Redox Biology
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2022
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IF 10.787
Chenxu Ge,Jun Tan,Deshuai Lou,Liancai Zhu,Zixuan Zhong,Xianling Dai,Yan Sun,Qin Kuang,Junjie Zhao,Longyan Wang,Jin Liu,Bochu Wang,Minxuan Xu
Mulberrin (Mul) is a key component of the traditional Chinese medicine Romulus Mori with various biological functions. However, the effects of Mul on liver fibrosis have not been addressed, and thus were investigated in our present study, as well as the underlying mechanisms. Here, we found that Mul administration significantly ameliorated carbon tetrachloride (CCl 4 )-induced liver injury and dysfunction in mice. Furthermore, CCl 4 -triggerd collagen deposition and liver fibrosis were remarkably attenuated in mice with Mul supplementation through suppressing transforming growth factor β1 (TGF-β1)/SMAD2/3 signaling pathway. Additionally, Mul treatments strongly restrained the hepatic inflammation in CCl 4 -challenged mice via blocking nuclear factor-κB (NF-κB) signaling. Importantly, we found that Mul markedly increased liver TRIM31 expression in CCl 4 -treated mice, accompanied with the inactivation of NOD-like receptor protein 3 (NLRP3) inflammasome. CCl 4 -triggered hepatic oxidative stress was also efficiently mitigated by Mul consumption via improving nuclear factor E2-related factor 2 (Nrf2) activation. Our in vitro studies confirmed that Mul reduced the activation of human and mouse primary hepatic stellate cells (HSCs) stimulated by TGF-β1. Consistently, Mul remarkably retarded the inflammatory response and reactive oxygen species (ROS) accumulation both in human and murine hepatocytes. More importantly, by using hepatocyte-specific TRIM31 knockout mice (TRIM31 Hep-cKO ) and mouse primary hepatocytes with Nrf2-knockout (Nrf2 KO ), we identified that the anti-fibrotic and hepatic protective effects of Mul were TRIM31/Nrf2 signaling-dependent, relieving HSCs activation and liver fibrosis. Therefore, Mul-ameliorated hepatocyte injury contributed to the suppression of HSCs activation by improving TRIM31/Nrf2 axis, thus providing a novel therapeutic strategy for hepatic fibrosis treatment.
研究领域:
药理学
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肝病学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
EXPERIMENTAL GERONTOLOGY
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2024
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IF 3.3
Baoying Wang,Lei Tian,Mengdi Wu,Duo Zhang,Xiangli Yan,Ming Bai,Yucheng Li,Pan Su,Erping Xu
The NLRP3 inflammasome is critically involved in the development of depression. The E3 ubiquitin ligase TRIM31 negatively regulates this process by promoting the degradation of NLRP3 through the ubiquitin-proteasome pathway. Modified Danzhi Xiaoyaosan (MDZXYS) has shown good therapeutic effect in both preclinical and clinical depression treatments, yet the underlying mechanisms of its antidepressant effects are not fully understood. In the present study, we aimed to explore the antidepressant mechanisms of MDZXYS, focusing on NLRP3 activation and ubiquitin-mediated degradation. We employed rats with depression induced by chronic unpredictable mild stress (CUMS) and conducted various behavioral tests, including the sucrose preference, forced swimming, and open field tests. Neuronal damage in CUMS-treated rats was assessed using Nissl staining. We measured proinflammatory cytokine levels using ELISA kits and analyzed NLRP3/TRIM31 protein expression via Western blotting and immunofluorescence staining. Our results disclosed that MDZXYS reversed CUMS-induced depression-like behaviors in rats, reduced proinflammatory cytokine levels (IL-1β), and ameliorated neuronal damage in the prefrontal cortex. Additionally, CUMS activated the NLRP3 inflammasome in the prefrontal cortex and upregulated the protein expression of TRIM31. After MDZXYS administration, the expression of NLRP3 inflammasome-associated proteins was reduced, while the expression level of TRIM31 was further increased. Through co-localized immunofluorescence staining, we observed a significant elevation in the co-localization expression of NLRP3 and TRIM31 in the prefrontal cortex of the MDZXYS group. These findings suggest that inhibiting NLRP3 inflammasome-mediated neuroinflammation by modulating the TRIM31signaling pathway may underlie the antidepressant effects of MDZXYS, and further support targeting NLRP3 as a novel approach for the prevention and treatment of depression.
