Cell Reports Medicine
·
2024
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IF 11.7
Weize Zhu,Ying Hong,Zhaowei Tong,Xiaofang He,Yan Li,Hao Wang,Xinxin Gao,Pengtao Song,Xianshan Zhang,Xiaochang Wu,Zhenhua Tan,Wenjin Huang,Zekun Liu,Yiyang Bao,Junli Ma,Ningning Zheng,Cen Xie,Xisong Ke,Wen Zhou,Wei Jia,Mingxiao Li,Jing Zhong,Lili Sheng,Houkai Li
Metabolic (dysfunction)-associated steatohepatitis (MASH) is the advanced stage of metabolic (dysfunction)-associated fatty liver disease (MAFLD) lacking approved clinical drugs. Adenosine A1 receptor (A 1 R), belonging to the G-protein-coupled receptors (GPCRs) superfamily, is mainly distributed in the central nervous system and major peripheral organs with wide-ranging physiological functions; however, the exact role of hepatic A 1 R in MAFLD remains unclear. Here, we report that liver-specific depletion of A 1 R aggravates while overexpression attenuates diet-induced metabolic-associated fatty liver (MAFL)/MASH in mice. Mechanistically, activation of hepatic A 1 R promotes the competitive binding of sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) to sequestosome 1 (SQSTM1), rather than protein kinase A (PKA) leading to SCAP degradation in lysosomes. Reduced SCAP hinders SREBP1c/2 maturation and thus suppresses de novo lipogenesis and inflammation. Higher hepatic A 1 R expression is observed in patients with MAFL/MASH and high-fat diet (HFD)-fed mice, which is supposed to be a physiologically adaptive response because A 1 R agonists attenuate MAFL/MASH in an A 1 R-dependent manner. These results highlight that hepatic A 1 R is a potential target for MAFL/MASH therapy.
研究领域:
肝病学
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药理学
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代谢性疾病
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分子生物学
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细胞信号传导
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DOI
高影响因子
Nutrients
·
2022
·Vol. 14
·期 12
·2411
·
IF 6.706
Zhuohui Zhao,Zhen-Tao Deng,Suling Huang,Mengmeng Ning,Ying Feng,Yu Shen,Qin-Shi Zhao,Ying Leng
Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease worldwide, with no effective therapies available. Discovering lead compounds from herb medicine might be a valuable strategy for the treatment of NASH. Here, we discovered Alisol B, a natural compound isolated fromAlisma orientalis(Sam.), that attenuated hepatic steatosis, inflammation, and fibrosis in high-fat diet plus carbon tetrachloride (DIO+CCl4)-induced and choline-deficient and amino acid-defined (CDA)-diet-induced NASH mice. RNA-seq showed Alisol B significantly suppressed CD36 expression and regulated retinol metabolism in NASH mice. In mouse primary hepatocytes, Alisol B decreased palmitate-induced lipid accumulation and lipotoxicity, which were dependent on CD36 suppression. Further study revealed that Alisol B enhanced the gene expression of RARα with no direct RARα agonistic activity. The upregulation of RARα by Alisol B reduced HNF4α and PPARγ expression and further decreased CD36 expression. This effect was fully abrogated after RARα knockdown, suggesting Alisol B suppressed CD36 via regulating RARα-HNF4α-PPARγ cascade. Moreover, the hepatic gene expression of RARα was obviously decreased in murine NASH models, whereas Alisol B significantly increased RARα expression and decreased CD36 expression, along with the downregulation of HNF4α and PPARγ. Therefore, this study showed the unrecognized therapeutic effects of Alisol B against NASH with a novel mechanism by regulating RARα-PPARγ-CD36 cascade and highlighted Alisol B as a promising lead compound for the treatment of NASH.Keywords:Alisol B;non-alcoholic steatohepatitis;RARα;CD36
研究领域:
药理学
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分子生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
Cell Metabolism
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2025
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IF 30.9
Jie Jiang,Yuqing Gao,Jiang Wang,Yan Huang,Rong Yang,Yongxin Zhang,Yuandi Ma,Yingquan Wen,Gongkai Luo,Shurui Zhang,Yutang Cao,Minjun Yu,Qinxue Wang,Shulei Hu,Kanglong Wang,Xiaozhen Guo,Frank J. Gonzalez,Yameng Liu,Hong Liu,Qing Xie,Cen Xie
Metabolic-dysfunction-associated steatohepatitis (MASH) remains a major health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption or pharmacological inhibition of SMPD3 alleviates MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. Although healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses sirtuin 1 (SIRT1), triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes disease progression by enhancing caveolae-dependent lipid uptake and extracellular vesicle secretion from steatotic hepatocytes to exacerbate inflammation and fibrosis. Consequently, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid metabolism and holds great promise for developing novel MASH therapies.
