FREE RADICAL BIOLOGY AND MEDICINE
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2023
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IF 7.4
Caihua Wang,Xiaofang Li,Wei Zhang,Wenxuan Liu,Ziwei Lv,Runlin Gui,Man Li,Yujia Li,Xiaomin Sun,Ping Liu,Xiaobin Fan,Shiyao Yang,Yuyan Xiong,Lu Qian
Excessive free fatty acids (FFAs) accumulation is a leading risk factor for the pathogenesis of insulin resistance (IR) in metabolic tissues, including the liver. Ethanolamine-phosphate phospho-lyase (ETNPPL), a newly identified metabolic enzyme , catalyzes phosphoethanolamine (PEA) to ammonia, inorganic phosphate, and acetaldehyde and is highly expressed in hepatic tissue. Whether it plays a role in regulating FFA-induced IR in hepatocytes has yet to be understood. In this study, we established an in vitro palmitic acid (PA)-induced IR model in human HepG2 cells and mouse AML12 cells with chronic treatment of PA. Next, we overexpressed ETNPPL by using lentivirus-mediated ectopic to investigate the effects of ETNPPL per se on IR without PA stimulation. We show that ETNPPL expression is significantly elevated in PA-induced IR and that silencing ETNPPL ameliorates this IR in hepatocytes. Inversely, overexpressing ETNPPL under normal conditions without PA promotes IR, reactive oxygen species generation, and ARG2 activation in both HepG2 and AML12 cells. Moreover, ETNPPL depletion markedly down-regulates ARG2 expression in hepatocytes. Besides, silencing ARG2 prevents ETNPPL-induced ROS accumulation and inhibition of autophagic flux and IR in hepatocytes. Finally, we found that phytopharmaceutical disruption of ETNPPL by quercetin ameliorates PA-induced IR in hepatocytes. Our study discloses that ETNPPL inhibiting autophagic flux mediates insulin resistance triggered by PA in hepatocytes via ARG2/ROS signaling cascade. Our findings provide novel insights into elucidating the pathogenesis of obesity-associated hepatic IR, suggesting that targeting ETNPPL might represent a potential approach for T2DM therapy.
研究领域:
代谢
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分子生物学
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细胞生物学
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内分泌学
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药理学
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2023
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IF 12.4
Mingrui Xiong,Hong Chen,Yu Fan,Muchuan Jin,Dong Yang,Yuchen Chen,Yu Zhang,Robert B. Petersen,Hua Su,Anlin Peng,Congyi Wang,Ling Zheng,Kun Huang
Rationale: Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear. Methods: Renal tubule specific ELA knockout ( Apela Ksp KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of Apela Ksp KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination. Results: ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in Apela Ksp KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured Apela Ksp KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in Apela Ksp KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol. Conclusions: An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.
研究领域:
肾病学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2024
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IF 6.1
Wenxuan Liu,Runlin Gui,Yang Li,Man Li,Zhen Lei,Yanyan Jin,Yi Yu,Yujia Li,Lu Qian,Yuyan Xiong
Insulin resistance (IR) is a central pathophysiological process underlying numerous chronic metabolic disorders, including type 2 diabetes and obesity. Lycii Cortex, a widely used traditional Chinese herb, has demonstrated potential benefits in preventing and managing diabetes and IR. Whereas, the specific bioactive compounds responsible for these protective effects and their underlying mechanisms of action remain elusive. This study aimed to identify the bioactive components within Lycii Cortex that contribute to its anti-diabetic effects and to elucidate the molecular mechanisms underlying its beneficial actions on insulin resistance. Network pharmacology and molecular docking analyses were employed to identify the potential active compounds in Lycii Cortex and their corresponding target proteins. An in vitro model of IR was established using palmitic acid (PA)-treated HepG2 cells. Cell viability was assessed using the CCK-8 assay, while glucose uptake was evaluated by 2-NBDG staining and extracellular glucose measurement. To validate the in vitro findings, an in vivo model of obesity-induced IR was established using high-fat diet (HFD)-fed mice. The network pharmacology analysis preliminarily identified 13 candidate chemicals and 10 hub LyC and IR-related genes (LIRRGs). Molecular docking analysis demonstrates that Linarin as the potential active component exhibits the greatest potential to target c-FOS for preventing obesity-induced IR. Enrichment analysis suggested that Linarin-targeted pathways are correlated with inflammation. In vitro experimental validation demonstrated that Linarin was capable of protecting against PA-induced IR in HepG2 cells evidenced by improving glucose uptake ability and reducing extracellular glucose content. Additionally, we found that Linarin ablated PA-induced increase in the expression of c-FOS and inflammatory cytokines. Furthermore, in PA-treated cells, silencing c-FOS markedly improved glucose consumption, and reduced inflammation and Arginase 2 (ARG2) expression. Similarly, as exposure to PA, silencing ARG2 also ameliorated glucose uptake and inflammation, while not affecting c-FOS expression. In vivo experiments further showed that Linarin administration remarkably improved glucose tolerance and insulin sensitivity, and reduced the fat mass and body weight in HFD-induced obese mice. In this study, Linarin has been identified as the bioactive compound of Lycii Cortex to ameliorate obesity-related IR and inflammation through the c-FOS/ARG2 signaling cascade. These findings underscore the therapeutic potential of Linarin and provide valuable insights into developing novel intervention strategies for type 2 diabetes therapy.
研究领域:
药理学
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分子生物学
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内分泌学
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代谢性疾病
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中医药
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2025
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IF 11.3
Chao Wang,Junhao Lin,Jiewei Deng,Xinyan Li,Junqiu Zhai,Yunyun Yang,Tiangang Luan
N-(1,3-Dimethylbutyl)-N’-phenyl-p-phenylenediamine (6PPD) is a widely used antioxidant in tire rubber. Exposure to 6PPD and its quinone derivative, 6PPDQ, has increasingly been linked to environmental pollution and potential health risks. Given the established association between environmental contaminants and the incidence of lung cancer—particularly the prevalence of non-small cell lung cancer (NSCLC) as a major malignancy—the specific effects of 6PPD and 6PPDQ on NSCLC progression remain unexplored. Here, we demonstrate that 6PPD and 6PPDQ significantly promote NSCLC cell proliferation and migration by targeting the PTEN-PI3K/AKT signaling axis and inducing ARG2-mediated metabolic reprogramming. Using single-cell metabolomics, we identified shared metabolic characteristics in NSCLC cells exposed to 6PPD/6PPDQ, including disruptions in amino acid metabolism, tricarboxylic acid (TCA) cycle, and nucleotide synthesis. Mechanistically, 6PPD and 6PPDQ interacted with key residues in the C2 domain of PTEN, reducing its catalytic activity and leading to sustained activation of the PI3K/AKT pathway. Activation of the PI3K/AKT pathway further enhanced ARG2 expression, thereby promoting metabolic reprogramming to support NSCLC cell proliferation and migration. These results confirmed the pivotal role of the PI3K/AKT pathway in 6PPD and 6PPDQ-induced NSCLC progression. Our findings revealed novel molecular mechanisms by which 6PPD and 6PPDQ drove NSCLC progression, and confirmed their carcinogenic potential and role in pollution-related lung cancer risk. Moreover, the study highlighted the urgent need for further investigation into their health impacts.
✓ 已验证
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）