JOURNAL OF PHARMACY AND PHARMACOLOGY
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2023
·Vol. 75
·期 3
·407-414
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IF 3.3
Yin Xiaoting,Ma Suzhen,Li Mengyuan,Lu Shuaifei,Zhang Changjing,Liu Hui,Li Caiyin,Su Pan,Bai Ming,Li Yucheng
ObjectivesGefitinib is mainly used for the treatment of non-small-cell lung cancer. Hepatotoxicity is one of the main side effects of gefitinib, and seriously affects the treatment process of the disease. However, the hepatotoxicity mechanism of gefitinib remains unclear.MethodsThe hepatotoxicity of different doses of gefitinib was investigated in mice and AML-12 cells, and the possible correlation of hepatotoxicity with CYP450 was analysed.Key findingsThe toxic effects of gefitinib were confirmed by the increased liver index, decreased body weight and survival rate, injured liver function and histopathology followed 16 days of oral administration. Gefitinib (400 mg/kg) upregulated the hepatic mRNA expression of CYP1A1 and downregulated the CYP2D9 and CYP2D10 in mice. Furthermore, we verified that gefitinib produced cytotoxicity on AML-12 cells in a dose and time-dependent manner, and confirmed that gefitinib (20 μM) induced cell apoptosis, upregulated mRNA expression of CYP1A1 and downregulated CYP2D9 and CYP2D10. Pearson correlation analysis also showed that the hepatotoxicity of gefitinib was positively correlated with CYP1A1 and negatively correlated with CYP2D9 and CYP2D10.ConclusionsOur results suggested that the hepatotoxicity gefitinib may be associated with CYP1A1, CYP2D9 and CYP2D10. These findings will contribute to a better understanding of the mechanism of gefitinib hepatotoxicity.
研究领域:
药理学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
LIPIDS
·
2022
·Vol. 57
·期 3
·153-162
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IF 1.646
Danping Wang,Jinglong Chen,Huangbing Sun,Wenjing Chen,Xiaojing Yang
Oxidative stress is an important factor in the occurrence and development of liver disease. Medium-chain fatty acids (MCFAs) have potential antioxidant function, whereas the exact underlying mechanism of MCFA in oxidative injury of hepatocytes remains unclear. In our present study, three different MCFAs, 8-carbon octanoic acid (OA), 10-carbon capric acid (CA), and 12-carbon lauric acid (LA), have been performed to observe their protective action for hepatocyte under the H 2 O 2 challenge. The result showed that MCFA treatment significantly increased the cell viability, T-AOC, and expression of antioxidant-related genes in AML12 cells under oxidative stress condition, and reduced reactive oxygen species (ROS) production. Moreover, MCFA treatment significantly increased the protein expression of Nrf2 and the phosphorylation level of ERK1/2; LA treatment significantly promoted the Nrf2 nuclear translocation. With a further test, the rescue ability of MCFA was blocked by treating with the ERK inhibitor U0126. Overall, our data suggested that MCFA treatment has positive impact on protecting AML12 cells against oxidative stress through ERK1/2/Nrf2 pathway.
研究领域:
细胞生物学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
XENOBIOTICA
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2023
·
IF 1.8
Chunhong Wu,Yifei Xiao,Caimei Wu,Dihao Xie,Meixue Luo,Dingyi Yao,Min Chen,Danyi Lu
BCRP (breast cancer resistance protein) is a crucial efflux transporter involved in the regulation of the pharmacokinetics and pharmacodynamics of a wide range of drugs. Herein, we aimed to investigate a potential role for the nuclear receptor REV-ERBα in the regulation of BCRP expression and sulfasalazine (a BCRP probe substrate) pharmacokinetics.Regulation of BCRP expression by REV-ERBα was assessed using Rev-erbα-/- mice and AML12 and CT26 cells. Pharmacokinetic analysis was performed with Rev-erbα-/- and wild-type mice after sulfasalazine administration.We found that the expression levels of BCRP mRNA and protein were downregulated in the liver and small intestine of Rev-erbα-dificient mice. In line with this, Rev-erbα ablation increased the systemic exposures of oral sulfasalazine.Positive regulation of BCRP expression and function by REV-ERBα was furtherly confirmed in AML12 and CT26 cells. Moreover, indirect regulation of Bcrp expression by REV-ERBα was potentially mediated by a negative transcription factor DEC2, which is a downstream target of REV-ERBα.In conclusion, REV-ERBα positively regulates BCRP expression in mice, thereby affecting sulfasalazine pharmacokinetics.