研究领域:
生物化学
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肝脏病学
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代谢医学
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产品关联
DOI
PubMed
高影响因子
Portal Hypertension & Cirrhosis
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2025
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IF 1.8
Wenying Qi,Xu Cao,Yue Chen,Hening Chen,Xiaoke Li,Ningyi Zhang,Ruijia Liu,Wei Wang,Shihao Zheng,Size Li,Qiyao Liu,Xiaobin Zao,Yong-An Ye
Aims: The TiaoGanXiaoZhi formula (TGXZ), a traditional Chinese medicine, has been shown to alleviate the progression of metabolic-associated fatty liver disease (MAFLD) clinically. However, its underlying mechanism remains unclear. This study aimed to investigate the effects and mechanisms of TGXZ in treating MAFLD in mouse models. Methods: The MAFLD mouse model was established using a high-fat diet and 5% fructose water over 16 weeks. At Week 8, mice exhibited significant steatosis, inflammation, and insulin resistance. A total of 42 mice were divided into the normal feed diet (NFD) group ( n = 18) and the high-fat feed diet (HFD) group ( n = 24). Six mice from each group were killed at Week 8 for serological and histopathological assessments. The remaining mice were allocated into NFD ( n = 6), HFD ( n = 6), HFD + TGXZ ( n = 6), NFD + TGXZ ( n = 6), and HFD + Placebo ( n = 6) groups. TGXZ (or placebo) was administered at a clinical equivalent dose of 7.699 g/(kg·d) to the respective groups, while NFD and HFD groups received distilled water. Daily gavage started in Week 9. At Week 16, after fasting, body weight and liver condition were recorded, and mice were euthanized with pentobarbital sodium. Liver tissue was collected for further analysis, and the remaining tissue and feces were stored at -80°C. Data were graphed using GraphPad Prism 8.0.0 and analyzed with SPSS Statistics 25.0. Results are expressed as mean ± standard deviation. Statistical comparisons were made using Student's t -test for two groups and one-way ANOVA for more than two groups, with significance set at p < 0.05. Results: Compared to the MAFLD mouse model group, TGXZ treatment significantly downregulated the weight of white adipose tissue (1.61 ± 0.66 vs. 3.06 ± 0.34 g, p < 0.0010), liver weight (1.22 ± 0.16 vs. 1.98 ± 0.39 g, p = 0.0031), and the levels of alanine aminotransferase (20.6 ± 3.4 vs. 46.1 ± 12.3 U/L, p < 0.0010), aspartate aminotransferase (99.9 ± 19.1 vs. 168.4 ± 34.3 U/L, p = 0.0014), cholesterol (2.95 ± 0.56 vs. 4.38 ± 0.34 mmol/L, p = 0.0053), triglycerides (2.25 ± 0.41 vs. 4.18 ± 0.67 mmol/L, p < 0.0010), low-density lipoprotein (0.66 ± 0.11 vs. 1.41 ± 0.52 mmol/L, p = 0.0073), and total bile acid (0.71 ± 0.41 vs. 2.18 ± 0.61 mmol/L, p = 0.0017), except for high-density lipoprotein (2.41 ± 0.81 vs. 2.55 ± 0.31 mmol/L, p = 0.5655). The liver transcriptome, fecal microbiota sequencing, and fecal lipidomics analysis demonstrated that TGXZ treatment improved the expression of genes related to lipid metabolism, alleviated intestinal microbiota disorders, and mitigated lipid disturbances caused by MAFLD. Conclusions: Our study demonstrated that TGXZ treatment effectively alleviated the progression of MAFLD. The inhibitory effects of TGXZ on MAFLD may be attributed to its regulation of gut microbiota, lipid metabolism, and hepatic inflammation.
