BIOCHEMICAL PHARMACOLOGY
·
2024
·
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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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Hao Zhang,Jia-Gen Cui,Ming-Shan Chen,Jia-Xin Wang,Xiao-Han Sun,Yi Zhao,Jin-Long Li
Di(2-ethylhexyl) phthalate (DEHP), which is widely used in agricultural plastics, accumulates in humans and animals through the food chain over time, resulting in liver toxicity. Recent studies have reported that pyroptosis and mitochondrial damage are closely related to a variety of liver diseases, but the specific mechanism is still unclear. To address this issue, in vitro and in vivo hepatotoxicity models were established. The results demonstrated that exposure to DEHP caused a buildup of MEHP in livers, altered liver metabolite composition, and caused pyroptosis-like changes in hepatocytes. After DEHP treatment, REDOX homeostasis was unbalanced, and mitochondrial reactive oxygen species (mtROS) were overproduced. MEHP exposure activates pyroptosis mediated by TNF/TNFR1 signaling and upregulates the perforating protein GSDMD-N to destroy the mitochondrial membrane of hepatocytes. Above all, this study elucidates the potential involvement of TNF/TNFR1 signaling-mediated pyroptosis in mitochondrial damage and confirms that the regulation of pyroptosis is helpful in maintaining normal mitochondrial function.
研究领域:
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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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Yanfang Zheng,Jiaying Chen,Ying Zhang,Huaying Guan,Shan Deng,Dennis Chang,Yitao Wang,JinJian Lu,Xian Zhou,Qin Xie,Jianyuan Song,Mingqing Huang
Gut microbiota and bile acid metabolism play crucial roles in the progression of nonalcoholic fatty liver disease (NAFLD). Early evidence demonstrates that Ginsenoside Re (Re) possesses pharmacological effects on NAFLD, but its mechanisms of action are not well understood. This study aimed to investigate the hepatic protective effects of Re in NAFLD and elucidate relevant mechanisms. The effects of Re treatments (10, 20, or 40 mg/kg) against high-fat diet-induced NAFLD were initially tested on male C57BL/6 mice. Then, a separate mouse group received Re with or without antibiotics to confirm the regulatory role of microbiota in the effect of Re. Finally, another group of mice received fecal microbiota transplantation (FMT) from the initial experiment of NAFLD mice to further investigate the mechanistic role of gut microbiota. Re significantly improved liver function by reducing hepatic lipid accumulation, injury and hepatocyte steatosis, and inflammation. The liver protection was mediated by the regulation of gut microbiota as evidenced by restored intestinal barrier integrity, normalized Firmicutes/Bacteroidota ratio, enhanced abundances of Adlercreutzia equolifaciens , and reduced Faecalibaculum rodentium . Following that, Re reduced total and primary bile acids and downregulated bile acid synthesis genes and proteins such as farnesoid X receptor and cytochrome P450 family 7 subfamily A member 1. The co-administration of antibiotic cocktail counteracted the effect of Re against NAFLD. Further, the results obtained from the FMT animal study confirmed that Re's liver protective effects were at least partly driven by the regulation of gut microbiota. Re modulated bile salt hydrolase-related microbial genera to alter bile acid synthesis pathways, thereby inhibiting NAFLD progression.
