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Enhanced autophagic clearance of amyloid-βvia histone deacetylase 6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo
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作者 Zhimin Long Chuanhua Ge +5 位作者 Yueyang Zhao Yuanjie Liu Qinghua Zeng Qing Tang Zhifang Dong Guiqiong He 《Neural Regeneration Research》 SCIE CAS 2025年第9期2633-2644,共12页
Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal funct... Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification. 展开更多
关键词 Alzheimer's disease amyloid-β APP/PS1 mice autophagy cognitive impairment histone deacetylase 6 lysosomal acidification microtubule acetylation valproic acid V-ATPASE
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Down-regulation of histone deacetylase 7 reduces biological activities of retinal microvascular endothelial cells under high glucose condition and related mechanism
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作者 Jia-Yi Ning Han-Yi Yang +2 位作者 Ting-Ke Xie Yi-Xuan Chen Jing Han 《International Journal of Ophthalmology(English edition)》 SCIE CAS 2023年第8期1210-1217,共8页
AIM:To investigate the expression and effect of histone deacetylase 7(HDAC7)in human retinal microvascular endothelial cells(HRMECs)under high glucose condition and related mechanism,and the expression of HDAC7 in the... AIM:To investigate the expression and effect of histone deacetylase 7(HDAC7)in human retinal microvascular endothelial cells(HRMECs)under high glucose condition and related mechanism,and the expression of HDAC7 in the retinal tissue in diabetic rats.METHODS:The expression of HDAC7 in HRMECs under high glucose and the retinal tissue from normal or diabetic rats were detected with immunohistochemistry and Western blot.LV-shHDAC7 HRMECs were used to study the effect of HDAC7 on cell activities.Cell count kit-8(CCK-8),5-ethynyl2’-deoxyuridine(EdU),flow cytometry,scratch test,Transwell test and tube formation assay were used to examine the ability of cell proliferation,migration,and angiogenesis.Finally,a preliminary exploration of its mechanism was performed by Western blot.RESULTS:The expression of HDAC7 was both upregulated in retinal tissues of diabetic rats and high glucosetreated HRMECs.Down-regulation of HDAC7 expression significantly reduced the ability of proliferation,migration,and tube formation,and reversed the high glucose-induced high expression of CDK1/Cyclin B1 and vascular endothelial growth factor in high glucose-treated HRMECs.CONCLUSION:High glucose can up-regulate the expression of HDAC7 in HRMECs.Down-regulation of HDAC7 can inhibit HRMECs activities.HDAC7 is proposed to be involved in pathogenesis of diabetic retinopathy and a therapeutic target. 展开更多
关键词 human retinal microvascular endothelial cells histone deacetylase 7 high glucose diabetic rat vascular endothelial growth factor
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Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells 被引量:10
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作者 Viola Baradari Michael Hpfner +2 位作者 Alexander Huether Detlef Schuppan Hans Scherübl 《World Journal of Gastroenterology》 SCIE CAS CSCD 2007年第33期4458-4466,共9页
AIM: To investigate the antiproliferative effect of the histone deacetylase (HDAC) inhibitor MS-275 on cholangiocarcinoma cells alone and in combination with conventional cytostatic drugs (gemcitabine or doxorubicin) ... AIM: To investigate the antiproliferative effect of the histone deacetylase (HDAC) inhibitor MS-275 on cholangiocarcinoma cells alone and in combination with conventional cytostatic drugs (gemcitabine or doxorubicin) or the novel anticancer agents sorafenib or bortezomib. METHODS: Two human bile duct adenocarcinoma cell lines (EGI-1 and TFK-1) were studied. Crystal violet staining was used for detection of cell number changes. Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydrogenase (LDH). Apoptosis was determined by measuring the enzyme activity of caspase-3. Cell cycle status reflected by the DNA content was detected by flow cytometry.RESULTS: MS-275 treatment potently inhibited the proliferation of EGI-1 and TFK-1 cholangiocarcinoma cells by inducing apoptosis and cell cycle arrest. MS-275-induced apoptosis was characterized by activation of caspase-3, up-regulation of Bax and down-regulation of Bcl-2. Cell cycle was predominantly arrested at the G1/S checkpoint, which was associated with induction of the cyclin-dependent kinase inhibitor p21Waf/CIP1. Furthermore, additive anti-neoplastic effects were observed when MS-275 treatment was combined with gemcitabine or doxorubicin, while combination with the multi-kinase inhibitor sorafenib or the proteasome inhibitor bortezomib resulted in overadditive anti-neoplastic effects.CONCLUSION: The growth of human cholangiocarcinoma cells can be potently inhibited by MS-275 alone or in combination with conventional cytostatic drugs or new, targeted anticancer agents. 展开更多
