Oncotarget
·
2017
·
IF 5.168
Jie Gao,Gao-Ju Wang,Zhao Wang,Na Gao,Jing Li,Yun-Fei Zhang,Jun Zhou,Hong-Xin Zhang,Qiang Wen,Han Jin,Hai-Ling Qiao
Hepatofibrosis, which leads to cirrhosis and eventual hepatocellular carcinoma, is a common response to chronic toxin-mediated liver injury. Nitrosamines are potent hepatotoxic agents that cause necrosis and subsequent fibrosis in the liver as a result of cytochrome P450 2E1 (CYP2E1)-dependent metabolism, which generates toxic metabolites that form adducts with nucleic acids, leading to hepatotoxicity and mutagenesis. Herein, CYP2E1 activity and content were determined in fibrotic liver tissue from patients with hepatocellular carcinoma. The relationship between CYP2E1 innate activity and hepatofibrogenesis was evaluated, the effect of inhibition of CYP2E1 activity on hepatofibrosis was determined in a Sprague-Dawley rat model of diethylnitrosamine-induced hepatofibrosis. The results demonstrated that the CYP2E1 activities in human fibrotic tissues are significantly higher than that in normal liver tissues. In rats treated with diethylnitrosamine, the livers demonstrated various degree of fibrotic changes and collagen deposition in individual rats. The Ishak score, which determines the stage of fibrosis, correlated with CYP2E1 innate activity, with greater fibrosis in rat livers with higher CYP2E1 innate activity. Inhibition of CYP2E1 during diethylnitrosamine treatment decreased hepatofibrosis and there was an inverse correlation between the degree of inhibition and the extent of hepatofibrosis. Therefore, high CYP2E1 activity is a risk factor for hepatofibrogenesis induced by nitrosamines.
研究领域:
医学
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毒理学
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肝脏研究
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Si Qin,Xuening Du,Kaili Wang,Da Wang,Jiani Zheng,Haiyan Xu,Xiuyan Wei,Yue Yuan
Liver fibrosis (LF) is one of the major diseases that threaten human health. Until now, no effective drugs have been approved for clinical anti-liver fibrosis treatment. In this study, zeolitic imidazolate framework-8 (ZIF-8) lipid nanoparticles loaded with pirfenidone (PFD) and modified with vitamin A (VA) were constructed (VA-PFD@ZIF-8@DMPC NPs). PFD was embedded in ZIF-8 by the “one-pot” method, and the prepared ZIF-8 had a small particle size (84.3 nm) and high drug loading (54.46%). Moreover, the inherent pH sensitivity of ZIF-8 makes it stable in a normal physiological environment and collapsed in an acidic environment, thus controlling drug release and preventing drug leakage. Besides, the phospholipid layer makes the nano-drug delivery system dispersible and improves its biocompatibility . More importantly, VA is modified on the surface of nanoparticles (NPs), which can target the highly expressed retinol-binding protein receptor (RBPR) on the surface of hepatic stellate cells (HSCs), thereby accurately increasing the local drug concentration at the site of LF. In vivo experiments showed that VA-PFD@ZIF-8@DMPC NPs can reduce liver injury, improve the degree of LF, and exert specific therapeutic effects on LF. In conclusion, this nano-delivery system may become a novel and effective anti-liver fibrosis treatment.
