CELLULAR SIGNALLING
·
2025
·
IF 3.7
Tingjuan Huang,Ziyi Shang,Lina Nie,Haichao Diao,Qizhi Shuai,Junjie Ren,Jun Xu,Jun Xie
Hepatic stellate cells (HSCs) are the central link of the occurrence and development of hepatic fibrosis, and autophagy promotes HSCs activation. N6-methyladenosine (m6A) RNA modification can also control autophagy by targeting selected autophagy-associated genes. but up to now, little research has been done on the m6A modification autophagy-related genes (ATGs) in hepatic fibrosis. Here, we identify ATG9A as a previously unrecognized m6A modified ATG using m6A-sequencing (m6A-seq). Importantly, ATG9A is upregulated in liver fibrosis mice and primary biliary cirrhosis (PBC) patient liver tissue. Mechanistically, based on the presence of m6A binding sites on ATG9A, ATG9A promotes HSCs autophagy in an m6A dependent manner, thereby enhancing HSCs activation. Noteworthy, FTO is identified as the upstream of ATG9A, and knockdown of ATG9A can prevent FTO-induced HSCs autophagy and activation. In bile duct ligation (BDL) or CCL4-induced liver fibrosis mouse models, lowering ATG9A alleviated liver fibrosis through PI3K/AKT/mTOR pathway and TGFβ1/smad3 pathway. Taken together, our results provided that ATG9A is a potential prognostic biomarker and therapeutic target for patients with liver fibrosis.
研究领域:
分子生物学
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遗传学
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肝病学
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DOI
PubMed
高影响因子
Scientific Reports
·
2017
·Vol. 7
·期 1
·1-10
·
IF 4.259
Yuan Yi,Han Qiuju,Li Siyu,Tian Zhigang,Zhang Jian
The Wingless-type MMTV integration site family member 2b (Wnt2b) has been found to be a principal mediator of liver development and regeneration. However, the significance of Wnt2b in the pathogenesis of fibrosis-related liver diseases remains undefined. Here, we report that Wnt2b was highly expressed in the fibrotic liver tissues, exhibiting protective effects against activation of hepatic stellate cells (HSCs) and fibrosis progression. We identified a negative regulation of Wnt2b on the toll-like receptor 4 (TLR4) activation-mediated pro-fibrogenic effects. Wnt2b was shown not only to directly suppress LPS-induced HSCs activation, but also to inhibit TLR4-enhanced the sensitivity of HSCs to transforming growth factor beta (TGF-β). Mechanistic study showed that Wnt2b suppresses TLR4 signaling through inhibiting the expression of TLR4 as well as the activation of NF-κB and MAPKs. These findings provided new insights into the pathophysiology of liver fibrosis by characterizing Wnt2b as a novel endogenous suppressor of TLR4 signaling, maintaining tissue homeostasis during the early stage of hepatic fibrosis-associated liver diseases.
