The Protective Mechanism of CAY10683 on Intestinal Mucosal Barrier in Acute Liver Failure through LPS/TLR4/MyD88 Pathway

Wang, Yao; Chen, Hui; Chen, Qian; Jiao, Fangzhou; Zhang, Wenbin; Gong, Zuojiong

doi:10.1155/2018/7859601

Cited by 26 publications

(21 citation statements)

References 32 publications

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“…These results are consistent with our previous findings that TSA can effectively inhibit the release of multiple inflammatory factors, improve hepatocyte injury, and improve the survival rate of rats with acute-on-chronic liver failure [16]. The HDAC2 inhibitor CAY10683 achieves the goal of treating acute liver failure by protecting the damaged intestinal mucosa and reducing intestinal endotoxemia [17]. Most of these studies are based on the mechanism association with acetylation in the process of inflammation.…”

Section: Introductionsupporting

confidence: 90%

Modulations of Histone Deacetylase 2 Offer a Protective Effect through the Mitochondrial Apoptosis Pathway in Acute Liver Failure

Wang

Yang

Jiao

et al. 2019

Oxidative Medicine and Cellular Longevity

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The purpose of this study was to investigate the modulation of histone deacetylase 2 (HDAC2) on mitochondrial apoptosis in acute liver failure (ALF). The cellular model was established with LO2 cells stimulated by tumor necrosis factor alpha (TNF-α)/D-galactosamine (D-gal). Rats were administrated by lipopolysaccharide (LPS)/D-gal as animal model. The cell and animal models were then treated by HDAC2 inhibitor CAY10683. HDAC2 was regulated up or down by lentiviral vector transfection in LO2 cells. The mRNA levels of bcl2 and bax were detected by real-time PCR. The protein levels of HDAC2, bcl2, bax, cytochrome c (cyt c) in mitochondrion and cytosol, apoptosis protease activating factor 1 (apaf1), caspase 3, cleaved-caspase 3, caspase 9, cleaved-caspase 9, acetylated histone H3 (AH3), and histone H3 (H3) were assayed by western blot. Apoptosis was detected by flow cytometry. The serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) levels were also assayed. The openness degree of the mitochondrial permeability transition pore (MPTP) was detected by ultraviolet spectrophotometry. The apoptosis of hepatocytes in liver tissues was determined by tunnel staining. The liver tissue pathology was detected by hematoxylin eosin (HE) staining. The ultrastructure of liver tissue was observed by electron microscopy. Compared with cell and rat model groups, the bax mRNA level was decreased, and bcl2 mRNA was increased in the CAY10683 treatment group. The protein levels of HDAC2, bax, cyt c in cytosol, apaf1, cleaved-caspase 3, and cleaved-caspase 9 were decreased, and the apoptosis rate was decreased (P<0.05), whereas the protein level of bcl2 and cyt c in the mitochondrion was elevated (P<0.05) in the CAY10683 treatment group. In the HDAC2 down- or upregulated LO2 cells, the mitochondrial apoptosis pathway was inhibited or activated, respectively. After being treated with TNF-α/D-gal in HDAC2 down- or upregulated LO2 cells, the mitochondrial apoptosis pathway was further suppressed or activated, respectively. The MPTP value was elevated in CAY10683-treated groups compared with the rat model group (P<0.05). Liver tissue pathological damage and apoptotic index in the CAY10683-treated group were significantly reduced. In addition, AH3 was elevated in both cell and animal model groups (P<0.05). Downregulated or overexpressed HDAC2 could accordingly increase or decrease the AH3 level, and TNF-α/D-gal could enhance the acetylation effect. These results suggested that modulations of histone deacetylase 2 offer a protective effect through the mitochondrial apoptosis pathway in acute liver failure.

