BIOCHEMICAL PHARMACOLOGY
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2023
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IF 5.8
Xinyu Guo,Mengqing Liu,Bing Han,Yeqing Zheng,Kaina Zhang,Gaowa Bao,Chenying Gao,Hongwen Shi,Qiang Sun,Zhenghang Zhao
The clinic application of doxorubicin (DOX) is severely limited by its severe cardiotoxicity. Tripartite motif-containing protein 16 (TRIM16) has E3 ubiquitin ligase activity and is upregulated in cardiomyocytes under pathological stress, yet its role in DOX-induced cardiotoxicity remains elusive. This study aims to investigate the role and mechanism of TRIM16 in DOX cardiotoxicity. Following TRIM16 overexpression in hearts with AAV9-TRIM16, mice were intravenously administered DOX at a dose of 4 mg/kg/week for 4 weeks to assess the impact of TRIM16 on doxorubicin-induced cardiotoxicity. Transfection of OE-TRIM16 plasmids and siRNA-TRIM16 was performed in neonatal rat cardiomyocytes (NRCMs). Our results revealed that DOX challenge elicited a significant upregulation of TRIM16 proteins in cardiomyocytes. TRIM16 overexpression efficiently ameliorated cardiac function while suppressing inflammation, ROS generation, apoptosis and fibrosis provoked by DOX in the myocardium. TRIM16 knockdown exacerbated these alterations caused by DOX in NRCMs. Mechanistically, OE-TRIM16 augmented the ubiquitination and degradation of p-TAK1, thereby arresting JNK and p38MAPK activation evoked by DOX in cardiomyocytes. Furthermore, DOX enhanced the interaction between p-TAK1 and YAP1 proteins, resulting in a reduction in YAP and Nrf2 proteins in cardiomyocytes. OE-TRIM16 elevated YAP levels and facilitated its nuclear translocation, thereby promoting Nrf2 expression and mitigating oxidative stress and inflammation. This effect was nullified by siTRIM16 or TAK1 inhibitor Takinib. Collectively, the current study elaborates that upregulating TRIM16 mitigates DOX-induced cardiotoxicity through anti-inflammation and anti-oxidative stress by modulating TAK1-mediated p38 and JNK as well as YAP/Nrf2 pathways, and targeting TRIM16 may provide a novel strategy to treat DOX-induced cardiotoxicity.
研究领域:
心脏病学
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分子生物学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
Current Computer-Aided Drug Design
·
2024
·Vol. 21
·期 4
·503-516
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IF 1.5
Xiaoyan Meng,Xinming Yan,Peng Xue,Zhaoqing Xi
ObjectiveThis study utilized transcriptomic sequencing combined with cellular and animal models to explore the potential mechanisms of Xuebijing in treating sepsis-induced myocardial dysfunction, also known as sepsis-induced myocardial injury.MethodsWe investigated potential targets and regulatory mechanisms of XBJ injection using network pharmacology and RNA sequencing. The effects of XBJ on oxidative stress and apoptosis levels in human cardiac myocytes (AC16) and C57BL/6 mice exposed to lipopolysaccharide (LPS) were evaluated by Enzyme-Linked Immunosorbent Assay (ELISA), fluorescent probe, Fluorescent Quantitative Polymerase Chain Reaction (qPCR), Western Blot, Transmission Electron Microscopy, oxidative stress-related indicators detection kit, flow cytometry, and Immunohistochemistry (IHC).ResultsFirst, it was verified that XBJ can reduce the deformation of AC16 cardiomyocytes induced by LPS and the production and secretion of ROS (P <0.01). The transcriptome sequencing results showed that the TRIM16 gene was significantly increased after XBJ treatment, and the data of KEGG and GO analyses demonstrated that XBJ could inhibit the pathway expression of oxidative stress damage in AC16 cells, and PCR verified that XBJ could indeed increase the expression level of TRIM16 gene in AC16 cells (P <0.01). Basic animal and cell experiments showed that LPS could inhibit the expression of TRIM16 and NRF2 in cardiomyocytes (P <0.05) and promote the expression of Keap1 (P <0.01), while XBJ could significantly up-regulate the expression levels of TRIM16 and NRF2 (P <0.01) and inhibit the expression of Keap1 (P <0.01), thereby affecting the expression levels of downstream proinflammatory cytokines and alleviating LPS-induced oxidative stress damage. In addition, XBJ also inhibited the expression of the pro-apoptotic proteins Bax and c-caspase3 (P <0.01), promoted the expression of the anti-apoptotic protein Bcl2 (P <0.01), and reduced LPS-induced apoptosis by upregulating TRIM16.ConclusionOur comprehensive data demonstrated that TRIM16 is a key gene in the therapeutic action of Xuebijing in sepsis-induced myocardial dysfunction, protecting myocardial cells from injury through antioxidative stress and anti-apoptotic mechanisms.
