Epigenetic modifications by histone deacetylases: Biological implications and therapeutic potential in liver fibrosis

Chen, Peijie; Huang, Cheng; Meng, Xiao‐Ming; Li, Jun

doi:10.1016/j.biochi.2015.06.016

Cited by 34 publications

(46 citation statements)

References 88 publications

(131 reference statements)

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“…Also our results showed that VPA has an effect on serological marker for liver fibrosis (TGF‐β1) and liver enzymes (ALT and AST) suggesting that inhibition of HDACs may suppress EMT through effects on TGF‐β1 signaling as the level of TGF‐β1 started to decline in VPA‐treated animals compared to fibrotic animals. This confirms the fundamental role of histone deacetylation in liver fibrosis and the contribution of the complexity of gene regulation by the acetylation state of histone molecules in HSCs .…”

Section: Discussionsupporting

confidence: 74%

“…To determine if resolution of liver fibrosis is associated with concomitant reduction of HSCs activation, expression of a-SMA was examined. Our results showed remarkable upregulation of a-SMA mRNA which indicates the activation of HSCs (22) and its expression was significantly declined by VPA Previous studies have revealed that therapeutic interventions of hepatocyte growth factor (HGF) as remarkable antifibrotic effects in induced-liver fibrosis by CCl 4 is associated with decreased a-SMA expression, attenuated deposition of collagen and reduced serum level of ALT and AST (39,40) confirming that inhibition of HSC activation are pivotal goals for intervention in the hepatic fibrogenesis cascade (1).…”

Section: Discussionmentioning

confidence: 97%

“…Previous studies have revealed that therapeutic interventions of hepatocyte growth factor (HGF) as remarkable anti‐fibrotic effects in induced‐liver fibrosis by CCl 4 is associated with decreased α‐SMA expression, attenuated deposition of collagen and reduced serum level of ALT and AST confirming that inhibition of HSC activation are pivotal goals for intervention in the hepatic fibrogenesis cascade .…”

Section: Discussionmentioning

confidence: 99%

“…Valproic acid (VPA), a branched short‐chain fatty acid and a known treatment for several conditions including epilepsy and bipolar disorder , is a selective class I‐ histone deacetylase inhibitor which can prevent death in experimental models following hemorrhagic shock . Recently, a great number of the studies linking VPA with liver disease have suggested an essential role for VPA and its sodium salt in remodeling fibrosis as inhibition of HDACs may suppress EMT through their effects on TGF‐β1 signaling . Previously, it has been reported that inhibition of HDAC activity suppresses EMT induced by transforming growth factor‐β (TGF‐β) in human renal epithelial cells .…”

Section: Introductionmentioning

confidence: 99%

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Effect of histone deacetylase inhibitor on epithelial‐mesenchymal transition of liver fibrosis

et al. 2018

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Liver fibrosis is an excessively reversible wound healing process and the fibrotic disorder is the activation of hepatic stellate cell that requires extensive alterations in gene expression. As reversible deacetylation of histone proteins modulate gene expression, we examined the effect of valproic acid (VPA) as selective histone deacetylase inhibitor on CCl-4 induced liver fibrosis. Thirty rats were divided into three equal groups; control group, fibrotic group and VPA-treated group. The rats were sacrificed after 6 weeks of liver fibrosis induction. The histopathological effect on liver tissue was examined. The expression of α-SMA and Smad-4 mRNA and serum levels of TGF-β1, alanine aminotransferase, and aspartate aminotransferase were determined. Treatment of rats with VPA attenuated carbon tetrachloride-induced liver fibrosis. Moreover, α-SMA and Smad-4 expression was repressed under VPA treatment and both serum TGF-β1 and liver enzymes were significantly decreased. The histone deacetylase inhibitor-1 VPA inhibits the epithelial-mesenchymal transition and affects hepatic stellate cell activation during liver fibrosis through downregulation of Smad4 and α-SMA expression which may serve as a promising agent in liver fibrosis treatment. © 2018 IUBMB Life, 70(6):511-518, 2018.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of histone deacetylase inhibitor on epithelial‐mesenchymal transition of liver fibrosis

et al. 2018

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“…At present, there are a total of 11 HDAC family members identified on the basis of their similarity chain (Figure 1). 3,4 HDACs are enzymes that catalyze the deacetylation of lysine remnants located at the N-terminal of several protein substrates, such as nucleosomal histones. Histone acetylation has an important role in gene expression.…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitors: A Prospect in Drug Discovery