研究领域:
药理学
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代谢组学
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微生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2025
·
IF 3.9
Yijun Yang,Nengyi Wang,Yuankun Chen,Tianpeng Ma,Minhua Weng,Haifeng Wu,Qiuping Wu,Yiqiang Xie,Chuanwu Zhu,Wenting Li
Nonalcoholic fatty liver disease (NAFLD) has posed a huge threat to public health globally, but there are currently no approved drugs available. Growing evidence has proved the close association between increased Th17 cells and NAFLD progression. Interleukin-4 induced protein 1 (IL4I1), an amino acid oxidase secreted by immune cells, was reported to regulate the Th17 cells, but its exact role in NAFLD progression has not been fully explained yet. We found that IL4I1 was highly expressed in the liver of C57BL/6J mice with NAFLD induced by an 8-weeks western diet. To explore the IL4I1’s effect, mice were injected with AAV8 encoding IL4I1 1 week before western diet administration. The results showed that IL4I1 overexpression inhibited the NAFLD progression, demonstrated by relieved liver damage and lipid accumulation. The underlying mechanism in which IL4I1 acts on NAFLD might be attributed to the inactivated AKT/forkhead box protein O1 (FOXO1) signaling pathway–mediated decrease of Th17 cells in liver tissues. Subsequently, by culturing naive CD4 + T cells isolated from the spleen of mice in Th17 cell-polarizing conditions, we determined that IL4I1 overexpression inhibited Th17 cell differentiation by inactivating the AKT/FOXO1 pathway, whereas its knockdown exhibited opposite effects. Further, the AKT activator SC79 reversed the effect of IL4I1 overexpression on Th17 cell differentiation. Collectively, our study supports that compensatory upregulation of IL4I1 protects against liver damage and lipid accumulation in NAFLD progression, partially by inhibiting the activated AKT/FOXO1 signaling pathway-induced Th17 cell differentiation.
研究领域:
免疫学
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肝病学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2025
·
IF 8.4
Xia Ling-yan,Yu Nai-rong,Huang Su-ling,Qu Hui,Qin Li,Zhao Qin-shi,Leng Ying
Non-alcoholic steatohepatitis (NASH) has emerged as a prevalent chronic liver disease with a huge unmet clinical need. A few studies have reported the beneficial effects of Poria cocos Wolf ( P. cocos ) extract on NASH mice, but the active components were still unknown. In this study we investigated the therapeutic effects of dehydrotrametenolic acid methyl ester (ZQS5029-1), a lanosterol-7,9(11)-diene triterpenes in P. cocos , in a high-fat diet plus CCl 4 induced murine NASH model and a GAN diet induced ob/ob murine NASH model. The NASH mice were treated with ZQS5029-1 (75 mg·kg –1 ·d –1 , i.g.) for 6 and 8 weeks, respectively. We showed that ZQS5029-1 treatment markedly relieved liver injury, inflammation and fibrosis in both the murine NASH models. We found that ZQS5029-1 treatment significantly suppressed hepatic NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in both the NASH murine models, and blocked lipopolysaccharides (LPS)+adenosine 5’-triphosphate (ATP)/Nigericin-induced NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs) and Kupffer cells in vitro. We demonstrated that ZQS5029-1 directly bound to the H236 residue of mouse Caspase-1, thereby inhibiting NLRP3 inflammasome activation. The effects of ZQS5029-1 on macrophage-hepatocyte/HSC crosstalk were analyzed using the supernatants from macrophages preconditioned with LPS + ATP introduced into hepatocytes and hepatic stellate cells (HSCs). We found that the conditioned medium from the BMDMs induced injury and death, as well as lipid accumulation in hepatocytes, and activation of HSCs; these effects were blocked by conditioned medium from BMDMs treated with ZQS5029-1. Moreover, the protective effects of ZQS5029-1 on hepatocytes and HSCs were eliminated by H236A-mutation of Caspase-1. We conclude that ZQS5029-1 is a promising lead compound for the treatment of NASH by inhibiting NLRP3 inflammasome activation through targeting Caspase-1 and regulating the macrophage-hepatocyte/HSC crosstalk.
研究领域:
药理学
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肝脏病学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Chemical Biology & Drug Design
·
2025
·Vol. 105
·期 5
·e70113
·
IF 3.3
Ming Tong,Meng Liu,Liang Chen,Yi-he Lin,Qing Zheng
Liver fibrosis is pathologically associated with ferroptosis. Osthole (OST) has good therapeutic effects on liver fibrosis. Our study sought to investigate the pharmacological effects of OST on ferroptosis in hepatic stellate cells (HSCs) during the development of liver fibrosis and define the mechanisms involved. The in vivo model of liver fibrosis was established by CCl 4 treatment. MTT and EDU assays were used to assess cell viability and proliferation, respectively. The interaction between myocyte enhancer factor 2A (MEF2A) and Y-box binding protein 1 (YBX1) was analyzed by dual luciferase reporter and chromatin immunoprecipitation (ChIP) assays. OST treatment alleviated CCl 4 -induced liver fibrosis in mice by activating ferroptosis. OST induced ferroptosis in HSCs and inhibited the activation of HSCs in vitro, while these effects of OST were reversed by MEF2A overexpression or YBX1 overexpression. Mechanistically, MEF2A activated the Wnt/β-catenin signaling by transcriptionally facilitating YBX1 expression. As expected, the inactivation of Wnt/β-catenin signaling or YBX1 knockdown could reverse the regulatory effect of MEF2A upregulation on the activation of HSCs and ferroptosis in OST-treated HSCs. OST mitigated liver fibrosis by inducing ferroptosis in HSCs and repressing the activation of HSCs through inhibiting the MEF2A/YBX1/Wnt/β-catenin axis.
