预约演示

更新于：2025-01-23

TNF-α x HDAC4

更新于：2025-01-23

基本信息

关联

项与 TNF-α x HDAC4 相关的药物

KAR-1641

靶点

HDAC4 x TNF-α

作用机制

HDAC4抑制剂 [+1]

在研机构-

原研机构

Karus Therapeutics Ltd.

在研适应症-

非在研适应症

炎症

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 TNF-α x HDAC4 相关的临床结果

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100 项与 TNF-α x HDAC4 相关的转化医学

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0 项与 TNF-α x HDAC4 相关的专利（医药）

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项与 TNF-α x HDAC4 相关的文献（医药）

2024-11-01·Combinatorial Chemistry & High Throughput Screening

Qingrexiaoji Recipe Regulates the Differentiation of M2 TAM via miR-29 in GC

Article

作者: Chen, Peifeng ; Pan, Lei ; Fei, Yuchang ; Zhang, Yiqiong ; Chen, Luting

Background:Gastric cancer, one of the most familiar adenocarcinomas of the gastrointestinal tract, ranks third in the world in cancer-related deaths. Traditional Chinese medicine can suppress the growth of tumors, and the underlying mechanism may be associated with the tumor microenvironment. Here, we investigated the anti-cancer effects of the Qingrexiaoji recipe on gastric cancer and the underlying molecular mechanism.Methods:An in vivo nude mouse model was established, and the expression of CD206, CD80, and M2 phenotype-related proteins (Arg-1, Fizz1) was obtained by flow cytometry and western blotting. The expressions of the M2 phenotype-related cytokines were examined by ELISA.Results:Qingrexiaoji recipe inhibited gastric tumor growth and downregulated the expression of CD206, IFN-γ, IL-13, IL-4, and TNF-α in vivo. Qingrexiaoji recipe deceased M2 phenotypic polarization by upregulating microRNA (miR)-29a-3p level. Luciferase activity assays showed that HDAC4 is a potential target of miR-29a-3p. In cells co-transfected with HDAC4 siRNA and miR-29a-3p inhibitor and treated with IL-4 and Qingrexiaoji recipe, the miR-29a-3p inhibitorinduced increase of M2 phenotypic polarization was reversed.Conclusion:In summary, these results suggested that the Qingrexiaoji recipe regulated M2 macrophage polarization by regulating miR-29a-3p/HDAC4, providing a different and innovative treatment for gastric cancer.

2024-08-01·Environmental Pollution

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

Article

作者: Zeng, Zhuotong ; Tang, Rui ; Zhan, Yi ; 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.

2023-05-01·eBioMedicine

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

Article

作者: Lo Conte, Marta ; Ungaro, Federica ; Nobili, Angelica ; Liang, Wenjie ; Palmieri, Vittoria ; Massimino, Luca ; Antonini Cencicchio, Martina ; Devecchi, Elisabetta ; Diana, Julien ; Ferrarese, Roberto ; Mancini, Nicasio ; Scavini, Marina ; Riba, Michela ; Cosorich, Ilaria ; Lamparelli, Luigi Antonio ; Bosi, Emanuele ; Fasano, Alessio ; 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).

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