Last update 01 Nov 2024

TNF-α x HDAC4

Last update 01 Nov 2024

Basic Info

Related Targets

TNF-αHDAC4

Drugs associated with TNF-α x HDAC4

KAR-1641

Target

HDAC4 x TNF-α

Mechanism

HDAC4 inhibitors [+1]

Active Org.-

Originator Org.

Karus Therapeutics Ltd.

Active Indication-

Inactive Indication

Inflammation

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TNF-α x HDAC4

100 Translational Medicine associated with TNF-α x HDAC4

0 Patents (Medical) associated with TNF-α x HDAC4

Literatures (Medical) associated with TNF-α x HDAC4

01 Aug 2024·Environmental Pollution

Silica's silent threat: Contributing to skin fibrosis in systemic sclerosis by targeting the HDAC4/Smad2/3 pathway

Article

Author: Zeng, Zhuotong ; Zhan, Yi ; Tang, Rui ; Shi, Yaqian ; He, Xinglan ; Chai, Ke ; Xiao, Yangfan ; Yu, Jiangfan ; Xiao, Rong ; Qiu, Xiangning ; Liu, Licong ; Tang, Bingsi ; Liu, Jiani

Nowadays, silica products are widely used in daily life, especially in skin applications, which inevitably increases the risk of silica exposure in general population. However, inadequate awareness of silica's potential hazards and lack of self-protection are of concern. Systemic sclerosis (SSc) is characterized by progressive tissue fibrosis under environmental and genetic interactions. Silica exposure is considered an important causative factor for SSc, but its pathogenesis remains unclear. Within this study, we showed that lower doses of silica significantly promoted the proliferation, migration, and activation of human skin fibroblasts (HSFs) within 24 h. Silica injected subcutaneously into mice induced and exacerbated skin fibrosis. Notably, silica increased histone deacetylase-4 (HDAC4) expression by inducing its DNA hypomethylation in normal HSFs. The elevated HDAC4 expression was also confirmed in SSc HSFs. Furthermore, HDAC4 was positively correlated with Smad2/3 phosphorylation and COL1, α-SMA, and CTGF expression. The HDAC4 inhibitor LMK235 mitigated silica-induced upregulation of these factors and alleviated skin fibrosis in SSc mice. Taken together, silica induces and exacerbates skin fibrosis in SSc patients by targeting the HDAC4/Smad2/3 pathway. Our findings provide new insights for evaluating the health hazards of silica exposure and identify HDAC4 as a potential interventional target for silica-induced SSc skin fibrosis.

01 May 2023·eBioMedicine

Alterations of the intestinal mucus layer correlate with dysbiosis and immune dysregulation in human Type 1 Diabetes

Article

Author: Lo Conte, Marta ; Ungaro, Federica ; Nobili, Angelica ; Liang, Wenjie ; Palmieri, Vittoria ; Massimino, Luca ; Diana, Julien ; Devecchi, Elisabetta ; Antonini Cencicchio, Martina ; Ferrarese, Roberto ; Mancini, Nicasio ; Scavini, Marina ; Riba, Michela ; Cosorich, Ilaria ; Lamparelli, Luigi Antonio ; Fasano, Alessio ; Bosi, Emanuele ; Bolla, Andrea Mario ; Falcone, Marika ; Pedone, Erika

BACKGROUNDIn preclinical models of Type 1 Diabetes (T1D) the integrity of the gut barrier (GB) is instrumental to avoid dysregulated crosstalk between the commensal microbiota and immune cells and to prevent autoimmunity. The GB is composed of the intestinal epithelial barrier (IEB) and of the mucus layer containing mucins and antimicrobial peptides (AMPs) that are crucial to maintain immune tolerance. In preclinical models of T1D the alterations of the GB primarily affect the mucus layer. In human T1D increased gut permeability and IEB damage have been demonstrated but the integrity of the mucus layer was never assessed.METHODSWe evaluated GB integrity by measuring serological markers of IEB damage (serological levels of zonulin) and bacterial translocation such as lipopolysaccharide binding protein (LBP) and myeloid differentiation protein 2 (MD2), and mRNA expression of tight junction proteins, mucins and AMPs in intestinal tissue of T1D patients and healthy controls (HC). Simultaneously, we performed immunological profiling on intestinal tissue and 16S rRNA analysis on the mucus-associated gut microbiota (MAGM).FINDINGSOur data show a GB damage with mucus layer alterations and reduced mRNA expression of several mucins (MUC2, MUC12, MUC13, MUC15, MUC20, MUC21) and AMPs (HD4 and HD5) in T1D patients. Mucus layer alterations correlated with reduced relative abundance of short chain fatty acids (SCFA)-producing bacteria such as Bifidobacterium dentium, Clostridium butyricum and Roseburia intestinalis that regulate mucin expression and intestinal immune homeostasis. In T1D patients we also found intestinal immune dysregulation with higher percentages of effector T cells such as T helper (Th) 1, Th17 and TNF-α⁺ T cells.INTERPRETATIONOur data show that mucus layer alterations are present in T1D subjects and associated with dysbiosis and immune dysregulation.FUNDINGResearch Grants from the Juvenile Diabetes Foundation (Grant 1-INO-2018-640-A-N to MF and 2-SRA-2019-680-S-B to JD) and from the Italian Ministry of Health (Grant RF19-12370721 to MF).

01 Jan 2023·The Journal of toxicological sciences

Propofol improves ischemia reperfusion-induced liver fibrosis by regulating lncRNA HOXA11-AS.

Article

Author: Luo, Jia ; Liu, Jitong ; Luo, Feng ; Liao, Yongqiong ; Liao, Qian ; Mou, Yan

Liver ischemia reperfusion (IR) injury induces hepatic stellate cell (HSC) activation and liver fibrosis. Propofol (PRO) possesses a positive protective effect on liver ischemia reperfusion injury. We aimed to investigate PRO function and mechanism in IR-induced liver fibrosis. A mice model of liver IR was established. Hematoxylin-eosin (HE) staining was utilized to evaluate liver tissue's pathological changes. Masson staining was applied to evaluate liver fibrosis. The expression level of α-SMA was measured by immunohistochemical (IHC). The expressions of lncRNA HOXA11-AS (HOXA11-AS), PTBP1, HDAC4, α-SMA, COL1A1 and Fibronectin were tested by qRT-PCR or Western blot. The commercial kits detected alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations in serum. Enzyme-linked immunosorbent assay (ELISA) measured TNF-α and IL-6 levels. The binding relationship between HOXA11-AS, PTBP1 and HDAC4 was verified by RNA immunoprecipitation (RIP). Our results showed that PRO alleviated liver fibrosis and the inflammation in IR-induced mice. PRO decreased the expression levels of HOXA11-AS, PTBP1 and HDAC4. Furthermore, HOXA11-AS overexpression abolished the protective effect of PRO against liver fibrosis in mice with IR-disposed. HOXA11-AS interacted with PTBP1 to regulate HDAC4 level and prevented its degradation in JS-1 cells. HDAC4 silencing eliminated the regulatory of HOXA11-AS overexpression on fibrosis and inflammation in IR-induced mice PRO inhibited HOXA11-AS expression to regulate HDAC4, thereby influencing liver fibrosis and inflammation induced by IR. It suggesting that PRO plays a protective role in liver fibrosis induced by ischemia-reperfusion in mice by regulating HOXA11-AS/PTBP1/HDAC4 axis.

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