研究领域:
药理学
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分子生物学
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肝脏病学
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产品关联
DOI
PubMed
高影响因子
DRUG AND CHEMICAL TOXICOLOGY
·
2025
·
IF 1.9
Aicun Tang,Luying Wei,Jiayi Gao,Zheng Zhang,Bingyu Xia,Xin Li,Qiuyu Lu
To analyze tadehaginoside (TA) for its effect on liver fibrosis and the associated mechanism. Mice with CCl4-mediated liver fibrosis were administered TA treatment for 6 weeks. Histopathological alterations in liver tissues were evaluated, and serum markers of hepatic injury, as well as the hepatic profibrotic gene and protein levels were detected. Transforming growth factor-β1 (TGF-β1) was adopted for inducing LX-2 cells. Following a 24-h TA intervention, we assessed pro-fibrotic gene and protein activation, proliferation and levels of TGF-β1-activated LX-2 cells. miR-155 and FOXO3 expressions were quantified in mice liver tissues and cells. The targeting relation of miR-155 with FOXO3 was verified. After regulating miR-155 and FOXO3 expression, the function of TA in cell activation, proliferation, and collagen accumulation was evaluated. The results indicated that TA treatment markedly alleviated CCl4-mediated mouse liver injury, inhibited collagen fiber deposition, and downregulated the hepatic pro-fibrotic gene and protein levels. Additionally, TA treatment suppressed TGF-β1-induced cell activation and proliferation, thus significantly reducing pro-fibrotic marker levels within cells. Furthermore, treatment with TA down-regulated miR-155 and up-regulated FOXO3 within CCl4-induced liver tissues as well as TGF-β1-induced cells. However, miR-155 overexpression or FOXO3 silencing partially mitigated the inhibition of TA against TGF-β1-mediated activation, proliferation, and fibrosis in cells. In conclusion, TA inhibits the activation of hepatic stellate cell (HSC) via miR-155/FOXO3 axis, thereby exerting its anti-hepatic fibrosis effect.
研究领域:
药理学
·
分子生物学
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肝脏病学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGICAL SCIENCES
·
2016
·Vol. 152
·期 2
·417-428
·
IF 3.88
Guo Hong-Li,Hassan Hozeifa M.,Zhang Yun,Dong Si-Zhe,Ding Ping-Ping,Wang Tao,Sun Li-Xin,Zhang Lu-Yong,Jiang Zhen-Zhou
Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of tuberculosis which may cause serious hepatotoxicity; however, the mechanisms underlying these toxicities are poorly understood. Cholestasis plays an important role in drug-induced liver injury. Since there were no previous published works reported cholestasis and PZA hepatotoxicity relationship, this study aimed to identify whether PZA can induce liver injury with characterized evidences of cholestasis and to clarify expression changes of proteins related to both bile acid synthesis and transport in PZA-induced liver injury. PZA (2 g/kg) was administered for 7 consecutive days by oral gavage. Results showed there were 2-fold elevation in both ALT and AST serum levels in PZA-treated rats. In addition, a 10-fold increment in serum total bile acid was observed after PZA administration. The mRNA and protein expressions of bile acid synthesis and transport parameters were markedly altered, in which FXR, Bsep, Mrp2, Mdr2, Ostα/β, Oatp1a1, Oatp1b2, and Cyp8b1 were decreased (P < .05), while Mrp3, Ntcp, Oatp1a4, and Cyp7a1 were increased (P < .05). Moreover, treatment with the FXR agonist obeticholic acid (OCA) generated obvious reductions in serum ALT, AST, and TBA levels in PZA-treated rats. Those effects were due to transcriptional regulation of pre-mentioned target genes by OCA. Taken together, these results suggested that PZA-induced cholestatic liver injury was related to FXR inhibition, leading to the dysfunction in bile acid synthesis and transport.
