PHARMACOGENOMICS
·
2020
·
IF 2.339
Keguang Chen,Ruichen Guo,Chunmin Wei
Aim: To evaluate whether the synonymous mutant rs2515641 could affect cytochrome P450 2E1 (CYP2E1) expression and the response to acetaminophen (APAP) or triptolide (TP) treatment. Materials & methods: HepG2 cells were transfected with lentiviral vector containing either CYP2E1-1263C or CYP2E1-1263T. Some of these recombinant cells were then treated with APAP or TP. CYP2E1 gene expression was detected by PCR and western blot. Results:CYP2E1 gene expression decreased significantly both in mRNA and protein level after rs2515641 mutation, indicating that this polymorphism can affect both transcription and translation. Furthermore, rs2515641 mutation dramatically changes the response of CYP2E1 expression to APAP or TP treatment. Conclusion: Rs2515641 significantly changes CYP2E1 expression and function, which would be expected to affect drug disposition and response.
研究领域:
药理学
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分子生物学
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遗传学
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毒理学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Yiqiong Wang,Yi Tao,Shujing Zhang,Qiuru Wang,Zheting Liu,Shudong Lin,Yaoting Wang,Yunchao Huang,Ting Zhang,Henry Anselmo Mayala,Wenming He,Hui Shen,Ling Zhang,Hui Chai
Background Diabetes mellitus (DM) and its complications pose a significant threat to human health. Diabetes-related lower limb ischemia (DLLI), as a severe complication of diabetic macrovascular disease, presents substantial challenges in clinical management. Purpose The pharmacodynamic profile and mode of action of Pseudostellaria heterophylla polysaccharides (PHP) in DLLI treatment constitute the core investigative objectives herein. Study Design Using complementary in vivo (DLLI murine model) and in vitro (high glucose (HG)-exposed human umbilical vein endothelial cells (HUVECs)) systems, PHP's bioactivity was systematically profiled. Methods In vivo: The effects of PHP on blood perfusion, microvessel density, and PANoptosome assembly in the ischemic limbs of DLLI mice were evaluated. In vitro: HUVECs treated with HG were used to assess PHP’s regulatory effects on angiogenesis functions (cell migration, proliferation, tube formation), PANoptosome/inflammasome formation, key components of the PANoptotic pathway, reactive oxygen species (ROS/mtROS), mitochondrial homeostasis, and autophagy. Transcriptomic analysis was conducted to identify potential target genes. Results In vivo: PHP significantly improved blood perfusion, increased microvessel density, and modulated PANoptosome assembly in ischemic limbs. In vitro: PHP reversed HG-induced angiogenesis dysfunction, inhibited PANoptosis and oxidative stress, restored mitochondrial function, and enhanced autophagic activity. Mechanism: PHP exerted its effects by targeting cytochrome P450 enzyme CYP2E1 through downregulating its expression, thereby alleviating mitochondrial damage and PANoptosis. Additionally, CYP2E1 downregulation promoted endothelial cell migration. Conclusion We pioneered a PANoptosome-centric framework for DLLI, proving that PHP targets CYP2E1 to restore mitochondrial homeostasis, inhibit PANoptosis, and drive angiogenesis, thereby offering a novel natural product-derived therapeutic strategy. Collectively, this work establishes PHP as a promising candidate for DLLI treatment through CYP2E1-mediated restoration of mitochondrial homeostasis and PANoptosis suppression.
研究领域:
药理学
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内分泌学
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心血管研究
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分子生物学
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天然产物
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线粒体生物学
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细胞死亡机制
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Wan Wang,Hang Shang,Jinzhe Li,Yue Ma,Cong Xu,Jiage Ma,Juncai Hou,Zhanmei Jiang
Polyphenols have received attention as dietary supplements for the relief of alcoholic liver disease (ALD) due to various bioactivities. Ethanol-induced rat small intestinal epithelial cell 6 (IEC-6) and alpha mouse liver 12 (AML-12) cell models were pretreated with four dietary polyphenols with different structures to explore their effects on cytotoxicity and potential protective mechanisms. The results showed that polyphenols had potential functions to inhibit ethanol-induced AML-12 and IEC-6 cell damage and oxidative stress, and restore ethanol-induced IEC-6 permeability and tight junction gene expression. Especially, dihydromyricetin (DMY) had the best protective effect on ethanol-induced cytotoxicity, followed by apigenin (API). Western blot results showed that DMY and API had the best ability to inhibit CYP2E1 and Keap1, and promote nuclear translocation of Nrf2, which might be the potential mechanism by which DMY and API attenuate ethanol-induced cytotoxicity. Moreover, the molecular docking results predicted that DMY and API could bind more tightly to the amino acid residues of CYP2E1 and Keap1, which might be one of the inhibitory modes of dietary polyphenols on CYP2E1 and Keap1. This study provided a rationale for the subsequent protective effect of dietary polyphenols on alcohol-induced liver injury in animal models and provided new clues on bioactive components for ALD-protection based on the gut-liver axis.
