FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Xiao-Yi Zhang,Yi-Hao Zhang,Nan-Nan Liang,Shan-Shan Xu,Qiang-Sheng Li,Ya-Ping Song,Wei-Wei Zhang,Bo Wang,Hua Wang,Yi-Chao Huang,De-Xiang Xu
Accumulating evidence indicates that arsenic (As) exposure causes a decline in sperm quality. This study aimed to investigate the impact of As exposure on spermatogonial senescence. GC-1 cells were exposed to NaAsO 2 (10 μM). RNA sequencing and ribosome profiling sequencing were performed to identify key regulators of cellular senescence. Methylated RNA immunoprecipitation-qPCR was used to determine N 6 -methyladenosine (m6A) modification. The results revealed that the differentially expressed genes were enriched in pathways related to cellular senescence. Several established senescence markers, β-galactosidase activity, γ-H2AX, and P16, were elevated in As-exposed GC-1 cells. Further analysis revealed that P21 and its transcription factor ETS2 were upregulated. ETS2 knockout prevented As-induced P21 upregulation and cell senescence. The multi-omics joint analysis indicated that As exposure elevated ETS2 translation efficiency by YTHDC2-dependent m6A modification. Mechanistically, As exposure induced mitochondrial dysfunction. Alpha-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate and RNA demethylase cofactor, was reduced in As-exposed GC-1 cells. Additional experiments showed that As exposure induced NAD + depletion and suppressed SIRT3 activity. Supplementation with nicotinamide mononucleotide, an NAD + precursor, attenuated As-evoked α-KG reduction and ETS2 upregulation. These findings suggest that As induces spermatogonial senescence via m6A modification-mediated upregulation of ETS2 translation and identify NAD + replenishment as a potential countermeasure.
研究领域:
毒理学
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分子生物学
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表观遗传学
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生殖生物学
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生物信息学
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DOI
PubMed
高影响因子
Nature Microbiology
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2025
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IF 19.4
Jin Shouheng,He Xing,Wang Zheyu,Zhou Tao,Wang Jun,Pan Guihong,Zhang Yin,Ma Ling,Yang Shuai,Wang Liqiu,Wu Yaoxing,Zou Yilin,Qi Nan,Cui Jun
Metabolic pathways determine cellular fate and function; however, the exact roles of metabolites in host defence against influenza virus remain undefined. Here we employed pharmacological inhibition and metabolomics analysis to show that the metabolic pathways of oxaloacetate (OAA) are integrated with antiviral responses to influenza virus. Cytosolic malate dehydrogenase 1 senses intracellular OAA to undergo dimerization and functions as a scaffold to recruit the transcription factor ETS2 for phosphorylation by the kinase TAOK1 at serine 313. The phosphorylated ETS2 translocates into the nucleus and supports optimal expression of TBK1, an indispensable activator of type I interferon responses. OAA supplementation provides a broad-spectrum antiviral ability, and OAA deficiency caused by Acly genetic ablation decreases antiviral immunity and renders mice more susceptible to lethal H1N1 virus infection. Our results uncover a signalling pathway through cellular OAA sensing that links metabolism and innate immunity to coordinate defence against viral challenge.
研究领域:
免疫学
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病毒学
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代谢生物学
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分子生物学
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信号转导
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感染与免疫
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DOI
PubMed
高影响因子
BIOCHEMICAL GENETICS
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2024
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IF 2.1
Wang Song,Bao Ning,Li Mohan,Liu Dongwei,Tao Liming
Proliferative diabetic retinopathy (PDR), the most common type of diabetic retinopathy, is a main cause of visual and impairment blindness. Abnormal neovascularization, endothelial dysfunction, and vascular inflammation are important mechanisms for the development of PDR. Ets2 regulates angiogenesis-related genes and inflammation, however, the effect of Ets2 in PDR procession has not been clarified. Thus, this study is performed to investigate whether Ets2 exerts key functions in PDR. In this study, 10-week-old mice were used for establishing STZ-induced diabetic mice, and Ets2 expression was analyzed in retina tissues. Besides, newborn mice were applied to construct oxygen-induced retinopathy (OIR) models. The Ets2 expression, oxidative stress, and inflammation were detected in retina tissues. We found that Ets2 was highly expressed in retina tissues both in diabetic mice and OIR mice. Oxidative stress and inflammatory processes are two factors contributing to the pathogenesis of PDR. In retinal tissues of OIR mice, Ets2 knockdown inhibited expression of inflammatory mediators VEGFA, IL-6, and IL-8, and biomarkers of oxidative stress MCP-1, VCAM-1, and iNOS. ROS production was also inhibited by silencing Ets2. Ets2 deficiency inhibited endothelial cell proliferation in the retina. Furthermore, Ets2 knockdown contributed to suppressing the expression of angiogenesis-related genes VEGFA, JUNB, MMP-9, Tie2, Ang-2, and EphB4. Our study highlights that Ets2 accelerates PDR procession by promoting the proliferation of endothelial cells, oxidative stress, and inflammation, which provides a novel target against PDR.
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DOI
PubMed
高影响因子
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