研究领域:
药理学
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毒理学
·
肝病学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2024
·
IF 3.1
Zihan Zhu,Yun Zhang,Jun Li,Yuhao Han,Lei Wang,Yaqi Zhang,Haoyuan Geng,Yurong Zheng,Xiao Wang,Chenglong Sun,Baoguo Li,Panpan Chen
Liver's distinctive function renders it highly susceptible to diverse damage sources. Characterizing the metabolic profiles and spatial signatures in different liver injuries is imperative for early diagnosis and etiology-oriented treatment. In this comparative study, we conducted whole-body spatial metabolomics on zebrafish with liver injury induced by ethanol (EtOH), acetaminophen (APAP), and thioacetamide (TAA). The two specific levels, the whole-body and liver-specific metabolic profiles, as well as their regional distributions, were systematically mapped in situ by mass spectrometry imaging, which is distinct from conventional LC-MS and GC-MS methods. We found that liver injury regions exhibited more pronounced metabolic reprogramming than the entire organism, leading to significant alterations in eight fatty acids, three phospholipids, and four low-molecular-weight metabolites. More importantly, fatty acids as well as small molecule metabolites including glutamine, glutamate, taurine and malic acid displayed contrasting changes between alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). In addition, phospholipids, including Lyso PC (16:0) and Lyso PE (18:0), demonstrated notable down-regulation in all damaged liver, whereas PC (34:1) underwent upregulation. This study not only deepens insights into distinct potential biomarkers for liver injuries, but also underscores spatial metabolomics as a powerful tool to elucidate possible pathogenic mechanisms in other metabolic diseases.
研究领域:
代谢组学
·
药理学
·
病理学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Weiqi Cui,Qianwen Cao,Luyao Liu,Xuecui Yin,Xiaohan Wang,Yang Zhao,Yanhong Wang,Bo Wei,Xia Xu,Youcai Tang
Background The hepatotoxicity induced by acetaminophen (APAP), a commonly used antipyretic, analgesic and anti-inflammatory drug in clinical practice, has received accumulated attention. Artemisia argyi essential oil (AAEO), a volatile oil component extracted from traditional Chinese medicine Artemisia argyi H.Lév. & Vaniot, has great hepatoprotective effects. However, the potential role of AAEO in APAP-induced hepatotoxicity has not been characterized. The present study aimed to investigate the effects of AAEO on hepatic metabolic changes in mice exposed to APAP. Methods In this study, 300.00 mg/kg acetaminophen was used to establish liver injury model in C57BL/6 J mice. Hepatoprotective effect of AAEO on APAP-induced hepatotoxicity in mice was investigated by detecting liver function enzymes and histopathological examination. Secondly, UPLC-MS/MS was used to analyze the to analyze the small molecule metabolites and metabolic pathways induced by AAEO treatment; In addition, the effect of AAEO on APAP-induced oxidative stress and inflammation were evaluated by detecting the levels of glutathione peroxidase 4, malondialdehyde, reactive oxygen species and inflammatory factors. Finally, the active components of AAEO were preliminarily screened by cellular assays. The hepatoprotective effect of AAEO against APAP-induced hepatotoxicity was examined through the Western blotting, after the CYP2E1 gene was knocked down in AML12 cells by siRNA transfection. Results Compared with the APAP group, AAEO could reduce the abnormal increase in the levels of liver function enzymes caused by APAP. AAEO could enhance the antioxidant capacity by down-regulating the biosynthesis pathway of unsaturated fatty acids and promoting the activity of antioxidant enzymes SOD and CAT in liver tissue induced by APAP. Our study revealed that AAEO promoted GSH synthesis and covalently combined to form APAP-GSH conjugates to reduce the accumulation of APAP in liver tissue. In addition, the chemical constituents in AAEO were analyzed by GC–MS/MS, and it was determined to identify that dihydro-beta-ionone and (-)-verbenone in AAEO might have a significant protective effect on hepatocyte survival after APAP exposure. Further studies on the hepatoprotective mechanism of AAEO indicated that it might reduce the production of toxic metabolites by regulating CYP2E1 levels. Conclusion AAEO exerted hepatoprotective effects on acetaminophen-induced hepatotoxicity in mice via regulating the activity of CYP2E1 and regulating the γ-glutamyl cycle pathway.