研究领域:
传统中医药
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肝脏疾病
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微生物学
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药理学
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营养学
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产品关联
DOI
高影响因子
International Journal of Nanomedicine
·
2025
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IF 6.5
Shuying He,Yuerong Lv,Zixian Gao,Liang Peng
Objective The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing because people’s dietary habits are dominated by high caloric intake and sedentary lifestyles, leading to the accumulation of lipid, reactive oxygen species (ROS) and inflammation. However, treating MASH remains a challenge.Methods Two-dimensional (2D) niobium carbide (Nb4C3) MXene nanoenzymes (MXenzymes) possess both antioxidant and anti-inflammatory properties and have attracted considerable attention in the tumor and engineering fields. The Nb4C3 MXenzyme was developed for MASH therapy and exhibited biosafety and antilipid peroxidation activity.Results Nb4C3 reduced excessive ROS and proinflammatory cytokine levels through its antilipid peroxidation activities, resulting in the inhibition of hepatocyte lipid accumulation and inflammation in a methionine–choline-deficient diet (MCD)-induced murine MASH model. Mechanistically, Nb4C3 not only inhibited lipid accumulation and disrupted lipid metabolism in hepatocytes but also attenuated fatty acid-induced cell death by reducing intracellular ROS levels, which significantly promoted the polarization of M1 macrophages to M2 macrophages by alleviating oxidative stress and suppressing inflammatory factor expression.Conclusion The Nb4C3 MXenzyme can be used as a multifunctional bioactive material to alleviate hepatic steatosis and inflammation in MASH mice through its robust antioxidant and anti-inflammatory activities.
研究领域:
生物医学工程
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肝脏疾病研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2023
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IF 3.4
Si-Tao Xu,Hao-Wen Jin,Xin Jin,Bi-Xin Xu,Yu Zhang,Tao Xie,Guangji Wang,Jiankun Wang,Le Zhen
VK2809 is a promising drug candidate in Phase II clinical trials for the treatment of non-alcoholic steatohepatitis (NASH). It is a prodrug with a HepDirect strategy, which can achieve selective hepatic metabolic activation , generating an active metabolite VK2809A as a potent and selective agonist for thyroid hormone receptor beta (TRβ), a concomitant reactive metabolite VK2809B, and a glutathione (GSH) conjugate MB06588. Currently, there is no convenient and sensitive bioanalytical method for the simultaneous determination of the above three metabolites. Herein, we established an LC-MS/MS method to separate VK2809 and its metabolites on the XSelect HSS T3 column and quantified them in negative electrospray ionization mode. Subsequently, several factors were investigated such as the use of 60% acetonitrile for homogenization to stabilize the analytes, the addition of 20 mM glutathione for the derivation of VK2809B, and the protein precipitation with methanol containing Sobetirome as the internal standard (IS). The method exhibited good linearity for all compounds (19.4–388.4 nM for VK2809; 27.4–2744.4 nM for VK2809A and 10.6–211.0 nM for MB06588) with great correlation coefficients (r > 0.996). The method validation also demonstrated acceptable precision (RSD < 13.0% for VK2809, RSD < 7.9% for VK2809A, RSD < 14.4% for MB06588) and accuracy (92.7%−103% for VK2809, 91.2%−107.3% for VK2809A, 96%−106.7% for MB06588). The matrix effect, recovery, and stability were also suitable to determine all the analytes. This method is suitable for the bioanalysis of VK2809 and its metabolites and has been successfully applied to the study of intrahepatic exposure in rats. It is expected to be further practiced in drug design , optimization, and metabolism study in the following research.
研究领域:
药理学
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分析化学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Toxicology Research
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2024
·Vol. 13
·期 3
·
IF 2.2
Ma Peng,Wang Xu,Wen Xiuqi,Pu Lingyun,Ou Yu
IntroductionCurrently, the role and mechanism of dopamine in non-alcoholic steatohepatitis (NASH) remains unclear.MethodsIn vitro experiments utilized FFA and LPS to establish NASH cell models, while a fibrotic cell model was created using TGFβ1 to investigate the impact of dopamine on cellular lipid metabolism, inflammation, and fibrosis. In vivo experiments involved the use of MCD and HFD diets to induce NASH in mouse models for observing the effects of dopamine on NASH disease progression.ResultsOur study showed that dopamine significantly downregulated the expression levels of Caspase 1, IL-1β and IL18 in the HepG2 NASH cell model. In addition, dopamine could inhibit the TGF-β1-induced accumulation of collagen I and α-SMA in LX2 cells. In vivo experiments have shown that dopamine attenuation in mice is associated with MCD diet-induced and HFD-induced steatohepatitis. Mechanically, dopamine inhibits the p65 signaling pathway in NASH.ConclusionIn conclusion, the present study demonstrates the role of dopamine in ameliorating the symptoms of NASH and provides a direction for future research on the application of the dopaminergic system to liver disease.