研究领域:
药理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Frontiers in Endocrinology
·
2025
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IF 4.6
Yuanfan Wu,Xia Sun,Yuhan Jia,Tianshu Gao,Jin Xu,Youqiao Qian,Naiqi Pei,Lilin Wang,Qiaohong Zheng,Honglei Li,Zhen Chen,Yijiao Liu,Yang Ma,Hui Chen,Yuanyuan Ye,Jiaxin Zhao,Yi Zhou,Xiaoqing Chen,Baosheng Huang,Yefeng Liu,Yin Zhu,Ning Xue,Juan Zhang,Guangfeng Ji,Xing Wang
This study aimed to evaluate the therapeutic effects of gigantol on hyperuricemia (HUA) and investigate the underlying mechanism of HUA. A mouse model of HUA was made by gavage of potassium oxonate, and HK-2 and AML12 cell models were made by adenosine and xanthine oxidase (XOD) induction. We tested the levels of uric acid (UA), creatinine (CRE), blood urea nitrogen (BUN), cellular UA, and XOD activity. The levels of NOD-like receptor thermal protein domain 3 (NLRP3) and other inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA) kits. XOD is a protein related to the NLRP3 pathway and also serves as an UA transporter. We found that the levels of UA, CRE, and BUN increased in serum but decreased in urine in HUA model mice. After gigantol treatment, UA, CRE, and BUN levels in serum decreased, whereas their levels in urine increased. The levels of NLRP3 and interleukin-1β (IL-1β) were lower and the expression of NLRP3-related protein decreased after gigantol treatment. In conclusion, gigantol exhibits a therapeutic effect on HUA, and the mechanism may be related to inhibiting XOD activity to reduce UA production, regulating the expression of UA transporters to increase UA excretion, and inhibiting the activation of NLRP3 inflammatory signaling.
研究领域:
药理学
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生物化学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
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IF 5.3
Guanlin Wu,Yan Zhang,Bo Liang,Lianhong Yin,Meng Gao,Han Zhang,Youwei Xu,Xu Han,Yan Qi,Fang Liu,Lina Xu
Investigating and identifying pathogenic molecules of non-alcoholic fatty liver disease (NAFLD) has become imperative, which would serve as effective targets in the future. We established high-fat diet (HFD)-induced NAFLD model in mice and palmitic acid (PA)-induced model in mouse AML12 cells. The level of miR-218-5p was examined by qRT-PCR, and Elovl5 was identified as the potential target gene of miR-218-5p . The binding relationship between miR-218-5p and Elovl5 was validated by double luciferase reporter gene assay, and inhibition/overexpression of miR-218-5p in vitro . The functional mechanisms of miR-218-5p / Elovl5 in regulating lipogenesis in NAFLD were investigated in vivo and in vitro through gain- and loss-of-function studies. MiR-218-5p was significantly increased, and Elovl5 was decreased in model group. According to the double luciferase reporter and gene interference experiments in AML12 cells, Elovl5 was a target gene of miR-218-5p and its expression was regulated by miR-218-5p . The SREBP1-mediated lipogenesis signaling pathway regulated by Elovl5 was upregulated in model group. Moreover, silencing of miR-218-5p significantly upregulated Elovl5 expression, and suppressed SREBP1 signaling pathway in PA-induced AML-12 cells. Correspondingly, the cell injury, elevated TC, TG contents and lipid droplet accumulation were ameliorated. Furthermore, the effect of miR-218-5p on lipogenesis in vitro and in vivo was obstructed by si-Elovl5 , implicating that miR-218-5p promotes lipogenesis by targeting ELOVL5 in NAFLD. miR-218-5p could promote fatty acid synthesis by targeting Elovl5 , thereby accelerating the development of NAFLD, which is one of the key pathogenic mechanisms of NAFLD and provides a new molecular target for the management of NAFLD.