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Section: Introductionsupporting

confidence: 90%

Modulations of Histone Deacetylase 2 Offer a Protective Effect through the Mitochondrial Apoptosis Pathway in Acute Liver Failure

Wang

Yang

Jiao

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…LPS was used to induce damage to the mucosal barrier of NCM460 cells. The NCM460 cells treated with the HDAC2 inhibitor (CAY10683) increased mRNA and protein levels of ZO-1 (Wang et al, 2018). Collectively, this suggests that HDAC2 plays differential roles in the increase or reduction of epithelial barrier integrity depending on the site of the human epithelial cells.…”

Section: Histone Deacetylases (Hdacs) In Armentioning

confidence: 90%

“…TSA treatment in this study decreased the association between HDAC2 with the promoter region of ZO-1 as demonstrated by chromatin immunoprecipitation assay ( Ganatra et al, 2018 ). The effect of HDAC2 inhibitor CAY10683 was investigated on the expression on ZO-1 at the intestinal mucosal barrier of lipopolysaccharide (LPS)-stimulated NCM460 cells (a normal human colon mucosal epithelial cell line) ( Wang et al, 2018 ). LPS was used to induce damage to the mucosal barrier of NCM460 cells.…”

Section: Survey Methodologymentioning

confidence: 99%

Zonula occludens and nasal epithelial barrier integrity in allergic rhinitis

Sarah

Shukri

Ashari

et al. 2020

PeerJ

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Allergic rhinitis (AR) is a common disease affecting 400 million of the population worldwide. Nasal epithelial cells form a barrier against the invasion of environmental pathogens. These nasal epithelial cells are connected together by tight junction (TJ) proteins including zonula occludens-1 (ZO-1), ZO-2 and ZO-3. Impairment of ZO proteins are observed in AR patients whereby dysfunction of ZOs allows allergens to pass the nasal passage into the subepithelium causing AR development. In this review, we discuss ZO proteins and their impairment leading to AR, regulation of their expression by Th1 cytokines (i.e., IL-2, TNF-α and IFN-γ), Th2 cytokines (i.e., IL-4 and IL-13) and histone deacetylases (i.e., HDAC1 and HDAC2). These findings are pivotal for future development of targeted therapies by restoring ZO protein expression and improving nasal epithelial barrier integrity in AR patients.

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“…Santacruzamate A is a selective HDAC2 inhibitor. Treatment with Santacruzamate A shows the protection of the intestinal mucosal barrier with increased expression of ZO-1 and occludin in a rat model of galactosamine/LPS-induced acute liver failure (ALF) [62]. Moreover, the treatment with Trichostatin A (TSA), a prototypical pan-HDAC inhibitor, dramatically improves intestinal permeability in the ALF rat model [63].…”

Section: Effect Of Hdac Inhibitors On the Intestinal Barrier Damaged mentioning

confidence: 99%

Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

Kim

Santhanam²,

Lim

et al. 2020

IJMS

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic strategy for patients with both malignant and nonmalignant disorders. The therapeutic benefits of allo-HSCT in malignant disorders are primarily derived from the graft-versus-leukemia (GvL) effect, in which T cells in the donor graft recognize and eradicate residual malignant cells. However, the same donor T cells can also recognize normal host tissues as foreign, leading to the development of graft-versus-host disease (GvHD), which is difficult to separate from GvL and is the most frequent and serious complication following allo-HSCT. Inhibition of donor T cell toxicity helps in reducing GvHD but also restricts GvL activity. Therefore, developing a novel therapeutic strategy that selectively suppresses GvHD without affecting GvL is essential. Recent studies have shown that inhibition of histone deacetylases (HDACs) not only inhibits the growth of tumor cells but also regulates the cytotoxic activity of T cells. Here, we compile the known therapeutic potential of HDAC inhibitors in preventing several stages of GvHD pathogenesis. Furthermore, we will also review the current clinical features of HDAC inhibitors in preventing and treating GvHD as well as maintaining GvL.

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The Protective Mechanism of CAY10683 on Intestinal Mucosal Barrier in Acute Liver Failure through LPS/TLR4/MyD88 Pathway

Cited by 26 publications

References 32 publications

Modulations of Histone Deacetylase 2 Offer a Protective Effect through the Mitochondrial Apoptosis Pathway in Acute Liver Failure

Modulations of Histone Deacetylase 2 Offer a Protective Effect through the Mitochondrial Apoptosis Pathway in Acute Liver Failure

Zonula occludens and nasal epithelial barrier integrity in allergic rhinitis

Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

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