研究领域:
药理学
·
肝病学
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毒理学
·
代谢组学
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中药学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2025
·
IF 7.3
Peng Zhang,Guanghua Lu,Leibo Zhang,Zhenhua Yan,Min Wang
Microplastics (MPs) can accumulate and enrich antibiotics in aquatic environments, with their interactions exacerbating threats to aquatic organisms and complicating hepatotoxicity. Therefore, this study aimed to elucidate the effects of single or combined exposure to polyethylene MPs and ciprofloxacin (CIP) on hepatic injury in crucian carp, and to reveal the potential gut-liver axis toxicity mechanisms. The results showed that MPs enhanced the bioaccumulation of CIP, which increased with increasing MPs concentration. Co-exposure induced extensive eosinophilic necrosis and localised hepatocyte clustering in hepatocytes, alongside severe vacuolization and lymphocytic infiltration in intestinal cells. Glutamate aminotransferase and alanine aminotransferase activities, and total antioxidant capacity levels in the liver were significantly elevated, whilst glutamyltransferase activities were suppressed by the co-exposure. High-concentration MPs in combination with CIP significantly enriched the pathways of amino acid metabolism, glycerophospholipid metabolism, and primary bile acid biosynthesis in the liver. Moreover, co-exposure markedly suppressed the abundance of Cetobacterium while promoting that of Gemmobacter and Bosea . The imbalances in Bacteroides and pathogens ( Aeromonas and Bose ) are closely associated with related products in primary bile acid biosynthesis and glycerophospholipid metabolism pathways. These findings underscore that exposure to MPs and CIP induces hepatitis and reveal the pivotal role of the indirect gut-liver axis in elucidating the potential mechanisms underlying hepatotoxicity induced by co-exposure, thereby furnishing critical evidence for the holistic assessment of health hazards posed by these pollutants.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2025
·
IF 20.3
Jiabin Zhang,Xiaodie Chen,Yurong Chai,Yuanyuan Jin,Fenfang Li,Chenya Zhuo,Yanteng Xu,Haixia Wang,Enguo Ju,Yeh-Hsing Lao,Xi Xie,Mingqiang Li,Yu Tao
Acute liver failure (ALF) is a highly lethal condition characterized by massive tissue necrosis, excessive oxidative stress, and serious inflammatory storms, necessitating prompt medical intervention. Although hepatocyte-like cells (HLCs) derived from mesenchymal stromal/stem cells (MSCs) offer a promising alternative cell source for hepatocyte therapy, their low in-vivo integration and differentiation efficiency may compromise the eventual therapeutic efficacy. To this end, MSCs are bioengineered into multicellular spheroids in the present study. The proteomic analyses and experimental results reveal that extracellular vesicles (EVs) derived from these MSC spheroids (SpEV) contain abundant highly expressed bioactive proteins and can be efficiently endocytosed by recipient cells, resulting in enhanced pro-angiogenic and antioxidative effects. In addition, MSC spheroids exhibit superior hepatic cell differentiation compared to an equivalent number of dissociated single MSCs, particularly when being co-cultured with hexagonally patterned endothelial cells in a liver lobule-like arrangement. Following orthotopic implantation in the mouse model, the enhanced paracrine effects of SpEV, combined with an immunoregulatory decellularized extracellular matrix hydrogel carrier and functional artificial liver lobules (ALL), synergically contribute to the effective amelioration of ALF, highlighting the substantial potential for clinical translation.
研究领域:
再生医学
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肝脏疾病
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生物工程
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细胞治疗
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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）