研究领域:
肝病学
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分子生物学
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细胞信号传导
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PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2021
·Vol. 25
·期 8
·4073-4087
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IF 5.31
Farooq Riaz,Qian Chen,Kaikai Lu,Ezra Kombo Osoro,Litao Wu,Lina Feng,Rong Zhao,Luyun Yang,Yimeng Zhou,Yingli He,Li Zhu,Xiaojuan Du,Muhammad Sadiq,Xudong Yang,Dongmin Li
Persistent hepatic damage and chronic inflammation in liver activate the quiescent hepatic stellate cells (HSCs) and cause hepatic fibrosis (HF). Several microRNAs regulate the activation and proliferation of HSCs, thereby playing a critical role in HF progression. Previous studies have reported that miR-188-5p is dysregulated during the process of HF. However, the role of miR-188-5p in HF remains unclear. This study investigated the potential role of miR-188-5p in HSCs and HF. Firstly, we validated the miR-188-5p expression in primary cells isolated from liver of carbon tetrachloride (CCl 4 )-induced mice, TGF-β1-induced LX-2 cells, livers from 6-month high-fat diet (HFD)-induced rat and 4-month HFD-induced mice NASH models, and human non-alcoholic fatty liver disease (NAFLD) patients. Furthermore, we used miR-188-5p inhibitors to investigate the therapeutic effects of miR-188-5p inhibition in the HFD + CCl 4 induced in vivo model and the potential role of miR-188-5p in the activation and proliferation of HSCs. This present study reported that miR-188-5p expression is significantly increased in the human NAFLD, HSCs isolated from liver of CCl 4 induced mice, and in vitro and in vivo models of HF. Mimicking the miR-188-5p resulted in the up-regulation of HSC activation and proliferation by directly targeting the phosphatase and tensin homolog (PTEN). Moreover, inhibition of miR-188-5p reduced the activation and proliferation markers of HSCs through PTEN/AKT pathway. Additionally, in vivo inhibition of miR-188-5p suppressed the HF parameters, pro-fibrotic and pro-inflammatory genes, and fibrosis. Collectively, our results uncover the pro-fibrotic role of miR-188-5p. Furthermore, we demonstrated that miR-188-5p inhibition decreases the severity of HF by reducing the activation and proliferation of HSCs through PTEN/AKT pathway.
研究领域:
肝病学
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分子生物学
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微小RNA研究
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Li Xiang,Yuting Qin,Lei Li,Xianjing Xiang,Wenhui Zhang,Qiangqiang Jiao,Yaru Shao,Xinqiong Huang,Meichun Wu,Tianle Zhou,Yukang Lin,Yuping Chen
Liver fibrosis is a pathological condition marked by the excessive buildup of extracellular matrix primarily resulting from the transformation of quiescent hepatic stellate cells (HSCs) to myofibroblastic (MF) phenotype and their resultant over-expansion. Activated HSCs completely rely on their hyperactive mitochondria to supply the energy and biomass for their rapid proliferation and collagen secretion, so an intervention targeting their mitochondria can effectively restrict their pathological amplification and contribution to liver fibrosis. Here we tried sorafenib, a drug that plays anticancer roles by inducing the disruption and loss of mitochondrial functions, to reach an antifibrotic goal. And a complex micellar system, VA-PEG-PCL/TPGS (VPP/TPGS), was specifically designed and fabricated to encapsulate and deliver sorafenib selectively to activated HSCs to overcome its application limitations in bioavailability, toxicity and intracellular stay, and eventually maximize its induction of mitochondrial dysfunction and therapeutically antifibrotic efficacy. The prepared sorafenib complex micelles not only exhibited a suitable particle size, uniform morphology, and nice stability, but also performed excellently in the biosafety and HSCs-targetability in vitro and in vivo . In human active HSC cell lines, they markedly attenuated mitochondrial hyperactivity, induced apoptosis, and downregulated fibrosis markers as expected; while in a CCl 4 -induced murine model of hepatic fibrosis, they effectively restricted the expansion of MF-HSCs, reduced collagen deposition, and promoted the healing of liver damage, showing a good potential in fibrosis curation. Collectively, our VPP/TPGS complex micelles provide an ideal drug delivery platform that has the potential to revolutionize the treatment of liver fibrosis via addressing its cellular and metabolic underpinnings and thus improve patient outcomes.