研究领域:
分子生物学
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肝病学
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病理学
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DOI
PubMed
高影响因子
Probiotics and Antimicrobial Proteins
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2024
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IF 4.4
Wang Fei,Li Xiang,Wang Qi,Jin Qian,Xu Shujie,Tang Li,Zeng Zihan,Fu Aikun,Zhu Jinhui,Zhang Qiao,Yang Rongchang,Xiao Yingping,Li Weifen
Suanshui is a traditional fermented vegetable food in the southwest of China that is a rich source of probiotics. This study aimed to screen probiotics from Suanshui that have a protective effect against liver injury using in vivo and in vitro experiments. Eleven strains were isolated according to acid-producing capacity and probiotic properties, including antibacterial activity against pathogenic bacteria, tolerance to artificial gastrointestinal fluid and bile salts, heat resistance, antioxidant capacity, hydrophobicity, autoaggregation capacity, and adhesion capacity. Three probiotic strains, LAB36 ( Lacticaseibacillus paracasei , ( L . paracasei )), LAB19 ( Lactiplantibacillus plantarum ( L . plantarum )), and LAB51 ( Limosilactobacillus fermentum ( L . fermentum )), were obtained by the TOPSIS comprehensive evaluation. Furthermore, in an in vitro model of inflammation induced by LPS treatment of AML12, metabolites derived from the intestinal contents of mice treated with the three strains significantly decreased the gene expression of IL-1β , TNF-α , and Caspase 3 in the LAB (19, 36, 51) + LPS group ( P < 0.05) and significantly increased the gene expression of Bcl-2 compared with those in the untreated LPS group ( P < 0.05). In addition, the LAB36 + LPS group also exhibited significantly decreased gene expression of TLR4 and Bax ( P < 0.05). In vivo experiments, LAB36 pretreatment significantly decreased the levels of ALT, AST, and inflammatory factors (IL-1β and IL-6) in the serum, improved the antioxidant capacity, and reduced apoptosis in the livers of the model mice (liver injury induced by D-GalN/LPS). In summary, LAB36 isolated from Suanshui has a protective effect on liver injury.
研究领域:
微生物学
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食品科学
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肝脏病学
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分子生物学
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DOI
PubMed
高影响因子
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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DOI
PubMed
高影响因子
CHEMOSPHERE
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2023
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IF 8.8
Jian Sun,Huayi Qu,Waseem Ali,Yan Chen,Tao Wang,Yonggang Ma,Yan Yuan,Jianhong Gu,Jianchun Bian,Zongping Liu,Hui Zou
Microplastics (MPs) and cadmium (Cd) are important environmental pollutants, that damage the liver. However, the effect and mechanism of combined Cd and MPs exposure on liver fibrosis are still largely unknown. In this study investigated, Cd + MPs exposure increased superoxide anion production and promoted extracellular ATP release compared with exposure to Cd or MPs individually. Cd + MPs increased inflammatory cell infiltration , activated the P2X7-NLRP3 signaling pathway, and promoted inflammatory factor release. Cd + MPs aggravated Cd- or MPs-induced liver fibrosis and induced liver inflammation. In AML12/HSC-T6 cell in vitro poisoning model, exposure of AML12 cells to Cd + MPs increased the opening of connexin hemichannels and promoted extracellular ATP release. Treatment of HSC-T6 cells with the supernatant of AML12 cells exposed to Cd + MPs significantly promoted HSC-T6 cell activation. Treatment of HSC-T6 cells with different concentrations of ATP produced similar results. TAT-Gap19TFA, an inhibitor of connexin hemichannels, significantly inhibited the ATP release and activation of Cd + MPs-treated HSC-T6 cells. Finally, the expression of the ATP receptor P2X7 was silenced in HSC-T6 cells, which significantly inhibited their activation. In conclusion, exposure to Cd + MPs promoted liver fibrosis through the ATP-P2X7 pathway and synergistically affected liver inflammation and fibrosis.