关键词 Apoptosis CHOLANGIOCARCINOMA BORTEZOMIB Combination treatment histone deacetylase inhibitor MS-275 Proteasome inhibitor SORAFENIB
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QSAR Studies on the Inhibitory Activityof Levofloxacin-thiadiazole HDACi Conjugates to Histone Deacetylases 被引量:23
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作者 王超 冯长君 《Chinese Journal of Structural Chemistry》 SCIE CAS CSCD 2018年第11期1679-1688,共10页
A molecular electronegativity distance vector(M)based on 13 atomic types has been used to describe the structures of 19 conjugates(LHCc)of levofloxacin-thiadiazole HDAC inhibitor(HDACi)and related inhibitory activitie... A molecular electronegativity distance vector(M)based on 13 atomic types has been used to describe the structures of 19 conjugates(LHCc)of levofloxacin-thiadiazole HDAC inhibitor(HDACi)and related inhibitory activities(pH,i=1,2,6)of LHCc against histone deacetylases(HDACs,such as HDAC1,HDAC2 and HDAC6).The quantitative structure-activity relationships(QSAR)were established by using leaps-and-bounds regression analysis for the inhibitory activities(pH)of 19 above compounds to HDAC1,HDAC2 and HDAC6 along with M.The correlation coefficients(R~2)and the leave-one-out(LOO)cross validation Rfor the pH,pHand pHmodels were 0.976 and 0.949;0.985 and 0.977;0.976 and 0.932,respectively.The QSAR models had favorable correlations,as well as robustness and good prediction capability by R~2,F,R~2,A,Fand Vtests.Validated by using 3876 training sets,the models have good external prediction ability.The results indicate that the molecular structural units:–CH–(g=1,2),–NH,–OH,=O,–O–and–S–are the main factors which can affect the inhibitory activity of pH,pHas well as pHbioactivities of these compounds directly.Accordingly,the main interactions between HDACs inhibitor and HDACs are hydrophobic interaction,hydrogen bond,and coordination with Znto form compounds,which is consistent with the results in reports. 展开更多
关键词 levofloxacin-thiadiazole HDACi conjugates(LHCc) histone deacetylases(HDACs) inhibitory activity(pHi i = 1 2 6) molecular electronegativity distance vector quantitative structure-activity relationship(QSAR)
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Targeting histone deacetylases: perspectives for epigenetic-based therapy in cardio-cerebrovascular disease 被引量:7
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作者 Zi-Ying WANG Wen QIN Fan YI 《Journal of Geriatric Cardiology》 SCIE CAS CSCD 2015年第2期153-164,共12页
Although the pathogenesis of cardio-cerebrovascular disease (CCVD) is multifactorial, an increasing number of experimental and clinical studies have highlighted the importance of histone deacetylase (HDAC)-mediate... Although the pathogenesis of cardio-cerebrovascular disease (CCVD) is multifactorial, an increasing number of experimental and clinical studies have highlighted the importance of histone deacetylase (HDAC)-mediated epigenetic processes in the development of cardio-cerebrovascular injury. HDACs are a family of enzymes to balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. To date, 18 mammalian HDACs are identified and grouped into four classes based on similarity to yeast orthologs. The zinc-dependent HDAC family currently consists of 11 members divided into three classes (class I, II, and IV) on the basis of structure, sequence homology, and domain organization. In comparison, class III HDACs (also known as the sirtuins) are composed of a family of NAD+-dependent protein-modifying enzymes related to the Sir2 gene. HDAC inhibitors are a group of compounds that block HDAC activities typically by binding to the zinc-containing catalytic domain of HDACs and have displayed an- ti-inflammatory and antifibrotic effects in the cardio-cerebrovascular system. In this review, we summarize the current knowledge about classifications, functions of HDACs and their roles and regulatory mechanisms in the cardio-cerebrovascular system. Pharmacological tar- geting of HDAC-mediated epigenetic processes may open new therapeutic avenues for the treatment of CCVD. 展开更多
关键词 histone deacetylase Epigenetic modification Heart failure ATHEROSCLEROSIS STROKE