研究领域:
药理学
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肝脏病学
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药物递送系统
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细胞生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2020
·
IF 3.943
Ruoyu Wang,Dong Zhang,Dan Tang,Kewei Sun,Jianping Peng,Wenfang Zhu,Sihan Yin,Yunan Wu
The activation of hepatic stellate cells (HSCs) has been considered one of the major events in hepatic fibrosis. Amygdalin has been used to treat cancers and alleviate pain; however, its role and mechanism in HSC activation and hepatic fibrosis remain unclear. In the present study, transforming growth factor-beta 1 (TGF-β1) stimulated the activation of HSCs, as indicated by significantly increased alpha-smooth muscle actin (α-SMA), desmin, collagen I, and tissue inhibitor of metalloproteinase-1 (TIMP-1) protein levels. Amygdalin treatment dramatically suppressed TGF-β1-induced HSC proliferation and activation. Moreover, amygdalin treatment also reduced the TGF-β1-induced secretion of cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), platelet-derived growth factor (PDGF), and chemokine (C-C motif) ligand 2 (CCL2), as well as the phosphorylation of Smad2, Smad3, and p65. In the CCl 4 -stimulated liver fibrosis rat model, amygdalin treatment improved liver fibrosis and liver damage by reducing focal necrosis, collagen fiber accumulation, and the protein levels of α-SMA, desmin, collagen I, and TIMP-1 in hepatic tissue samples and reducing serum alanine transaminase (ALT) and aspartate transaminase (AST) levels. In conclusion, we demonstrated the suppressive effects of amygdalin in TGF-β1-induced HSC activation through modulating proliferation, fibrogenesis, and inflammation signaling in vitro and the antifibrotic effects of amygdalin in CCl 4 -stimulated hepatic fibrosis in rats in vivo .
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
CELL PROLIFERATION
·
2023
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IF 8.5
Ning Chen,Shenghui Liu,Dan Qin,Dian Guan,Yaqing Chen,Chenjiao Hou,Songyun Zheng,Liqiang Wang,Xiangmei Chen,Wei Chen,Lisheng Zhang
The activation of hepatic stellate cells (HSCs) is the main cause of liver fibrogenesis in response to different etiologies of chronic liver injuries. HSCs are heterogeneous, but the lack of specific markers to distinguish different HSC subset hinders the development of targeted therapy for liver fibrosis. In this study, we aim to reveal new HSC subsets by cell fate tracking. We constructed a novel ReelinCreERT2 transgenic mouse model to track the fate of cells expressing Reelin and their progeny (Reelin + cells). And we investigated the property of Reelin + cells, such as differentiation and proliferation, in hepatotoxic (carbon tetrachloride; CCl 4 ) or cholestatic (bile duct ligation; BDL) liver injury models by immunohistochemistry. Our study revealed that Reelin + cells were a new HSC subset. In terms of activation, migration, and proliferation, Reelin + HSCs displayed different properties from Desmin + HSCs (total HSCs) in cholestatic liver injury model but shared similar properties to total HSCs in hepatotoxic liver injury model. Besides, we did not find evidence that Reelin + HSCs transdifferentiated into hepatocytes or cholangiocytes through mesenchymal-epithelial transition (MET). In this study, our genetic cell fate tracking data reveal that ReelinCreERT2-labelled cells are a new HSC subset, which provides new insights into targeted therapy for liver fibrosis.
研究领域:
肝病学
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细胞生物学
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遗传学
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产品关联
DOI
PubMed
高影响因子
Chinese Medicine
·
2026
·Vol. 21
·期 1
·146
·
IF 7.4
Yang Junfa,Shu Min,Fang Hui,Yang Fan,Li Jiahe,Sun Yuansong,Li He,Xu Tao
