EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Liu-Gen Cui,Miao-Miao Zhai,Jian-Jian Yin,Zhi-Mo Wang,Shu-Hui Wang,Yue-Jiao Zhou,Pei-Pei Li,Yang Wang,Li Xia,Pei Wang,Xue-Xiang Cha,Li-Rong Zhang,Sheng-Na Han
Several studies have associated the epitranscriptomic RNA modification of N6-methyladenosine (m 6 A) with cardiovascular diseases; however, how m 6 A modification affects cardiomyocyte pyroptosis after myocardial infarction (MI) remains unknown. Here, we showed that AlkB homolog 5 (ALKBH5), an m 6 A demethylase, is crucial in cardiomyocyte pyroptosis after MI. We used MI rat and mouse models, a cell hypoxia model of rat primary cardiomyocytes (RCMs), and rat embryonic ventricle cell line (H9c2) to explore the functional role of m 6 A modification and ALKBH5 in the heart and cardiomyocytes. Using plasmids and small interfering RNAs, the expressions of ALKBH5 and NOD-like receptor family pyrin domain-containing 3 (NLRP3) were determined to study their functions in regulating cardiomyocyte m 6 A and pyroptosis, respectively. We characterized the role of ALKBH5, which exhibited elevated expression in the ischemic heart tissue of rats and mice and hypoxic cardiomyocytes (RCMs and H9c2 cells). ALKBH5 knockdown alleviated hypoxia-induced H9c2 cell pyroptosis by inhibiting NLRP3 inflammasome activation, whereas ALKBH5 overexpression had the opposite effect. NLRP3 knockdown alleviated hypoxia-induced H9c2 cardiomyocyte pyroptosis by inhibiting ALKBH5 expression, whereas NLRP3 overexpression had the opposite effect. Mechanistically, ALKBH5 mediated m 6 A modification of NLRP3 mRNA in an IGF2BP2-dependent manner, and NLRP3, as a nuclear transcription factor, regulated the ALKBH5 transcription process. Targeting the ALKBH5-NLRP3 loop with the small-molecule inhibitors alleviated cardiomyocyte pyroptosis. Our results highlight that ALKBH5-NLRP3 forms a positive feedback loop that promotes cardiomyocyte pyroptosis after MI. Therefore, inhibiting the ALKBH5-NLRP3 loop is a potential strategy for treating cardiovascular diseases.
研究领域:
心血管疾病
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表观转录组学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 20
·e70144
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IF 4.3
Qiying Yao,Xinrui Hu,Tiantian Bian,Qing Zhang,Zhao Xue,Yuesheng Lv,Shupeng Ren,Yue Chen,Dongmei Zhang,Liang Chen
Sialylation catalysed by sialyltransferase 7A (SIAT7A) plays a role in the development of cardiac hypertrophy. However, the regulatory mechanisms upstream of SIAT7A in this context remain poorly elucidated. Previous study demonstrated that KLF4 activates the SIAT7A gene in ischemic myocardium by binding to its promoter region. Nevertheless, the potential involvement of KLF4 in regulating SIAT7A expression in Ang II-induced hypertrophic cardiomyocytes remains uncertain. This study seeks to deepen the underlying mechanisms of the KLF4 and SIAT7A interaction in the progression of Ang II-induced cardiac hypertrophy. The results showed a concurrent increase in SIAT7A and KLF4 levels in hypertrophic myocardium of essential hypertension patients and in hypertrophic cardiomyocytes stimulated by Ang II. In vitro experiments revealed that reducing KLF4 levels led to a decrease in both SIAT7A synthesis and Sialyl-Tn antigen expression, consequently inhibiting Ang II-induced cardiomyocyte hypertrophy. Intriguingly, reducing SIAT7A levels also resulted in decreased KLF4 expression and suppression cardiomyocyte hypertrophy. Consistent with this, elevating SIAT7A levels increased KLF4 expression and exacerbated cardiomyocyte hypertrophy in both in vivo and in vitro experiments. Additionally, a time-course analysis indicated that KLF4 expression preceded that of SIAT7A. Luciferase reporter assays further confirmed that modulating SIAT7A levels directly influenced the transcriptional activity of KLF4 in cardiomyocytes. In summary, KLF4 expression is upregulated in cardiomyocytes treated with Ang II, which subsequently induces the expression of SIAT7A. The elevated levels of SIAT7A, in turn, enhance the transcription of KLF4 . These findings suggest a positive feedback loop between KLF4 and SIAT7A-Sialyl-Tn, ultimately promoting Ang II-induced cardiac hypertrophy.