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Arabidopsis thaliana histone deacetylase1(AtHD1)is localized in euchromatic regions and demonstrates histone deacetylase activity in vitro 被引量:6
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作者 Paulus M Fong Lu Tian Z Jeffrey Chen 《Cell Research》 SCIE CAS CSCD 2006年第5期479-488,共10页
Arabidopsis thaliana histone deacetylase 1 (AtHD1 or AtHDA19), a homolog ot yeast RPD3, is a global regulator ot many physiological and developmental processes in plants. In spite of the genetic evidence for a role ... Arabidopsis thaliana histone deacetylase 1 (AtHD1 or AtHDA19), a homolog ot yeast RPD3, is a global regulator ot many physiological and developmental processes in plants. In spite of the genetic evidence for a role of AtHD1 in plant gene regulation and development, the biochemical and cellular properties ofAtHD 1 are poorly understood. Here we report cellular localization patterns ofAtHD 1 in vivo and histone deacetylase activity in vitro. The transient and stable expression of a green fluorescent protein (GFP)-tagged AtHD1 in onion cells and in roots, seeds and leaves of the transgenic Arabidopsis, respectively, revealed that AtHD1 is localized in the nucleus presumably in the euchromatic regions and excluded from the nucleolus. The localization patterns ofAtHD 1 are different from those of AtHD2 and AtHDA6 that are involved in nucleolus formation and silencing of transgenes and repeated DNA elements, respectively. In addition, a histone deacetylase activity assay showed that the recombinant AtHD 1 produced in bacteria demonstrated a specific histone deacetylase activity in vitro. The data suggest that AtHD 1 is a nuclear protein and possesses histone deacetylase activities responsible for global transcriptional regulation important to plant growth and development. 展开更多
关键词 ARABIDOPSIS histone deacetylase RPD3 subcellular localization gene silencing CHROMATIN
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Inhibition of histone deacetylase for the treatment of biliary tract cancer:A new effective pharmacological approach 被引量:5
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作者 Thilo Bluethner Manuel Niederhagen +5 位作者 Karel Caca Frederik Serr Helmut Witzigmann Christian Moebius Joachim Mossner Marcus Wiedmann 《World Journal of Gastroenterology》 SCIE CAS CSCD 2007年第35期4761-4770,共10页
AIM: To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer. METHODS: Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was stud... AIM: To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer. METHODS: Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the antitumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21^WAFl/CIP-1, PARP assay, cell cycle analysis, TUNEL assay, and immunhistochemistry for MIB-1. RESULTS: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines [mean IC50 (3 d) 0.11 and 0.05 μmol/L, respectively], and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21^WAF-1/CIP-1, induction of apoptosis (PARP cleavage), and cell cycle arrest at G2/M checkpoint. After 28 d, NVP- LBH589 significantly reduced tumor mass by 66% (bile duct cancer) and 87% (gallbladder cancer) in vivo in comparison to placebo, and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis by TUNEL assay and reduced cell proliferation (MIB-1). CONCLUSION: Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended. 展开更多
关键词 histone deacetylase inhibitor Biliary tract cancer CHOLANGIOCARCINOMA NVP-LAQ824 NVP-LBH589
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Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque 被引量:4
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作者 Ji-Kan Ryu Woo-Jean Kim Min-Ji Choi Jin-Mi Park Kang-Moon Song Mi-Hye Kwon Nando-Dulal Das Ki-Dong Kwon Dulguun Batbold Guo-Nan Yin Jun-Kyu Suh 《Asian Journal of Andrology》 SCIE CAS CSCD 2013年第5期640-645,共6页
Epigenetic modifications, such as histone acetylation/deacetylation, have been shown to play a role in the pathogenesis of fibrotic disease. Peyronie's disease (PD) is a localized fibrotic process of the tunica alb... Epigenetic modifications, such as histone acetylation/deacetylation, have been shown to play a role in the pathogenesis of fibrotic disease. Peyronie's disease (PD) is a localized fibrotic process of the tunica albuginea, which leads to penile deformity. This study was undertaken to determine the anti-fibrotic effect of small interfering RNA (siRNA)-mediated silencing of histone deacetylase 2 (HDAC2) in primary fibroblasts derived from human PD plaque. PD fibroblasts were pre-treated with HDAC2 siRNA and then stimulated with