Background Liver fibrosis is a representative scarring response that can ultimately lead to liver cancer. However, relevant antifibrotic drugs for the effective treatment of liver fibrosis in humans have not yet been identified. 6-Shogaol is derived from natural products and exhibits multiple biological activities, including anti-inflammatory and antioxidant properties; however, its efficacy and potential mechanism of action against liver fibrosis remains unclear. This study aimed to examine the anti-fibrotic properties and potential mechanisms of action of 6-Shogaol. Methods Two liver fibrosis mouse models (carbon tetrachloride (CCl 4 ) and bile duct ligation (BDL)) were constructed to evaluate the anti-fibrotic properties of 6-Shogaol in vivo . Transforming growth factor-β1 (TGF-β1)-induced human hepatic stellate cells (HSCs) LX-2 cells were used as in vitro models. Network pharmacology analysis was introduced to explore the key targets of 6-Shogaol regarding the mechanisms on liver fibrosis. Molecular docking, molecular dynamics simulations, drug affinity reactivity target stability (DARTS) and isothermal titration calorimetry (ITC) were used to detect the affinity and binding between 6-Shogaol and its target. Additionally, we invested the mechanism of 6-Shogaol through RNA sequencing combined with Western blotting, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), immunofluorescence co-localization, histopathology, immunohistochemical staining and RT-qPCR. Results The results showed that 6-Shogaol remarkably alleviated CCl 4 - and BDL-induced liver fibrosis in mice, including observations of improved liver function, decreased activity of HSCs, and decreased extracellular matrix (ECM) deposition. In an in vitro model, 6-Shogaol suppressed TGF-β1-induced LX-2 activation. Mechanistically, RNA sequence analysis revealed that the effect of 6-Shogaol on liver fibrosis is linked to glycolytic reprogramming. 6-Shogaol suppressed HSCs glycolysis by decreasing glycolytic enzymes (HK2, PKM2, and GLUT1) and glycolytic metabolite levels (lactic acid and pyruvic acid). Furthermore, network pharmacology suggested HIF-1α as a potential 6-Shogaol target. Molecular docking, molecular dynamics simulations, DARTS, and ITC confirmed that 6-Shogaol could directly bind to HIF-1α. Interestingly, we demonstrated that HIF-1α knockout significantly inhibited HSCs glycolysis and activation, whereas the overexpression of HIF-1α increased HSCs glycolysis and activation. Moreover, specific knockout of HIF-1α did not enhance the suppressive effect of 6-Shogaol on HSCs activation or fibrosis-associated protein expression in vivo . Conclusion These findings showed that 6-Shogaol ameliorated liver fibrosis by modulating the expression of HIF-1α associated with glycolysis reprogramming and validate 6-Shogaol as a promising therapeutic strategy for liver fibrosis. Graphical
The alternative text for this image may have been generated using AI.
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DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2025
·
IF 4.5
Xianjing Xiang,Yaru Shao,Li Xiang,Qiangqiang Jiao,Wenhui Zhang,Yuting Qin,Yuping Chen
As the major driving factor of hepatic fibrosis, the activated hepatic stellate cells (aHSCs) rely on active glycolysis to support their aberrant proliferation and secretion of the extracellular matrix. Sorafenib (Sor) can combat liver fibrosis by suppressing HIF-1α and glycolysis, but its poor solubility, rapid metabolism, and low bioavailability restrict such a clinical application. Here, Sor was loaded onto polydopamine nanoparticles and then encapsulated by a retinoid-decorated red blood cell membrane, yielding HSC-targeted Sor nanovesicles (PDA/Sor@RMV-VA) with a high Sor-loading capacity and photothermally controlled drug release for antifibrotic treatment. These Sor RMVs not only exhibited a good particle size, dispersity and biocompatibility, prolonged circulation time, enhanced aHSC targetability, and hepatic accumulation both in vitro and in vivo, but also displayed a mild photothermal activity proper for promoting sorafenib release and accumulation in CCl4-induced fibrotic mouse livers without incurring phototoxicity. Compared with nontargeting Sor formulations, PDA/Sor@RMV-VA more effectively downregulated HIF-1α and glycolytic enzyme in both cultured aHSCs and fibrotic mice and reversed myofibroblast phenotype and amplification of aHSCs and thus more significantly improved liver damage, inflammation, and fibrosis, all of which could be even further advanced with NIR irradiation. These results fully demonstrate the antifibrotic power and therapeutic potential of PDA/Sor@RMV-VA as an antifibrotic nanomedicine, which would support a new clinical treatment for hepatic fibrosis.