研究领域:
药学
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生物医学工程
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肝脏病学
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DOI
PubMed
高影响因子
Hepatology International
·
2019
·Vol. 14
·期 1
·145-160
·
IF 5.49
Zhao Jing,Han Ming,Zhou Li,Liang Pu,Wang Yun,Feng Shenghu,Lu Hongping,Yuan Xiaoxue,Han Kai,Chen Xiaofan,Liu Shunai,Cheng Jun
Background This study aimed to investigate the roles and mechanisms of tenofovir alafenamide fumarate (TAF)/tenofovir disoproxil fumarate (TDF) in treating liver fibrosis. Methods The effects of TAF/TDF on carbon tetrachloride (CCl 4 )-induced liver fibrosis in C57BL/6 wild-type or nonstructural protein 5A transactivated protein 9 (NS5ATP9) knockout mice were studied. The differentiation, activation, and proliferation of LX-2 cells after TAF/TDF treatment were tested in vitro. The expression of NS5ATP9 and activities of transforming growth factor-β1 (TGFβ1)/Sekelsky mothers against decapentaplegic homolog 3 (Smad3) and NF-κB/NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome signaling pathways were detected in TAF/TDF-treated mice and LX-2 cells. The genes related to extracellular matrix accumulation were detected in vivo and in vitro after NS5ATP9 silencing or knockout. Results TAF/TDF significantly inhibited CCl 4 -induced liver fibrosis in mice, and regulated the differentiation, activation, and proliferation of hepatic stellate cells (HSCs). Furthermore, TAF/TDF suppressed the activities of TGFβ1/Smad3 and NF-κB/NLRP3 inflammasome signaling pathways in vivo and in vitro. NS5ATP9 inhibited liver fibrosis through TGFβ1/Smad3 and NF-κB signaling pathways. TAF/TDF upregulated the expression of NS5ATP9 in vivo and in vitro. Finally, TAF/TDF could only show marginal therapeutic effects when NS5ATP9 was silenced and knocked out in vivo and in vitro. Conclusions TAF/TDF prevented progression and promoted reversion of liver fibrosis through assembling TGFβ1/Smad3 and NF-κB/NLRP3 inflammasome signaling pathways via upregulating the expression of NS5ATP9. TAF/TDF also regulated the differentiation, activation, and proliferation of HSCs. The findings provided strong evidence for the role of TAF/TDF as a new promising therapeutic strategy in liver fibrosis.
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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DOI
PubMed
高影响因子
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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2018
·Vol. 365
·期 2
·398-407
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IF 3.706
Jie Gao,Zhao Wang,Gao-Ju Wang,Hong-Xin Zhang,Na Gao,Jie Wang,Cai-E. Wang,Zhao Chang,Yan Fang,Yun-Fei Zhang,Jun Zhou,Han Jin,Hai-Ling Qiao
Hepatocellular carcinoma (HCC) is one of the most common types of primary liver cancer and the third most frequent cause of cancer death worldwide. Diethylnitrosamine (DEN) is one of the recognized risk factors for hepatocarcinogenesis likely due to CYP2E1-mediated metabolic activation. However, CYP2E1-mediated DEN metabolic activity in non-neoplastic liver tissue from HCC patients has not been determined; the role of CYP2E1 activity, in particular CYP2E1 constitutive activity and CYP2E1 inhibited activity, with respect to the hepatocarcinogenesis induced by DEN is not yet clear. Herein, we determined CYP2E1-mediated DEN metabolic activity in non-neoplastic liver tissue from HCC patients and found that CYP2E1-mediated DEN metabolic activity was significantly elevated with a 43.3% positive rate, and clinicopathologic parameters did not affect the activity. Then, using a Sprague-Dawley rat liver tumor model induced by DEN, the relationship between CYP2E1 constitutive/inhibited activity and hepatocarcinogenesis was explored. The results showed that the CYP2E1 constitutive activity was strongly correlated with tumor incidence and severity of liver tumorigenesis (nodule numbers and size), whereas inhibition of CYP2E1 activity decreased hepatocyte proliferation, liver injury, and liver carcinogenesis in the presence of DEN. In conclusion, the higher CYP2E1 activity would lead to an increased incidence of HCC as a result of CYP2E1-mediated DEN activation. Therefore, higher CYP2E1 activity might be a risk factor for HCC induced by DEN.
