Nature Aging
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2025
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IF 19.4
Liu Liu,Wang Qianyue,Chen Meng,Zhou Haifeng,Li Xu,Yuan Ziqi,Hu Yong,Wang Chaoqun,Zhang Xiaohui,Hu Sheng,Wu Xiaoting,Li Meixin,Li Juanjuan,Chen Aijun,Yan Wei
Lung aging is a multifactorial series of molecular alterations that leads to gradual deterioration of lung function and increased vulnerability to cancer. Tumor communicates with host organs partially through extracellular vesicles; however, the mechanistic drivers and consequences of lung aging in the context of cancer remain unclear. Here we identify cancer cell-secreted dimethylarginine dimethylaminohydrolase-1 (DDAH1) protein induces citrulline accumulation and promotes lung fibrosis and aging. Mechanistically, our single-cell sequencing and genetic knockout mice evidence that citrulline availability elevation inhibits peptidyl arginine deiminase 4-mediated transforming growth factor-β1 (TGF-β1) citrullination, thereby inducing the TGF-β1/Smad3 signaling pathway in lung fibroblasts. Notably, vacuolar protein sorting assists the packaging of DDAH1 into the late endosomes. The administration of DDAH1 inhibitor reduces fibrosis and alleviates lung aging. Conclusively, our findings reveal tumor-derived DDAH1 protein contributes to citrulline accumulation to promote lung aging, shedding light on the treatment and diagnosis of tumors by inhibiting senescent lung fibroblasts.
研究领域:
肿瘤学
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呼吸系统生物学
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分子生物学
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细胞衰老
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信号转导
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转化医学
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肿瘤微环境
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Lulu Huang,Yun Xiao,Xiaoyu Han,Yang Yu,Chao Zheng,Xiangdong Fang,Qing Li,Fanglan Liu,Chunhua Xia,Yongjie Zhang,Jiake He
Objective: The objective of the study was to investigate whether bupropion (BUP) or its circulation metabolites could decrease plasma level of asymmetric dimethylarginine (ADMA) and ameliorate renal injury by modulation of Ddah1, Oatp4c1, Oct2, and Mate1 in rats with adenine-induced chronic renal injury.Methods: The study initially determined the effect of BUP and its metabolites on cell viability and apoptosis in HK2 cells in the presence and absence of ADMA. Secondly, the study explored whether long-term administration of BUP could reduce the plasma level of ADMA and mitigate renal damage. Thirdly, the expression and activity of Oct2, Ddah1, Mate1 and Oatp4c1 was determined by Western blot and UPLC-MS/MS.Results: With 0.5 μmol/L ADMA, hydroxybupropion (HBUP, 100 nmol/L), threo-hydrobupropion (TBUP, 10 nmol/L and 1 μmol/L) reduced N-Acetyl-β-D-glucosidase (NAG) level. At 5 μmol/L ADMA, BUP (1 nmol/L-1 μmol/L), HBUP (1–100 nmol/L), and BUP cocktail enhanced survival. At 50 μmol/L ADMA, HBUP (10 nmol/L and 1 μmol/L), TBUP/erythro-hydrobupropion (EBUP) (10–100 nmol/L), and BUP cocktail stimulated survival. EBUP (1 and 100 nmol/L) lowered LDH. BUP (100 nmol/L) and TBUP (1 μmol/L) decreased NAG. TBUP (10 nmol/L, 1 μmol/L) and EBUP (100 nmol/L) inhibited apoptosis. In adenine-induced chronic renal injury rats, long-term administration of BUP significantly decreased the serum concentration of ADMA and creatinine by 12.78% and 38.85%, respectively, ameliorated interstitial lesions and fibrosis and upregulated Ddah1, Oatp4c1, Oct2, Mate1. BUP increased metformin renal clearance without affecting digoxin disposition.Conclusion: Bupropion moderately decreases plasma levels of ADMA and ameliorates renal injury by modulation of Ddah1, Oatp4c1, Oct2, and Mate1.
研究领域:
药理学
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肾脏病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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