transforming growth factor-p1 (TGF-β1). Protein was extracted from treated fibroblasts for Western blotting and the membranes were probed with antibody to phospho-Smad2/Smad2, phospho-Smad3/Smad3, smooth muscle α-actin and extracellular matrix proteins, including plasminogen activator inhibitor-β 1, fibronectin, collagen I and collagen IV. We also performed immunocytochemistry to detect the expression of extracellular matrix proteins and to examine the effect of HDAC2 siRNA on the TGF-β1-induced nuclear translocation of Smad2/3 in fibroblasts. Knockdown of HDAC2 in PD fibroblasts abrogated TGF-β1-induced extracellular matrix production by blocking TGF-β1-induced phosphorylation and nuclear translocation of Smad2 and Smad3, and by inhibiting TGF-β1-induced transdifferentiation of fibroblasts into myofibroblasts. Decoding the individual function of the HDAC isoforms by use of siRNA technology, preferably siRNA for HDAC2, may lead to the development of specific and safe epigenetic therapies for PD. 展开更多
关键词 cell culture FIBROSIS histone deacetylase Peyronie's disease transforming growth factor-beta
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Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene a4 hydrolase and blocking LTB4 biosynthesis 被引量:4
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作者 Wei-qiang LU Jing-yuan WANG +4 位作者 Xue YAO Ping OUYANG Ning-ning DONG Dang WU Jin HUANG 《中国药理学与毒理学杂志》 CAS CSCD 北大核心 2017年第10期972-972,共1页
OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a pote... OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis. 展开更多
关键词 acute lung injury idiopathic pulmonary fibrosis histone deacetylase inhibitors alleviate neutrophilic inflammation leukotriene A4 hydrolase leukotriene B4
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Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer 被引量:4
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作者 Ramchandra Vigay Amnekar Shafqat Ali Khan +7 位作者 Mudasir Rashid Bharat Khade Rahul Thorat Poonam Gera Shailesh V Shrikhande Duane T Smoot Hassan Ashktorab Sanjay Gupta 《World Journal of Gastroenterology》 SCIE CAS 2020年第6期598-613,共16页
BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are f... BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are facing issues with toxicity and efficacy against solid tumors,which may be partly due to the lack of patient stratification for effective treatments.To study the need of patient stratification before HDACi treatment,and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer.METHODS The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues.The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays,chromatin remodeling and cell death.RESULTS In the present study,the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypoacetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer.The data highlights for the first time that pretreatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation,chromatin relaxation and cell cycle arrest.Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes,including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin,exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines.CONCLUSION Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification.Furthermore,HDACi therapy in pretreatment regimes is more effective with chemotherapy drugs,and may aid in predicting individual patient prognosis. 展开更多
关键词 Chemotherapy Combinatorial index Gastric cancer histone acetylation histone deacetylase inhibitor Patient stratification
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Correlation between Histone Deacetylase 9 and Regulatory T Cell in Patients with Chronic Heart Failure 被引量:3
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作者 Ping-ping LIAO Li-hua LIU +5 位作者 Bin WANG Xin FANG Shao-qiong ZHOU Wei LI Yan-qing ZHANG Si-ming GUAN 《Current Medical Science》 SCIE CAS 2018年第2期199-203,共5页