研究领域:
肝病学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2025
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IF 6.5
Feifei Han,Haiping Wang,Li Wang,Limei Fan,Sibei Peng,Xiaoying Hou,Xiji Shu,Binlian Sun,Yuchen Liu
Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by excessive fat accumulation in the liver, is the most prevalent cause of chronic liver disease globally. The clinical use of pharmacological agents such as silibinin and sorafenib is limited due to poor water solubility, low bioavailability, and potential side effects, necessitating innovative therapeutic approaches.Methods In this study, we developed self-assembled, carrier-free microparticles of silibinin and sorafenib (SIL-SOR-MPs) using magnetic stirring and evaluated their therapeutic effects on MASLD both in vitro and in vivo.Results Compared to free SIL and free SOR, SIL-SOR-MPs significantly reduced lipid accumulation in HepG2 cells and effectively alleviated hepatic steatosis and liver damage in mice. Mechanistic investigations further showed that SIL-SOR-MPs more effectively down-regulated lipid synthesis genes and up-regulated genes involved in lipid oxidation.Discussion In summary, our study highlights that carrier-free SIL-SOR-MPs demonstrate the ability to reverse the progression of MASLD and present a promising therapeutic strategy.
研究领域:
药理学
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肝脏病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
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2025
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IF 5.1
Shupei Li,Hanlong Zhu,Qi Zhai,Yu Hou,Ya Yang,Haifeng Lan,Mingzuo Jiang,Ji Xuan
Background Non-alcoholic steatohepatitis (NASH), as a progressive form of Non-alcoholic fatty liver disease (NAFLD), poses a significant threat to human health as a prevalent and common condition, with a lack of safe and effective therapeutic options. However, the therapeutic effects and potential mechanisms of Lang Qing Ata (LQAtta) against NASH remain elusive.Materials and Methods The components of LQAtta were identified using Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS). Subsequently, we employed network construction and analysis approaches within the field of network pharmacology. By integrating known databases and target prediction algorithms, which encompassed database-based target prediction, protein-protein interaction networks, as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, we unveiled the potential key targets and signaling pathways that these bioactive components might engage with. These discoveries were further validated in subsequent mouse models. An HFHC-induced NASH mouse model was used to validate the therapeutic effects and potential mechanisms of LQAtta on NASH.Results From the UHPLC-MS/MS analysis of LQAtta, a total of 1518 chemical components were identified, with 106 of them being absorbed into the bloodstream. Additionally, based on the acquisition of targets from both LQAtta and the NASH database, a total of 160 common targets were screened. KEGG enrichment analysis indicated that LQAtta may alleviate NASH by modulating pathways such as the Toll-like receptor signaling pathway, the NF-κB signaling pathway, and inflammation-related pathways. In vivo experimental results demonstrated that LQAtta could alleviate liver injury, steatosis, and inflammation induced by NASH, thereby slowing down the disease process. Additionally, LQAtta inhibited the expression and phosphorylation of NF-κB protein, playing a role in preventing NASH.Conclusion In this study, the combination of mass spectrometry analysis, network pharmacology, and animal experiments preliminarily elucidated the potential of LQAtta to treat NASH through NF-κB pathways.
研究领域:
药理学
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肝脏疾病
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代谢研究
✓ 已验证
DOI
PubMed
高影响因子
Nutrients
·
2024
·Vol. 16
·期 22
·3837
·
IF 4.8
Jianmei Yang,Wanyi Ou,Guiru Lin,Yuanfei Wang,Dongliang Chen,Ze Zeng,Zumin Chen,Xiaomin Lu,Aiping Wu,Chenli Lin,Yinji Liang
Objectives: Long-term Western diet-induced non-alcoholic steatohepatitis (NASH) can lead to liver cirrhosis and NASH-associated hepatocellular carcinoma, which are end-stage liver diseases. Meanwhile, NASH is associated with mental burden and worsens as the disease progresses. Atractylodes Macrocephala Koidz (AMK) is one of the main ingredients of Shenling Baizhu San, and the effect of Polysaccharide from AMK ameliorates (PAMK), as an important medicinal ingredient of AMK, on NASH and associated anxiety/depression-like behaviors is still unclear. Methods: This study investigated the protective effect of PAMK on NASH and associated anxiety/depression-like behaviors through a Western diet-induced NASH mice model. Results: showed that PAMK decreased the concentrations of liver TC, TG, and serum AST and ALT, improving glucose tolerance, and reducing liver steatosis and fibrosis. Moreover, the expression of liver IL-6, IL-1β, TNF-α, IL-18 and MCP-1 could be reduced by PAMK significantly. Additionally, PAMK decreased anxiety/depression-like behaviors and expression of IL-6, IL-1β, TNF-α, and MCP-1 in the hippocampus. 16S rRNA gene sequencing revealed that PAMK diminished the Firmicutes/Bacteroidetes ratio and abundance of Faecalibaculum_rodentium, and increased the abundance of Muribaculaceae. This might be related to gene abundance of Pentose, the glucuronate interconversions pathway and carbohydrate enzymes (GH1, GH4). Serum metabolomics suggested that PC (18:5e/2:0), PC (16:2e/2:0), Lysopc 20:4, PC (16:0/2:0), and LPC 19:0 upregulated significantly after PAMK intervention, together with the enrichment of carbon metabolism and Citrate cycle pathways specially. Conclusions: PAMK as a potential prebiotic ameliorated NASH and associated anxiety/depression-like behaviors in mice, probably by regulating Faecalibaculum_rodentium, carbohydrate enzymes and lipid metabolites.
