FEBS Journal
·
2019
·Vol. 287
·期 8
·1666-1680
·
IF 4.739
Chen-Yu Zhang,Jia-Xi Duan,Hui-Hui Yang,Chen-Chen Sun,Wen-Jing Zhong,Jia-Hao Tao,Xin-Xin Guan,Hui-Ling Jiang,Bruce D. Hammock,Sung Hee Hwang,Yong Zhou,Cha-Xiang Guan
Pulmonary fibrosis (PF) is a senescence-associated disease with poor prognosis. Currently, there is no effective therapeutic strategy for preventing and treating the disease process. Mounting evidence suggests that arachidonic acid (ARA) metabolites are involved in the pathogenesis of various fibrosis. However, the relationship between the metabolism of ARA and PF is still elusive. In this study, we observed a disorder in the cyclooxygenase-2/cytochrome P450 (COX-2/CYP) metabolism of ARA in the lungs of PF mice induced by bleomycin (BLM). Therefore, we aimed to explore the role of COX-2/CYP-derived ARA metabolic disorders in PF. PTUPB, a dual COX-2 and soluble epoxide hydrolase (sEH) inhibitor, was used to restore the balance of COX-2/CYP metabolism. sEH is an enzyme hydrolyzing epoxyeicosatrienoic acids derived from ARA by CYP. We found that PTUPB alleviated the pathological changes in lung tissue and collagen deposition, as well as reduced senescence marker molecules (p16 Ink4a and p53-p21 Waf1/Cip1 ) in the lungs of mice treated by BLM. In vitro , we found that PTUPB pretreatment remarkably reduced the expression of senescence-related molecules in the alveolar epithelial cells (AECs) induced by BLM. In conclusion, our study supports the notion that the COX-2/CYP-derived ARA metabolic disorders may be a potential therapeutic target for PF via inhibiting the cellular senescence in AECs.
研究领域:
药理学
·
肺病学
·
分子生物学
·
治疗学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Jiamin Dang,Ting Cai,Yuanrong Tuo,Siwang Peng,Jing Wang,Aiying Gu,Jialu Li,Long Ding,Shuangkui Du,Liying Wang
This study aimed to investigate the effects of corn gluten-derived soluble epoxide hydrolase (sEH) inhibitory peptides on nonalcoholic fatty liver fibrosis induced by a high-fat diet and carbon tetrachloride in mice. Mice treated with corn peptides at doses of 500 or 1000 mg/kg/d for 4 weeks exhibited reduced sEH activity in serum and liver, enhanced lipid metabolism, and decreased lipid accumulation and oxidative stress. Corn peptides effectively downregulated the mRNA levels of Pro-IL-1β, Pro-IL-18, NOD-like receptor protein 3 (NLRP3), ASC, Pro-caspase-1, Caspase-1, and GSDMD in the liver. This hepatoprotective effect of corn peptides by inhibiting NLRP3 inflammasome activation was further validated in H2O2-induced HepG2 cells. Moreover, corn peptides restored the composition of the gut microbiota and promoted short-chain fatty acid production. This study provides evidence that corn-derived sEH inhibitory peptides have hepatoprotective activity against nonalcoholic fatty liver fibrosis by suppressing NLRP3 inflammasome activation and modulating gut microbiota.
研究领域:
营养学
·
肝病学
·
微生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Shanshan Song,Xina Yu,Changming Xie,Zhanhua Li,Ying Zhang,Yan Liu,Zhongjue Qiu,Tiantian Wang,Hongna Su,Hui Huang,Pei Luo
Panaxynol (PA), a bioactive compound found in carrots and other Apiaceae plants, holds promise for managing diabetes-related vascular complications. This study investigated the long-term effects of PA on diabetes-induced vascular calcification (DVC) in db/db mice for up to 9 weeks. The impact of PA on DVC was evaluated both in vivo and in vitro using immunohistochemical staining, Western blotting, micro-computed tomography, and other analytical techniques. Results demonstrated that PA significantly attenuated arterial calcification and collagen hyperplasia in the aorta. Additionally, PA elevated levels of the lipid signaling molecule 14,15-EET, which preserved the vascular structure and function by reducing inflammatory macrophage infiltration in perivascular adipose tissue. This protective effect was partially attributed to the PA-mediated inhibition of soluble epoxide hydrolase (sEH) through Sirt6 activation. These findings highlight PA as a potential natural therapeutic strategy for mitigating diabetic vascular complications and offer an alternative to conventional pharmacological approaches.
研究领域:
生物学
·
医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2023
·
IF 11.4
Chen-Yu Zhang,Wen-Jing Zhong,Yu-Biao Liu,Jia-Xi Duan,Nan Jiang,Hui-Hui Yang,Sheng-Chao Ma,Ling Jin,Jie-Ru Hong,Yong Zhou,Cha-Xiang Guan
Alveolar epithelial cell (AEC) senescence is a key driver of a variety of chronic lung diseases. It remains a challenge how to alleviate AEC senescence and mitigate disease progression. Our study identified a critical role of epoxyeicosatrienoic acids (EETs), downstream metabolites of arachidonic acid (ARA) by cytochrome p450 (CYP), in alleviating AEC senescence. In vitro , we found that 14,15-EET content was significantly decreased in senescent AECs. Exogenous EETs supplementation, overexpression of CYP2J2, or inhibition of EETs degrading enzyme soluble epoxide hydrolase (sEH) to increase EETs alleviated AECs' senescence. Mechanistically, 14,15-EET promoted the expression of Trim25 to ubiquitinate and degrade Keap1 and promoted Nrf2 to enter the nucleus to exert an anti-oxidant effect, thereby inhibiting endoplasmic reticulum stress (ERS) and alleviating AEC senescence. Furthermore, in D-galactose (D-gal)-induced premature aging mouse model, inhibiting the degradation of EETs by Trifluoromethoxyphenyl propionylpiperidin urea (TPPU, an inhibitor of sEH) significantly inhibited the protein expression of p16, p21, and γH2AX. Meanwhile, TPPU reduced the degree of age-related pulmonary fibrosis in mice. Our study has confirmed that EETs are novel anti-senescence substances for AECs, providing new targets for the treatment of chronic lung diseases.
研究领域:
药理学
·
细胞生物学
·
分子生物学
·
呼吸医学
✓ 已验证
DOI
PubMed
高影响因子
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