Science Advances
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2024
·Vol. 10
·期 40
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IF 11.7
Lian Cui,You Wu,Zeyu Chen,Bingjie Li,Jiangluyi Cai,Zhanhe Chang,Weide Xiao,Yuanyuan Wang,Nan Yang,Yu Wang,Zengyang Yu,Lingling Yao,Rui Ma,Xin Wang,Youdong Chen,Qianyu Chen,Hao Mei,Zhiyi Lan,Yingyuan Yu,Rongfen Chen,Xingbiao Wu,Qian Yu,Jiajing Lu,Ning Yu,Xilin Zhang,Jun Liu,Lingjuan Zhang,Yuping Lai,Shaorong Gao,Yawei Gao,Chunyuan Guo,Yuling Shi
Disrupted N6-methyladenosine (m6A) modification modulates various inflammatory disorders. However, the role of m6A in regulating cutaneous inflammation remains elusive. Here, we reveal that the m6A and its methyltransferase METTL3 are down-regulated in keratinocytes in inflammatory skin diseases. Inducible deletion of Mettl3 in murine keratinocytes results in spontaneous skin inflammation and increases susceptibility to cutaneous inflammation with activation of neutrophil recruitment. Therapeutically, restoration of m6A alleviates the disease phenotypes in mice and suppresses inflammation in human biopsy specimens. We support a model in which m6A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m6A reader IGF2BP3, leading to a rewiring of fatty acid metabolism with a reduction in palmitic acid accumulation and, consequently, suppressing neutrophil chemotaxis in cutaneous inflammation. Our findings highlight a previously unrecognized epithelial-intrinsic m6A modification–lipid metabolism pathway that is essential for maintaining epidermal and immune homeostasis and lay the basis for potential therapeutic targeting of m6A modulators to attenuate inflammatory skin diseases.
研究领域:
免疫学
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分子生物学
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皮肤病学
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DOI
PubMed
高影响因子
Metabolomics
·
2023
·Vol. 19
·期 2
·1-13
·
IF 3.6
Zhang Rong,Zhang Zijia,Wu Wenyong,Shi Jingying,Berk Entezar,Li Wei,Deng Yanping,Wang Zhaojun,Hou Jinjun,Long Huali,Lei Min,Wu Wanying
Introduction Lipid metabolism participates in various biological processes such as proliferation, apoptosis, migration, invasion, and maintenance of membrane homeostasis of prostate tumor cells. Bufadienolides, the active ingredients of Chansu, show a robust anti-proliferative effect against prostate cancer cells in vitro, but whether bufadienolides could regulate the lipid metabolism in prostate cancer has not been evaluated. Objectives Our study explored the regulatory effects of bufadienolides on lipid metabolism in human prostate carcinoma cells (PC-3). Methods Untargeted lipidomics and transcriptomics were combined to study the effect of different bufadienolides interventions on lipid and gene changes of PC-3 cells. The key genes related to lipid metabolism and prostate cancer development were verified by qPCR and western blotting. Results Lipidomic analysis showed that the active bufadienolides significantly downregulated the content of long-chain lipids of PC-3 cells. Based on transcriptomic and qPCR analyses, many genes related to lipid metabolism were significantly regulated by active bufadienolides, such as ELOVL6 , CYP2E1 , GAL3ST1 , CERS1 , PLA2G10 , PLD1 , SPTLC3, and GPX2 . Bioinformatics analysis of the Cancer Genome Atlas database and literature retrieval showed that elongation of very long-chain fatty acids protein 6 ( ELOVL6 ) and phospholipase D1 ( PLD1 ) might be important regulatory genes. Western blot analysis revealed that active bufadienolides could downregulate PLD1 protein levels which might promote anti-prostate cancer effect. Conclusions All these findings support that bufadienolides might induce lipid metabolic remodeling by regulating long-chain lipids synthesis and phospholipid hydrolysis to achieve an anti-prostate cancer effect, and PLD1 would probably be the key protein.
研究领域:
肿瘤学
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药理学
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）