研究领域:
心脏病学
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分子生物学
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细胞生物学
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DOI
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-19
·
IF 15.7
Shen Xuecheng,Qiao Wenxuan,Yan Wei,Xie Hao,Zhang Chenyang,Sun Yang,Luo Qiong,Xu Qiang
IL-17 signaling contributes to the pathogenesis of psoriasis; however, IL-17 involvement in keratinocyte hyperactivation of epidermis remains unclear. Here, we describe an IL-17A-induced, skin-specific, positive feedback loop, which operates independently of canonical chemokine production, thus untangling skin inflammation and epithelial hyperproliferation in psoriasis. We show that IL-17A-induced, keratinocyte-specific KLK8 interacts with IL-17R to promote histone H4 lysine lactylation (H4K12la) catalyzed by the acetyltransferase HAT1. H4K12la further promotes IL-17A-mediated keratinocyte proliferation and the expression of KLK8 and IL-17R, creating a feedback loop that drives psoriasis progression. Importantly, excessive lactate in the microenvironment exacerbates H4K12la and psoriasis severity, thereby impairing the efficacy of anti-IL-17A antibody. Silencing KLK8, HAT1, or inhibiting lactate accumulation attenuates psoriasis in mice. Moreover, combining lactylation inhibition with anti-IL-17A therapy exhibits synergistic effects against antibody-resistant psoriasis. Thus, our findings unveil a lactylation-driven, keratinocyte-specific IL-17A signaling and offer a promising approach for psoriasis treatment, particularly in patients with comorbid metabolic syndrome.
研究领域:
皮肤生物学
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表观遗传学
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免疫学
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分子生物学
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炎症性疾病
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转化医学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR THERAPY
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2025
·
IF 12
Di Wang,Xiao-ya Wang,Wen-jing Li,Cheng-hui Liang,Yu-xin Zou,Jin-wei Xiao,Qing-mei Kang,Jun-han Wang,Ling Mao,Jun-jie Chen,Xue-jia Zhai,Ji-tao Zhuang,Xian-Yan Yang,Hong-ying Jiang,Tian-hua Shen,Jie Liu,Qian Wen,Jiang-jie Duan,Jun Wang,Shi-cang Yu
The oncoprotein c-Myc is a prominent target in cancer therapy and modulating its stability is a promising potential treatment strategy. Phosphorylation at Ser62 is the primary mechanism by which c-Myc degradation is suppressed, which extends its half-life. Consequently, identifying kinases that regulate the phosphorylation of c-Myc at Ser62 may pave the way for novel intervention strategies. In this study, we revealed that acetaldehyde dehydrogenase 18A1 (ALDH18A1), a key enzyme in glutamate-proline metabolism, acts as a protein kinase through its γ-glutamate kinase (γ-GK) domain, which mediates the phosphorylation of the Ser62 site of c-Myc and suppresses its degradation. In turn, stabilized c-Myc directly increases the transcription of ALDH18A1 . This positive feedback loop sustains the mutual high expression of both proteins, which promotes the development of various tumors. Thonzonium bromide (TB), a small-molecule inhibitor screened from a Food and Drug Administration-approved drug library, was found to block ALDH18A1-mediated phosphorylation of c-Myc at Ser62 and attenuate tumor progression in preclinical models. Overall, these findings reveal the therapeutic potential of inhibiting the ALDH18A1 - MYC regulatory circuit in human cancers.
研究领域:
肿瘤学
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分子生物学
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信号转导
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癌基因调控
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代谢酶功能
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蛋白质稳定性
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靶向治疗
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产品关联
DOI
PubMed
高影响因子
DEVELOPMENTAL CELL
·
2024
·
IF 10.7
Xiaoxin Guo,Juanyu Zhou,La Yan,Xingzhu Liu,Yu Yuan,Jinbao Ye,Zehong Zhang,Haiou Chen,Yongxin Ma,Zhendong Zhong,Guanzheng Luo,Haiyang Chen
Peroxisome dynamics are crucial for intestinal stem cell (ISC) differentiation and gut regeneration. However, the precise mechanisms that govern peroxisome dynamics within ISCs during gut regeneration remain unknown. Using mouse colitis and Drosophila intestine models, we have identified a negative-feedback control mechanism involving the transcription factors peroxisome proliferator-activated receptors (PPARs) and SOX21. This feedback mechanism effectively regulates peroxisome abundance during gut regeneration. Following gut injury, the released free very long-chain fatty acids (VLCFAs) increase peroxisome abundance by stimulating PPARs-PEX11s signaling. PPARs act to stimulate peroxisome fission and inhibit pexophagy. SOX21, which acts downstream of peroxisomes during ISC differentiation, induces peroxisome elimination through pexophagy while repressing PPAR expression. Hence, PPARs and SOX21 constitute a finely tuned negative-feedback loop that regulates peroxisome dynamics. These findings shed light on the complex molecular mechanisms underlying peroxisome regulation in ISCs, contributing to our understanding of gut renewal and repair.
研究领域:
分子生物学
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干细胞研究
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胃肠科学
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产品关联
DOI
PubMed
高影响因子
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