研究领域:
药理学
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毒理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Qing Yao,Yingying Tang,Sheng Dai,Lihui Huang,Zewei Jiang,Shiming Zheng,Meng Sun,Yitianhe Xu,Ruijie Lu,Tuyue Sun,Huirong Huang,Xinyu Jiang,Xiaomin Yao,Guangyong Lin,Longfa Kou,Ruijie Chen
Acute liver failure (ALF) is a severe liver disease caused by many reasons. One of them is the overdosed acetaminophen (APAP), which is metabolized into N -acetyl-p-benzoquinone imine (NAPQI), an excessive toxic metabolite, by CYP2E1, resulting in excessive reactive oxygen species (ROS), exhausted glutathione (GSH), and thereafter hepatocyte necrosis. N -acetylcysteine is the Food and Drug Administration-approved drug for detoxification of APAP, but it has limited clinical application due to the short therapeutic time window and concentration-related adverse effects. In this study, a carrier-free and bilirubin dotted nanoparticle (B/BG@N) is developed, which is formed using bilirubin and 18 β -Glycyrrhetinic acid, and bovine serum albumin (BSA) is then adsorbed to mimic the in vivo behavior of the conjugated bilirubin for hitchhiking. The results demonstrate that B/BG@N can effectively reduce the production of NAPQI as well as exhibit antioxidant effects against intracellular oxidative stress via regulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signal axis and reducing the production of inflammatory factors. In vivo study shows that B/BG@N can effectively improve the clinical symptom of the mice model. This study suggests that B/BG@N own increases circulation half-life, improves accumulation in the liver, and dual detoxification, providing a promising strategy for clinical ALF treatment.
研究领域:
药理学
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纳米技术
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肝病学
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毒理学
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产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2026
·
IF 3.6
Liyuan Gao,Hongming Yang,Mengyan Deng,Xia Hai,Rui Yang,Liming Tang,Qiang Wen,Haiwei Xu,Na Gao,Hailing Qiao
Rheumatoid arthritis (RA) is an autoimmune disease characterized by aberrant and persistent immune responses against self-antigens. However, the mechanisms of autoantibody production and the specific self-antigens in RA are not fully understood. CYP2E1 has been identified as a novel inflammatory target. It also exhibits immunogenicity and participates in autoimmune pathogenesis. Here, we explored the role of CYP2E1 in RA. In this study, we found that anti-CYP2E1 autoantibodies and CYP2E1 are elevated in RA and are closely related to inflammation and immunity. Cyp2e1 knockout protected RA rats against joint damage. Preclinical investigations further demonstrate that pharmacological inhibition of CYP2E1 by 1-(4-methyl-5-thiazolyl) ethenone (Q11) exhibits significant therapeutic efficacy in three RA animal models. Mechanistically, CYP2E1 inhibition attenuates inflammation by suppressing macrophage M1 polarization and exerts immunosuppressive effects via regulating the Th17/Treg balance. Our study first identifies elevated anti-CYP2E1 autoantibodies in RA patients, advancing understanding of RA pathogenesis and providing a novel potential biomarker. Furthermore, we demonstrate that CYP2E1 inhibition ameliorates RA by regulating inflammation and immunity, providing a promising dual-targeting therapeutic strategy for RA.