Heart failure (HF) is the end stage of various kinds of cardiovascular diseases and leads to a high mortality worldwide. Numerous studies have demonstrated that frequencies of CD4+CD25+Foxp3+ regulatory T cells ... Heart failure (HF) is the end stage of various kinds of cardiovascular diseases and leads to a high mortality worldwide. Numerous studies have demonstrated that frequencies of CD4+CD25+Foxp3+ regulatory T cells (Tregs) are reduced in HF patients and properly expanding Tregs attenuates HF progression. Histone deacetylase (HDAC) 9 has been revealed to contribute to several cardiovascular and cerebrovascular diseases. Plenty of studies showed that HDAC9 negatively regulated the number and function of Tregs. Thus, we aim to investigate the expression of HDAC 9 in patients with chronic heart failure (CHF) and the relationship among HDAC9, Tregs and CHF. Our research showed a reduced number of Tregs and an increased expression of HDAC9 mRNA in CHF patients. Patients with CHF were divided into two groups by heart function grade of New York Heart Association (NYHA), we found that the HDAC9 mRNA expression level in NYHA grade Ⅱ -Ⅲ group were lower than that in NYHA grade IV group. More importantly, the correlation study suggested that the expression of HDAC9 mRNA was negatively correlated to Tregs frequency and left ventricular ejection fraction (LVEF), whereas positively correlated to larger left ventricular end-diastolic dimension (LVEDD) and B-type natriuretic peptide (BNP) in patients with CHF. The correlation studies also showed a positive correlation between HDAC9 and the severity of CHF. Our research suggests that HDAC9 may be a new indicator for assessing CHF and it may offer a new direction for research of CHF. 展开更多
关键词 histone deacetylase 9 heart failure regulatory T cells B-type natriuretic peptide
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Experimental treatment of pancreatic cancer with two novel histone deacetylase inhibitors 被引量:2
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作者 Martin Haefner Thilo Bluethner +5 位作者 Manuel Niederhagen Christian Moebius Christian Wittekind Joachim Mossner Karel Caca Marcus Wiedmann 《World Journal of Gastroenterology》 SCIE CAS CSCD 2008年第23期3681-3692,共12页
AIM:To investigate in vitro and in vivo treatment with histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 in pancreatic cancer. METHODS:Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in... AIM:To investigate in vitro and in vivo treatment with histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 in pancreatic cancer. METHODS:Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 8 human pancreatic cancer cell lines using the 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide(MTT) assay. In addition,the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral activity of the drugs was assessed by immunoblotting for p21WAF-1,acH4,cell cycle analysis,TUNEL assay,and immunohistochemistry for MIB-1. RESULTS:In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines and was associated with hyperacetylation of nucleosomal histone H4,increased expression of p21WAF-1,cell cycle arrest at G2/M-checkpoint,and increased apoptosis. In vivo,NVP-LBH589 alone significantly reduced tumor mass and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed slightly increased apoptosis and no significant reduction of cell proliferation.CONCLUSION:Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human pancreatic cancer,although the precise mechanism of in vivo drug action is not yet completely understood. Therefore,further preclinical and clinical studies for the treatment of pancreatic cancer are recommended. 展开更多
关键词 histone deacetylase inhibitor Pancreatic cancer NVP-LAQ824 NVP-LBH589
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Combined inhibitors of angiogenesis and histone deacetylase:Efficacy in rat hepatoma 被引量:1
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作者 Marion Ganslmayer Annette Zimmermann +1 位作者 Steffen Zopf Christoph Herold 《World Journal of Gastroenterology》 SCIE CAS CSCD 2011年第31期3623-3629,共7页
AIM:To evaluate the antitumoral effect of combined inhibitors of angiogenesis and histone deacetylases in an experimental rat hepatoma model.METHODS:MH7777A hepatoma cells were injected into the liver of male Buffalo ... AIM:To evaluate the antitumoral effect of combined inhibitors of angiogenesis and histone deacetylases in an experimental rat hepatoma model.METHODS:MH7777A hepatoma cells were injected into the liver of male Buffalo rats.After 7 d treatment with the vascular endothelial growth factor receptor antagonist PTK787/ZK222584(PTK/ZK),the histone deacetylase inhibitor MS-275,tamoxifen(TAM) and/or retinoic acid was initiated(n ≥ 8 animals/group).Natural tumor development was shown in untreated control groups(control 1 with n = 12,control 2 with n = 8).The control groups were initiated at different time points to demonstrate the stability of the hepatoma model.For documentation of possible side effects,we documented any change in body weight,loss of fur and diarrhea.After 21 d treatment,the rats were euthanized.Main target parameters were tumor size and metastasis rate.Additionally,immunohistochemistry for the proliferating cell