研究领域:
医学
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药学
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生物技术
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 8.3
Chong Gao,Wei Liu,Sai-Hu Liu,Shuang Zheng,Chen-Yu Wang,Xu Dai,Li-Hua Lian,Zhen-Yu Cui,Ji-Xing Nan,Yan-Ling Wu
Background Reprogramming of aerobic glycolysis occurs with HSCs activation and is associated with regression of liver fibrosis. Trigonelline (TRG), a plant alkaloid extracted from Trigonella foenum-graecum L seeds, has a variety of pharmacological effect. Purpose The current study investigated the hepatoprotective effect and mechanism of TRG against hepatic fibrosis by regulating glycolysis. Methods Anti-hepatic fibrosis effects of TRG were detected in thioacetamide (TAA)-induced hepatic fibrosis mice. HSCs or LX-2 were stimulated with TGF-β or conditioned medium (CM) from LPS-stimulated THP-1, then incubated with TRG, phloretin (PHL), rosiglitazone (RGZ), siRNA Glut-1 or plasmid with Glut-1. Results TRG significantly reduced serum transaminase levels, liver histopathological changes, excessive collagen deposition, inflammatory response, and neutrophil recruitment in TAA-induced mice. TAA increased hepatic Glut-1, HIF-1α and key enzymes of glycolysis expressions, while TRG completely reversed this effect. TRG also obviously regulated the combination of Glut-1 and HIF-1α to affect glycolysis in activated HSCs. TRG could inhibit α-SMA, IL-6, IL1R1, and HIF-1α expressions accompanying inhibition of Glut-1, function as PHL (Glut-1 inhibitor). Glut-1 silencing weakened α-SMA, IL-6, IL1R1, and HIF-1α expressions and enhanced the effect of TRG in activated LX-2. TRG inhibited LX-2 activation caused by Glut-1 overexpression, even demonstrated in interaction between LX-2 and macrophages. Further, TRG shown that improved fibrogenesis and inflammatory response by inhibiting Glut-1 compared with PHL in vivo . Conclusion TRG could ameliorate hepatic fibrosis through inhibiting ECM excessive deposition and inflammatory response. Inhibiting Glut-1-HIF-1α axis and glycolysis was a potential therapeutic strategy for TRG ameliorating liver microenvironment, further against hepatic fibrosis.
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PubMed
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2020
·
IF 1.863
Yuanguo Xiong,Hao Lu,Hanlin Xu
Hepatic fibrosis (HF) is a common disease, with currently no available treatment. Galangin, a natural flavonoid extracted from Alpinia officinaruim Hance, has multiple effects demonstrated in previous studies. The aim of the present study was to explore the anti-fibrogenic effect of galangin in vitro, and research its potential molecular mechanisms. LX-2 cells were chosen as an in vitro HF model, and were treated with galangin in different concentrations. Cell viability was analyzed using Cell Counting Kit-8 (CCK-8) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis was measured using flow cytometry, and the anti-fibrogenic effect of galangin was determined using quantitative reverse transcription polymerase chain reaction (RT-qPCR), immunofluorescence, and western blotting. The results show that the proliferation of LX-2 cells was efficiently inhibited by galangin, and apoptosis was induced in a dose-dependent manner. Both the mRNA and protein expression of α-SMA and collagen I were markedly downregulated. Galangin also inhibited the PI3K/Akt and Wnt/β-catenin signaling pathways and increased the Bax/Bcl-2 ratio. The results of this study suggest that galangin has an anti-fibrogenic effect and may represent a promising agent in the treatment of hepatic fibrosis.