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DOI
PubMed
高影响因子
MOLECULAR CARCINOGENESIS
·
2018
·Vol. 57
·期 10
·1371-1382
·
IF 3.851
Jie Gao,Zhao Wang,Gao-Ju Wang,Na Gao,Jing Li,Yun-Fei Zhang,Jun Zhou,Hong-Xin Zhang,Qiang Wen,Han Jin,Hai-Ling Qiao
Hepatofibrosis is an important susceptibility factor for hepatocarcinogenesis. However, only a handful of cases of hepatofibrosis will develop into hepatocellular carcinoma (HCC). As cytochrome P450 2E1 (CYP2E1) is involved in the metabolism and activation of many known environmental toxicants and procarcinogens, this enzyme may play a role in the development of hepatocarcinogenesis subsequent to hepatofibrosis. Herein, we evaluated whether higher CYP2E1 activity is a risk factor for the development of hepatocarcinogenesis from hepatofibrosis. CYP2E1 activity in fibrotic tissues from 72 HCC patients and in normal liver tissues from 59 control subjects was determined along with the severity of hepatofibrosis in hepatocarcinogenesis patients. Similarly, using a rat diethylnitrosamine-induced hepatocarcinogenesis model, CYP2E1 activity at the hepatofibrosis and hepatocarcinogenesis stages was determined, the correlation between CYP2E1 activity at the hepatofibrosis stage and hepatocarcinogenesis was explored, and the impact of inhibition of CYP2E1 activity on hepatocarcinogenesis was studied. The results showed that while CYP2E1 activity in HCC patients with underlying hepatofibrosis was increased, the severity of hepatofibrosis did not correlate with CYP2E1 activity. In the rat hepatocarcinogenesis model, unexpectedly, CYP2E1 activity was found to decrease from hepatofibrosis to hepatocarcinogenesis. Importantly, however, hepatofibrotic rats with higher CYP2E1 activity developed a more severe form of HCC. Moreover, inhibition of CYP2E1 activity could decrease the occurrence and development of HCC in rats. In conclusion, higher CYP2E1 activity may be a risk factor for hepatocarcinogenesis from hepatofibrosis, which raises the possibility of screening patients with hepatofibrosis for CYP2E1 activity to better estimate their risk for hepatocarcinogenesis.
研究领域:
医学
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药理学
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毒理学
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产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2025
·
IF 4
Yong Li,Ying Ding,Chenxu Liu,Yunchao Li,Xinyu Guo,Meidan Huo,Linjing Jia,Haiwei Xu,Hailing Qiao,Na Gao
Cytochrome P450 2E1 (CYP2E1) plays an important role in inflammatory disease, but the role of CYP2E1 in gout remains elusive. The pharmacokinetics in rats of Q11, a CYP2E1 inhibitor synthesized by our group, were measured. The anti-inflammatory and uric acid (UA)-lowering levels mechanism of Q11 was investigated in hyperuricemic (HUA) mice and acute gouty arthritis (AGA) rats, and in macrophage cells stimulated by monosodium urate (MSU). The half-life (t 1/2 ) of Q11 in the ankle joint and kidney was approximately 9 h, which was more than 4 times longer than that in plasma. The expression of CYP2E1 was increased in the kidneys of HUA mice and in the ankles of AGA rats. Q11 reduced plasma UA levels in HUA mice by decreasing xanthine oxidase (XOD) activity. In addition, Q11 also decreased renal inflammatory injury in HUA mice. Moreover, Q11 decreased the levels of IL-1β and TNF-α in AGA rats, increased the levels of catalase (CAT) and glutathione (GSH), and blocked the activation of the NLRP3 inflammasome. A similar phenomenon was observed in J774A.1 and THP-1 cells treated with sodium urate.CYP2E1 may be a new therapeutic target for the treatment of gout and Q11 has the dual effect of being anti-inflammatory and lowering UA. Significance Statement The specific cytochrome P450 2E1 (CYP2E1) inhibitor Q11 reduced plasma uric acid (UA) levels by decreasing xanthine oxidase (XOD) activity in a gout animal model, while attenuating joint and renal inflammatory injury through the inhibition of oxidative stress and NLRP3 inflammasome activation.