nuclear antigen(PCNA) and TdT-mediated dUTP-biotin nick end labeling(TUNEL) assay were performed.RESULTS:The control groups developed large tumor nodules with extrahepatic tumor burden in the lung and abdominal organs(control 1:6.18 cm3 ± 4.14 cm3 and control 2:8.0 cm3 ± 4.44 cm3 28 d after tumor cell injection).The tumor volume did not differ significantly in the control groups(P = 0.13).As single agents MS-275 and PTK/ZK reduced tumor volume by 58.6% ± 2.6% and 48.7% ± 3.2% vs control group 1,which was significant only for MS-275(P = 0.025).The combination of MS-275 and PTK/ZK induced a nearly complete and highly significant tumor shrinkage by 90.3% ± 1%(P = 0.005).Addition of TAM showed no further efficacy,while quadruple therapy with retinoic acid increased antitumoral efficacy(tumor reduction by 93 ± 1%) and side effects.PCNA positive cells were not significantly reduced by the single agents,while dual therapy(MS-275 and PTK/ZK) and quadruple therapy reduced the PCNA-positive cell fraction significantly by 9.1 and 20.6% vs control 1(P < 0.05).The number of TUNEL-positive cells,markers for ongoing apoptosis,was increased significantly by the single agents(control 1:6.9%,PTK/ZK:11.4%,MS-275:12.2% with P < 0.05 vs control 1).The fraction of TUNEL-positive cells was upregulated highly significantly by dual therapy(18.4%) and quadruple therapy(24.8%,P < 0.01 vs control 1).For the proliferating(PCNA positive) and apoptotic cell fraction,quadruple therapy was significantly superior to dual therapy(P = 0.01).CONCLUSION:Combined PTK/ZK and MS-275 were highly effective in this hepatoma model.Quadruple therapy enhanced the effects microscopically,but not macroscopically.These results should be investigated further. 展开更多
关键词 PTK787 ZK222584 MS-275 Hepatocellular carcinoma histone deacetylase inhibitor
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Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases 被引量:1
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作者 Wynne Sim Wei-Meng Lim +2 位作者 Ling-Wei Hii Chee-Onn Leong Chun-Wai Mai 《World Journal of Gastroenterology》 SCIE CAS 2022年第18期1934-1945,共12页
The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypas... The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses,thus allowing continuous tumor growth and development.Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer.Compared with other cancers,pancreatic cancer has a tumor microenvironment that can resist most treatment modalities,including emerging immunotherapy.Sadly,the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients,suggesting that pancreatic cancer has successfully evaded immunomodulation.In this review,we summarize the impact of genetic alteration and epigenetic modification(especially histone deacetylases,HDAC)on immune evasion in pancreatic cancer.HDAC overexpression significantly suppresses tumor suppressor genes,contributing to tumor growth and progression.We review the evidence on HDAC inhibitors in tumor eradication,improving T cells activation,restoring tumor immunogenicity,and modulating programmed death 1 interaction.We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer. 展开更多
关键词 histone acetylation histone deacetylases inhibitors Immune evasion Pancreatic cancers Pancreatic ductal adenocarcinoma
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Histone Deacetylase Inhibition:An Important Mechanism in the Treatment of Lymphoma 被引量:1
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作者 Shan-qi Guo Yi-zhuo Zhang 《Clinical oncology and cancer researeh》 CAS CSCD 2012年第2期85-89,共5页
Lymphomas enconlpass a group of malignancies that originate in the lymph nodes or other lymphoid tissues. Epigenetic modification, especially by histone deacetylase (HDACs), plays a key role during the occurrence an... Lymphomas enconlpass a group of malignancies that originate in the lymph nodes or other lymphoid tissues. Epigenetic modification, especially by histone deacetylase (HDACs), plays a key role during the occurrence and development of lymphomas. Consequently, HDAC inhibitors (HDACIs), a class of gene expression-modulating drugs, have emerged as promising mechanism-based agents for the treatment of lymphomas. This review presents the rationale of HDAC inhibition, describes the epigenetic-based mechanisms of action of HDACIs, discusses their clinical efficiency, and summarizes the current and future developments in this field. 展开更多
关键词 LYMPHOMA histone deacetylases THERAPEUTICS EPIGENOMICS