研究领域:
肿瘤学
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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
FOOD AND CHEMICAL TOXICOLOGY
·
2025
·
IF 3.5
Jun Wang,Qiuyue Liao,Gai Liang,Yuruo Gong,Jiaxu Yao,Li Zhou,Wei Kevin Zhang,Xiaojun Li
Ethosomes are ethanol-based liposomes which may self-assemble in alcoholic beverages and exhibit dual effects: nanoscale ethanol has liver-targeting property with potential hepatotoxicity on the one side, while ethosomes can encapsulate active constituents that provide hepatoprotective benefits on the other side. This study investigated the dual role of ethosomes, focusing on their existence, characterization, potential toxicity, and toxicological mechanisms. Our results confirmed the existence of ethosomes in alcoholic beverages using particle size analysis, ultracentrifugation, liquid chromatography-mass spectrometry, and transmission electron microscopy. Both in vitro and in vivo experiments revealed that ethosomes can cause significant liver injury in a short period, associated with abnormal secretion of transforming growth factor-β ( TGF-β ) by parenchymal cells and subsequent apoptosis of Kupffer cells. Notably, the toxicity of ethosomes was significantly reduced when encapsulated natural active compounds like oleanolic acid. In conclusion, ethosomes could form self-assembly in the production progress of the integrated alcoholic beverages. The present study underscored the dual impact of ethosomes on alcoholic liver disease and offered new insights into the safety risk assessment of alcoholic beverages.
研究领域:
药剂学
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毒理学
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纳米技术
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肝病学
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食品科学
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生物技术
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DOI
PubMed
高影响因子
STEM CELLS AND DEVELOPMENT
·
2021
·Vol. 30
·期 22
·1126-1138
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IF 3.272
Nannan Zhang,Li Zhao,Daijiang Liu,Chaoqun Hu,Yi Wang,Tongchuan He,Yang Bi,Yun He
Urine-derived stem cells (USCs) are adult stem cells isolated from urine with strong proliferative ability and differentiation potentials. Cell transplantation of USCs could partly repair liver injury. It has been reported that the proliferative ability of bone mesenchymal stem cells in patients with chronic liver failure is significantly lower than in patients without liver disease. The aim of this study was therefore to evaluate the biological characteristics of USCs from end-stage liver disease patients (LD-USCs, USCs from patients with liver disease) compared with those from normal healthy individuals (N-USCs, USCs from normal individuals), with a view to determining whether autologous USCs can be applied to the treatment of liver disease. In this study USCs were isolated from urine samples of male patients with end-stage liver disease. Adherent USCs exhibit a spindle- or rice grain-like morphology, and express CD24, CD29, CD73, CD90, and CD146 surface markers, but not CD31, CD34, CD45, and CD105. We observed no differences in cell morphology or cell surface marker profile between LD-USCs and N-USCs. LD-USCs exhibited similar proliferative, colony-forming, apoptotic, and migratory abilities to N-USCs. Both USCs demonstrated similar capacities for osteogenic, adipogenic, and chondrogenic differentiation. When USCs were transplanted into CCl4 treatment-induced acute and chronic liver fibrosis mouse models, we observed a decrease in liver index, recovery of alanine aminotransferase and aspartate aminotransferase levels, alleviation of liver tissue injury, and dramatic improvement of liver tissue structure. USC transplantation can effectively recover liver function and improve liver tissue damage in acute or chronic liver injury mouse models. According to the results, we concluded that the biological characteristics of LD-USCs are not affected by basic liver disease. This study provides further evidence of the stem cell characteristics and liver repair function of LD-USCs, which may serve as a theoretical and experimental foundation for autologous USC transplantation technology in the treatment of liver failure and end-stage liver diseases.
研究领域:
干细胞生物学
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肝病学
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再生医学
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细胞治疗
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DOI
PubMed
高影响因子
JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE
·
2018
·Vol. 29
·期 5
·1-9
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IF 2.448
Zhang Binbin,Li Yang,Wang Gaoshang,Jia Zhidong,Li Haiyan,Peng Qing,Gao Yi
Liver is one of the most important organ in the body. But there are many limitations about liver transplantation for liver failure. It is quite important to develop the xenogeneic biological liver for providing an alternation to transplantation or liver regeneration. In this paper, we proposed a method to construct a novel kind of agarose 3D-culture concave microwell array for spheroids formation of hepatic cells. Using the 3D printing method, the microwell array was fabricated with an overall size of 6.4 mm × 6.4 mm, containing 121 microwells with 400 μm width/400 μm thickness. By exploiting the Polydimethylsiloxane (PDMS) membranes as a bridge, we finally fabricated the agarose one. We co-cultured three types of liver cells with bionics design in the microwell arrays. Using the methods described above, the resulting co-formed hepatocyte spheroids maintained the high viability and stable liver-specific functions. This engineered agarose concave microwell array could be a potentially useful tool for forming the elements for biological liver support. After developing the complete system, we also would consider to scale up the application of this system. It will be not only applied to the therapy of human organ damage, but also to the development of disease models and drug screening models.