研究领域:
药理学
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炎症
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风湿病学
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代谢性疾病
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药物研发
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产品关联
DOI
PubMed
高影响因子
Toxicology Research
·
2022
·Vol. 11
·期 2
·374-384
·
IF 2.68
Yang Bobo,Yin Changsheng,Zhang Yu,Xing Guangwei,Wang Suhua,Li Fang,Aschner Michael,Lu Rongzhu
BackgroundHydrogen sulfide (H2S), as the third gasotransmitter participates in both cellular physiological and pathological processes, including chemical-induced injuries. We recently reported acute acrylonitrile (AN) treatment inhibited endogenous H2S biosynthesis pathway in rat and astrocyte models. However, there is still no evidence to address the correlation between endogenous H2S and sub-chronic AN exposure.ObjectivesThis study aims to explore the modulatory effects of prolonged AN exposure on endogenous H2S levels and its biosynthetic enzymes in rat blood, brain and liver.MethodsA total of 50 male Sprague-Dawley rats were randomly divided into 5 groups, including the control group and AN-treated groups at dosages of 6.25, 12.5, 25 or 50 mg/kg. Rats received one exposure/day, 5 days/week, for 4 consecutive weeks. The rat bodyweight and brain/liver organ coefficient were detected, along with liver cytochrome P450 2E1(CYP2E1) expression. In addition, the H2S contents in rat serum and plasma, and in cerebral cortex and liver tissues were measured by methylene blue method. The expression of H2S-generating enzymes, including cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MPST) was also measured with Western blot both in rat cerebral cortex and liver.ResultsSubchronic exposure to AN significantly inhibited bodyweight-gain and increased the liver CYP2E1 expression compared with the control. In addition, AN significantly increased H2S levels in rat plasma and serum, but not in liver. The endogenous H2S level in rat cerebral cortex was also significantly increased upon AN treatment, when expression of the major H2S-generating enzymes, CBS and 3-MPST were significantly enhanced. However, hepatic protein levels of CBS and CSE were significantly increased, whereas hepatic levels of 3-MPST were significantly decreased.ConclusionThis study showed that sub-chronic AN exposure increased endogenous H2S contents in rat blood and brain tissues, but not liver, which may be resulted from the distinct expression profile of H2S-producing enzymes in response to AN. The blood H2S contents may be applied as a potential novel biomarker for surveillance of chronically AN-exposed populations.HighlightsSubchronic intraperitoneal exposure to acrylonitrile increased H2S content in rat blood and cerebral cortex, but not in liver.Distinct tissue expression profiles of H2S-producing enzymes contribute to the acrylonitrile-induced differential effects on the H2S level.Blood H2S level may be a biomarker for subchronic exposure to acrylonitrile.
研究领域:
毒理学
·
药理学
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生物化学
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DOI
PubMed
高影响因子
LIFE SCIENCES
·
2019
·
IF 3.448
Cheng Hu,Jiawen Ye,Licong Zhao,Xiulong Li,Yu Wang,Xinhua Liu,Lingyun Pan,Lisha You,Long Chen,Yiqun Jia,Jiaqi Zhang
Taxifolin (TAX) reportedly exerts protective and therapeutic effects in liver. Herein, the effects of TAX against acetaminophen (APAP)-induced hepatotoxicity were investigated. Pharmacodynamics, pharmacology and metabolomics analyses of TAX were assessed on C57 mice and L-02 cells. TAX was administered for 7 days, and APAP was given on the last day to establish an acute liver injury model. ALT and AST levels were determined, and liver ROS, MDA, GST, GSH and GPX1 were analysed. The expression and protein abundance of GPX1, GPS-Pi, GCLC and GCLM were assessed by PCR and western blotting, and metabolic changes in cells and serum were investigated by UPLC-Q-Orbitrap-MS. Serum ALT and AST, and liver ROS, MDA, GST, GSH and GPX1 levels confirmed the protective effects of TAX. Besides, we found Only treating with TAX decreased the expression of CYP2E1 in mice liver tissue. TAX reversed the APAP-induced decrease in cell viability in L-02 cells, and reduced cellular ROS levels. Furthermore, TAX reversed the APAP-induced decrease in antioxidant enzymes at both mRNA and protein levels. Metabolomics analysis identified metabolites mainly related to glutathione metabolism (36 in vivo and 23 in vitro ). The concentration of glutathione, oxidized glutathione, carnitine, succinic acid, pyroglutamic acid, citrulline, taurine, palmitoleic acid, phytoshingosine-1-P and sphingosine-1-P were close to normal levels after treating with TAX. These results indicate that TAX prevents APAP-induced liver injury by inhibiting APAP metabolic activation mediated by CYP450 enzymes, modulating glutathione metabolism, and expression of related antioxidative signals. These properties could be harnessed to prevent or treat hepatotoxicity.
研究领域:
药理学
·
肝病学
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代谢组学
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毒理学
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产品关联
DOI
PubMed
高影响因子
Marine Drugs
·
2025
·Vol. 23
·期 3
·134
·
IF 5.4
Yanglong Liu,Jiawei Sun,Qihao Yan,Bingjian Wen,Yan Bai,Qishi Che,Hua Cao,Jiao Guo,Zhengquan Su
Alcoholic liver disease (ALD) is a liver disorder resulting from excessive alcohol intake, and currently, there are no therapeutics approved by the FDA for its treatment. This study investigates the protective effects and underlying pharmacological mechanisms of two chitosan oligosaccharides, COST (MW ≤ 1000 Da) and COSM (MW ≤ 3000 Da), in mitigating alcohol-induced liver disease (ALD). In animal models, we evaluated the changes in ALD following treatment with COST and COSM. Histopathological analysis revealed that both COST and COSM interventions mitigated hepatic steatosis and inflammatory infiltration. Additionally, these compounds reduced various markers of liver injury, enhanced antioxidant enzyme levels, and significantly improved liver function. Western blot analysis demonstrated that COSM markedly decreased the expression of the hepatic metabolic enzyme CYP2E1, activated the Keap-1/Nrf-2/HO-1 pathway, and restrained the NF-κB and MAPK pathways. In an in vitro model of alcohol-induced hepatocyte L02 injury, both COST and COSM exhibited protective effects on hepatocytes, corroborating the findings from the animal studies. Collectively, in vivo and in vitro experiments confirmed that COST and COSM can reduce oxidative damage, enhance antioxidant capacity, and ameliorate steatosis and inflammatory damage in the liver, thereby significantly attenuating alcohol-induced injury. Notably, COSM exhibited slightly superior efficacy compared to COST.