研究领域:
环境科学
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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
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2024
·Vol. 25
·期 23
·12844
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IF 4.9
Zhining Gao,Haoyang Dai,Qinqin Zhang,Fan Yang,Chenxi Bu,Suiqing Chen
Acute liver injury (ALI) is an injury to liver tissue caused by viruses, drugs, alcohol, and oxygen deprivation, and is one of the most common and serious clinical disorders. Hydroxytyrosol (HT) is a naturally occurring polyphenolic compound isolated from forsythia and has excellent anti-inflammatory properties. However, the effect and mechanisms of HT in ALI remain unclear. We used the LPS/D-GalN induced experimental ALI mouse model and AML12 cells to reveal the efficacy and potential mechanisms of HT in ALI, and HE staining was used for the evaluation of pathologies. A biochemical assay was used to detect changes in liver function, RNA-seq was conducted to reveal the underlying mechanisms of HT for ALI, and WB, RT-qPCR, and IF were used to assess the effects of HT action. Furthermore, an in vitro ALI model against HT in AML12 cells induced by LPS/D-GalN was used to assess the HT protection mechanism. HT significant alleviated LPS/D-GalN-induced ALI in the mice by suppressing inflammatory. In terms of RNA-seq, HT improved the TNF, ECM-receptor interaction, and PI3K/AKT signaling pathway, and it downregulated the mRNA levels of VCAM-1, CXCL5, TNF-α and IL-6 in the liver. Mechanically, HT alleviated LPS/D-GalN in the mice by targeting TNF-α, thereby inhibiting the TNF-α/PI3K/AKT signaling pathway.
研究领域:
药理学
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肝病学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Jin-Quan Zhao,Qi-Qi Zhou,Ke Liu,Ping Li,Yan Jiang,Hui-Jun Li
Ethnopharmacological relevance Celosia Semen (CS) serves as a traditional Chinese medicine (TCM) for promoting liver health and enhancing vision, with extensive clinical applications. Triterpenoid saponins represent the primary active components of CS, with the highest concentration of Celosin I (CI) detected. The urgent need for effective NAFLD treatments motivated us assess the beneficial effects of total saponins from CS (TSCS) and CI. Aims of the study To investigate the therapeutic effects of TSCS and CI on NAFLD and its underlying molecular mechanisms. Materials and methods The impact of TSCS and CI on NAFLD was evaluated through in vitro and in vivo methodologies, utilizing high-fat diet (HFD) and palmitic acid/oleic acid modeling on C57BL/6J mice and AML12 cells, respectively. Biochemical analysis, H&E and Oil red O staining were used to characterize the lipid-lowering and hepatoprotective activities of TSCS and CI. Lipidomics discerned the impact of TSCS and CI interventions on liver lipid composition, distribution and alteration in NFALD mice. RT-qPCR and western blotting detected the influence of TSCS and CI on genes linked to de novo lipogenesis, fat calculation uptake, oxidation and esterification. The docking analysis anticipated the interaction of six major triterpenoid saponins within TSCS with SREBP1. Results TSCS and CI markedly diminished lipid accumulation induced by high fat both in vivo and in vitro . TSCS and CI also mitigated hepatic steatosis and liver injury induced by HFD through the reduction of TC, TG, FAs, ALT, and AST, even at minimal dose of 25 mg/kg. Lipidomics indicated that TSCS and CI had the potential to modulate the lipid metabolism network, rectify lipid metabolic dysregulation induced by NAFLD, decrease the levels of harmful lipids, and elevate the levels of advantageous lipids. Furthermore, TSCS and CI exhibited a strong affinity to SREBP1, thereby might directly influence the expression of SREBP1 and a cascade of essential enzymes involved in de novo lipogenesis, and finally resulting in a diminished synthesis of novel lipids. Conclusion TSCS and CI were confirmed firstly as key active components of CS in amending hepatic steatosis and mitigate liver damage in NAFLD, outlining the preliminary mechanism. They warrant further exploration as drug candidates for NAFLD treatment, especially in light of the current shortage of medications and limited therapeutic options.