研究领域:
医学
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分子生物学
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药理学
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DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Nannan Xu,Wenyi Fu,Jiake Wu,Shuai Zhao,Chunyang Tian
Rheumatoid arthritis (RA) is one of the most common chronic inflammatory autoimmune diseases, and ferroptosis has been associated with its pathogenesis. TRIM16 belongs to the TRIM protein family and possesses various biological function. However, the role of TRIM16 in RA has not been reported. Our results showed that TRIM16 was upregulated in collagen-induced arthritis (CIA) mice, and TRIM16 overexpression alleviated joint inflammation. Notably, the level of 4-HNE was decreased in CIA mice, whereas TRIM16 overexpression restored it. The expression of GPX4 and SLC7A11 was upregulated in CIA mice, whereas TRIM16 overexpression significantly suppressed their levels, suggesting that TRIM16 promotes ferroptosis. We then detected TRIM16 expression in TNF-α-induced fibroblast-like synoviocytes (FLS), and found that TNF-α stimulation reduced TRIM16 expression. Overexpression of TRIM16 increased the lipid ROS, Fe 2+ levels, and LDH activity, while reducing GSH-PX and GSH activities. Moreover, TNF-α treatment increased GPX4 and SLC7A11 expression but decreased ACSL4 levels, and TRIM16 overexpression reversed these effects. TRIM16 knockdown reduced lipid ROS levels and increased GPX4 and SLC7A11 expression. Furthermore, Fer-1 treatment reduced lipid ROS levels and increased GPX4 and SLC7A11 expression. Mechanistically, TRIM16 directly binds to Snai1, promoted its K48-linked ubiquitination, and specifically ubiquitinates Snai1 at the K146 site. Overexpression of Snai1 decreased the lipid ROS levels and increased the GSH content. Our study identifies TRIM16 as a promoter of ferroptosis in TNF-α-induced FLS by enhancing Snai1 ubiquitination and degradation. In summary, our study presented that TRIM16 plays a protective role in RA.
研究领域:
免疫学
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分子生物学
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风湿病学
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细胞死亡机制
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信号转导
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Sidi Yang,Kun Li,Lihong Liu,Linsen Zeng,Qifeng Deng,Jiacheng Huang,Xiaoran Dong,Xin Wang,Jianwei Liang,Hongchao Liu,Hong Peng,Yuxin Lin,Xiaolu Xie,Yuzhen Ye,Tiefeng Xu,Zhaohuan Wang,Chun-Mei Li,Deyin Guo
SARS-CoV-2 accessory protein ORF3a contributes to viral pathogenesis through membrane remodeling, immune evasion, and inflammation induction. However, the molecular mechanisms underlying ORF3a-mediated pathogenesis remain poorly characterized, and no therapeutic strategies targeting ORF3a currently exist. Here, we demonstrate that palmitoylation, a post-translational modification, governs ORF3a-mediated viral pathogenesis. Specifically, ORF3a undergoes ZDHHC18-mediated palmitoylation at evolutionarily conserved Cys130/Cys133 residues, which stabilizes the protein by masking an intrinsic proteasomal degradation signal. This palmitoylation competitively inhibits tripartite motif-containing 16 (TRIM16)-dependent K27-linked polyubiquitination, thereby preventing ORF3a degradation and enhancing viral replication and inflammatory responses. A designed ORF3a-mimicking palmitoylation-inhibitory peptide (OPIP) blocked ORF3a palmitoylation, promoted its degradation, and significantly reduced SARS-CoV-2 pathogenicity. Collectively, these findings establish ZDHHC18-mediated palmitoylation as a central regulator of ORF3a stability and virulence, revealing a potentially druggable axis for disrupting SARS-CoV-2 pathogenesis.
✓ 已验证
DOI
PubMed
高影响因子
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