研究领域:
药理学
·
肝脏病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PeerJ
·
2020
·
IF 2.379
Xiaoyan Li,Yiyan Lu,Xiaojun Ou,Sijing Zeng,Ying Wang,Xiaoxiao Qi,Lijun Zhu,Zhongqiu Liu
Background This study aimed to systematically profile the alterations and sex- and age-related differences in the drug metabolizing enzymes (DMEs) in a KRAS-mutant mouse model of lung cancer (KRAS mice). Methodology In this study, the LC-MS/MS approach and a probe substrate method were used to detect the alterations in 21 isoforms of DMEs, as well as the enzymatic activities of five isoforms, respectively. Western blotting was applied to study the protein expression of four related receptors. Results The proteins contents of CYP2C29 and CYP3A11, were significantly downregulated in the livers of male KRAS mice at 26 weeks (3.7- and 4.4-fold, respectively, p < 0.05). SULT1A1 and SULT1D1 were upregulated by 1.8- to 7.0- fold at 20 ( p = 0.015 and 0.017, respectively) and 26 weeks ( p = 0.055 and 0.031, respectively). There were positive correlations between protein expression and enzyme activity for CYP2E1, UGT1A9, SULT1A1 and SULT1D1 ( r 2 ≥ 0.5, p < 0.001). Western blotting analysis revealed the downregulation of AHR, FXR and PPARα protein expression in male KRAS mice at 26 weeks. For sex-related differences, CYP2E1 was male-predominant and UGT1A2 was female-predominant in the kidney. UGT1A1 and UGT1A5 expression was female-predominant, whereas UGT2B1 exhibited male-predominant expression in liver tissue. For the tissue distribution of DMEs, 21 subtypes of DMEs were all expressed in liver tissue. In the intestine, the expression levels of CYP2C29, CYP27A1, UGT1A2, 1A5, 1A6a, 1A9, 2B1, 2B5 and 2B36 were under the limitation of quantification. The subtypes of CYP7A1, 1B1, 2E1 and UGT1A1, 2A3, 2B34 were detected in kidney tissue. Conclusions This study, for the first time, unveils the variations and sex- and age-related differences in DMEs in C57 BL/6 (WT) mice and KRAS mice.
研究领域:
药理学
·
肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2021
·
IF 3.739
Bei Tan,Jie Chen,Siyuan Qin,Chuyao Liao,Ying Zhang,Di Wang,Siqi Li,Zunjian Zhang,Pei Zhang,Fengguo Xu
Cisplatin is a chemotherapeutic agent widely employed in the treatment of various solid tumors. However, its use is often restricted by acute kidney injury (AKI) which is the dose-limiting adverse effect of cisplatin. While numerous studies aiming to alleviate the AKI have been conducted, there are no effective remedies in clinical practice. In this paper, a targeted metabolomics study was performed to reveal the potential relationship between tryptophan metabolism and cisplatin-induced AKI. A chemical derivatization integrated liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) approach was utilized to quantify 29 metabolites in the tryptophan pathway in rat kidney medulla and cortex after cisplatin administration. Results showed that tryptophan metabolism was remarkably disturbed both in the medulla and cortex after cisplatin administration. We also found that the tryptophan pathway in the medulla was more sensitive to cisplatin exposure compared with the cortex. Among these metabolites, indoxyl sulfate was focused for further study because it accumulated most significantly in the kidney cortex and medulla in a dose-dependent manner. A function verification study proved that chlormethiazole, a widely used CYP2E1 inhibitor, could reduce the production of indoxyl sulfate in the liver and attenuate cisplatin-induced AKI in rats. In conclusion, our study depicted the tryptophan pathway in cisplatin-induced AKI for the first time and demonstrated tryptophan metabolism is closely associated with the renal toxicity caused by cisplatin, which can be of great use for the discovery of renal toxicity attenuating remedies.
研究领域:
药理学
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肾病学
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代谢组学
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毒理学
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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）