研究领域:
医学
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药理学
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微生物学
✓ 已验证
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2021
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IF 4.932
Hui-Jie Liu,Sheng-Tian Cao,Bao-Ying Wen,Xue Han,Yong Li,Shan Li,Jing Li,Lei Zhang
Non-alcoholic steatohepatitis (NASH) is a devastating form of non-alcoholic fatty liver disease (NAFLD) with distinguished hallmarks of steatosis and inflammation. Rotundic acid (RA) is a natural pentacyclic triterpene compound extracted from the bank of Ilex rotunda Thunb with a wide range of biological activities. The aim of the study is to evaluate the pharmacological effect and action mechanism of RA on NASH in vitro and in vivo . RA has weak lipid lowering ability in rat primary hepatocytes, significantly decreases serum LDL level, hepatic TG and TC levels and lipid droplets, reduces NAS compared with the NASH group, and alleviates hepatic inflammation. RA also enhances the recovery of intestinal bacterial community and intestinal-derived short-chain fatty acid caused by high food diet (HFD). Further investigation shows that RA protects against HFD-induced NASH via downregulating the expression of SREBP-1c/SCD1 signaling pathway and improving gut microbiota. These findings imply that RA might be helpful for the alleviation of NASH.
研究领域:
药理学
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肝病学
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胃肠病学
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微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
·
IF 3.322
Zi-Xin Xu,Jing-Ze Li,Qin Li,Ming-Yi Xu,Hui-Yi Li
Background Increasing evidences have confirmed the relationship between mitophagy and nonalcoholic steatohepatitis (NASH). The exact mechanism of upstream circular RNAs (circRNAs) regulating PTEN-induced putative kinase 1 (PINK1) mediated mitophagy and its contribution to NASH-related liver fibrosis was explored in our study. Methods Primary hepatic stellate cells (PHSCs) from C57BL/6 mice transfected with small interfering RNAs against PINK1 (si-PINK1) and negative control (si-NC) were prepared to perform circRNA sequence. Differentially expressed circRNAs, bioinformatic analysis and predicting software were performed to select axis of circ608/miR-222/PINK1. The expressions of circ608/miR-222/PINK1 were verified by RT-qPCR. The mitochondrial function was evaluated by immunofluorescence staining of COX4 and LC3B. Results PINK1-mediated mitophagy was inhibited in NASH-related liver fibrosis mice. CircRNA sequence revealed there were 37 DE-circRNAs between si-PINK1 PHSCs and si-NC PHSCs. Bioinformatic analysis showed these DE-circRNAs were related to enriched signaling pathways (such as Wnt, Rap1, mTOR, Hippo) regulating liver fibrosis and mitophagy. Circ608 was significantly down-regulated in lipotoxic HSCs and in livers of NASH-related liver fibrosis mice. MiR222 was identified to be the target miRNA of circ608 and was negatively regulated by circ608 in lipotoxic HSCs. MiR222 also had a binding site with PINK1 and could negatively regulate PINK1. So, the axis of circ608-miR222-PINK1 was proved to participate in NASH-related liver fibrosis by regulating mitophagy. These results illustrated that circ608 might promote PINK1-mediated mitophagy though inhibiting miR222 in lipotoxic HSCs. Conclusion Circ608 could promote PINK1-mediated mitophagy of HSCs though inhibiting miR222 in NASH-related 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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基因组学
✓ 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）