研究领域:
药理学
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民族药理学
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脂质代谢
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分子生物学
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中药学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Sen Yang,Yang Zhang,Yan Zhang,Lianhong Yin,Xu Han,Xuerong Zhao,Ning Wang,Lina Xu
Long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). However, their biological roles and function mechanisms in NAFLD remain largely unknown. In this study, we found that Gm28382 may be a potential pathogenic lncRNA of NAFLD and highly expressed in NAFLD through RNA-seq. Overexpression of Gm28382 significantly enhanced the lipid accumulation in AML12 cells, whereas Gm28382 silencing reduced lipogenesis both in palmitic acid (PA)-induced AML12 cells and high fat diet (HFD)-induced mice. Then, bioinformatics were employed to speculate the potential interacting genes of Gm28382, and found that Gm28382 may regulate ChREBP expression through binding with miR-326-3p. Fluorescence in situ hybridization (FISH), dual luciferase reporter assay, immunofluorescence RNA pull-down and RNA immunoprecipitation (RIP) assays were used to validate the binding and targeting relationship of these genes, and we confirmed that Gm28382 competitively binds to miR-326-3p to increase ChREBP expression as a ceRNA. Mechanistically, overexpression of Gm28382 upregulated the ChREBP-mediated lipid synthesis signaling pathway, but the function was sabotaged by miR-326-3p deletion or ChREBP overexpression. Furthermore, in PA-challenged AML12 cells or HFD-induced mice, silencing of Gm28382 reversed the aberrant ChREBP signaling pathway and lipid accumulation, whereas ChREBP overexpression or liver-specific silencing of miR-326-3p blocked this function of Gm28382. Collectively, these findings reveal a critical role of Gm28382 in the promotion of lipogenesis in NAFLD by regulating the ChREBP signaling pathway through interaction with miR-326-3p, which could serve as a potential therapeutic target for NAFLD treatment.
研究领域:
分子生物学
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生物化学
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肝病学
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基因组学
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病理学
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产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
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2024
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IF 5.2
Kai Yang,Xiaoxiao Yu,Zihao Guo,Zhihao Fang,Hongyu Zhang,Wanyangchuan Zhang,Changxu Liu,Yanchao Ji,Zhichao Dong,Qiang Gu,Jiahao Yao,Chang Liu
Aims Non-alcoholic fatty liver disease (NAFLD) has risen as a significant global public health issue, for which vertical sleeve gastrectomy (VSG) has become an effective treatment method. The study sought to elucidate the processes through which PIM1 mitigates the advancement of NAFLD. The Pro-viral integration site for Moloney murine leukemia virus 1 (PIM1) functions as a serine/threonine kinase. Bioinformatics analysis revealed that reduced PIM1 expression in NAFLD. Methods To further prove the role of PIM1 in NAFLD, an in-depth in vivo experiment was performed, in which male C57BL/6 mice were randomly grouped to receive a normal or high-fat diet for 19 weeks. They were operated or delivered the loaded adeno-associated virus which the PIM1 was overexpressed (AAV-PIM1). In an in vitro experiment, AML12 cells were treated with palmitic acid to induce hepatic steatosis. Key findings The results revealed that the VSG surgery and virus delivery of mice alleviated oxidative stress, and apoptosis in vivo. For AML12 cells, the levels of oxidative stress, apoptosis, and lipid metabolism were reduced via PIM1 upregulation. Moreover, ML385 treatment resulted in the downregulation of the NRF2/HO-1/NQO1 signaling cascade, indicating that PIM1 mitigates NAFLD by targeting this pathway. Significance PIM1 alleviated mice liver oxidative stress and NAFLD induced by High-fat diet by regulating the NRF2/HO-1/NQO1 signaling Pathway.
研究领域:
肝病学
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分子生物学
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病理学
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药理学
✓ 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）