研究领域:
组织工程
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细胞生物学
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生物医学工程
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再生医学
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DOI
PubMed
高影响因子
JOURNAL OF BIOMATERIALS APPLICATIONS
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2022
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IF 2.712
Junjing Zhou,Xinglian Wu,Chaochen Zhao
Hepatocyte scaffold is an essential part in bioartificial liver device. We have designed a novel hepatocyte scaffold based on porcine liver extracellular matrix (ECM) and chitosan (CTS) fabrics. This CTS-ECM scaffold can improve cell adhesion and proliferation. In the present study, an orthogonal test was designed to optimize the CTS/ECM composite scaffold, in which ECM concentration, EDC concentration and EDC to NHS ratio were taken as factors, proportion of nitrogen element and hydroxyproline content as indicators. The cytocompatibility of the novel scaffold for C3A hepatocytes was analyzed in vitro. The orthogonal test demonstrated that the optimal scaffold should be based on ECM concentration of 5 mg/mL, EDC concentration of 5 mg/mL, and EDC to NHS ratio 1:1. C3A hepatocytes cultured on the optimized CTS-ECM scaffolds showed stronger proliferation and functionality than those on Cytodex3 microcarriers (p < 0.05). The CTS/ECM composite scaffold may be widely used as a promising hepatocyte culture carrier, especially in bioartificial liver support systems.
研究领域:
组织工程
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生物医学工程
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细胞生物学
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DOI
PubMed
高影响因子
Chemical Biology & Drug Design
·
2025
·Vol. 105
·期 4
·e70097
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IF 3.3
Wei-fang Song,Sheng-nan Li,Rui-xin Yao,Qiu-yan Jiang,Ting Shi,Dan-dan Fan,Hai-juan Zhang,Wen-hui Zhang,Rui-jun Wang
The primary objective aims to evaluate the therapeutic efficacy of echinacoside in ameliorating hepatic steatosis and exploring its role in modulating autophagic flux through AMP-activated protein kinase (AMPK) signaling, positioning it as a potential treatment for non-alcoholic fatty liver disease (NAFLD). A well-established NAFLD rat model was employed, administering varying concentrations of echinacoside. Biochemical parameters, including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alongside liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), were measured to assess liver function. To elucidate the molecular mechanisms, western blot analyses were performed to assess the expressions of p-AMPK, total AMPK, and key autophagy markers LC-3 I/II and Beclin-1. Echinacoside significantly improved the lipid profile by lowering plasma TG, TC, and LDL-C levels while increasing HDL-C. It also reduced serum ALT, AST, and ALP activities, demonstrating hepatoprotective effects. Notably, echinacoside reversed the p-AMPK levels in NAFLD rats in a dose-dependent manner, with the highest dosage showing the strongest effect. This was accompanied by increased expression of LC-3 I/II and Beclin-1. Echinacoside is expected to be a therapeutic drug for NAFLD by activating AMPK activity and enhancing autophagy to improve liver function. These findings suggest its clinical potential, with autophagy modulation via the AMPK pathway as a possible therapeutic mechanism for NAFLD treatment.