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Peanut testa extracts enhance anticancer effect of cisplatin against human cholangiocarcinoma cells via modulation of histone deacetylase inhibitory activity
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作者 Somprasong Saenglee Gulsiri Senawong +4 位作者 Jarckrit Jeeunngoi Sanun Jogloy Albert JKetterman Banchob Sripa Thanaset Senawong 《Asian Pacific Journal of Tropical Biomedicine》 SCIE CAS 2020年第8期369-378,共10页
Objective:To investigate the effect of combination treatments of cisplatin and KK4 and ICG15042 peanut testa extracts against cholangiocarcinoma cells in vitro.Methods:The growth inhibition,cell cycle arrest and apopt... Objective:To investigate the effect of combination treatments of cisplatin and KK4 and ICG15042 peanut testa extracts against cholangiocarcinoma cells in vitro.Methods:The growth inhibition,cell cycle arrest and apoptosis of cholangiocarcinoma cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry analysis,respectively.The levels of proteins involved in apoptosis were assessed using Western blotting assays.The caspase activity was assessed using a colorimetric caspase activity assay.Results:Cisplatin and peanut(KK4 and ICG15042)testa extracts inhibited the growth of cholangiocarcinoma cell lines(KKUM214 and KKU-100 cells)in a dose-and time-dependent manner.The combination treatments reduced cell viability and induced apoptosis of cholangiocarcinoma cells more efficiently than singledrug treatments.Cancer cell death synergistically mediated by cisplatin and peanut testa extracts was observed in KKU-M214 cells(combination index<1.0)but not in KKU-100 cells(combination index>1.0).The combination treatments also increased the subG1 population and caused KKU-M214 cell cycle arrest at S and G2/M phases,which were the combined effects of cisplatin(S phase arrest)and peanut testa extracts(G2/M phase arrest).In addition,p ERK1/2,Ac-H3,Bcl-2 and proteins related to apoptosis,including Bax and caspases 3,8,9,exhibited enhanced expression in KKUM214 cells.The combination treatments caused down-regulation of p53,whereas the expression of p21 was fairly constant when compared with cisplatin single drug treatment.Conclusions:Peanut testa extracts in combination with cisplatin synergistically reduce cell viability and induce apoptosis through stimulation of caspases 3,8 and 9 in KKU-M214 cells. 展开更多
关键词 Apoptosis CASPASES CHOLANGIOCARCINOMA CISPLATIN Natural histone deacetylase inhibitor Peanut testa extracts
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Effects of histone deacetylase inhibitors on transcriptional regulation of the hsp70 gene in Drosophila
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作者 Yan Mei Zhao Xia Chen Hui Sun Zhi Gen Yuan Guo Ling Ren Xiao Xue Li Jun Lu Bai Qu Huang 《Cell Research》 SCIE CAS CSCD 2006年第6期566-576,共11页
Histone acetyltransferases/deacetylases contribute to the activation or inactivation of transcription by modifying the structure of chromatin. Here we examined the effects ofhistone deacetylase inhibitors (HDIs), tr... Histone acetyltransferases/deacetylases contribute to the activation or inactivation of transcription by modifying the structure of chromatin. Here we examined the effects ofhistone deacetylase inhibitors (HDIs), trichostatin A, and sodium butyrate on hsp70 gene transcriptional regulation in Drosophila. The chromatin immunoprecipitation assays revealed that HDI treatments induced the hyperacetylation of histone H3 at the promoter and the transcribing regions of hsp 70 gene, increased the accessibility of heat-shock factor to target heat-shock element, and promoted the RNA polymerase Ⅱ-mediated transcription. Moreover, the quantitative real-time PCR confirmed that the HDI-induced hyperacetylation of histone H3 enhanced both the basal and the inducible expression of hsp70 mRNA level. In addition, the acetylation level ofhistone H3 at the promoter exhibited a fluctuated change upon the time of heat shock. These experimental data implicated a causal link between histone acetylation and enhanced transcription initiation of hsp 70 gene in Drosophila. 展开更多
关键词 histone acetylation hsp 70 histone deacetylase inhibitor Drosophila melanogaster
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Induction of Myelogenous Leukemia Cells with Histone Deacetylase Inhibitors through Down-regulating the Daxx Protein Expression
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作者 李春蕊 周剑峰 +3 位作者 吴雪琼 田野 邓金牛 刘文励 《Journal of Huazhong University of Science and Technology(Medical Sciences)》 SCIE CAS 2009年第5期546-550,共5页