研究领域:
药理学
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细胞生物学
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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
Acta Biomaterialia
·
2022
·
IF 10.633
Liyue Zhou,Qiangwei Liang,Yifan Li,Yongjing Cao,Juan Li,Jiayu Yang,Jinxia Liu,Jiawei Bi,Yanhua Liu
Liver fibrosis is a pathological process of multiple chronic liver diseases progressing to cirrhosis for which there are currently no effective treatment options. During fibrosis progression, the overproduction of extracellular matrix (ECM) collagen secreted by hepatic stellate cells (HSCs) greatly impedes drug delivery and reduces drug therapeutic effects. In this study, a glycyrrhetinic acid (GA)-conjugated prodrug micellar system with collagenase I (COL) decoration (COL-HA-GA, abbreviated as CHG) was designed to codelivery sorafenib (Sora/CHG, abbreviated as S/CHG) for potentiating ECM degradation and HSCs targeting on liver fibrosis therapy. In ECM barrier models established in vitro or in vivo , CHG micelles efficiently degraded pericellular collagen and demonstrated enormous ECM penetration abilities as well as superior HSCs internalization . Moreover, CHG micelles exhibited more Sora & GA accumulations and activated HSCs targeting efficiencies in the fibrotic livers than those in the normal livers. More importantly, S/CHG micelles were more effective in anti-liver fibrosis by lowering the collagen content, inhibiting the HSCs activation, as well as down-regulating the fibrosis-related factors, leading to reverse the fibrotic liver to normal liver through the multi-mechanisms including angiogenesis reduction, liver fibrosis microenvironment regulation, and epithelial-mesenchymal transition inhibition. In conclusion, the developed COL decorated nano-codelivery system with fibrotic ECM collagen degradation and activated HSCs targeting dual-functions exhibited great potential for liver fibrosis therapy. Statement of significance A glycyrrhetinic acid (GA)-conjugated prodrug with collagenase I (COL) decoration (CHG) was designed for codelivery with sorafenib (S/CHG), potentiating extracellular matrix (ECM) degradation-penetration and hepatic stellate cells (HSCs) targeting on liver fibrosis therapy. In ECM barrier models, CHG micelles efficiently degraded pericellular collagen and demonstrated ECM penetration abilities, as well as displayed superior HSCs internalization. Moreover, S/CHG micelles were more effective in anti-liver fibrosis by lowering the collagen content, inhibiting the HSCs activation, as well as down-regulating cytokines, reversing the fibrotic liver to normal through various mechanisms. In conclusion, the developed fibrotic ECM degradation and HSCs targeting dual-functional nano-codelivery system provided a prospective potentiality in liver fibrosis therapy.
研究领域:
药理学
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纳米技术
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肝病学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Stem Cell Reviews and Reports
·
2022
·Vol. 18
·期 3
·1168-1180
·
IF 6.692
Wang Jin,Xiong Minghao,Sun Qihao,Tan Wen-Song,Cai Haibo
The existing approaches of hematopoietic stem cells (HSCs) expansion in vitro were difficult to meet the needs of clinical application. While in vivo, HSCs efficiently self-renew in niche where they interact with three dimension extracellular matrix and stromal cells. Osteoblasts (OBs) are one of most significant stromal cells of HSCs niche. Here, we proposed a three-dimensional environment based on gallic acid grafted-chitosan ( 2c ) scaffold and OBs differentiated from human umbilical cord mesenchymal stem cells (HUMSCs) to recapitulate the main components of HSCs niche. The results of alkaline phosphatase staining and alizarin red staining demonstrated that HUMSCs were successfully induced into OBs. The results showed that the expansions of CD34 + cells, CD34 + CD38 − cells and CD34 + CD38 − CD45RA − CD49f + CD90 + cells (primitive hematopoietic stem cells, pHSCs) harvested from the biomimetic HSCs niche based on 2c scaffold and OBs ( IV) group were larger than those harvested from other three culture groups. Importantly, it was found that the CD34 + cells harvested from IV group had better secondary expansion capability and colony forming potential, indicating better self-renewal ability. In addition, the biomimetic HSCs niche based on 2c scaffold and OBs protected HSCs apoptosis and promoted HSCs division. Taken together, the biomimetic HSCs niche based on 2c scaffold and OBs was an effective strategy for ex vivo expansion of HSCs in clinical scale. Graphical abstract
研究领域:
生物医学工程
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干细胞生物学
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组织工程
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再生医学
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DOI
PubMed
高影响因子
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