研究领域:
药理学
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代谢生物学
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肝脏疾病研究
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DOI
PubMed
高影响因子
TOXICOLOGY IN VITRO
·
2025
·
IF 2.7
Yuhui Yan,Wenyu Wang,Aiwen Yan,Haonan Zhu,Qiang Meng
Cholestasis, a condition marked by bile acid accumulation in the liver and body systems, leads to liver dysfunction and cirrhosis. Currently, ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only two FDA-approved drugs for Cholestasis. Thus, new therapeutic approaches need to be developed. In this study, we validated the liver-protective properties of β-sitosterol (SIT), a key bioactive element abundant in plants, against hepatic toxicity and cholestasis induced by alpha-naphthylisothiocyanate(ANIT), while elucidating its mechanisms of action both in vivo and in vitro. SIT's FXR activation was confirmed via molecular docking and dual-luciferase assays. In the mechanisms of SIT hepatoprotection, the expression levels of bile salt export pump (Bsep) and multidrug resistance protein2 (Mrp2) which are bile acid efflux transporter, and sulfate transferase 2a1 (Sult2a1) which is a bile acid metabolizing enzyme were all increased by SIT, whereas the expression of uptake transporter sodium taurocholate transporting polypeptide (Ntcp), bile acid synthesis enzyme cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1) was decreased by SIT. In addition, SIT alleviated liver inflammation by suppressing inflammatory factor expression. However, FXR antagonist guggulsterone and FXR siRNA abolished SIT's improvements in liver histology, bile acid transporters, and enzymes. Conclusively, through activating FXR, SIT provides a protective effect against hepatotoxicity and cholestasis. SIT might serve as a new potential therapeutic strategy for the treatment of cholestatic liver diseases.
研究领域:
药理学
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分子生物学
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肝脏疾病
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DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Shicheng Fan,Yue Gao,Pengfei Zhao,Guomin Xie,Yanying Zhou,Xiao Yang,Xuan Li,Shuaishuai Zhang,Frank J. Gonzalez,Aijuan Qu,Min Huang,Huichang Bi
Fenofibrate, a peroxisome proliferator-activated receptor α (PPAR α ) agonist, is widely prescribed for hyperlipidemia management. Recent studies also showed that it has therapeutic potential in various liver diseases. However, its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear. Here, the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice, which was dependent on hepatocyte-expressed PPAR α . Yes-associated protein (YAP) is pivotal in manipulating liver growth and regeneration. We further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination, promoting its K63-linked ubiquitination, and enhancing the interaction and transcriptional activity of the YAP–TEAD complex. Pharmacological inhibition of YAP–TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly. Other factors, such as MYC, KRT23, RAS, and RHOA, might also participate in fenofibrate-promoted hepatomegaly and liver regeneration. These studies demonstrate that fenofibrate-promoted liver enlargement and regeneration are PPAR α -dependent and partially through activating the YAP signaling, with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.
研究领域:
药理学
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肝脏生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
·
2021
·
IF 6.684
Zhu Yiming,Zhang Chihao,Huang Mingzhe,Lin Jiayun,Fan Xiao,Ni Tao
Hepatic stellate cells (HSCs) are activated by inflammatory mediators to secrete extracellular matrix for collagen deposition, leading to liver fibrosis. Ferroptosis is iron- and lipid hydroperoxide-dependent programmed cell death, which has recently been targeted for inhibiting liver fibrogenic processes. Tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase that functions as a tumor suppressor in hepatocellular carcinoma, while little is known about its function in liver fibrosis. In the present study, the differential expression of TRIM26 in normal and fibrotic liver tissues was examined based on both online databases and specimens collected from patient cohort. The effects of TRIM26 on HSCs ferroptosis were examined in vitro through evaluating cell proliferation, lipid peroxidation, and expression of key ferroptosis-related factors. In vivo function of TRIM26 in liver fibrosis was examined based on CCl4-induced mice model. We found that TRIM26 was downregulated in fibrotic liver tissues. The overexpression of TRIM26 inhibited HSCs proliferation, promoted lipid peroxidation, manipulated ferroptosis-related factor expressions, and counteracted the effect of iron inhibitor deferoxamine. Moreover, TRIM26 physically interacted with solute carrier family-7 member-11 (SLC7A11), a critical protein for lipid reactive oxygen species (ROS) scavenging, and mediated its ubiquitination. In addition, TRIM26 overexpression induced HSCs ferroptosis and mitigated CCl4-induced liver fibrosis in mice. In conclusion, TRIM26 promotes HSCs ferroptosis to suppress liver fibrosis through mediating the ubiquitination of SLC7A11. The TRIM26-targeted SLC7A11 suppression can be a novel therapeutic strategy for liver fibrosis.
研究领域:
分子生物学
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细胞生物学
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肝病学
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DOI
PubMed
高影响因子
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