研究领域:
神经科学
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药理学
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精神病学
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分子生物学
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DOI
PubMed
高影响因子
Human Genomics
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2024
·Vol. 18
·期 1
·1-18
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IF 3.8
Ding Yixin,Lu Yangyang,Guo Jing,Chen Shuming,Han Xiaoxi,Wang Shibo,Zhang Mengqi,Wang Rui,Song Jialin,Wang Kongjia,Qiu Wensheng,Qi Weiwei
Most TRIM family members characterized by the E3-ubiquitin ligases, participate in ubiquitination and tumorigenesis. While there is a dearth of a comprehensive investigation for the entire family in gastric cancer (GC). By combining the TCGA and GEO databases, common TRIM family members (TRIMs) were obtained to investigate gene expression, gene mutations, and clinical prognosis. On the basis of TRIMs, a consensus clustering analysis was conducted, and a risk assessment system and prognostic model were developed. Particularly, TRIM31 with clinical prognostic and diagnostic value was chosen for single-gene bioinformatics analysis, in vitro experimental validation, and immunohistochemical analysis of clinical tissue microarrays. The combined dataset consisted of 66 TRIMs, of which 52 were differentially expressed and 43 were differentially prognostic. Significant survival differences existed between the gene clusters obtained by consensus clustering analysis. Using 4 differentially expressed genes identified by multivariate Cox regression and LASSO regression, a risk scoring system was developed. Higher risk scores were associated with a poorer prognosis, suppressive immune cell infiltration, and drug resistance. Transcriptomic data and clinical sample tissue microarrays confirmed that TRIM31 was highly expressed in GC and associated with a poor prognosis. Pathway enrichment analysis, cell migration and colony formation assay, EdU assay, reactive oxygen species (ROS) assay, and mitochondrial membrane potential assay revealed that TRIM31 may be implicated in cell cycle regulation and oxidative stress-related pathways, contribute to gastric carcinogenesis. This study investigated the whole functional and expression profile and a risk score system based on the TRIM family in GC. Further investigation centered around TRIM31 offers insight into the underlying mechanisms of action exhibited by other members of its family in the context of GC.
研究领域:
分子生物学
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癌症研究
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生物信息学
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病理学
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产品关联
DOI
PubMed
高影响因子
ANTIOXIDANTS & REDOX SIGNALING
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2026
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IF 6.1
Ze Wang,Kejie Chang,Ke Zhang,Pei Wang,Guangjian Bai,Zhenhua Wang,Jian Xiao,Xin Tong,Jun Zhao
Aims:Esophageal squamous cell carcinoma (ESCC) is among the most lethal malignancies worldwide, with a five-year survival rate below 20%. Ferroptosis—a regulated form of cell death driven by iron-dependent lipid peroxidation—has emerged as a promising therapeutic strategy, yet its regulation in ESCC remains poorly understood. We investigated the role of tripartite motif-containing 31 (TRIM31), an E3 ubiquitin ligase, in ESCC progression and ferroptosis.Results:TRIM31 expression was significantly elevated in ESCC tissues compared with normal esophageal tissues (The Cancer Genome Atlas and Genotype-Tissue Expression datasets; p < 0.001) and correlated with advanced Tumor, Node, and Metastasis (TNM) stage (p = 0.004), lymph node metastasis (p = 0.024), and poor overall survival (p = 0.0027). Functional assays revealed that TRIM31 knockdown reduced ESCC cell proliferation, impaired colony formation, and suppressed migration (p < 0.01). In vivo, TRIM31 silencing decreased xenograft tumor volume by over 70% and Ki-67 expression by 73%. Mechanistically, TRIM31 directly interacted with VDAC1 via its coiled-coil domain, promoting VDAC1 ubiquitination and proteasomal degradation. This interaction inhibited ferroptosis, as evidenced by increased lipid reactive oxygen species, elevated intracellular Fe2+ levels, and mitochondrial damage upon TRIM31 knockdown. Conversely, TRIM31 overexpression attenuated ferroptosis induced by RSL3. We further identified hepatocyte nuclear factor 4 alpha as a transcriptional activator of TRIM31, binding to its promoter region. Importantly, TRIM31 knockdown synergized with the ferroptosis inducer imidazole ketone erastin, achieving a 90% reduction in tumor growth without significant toxicity.Conclusion:TRIM31 promotes ESCC progression by degrading VDAC1 and suppressing ferroptosis. Targeting TRIM31 enhances ferroptosis-based therapy and represents a novel, clinically actionable strategy for ESCC treatment. Antioxid. Redox Signal. 00, 000–000.
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高影响因子
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