The effects of two different histone deacetylase (HDAC) inhibitors, sodium butyrate (NAB) and trichostatin A (TSA),on apoptosis of human leukemic cells in vitro and the molecular mechanisms were investigated. Th... The effects of two different histone deacetylase (HDAC) inhibitors, sodium butyrate (NAB) and trichostatin A (TSA),on apoptosis of human leukemic cells in vitro and the molecular mechanisms were investigated. The experiments were divided up 5 groups: control group, NaB group, TSA group, NaB+Z-VAD-FMK group and TSA+Z-VAD-FMK group. The apoptosis rate was determined by mor- phological analysis and flow cytomytry. The expression of Daxx, Bcl-2, and Bcl-xl proteins was detected by Western blot. NaB and TSA could induce the apoptosis of HL-60 and K562 cells, and Z-VAD-FMK caused a marked decrease in apoptosis induced by HDAC inhibitors. HDAC inhibitors could down-regulate the expression of Daxx protein, but had no significant influence on the expression of Bcl-2 and Bcl-xl proteins. The results suggested that NaB and TSA induce distinct caspase-dependent apoptosis of human leukemic cells through down-regulating the expression of Daxx protein in vitro. 展开更多
关键词 histone deacetylase inhibitors apoptosis LEUKEMIA CASPASES DAXX
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The expression of histone deacetylases and the regenerative abilities of spinal-projecting neurons after injury
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作者 jie chen michael i.shifman 《Neural Regeneration Research》 SCIE CAS CSCD 2016年第10期1577-1578,共2页
Epigenetic control of regeneration after spinal cord injury: Com- plete spinal cord injury (SCI) in humans and other mammals leads to irreversible paralysis below the level of injury, due to failure of axonal regen... Epigenetic control of regeneration after spinal cord injury: Com- plete spinal cord injury (SCI) in humans and other mammals leads to irreversible paralysis below the level of injury, due to failure of axonal regeneration in the central nervous system (CNS). Previous work has shown that successful axon regeneration is dependent upon transcription of a large number of regeneration-associated genes (RAGs) and transcription factors (TFs) (Van Kesteren et al., 2011). A prominent theory in the field of axon regeneration is that the large differences in regenerative potential between peripheral nervous system (PNS) neurons, which regenerate well, and CNS neurons, which do not, reflect differences in intrinsic transcriptional net- works, rather than individual genes (Van Kesteren et al., 2011). 展开更多
关键词 HDAC gene The expression of histone deacetylases and the regenerative abilities of spinal-projecting neurons after injury
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Synergy of DNA methylation and histone deacetylase inhibitors in the re-expression of RASSF1A and P16 genes silenced in QBC cells
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作者 Hong Li Shaoqin Chen Yi Shu Yongjun Chen, Ying Su Xin Wang Shengquan Zou 《The Chinese-German Journal of Clinical Oncology》 CAS 2008年第11期627-630,共4页
Objective: To investigate the effects of DNA methylation and histone deacetylase inhibitors in the re-expression of P16 and RASSIF1A of QBC939. Methods: The QBC939 cells were treated with hydralazine and valproate eit... Objective: To investigate the effects of DNA methylation and histone deacetylase inhibitors in the re-expression of P16 and RASSIF1A of QBC939. Methods: The QBC939 cells were treated with hydralazine and valproate either alone or combined, and the control group was added with RPIM-1640 culture medium. After 48 h, the expression of P16 and RASSF1A genes were evaluated by reverse transcription-PCR, Western blot, and the methylation status of the two genes were detected with MSP (methylation specific PCR). Results: Hydralazine and valproate could induce demethylation of the promoter region of the two genes, and could make them re-active. The expressions of P16 and RASSF1A of cells treated with both drugs were higher than that of the cells treated with either hydralazine or valproate (P < 0.01). There was no RASSF1A gene, and few P16 gene expressing in the control group. The demethylation effect could be found in the groups treated with hydralazine or both drugs, whereas no demethylation effect happened in the valproate group. Conclusion: The two drugs could synergistically re-express P16 and RASSF1A genes silenced in QBC939, and they exerted a great anti-tumour effect on QBC cells. 展开更多
关键词 DNA methyltransferase inhibitor histone deacetylase inhibitor DNA hypermethylation gene re-expression
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