Yadav¹,

Mishra²,

Yadav³

2019

tjps

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Kanser tedavisi tüm toplum için büyük bir kışkırtıcıdır ve ilaç keşfi alanında bir araştırma hattını izlemektedir. Bu nedenle, işlemeyen ilaç hedeflerini iyileştirme yeterliliğine sahip, tıbbi aktif bir ajan keşfetmek için hayati bir gereklilik vardır. Artan pragmatik kanıtlar, histon deasetilazların (HDAC) kanserin ilerleme aşamasında deasetilasyonu arttırarak ve malignite değişikliklerini tetikleyerek kapana kısıldığını ifade etmektedir. HDAC inhibitörleri, ilaç keşfi bağlamında terapötik bir hedef olarak HDAC biyolojisiyle ilgili kimyasal varlığı araştırmak için, çığır açıcı iskele ve ulaşılabilir bir anahtar sağlarlar. HDAC inhibitörünün gen ekpresyonu yoluyla, kanserli hücrelere sitotoksisiteyi ihtiyatlı bir şekilde aktarmak için anti-kanser bir madde olarak geliştirilmesi yaklaşan bir gerekliliktir. Bu derlemede HDAC enziminin temelleri, inhibitörleri ve terapötik sonuçları üzerinde durulmuştur. Anahtar kelimeler: Histon deasetilaz inhibitörleri, apopitoz, çoklu tedavi yaklaşımı, kanser Cancer is a provocative issue across the globe and treatment of uncontrolled cell growth follows a deep investigation in the field of drug discovery. Therefore, there is a crucial requirement for discovering an ingenious medicinally active agent that can amend idle drug targets. Increasing pragmatic evidence implies that histone deacetylases (HDACs) are trapped during cancer progression, which increases deacetylation and triggers changes in malignancy. They provide a groundbreaking scaffold and an attainable key for investigating chemical entity pertinent to HDAC biology as a therapeutic target in the drug discovery context. Due to gene expression, an impending requirement to prudently transfer cytotoxicity to cancerous cells, HDAC inhibitors may be developed as anticancer agents. The present review focuses on the basics of HDAC enzymes, their inhibitors, and therapeutic outcomes.

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Aberrant expression of histone deacetylase 8 in endometriosis and its potential as a therapeutic target

Zheng

Liu

Guo

2023

Reprod Medicine & Biology

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PurposeTo screen Zn2+‐dependent histone deacetylase (HDAC) 1‐11 in endometriotic cells and then evaluated the HDACs identified from the screening in ovarian endometrioma (OE) and deep endometriotic (DE) lesions, and to evaluate the therapeutic potential of HDAC8 inhibition in mice.MethodsQuantification of gene and protein expression levels of HDAC1‐11 in endometriotic cells stimulated by TGF‐β1, and immunohistochemistry analysis of Class I HDACs and HDAC6 in OE/DE lesion samples. The therapeutic potential of HDAC8 inhibition was evaluated by a mouse model of deep endometriosis.ResultsThe screening identified Class I HDACs and HDAC6 as targets of interest. Immunohistochemistry analysis found a significant elevation in HDAC8 immunostaining in both OE and DE lesions, which was corroborated by gene and protein expression quantification. For other Class I HDACs and HDAC6, their lesional expression was more subtle and nuanced. HDAC1 and HDAC6 staining was significantly elevated in DE lesions while HDAC2 and HDAC3 staining was reduced in DE lesions. Treatment of mice with induced deep endometriosis with an HDAC8 inhibitor resulted in significantly longer hotplate latency, a reduction of lesion weight by nearly two‐thirds, and significantly reduced lesional fibrosis.ConclusionsThese findings highlight the progression‐dependent nature of specific HDAC aberrations in endometriosis, and demonstrate, for the first titme, the therapeutic potential of suppressing HDAC8.

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Epigenetic modifications by histone deacetylases: Biological implications and therapeutic potential in liver fibrosis

Cited by 34 publications

References 88 publications

Effect of histone deacetylase inhibitor on epithelial‐mesenchymal transition of liver fibrosis

Effect of histone deacetylase inhibitor on epithelial‐mesenchymal transition of liver fibrosis

Histone Deacetylase Inhibitors: A Prospect in Drug Discovery

Aberrant expression of histone deacetylase 8 in endometriosis and its potential as a therapeutic target

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