA）, and the inhibition rates of tumor growth were compared between groups. The results showed that combined use of P J34 and SAHA could synergistically inhibit the proliferation of liver cancer cell lines HepG2, Hep3B and HCC-LM3. The apoptosis rate of HepG2 cells treated with PJ34＋SAHA was significantly higher than that of HepG2 cells treated with PJ34 or SAHA alone （P〈0.05）. In vivo, the tumor inhibition rates were 53.5%, 61.4% and 82.6% in PJ34, SAHA and PJ34＋SAHA groups, respectively. The combined use of PJ34 and SAHA could significantly inhibit the xenograft tumor growth when compared with use of P J34 or SAHA alone （P〈0.05）. It was led to conclude that P J34 and SAHA can synergistically suppress the proliferation of liver cancer cells.

关键词： poly (ADP-ribose) polymerase-1 PJ34 histone deacetylase SAHA liver cancer prolif- eration

Expression of P53,P21 in Human Lung Adenocarcinoma A549 Cell Strains under Hypoxia Conditions and the Effect of TSA on Their Expression

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2003年第4期23卷 359-361页

作者：黄宏张珍祥徐永健邵静芳 Department of Respiratory Medicine

This paper was designed to investigate the expression of p53, p21of A549 cell strains under hypoxic condition and the effect of trichostatin A (TSA), the inhibitor of histone deacetylase1 (HDAC1) on their expression. The authors designed 1 normoxia group (control group) and 6 hypoxia groups (experiemntal group): hypoxia 6 h group (A), TSA+ hypoxia 6 h (B), hypoxia 12 h group (C) ,hypoxia 24 h group (D), TSA+hypoxia 24 h (E), hypoxia 48 h group (F). The expression of HDAC1 in A549 cells was examined by using Western blot and the expression of p53, p21 in A549 cells and the effect of TSA on them were determined by using immunohistochemistry and reverse transcription polymerase chain reaction (RT PCR). The A value expressed by HDAC1 in A549 cell strains was 138±11 in the control group, 78±4, 86±5, 124±3, 120±9 in experimental groups A, C, D, F, respectively. The A value of the expression of the protein and mRNA of p53 in A549 cell strains were 0.12±0.02, 0.62±0.02 in the control group, 0.10±0.03, 0.32±0.03; 0.11±0.01, 0.33±0.02; 0.13±0.03, 0.58±0.01; 0.12±0.02, 0.56±0.02 in experimental group A, B, D, E, respectively. The A value of the expression of the protein and mRNA of p21 in A549 cell strains were 0.17±0.03, 0.62±0.03 in the control group, 0.16±0.02, 0.50±0.02; 0.14±0.02, 0.36±0.02; 0.15±0.03, 0.49±0.03; 0.13±0.02, 0.33±0.02 in experimental groups A, B, D, E, respectively. These results indicate that the expression of HDAC1 is regulated by hypoxia and the effect of TSA is closely related to the expression of P21 under hypoxia condition.

关键词： p53 p21 histone deacetylase trichostain A hypoxia

Kinase inhibitors:look beyond the label on the bottle

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Cancer Drug Resistance 2019年第4期2卷 1032-1043页

作者： Paul Dent Andrew Poklepovic Laurence Booth John F.Hancock Department of Biochemistry and Molecular Biology1 Virginia Commonwealth UniversityRichmondVA 23298-0035USA Department of Medicine Virginia Commonwealth UniversityRichmondVA 23298-0035USA Department of Integrative Biology and Pharmacology University of Texas Health Science CenterHoustonTX 77030USA

The majority of scientists working in the field of cancer experimental therapeutics recognize that many drugs that claim to be“specific”for one target enzyme in fact regulate to varying degrees the activities of other additional protein *** of these targets are known and are recognized as being an essential component of a drug’s ***,many other targets fall into the category of“unknown unknowns”.Thus,the collective therapeutic outcome for almost all clinically relevant drugs is reliant on both the claimed primary and secondary“on”targets as well as some of the unexpected unknown“off”*** review discusses the biology of several FDA approved cancer therapeutic drugs whose initial reported targets only represented the tip-of-the-iceberg in terms of how each agent acted as an anti-tumor *** review also discusses a putative thorough pre-visualization methodology for drug-based research,prior to executing any wet *** approaches should be performed in an agnostic fashion and be based in part on the clinically safe drug’s C max and its area under the curve in a *** on tumor heterogeneity,considerations of how to approach developmental therapeutics in the age of“personalized medicine”are also discussed.

关键词： Autophagy histone deacetylase chaperone cancer

A new cluster of SOX2-positive progenitor cells in developing Xenopus tectum

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A new cluster of SOX2-positive progenitor cells in developin...