Hepatic Stellate Cells

肝星状细胞
  • 文章类型: Journal Article
    肝纤维化的特征是细胞外基质蛋白的过度积累,会导致肝硬化和肝癌.代谢功能障碍相关的脂肪变性肝病是肝纤维化的常见原因,与四氯化碳(CC4l)暴露具有相似的发病机理。该过程涉及肝星状细胞(HSC)活化为肌成纤维细胞。然而,详细的机制和有效的治疗策略需要进一步研究.在这项研究中,我们发现HSC中VDR表达与YAP呈负相关。随后,我们证明VDR对HSC的YAP转录活性有下调的影响.有趣的是,激活VDR通过抑制早期YAP的转录活性,有效抑制培养诱导的原代HSC活化。此外,体内结果表明,YAP/TAZ的肝特异性缺失可改善CCl4诱导的肝纤维化,并使VDR的抗纤维化功效无效。重要的是,YAP抑制剂挽救了肝特异性VDR基因敲除诱导的肝纤维化加重.此外,VDR激动剂和YAP抑制剂的联合药理学证明了减少CCl4诱导的肝纤维化的协同作用,原发性HSCs活化和体内肝损伤。这些作用的基础是它们通过AMPK激活来抑制HSC激活的集体能力,从而抑制ATP合成和HSC增殖。总之,我们的结果不仅揭示了VDR对YAP激活的肝星状细胞的抑制作用,而且还确定了VDR激动剂和YAP抑制剂以AMPKα依赖性方式的协同作用,为多靶向药物整合治疗CCl4诱导的肝纤维化提供了实践基础。
    Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins, which can lead to cirrhosis and liver cancer. Metabolic dysfunction-associated steatosis liver diseases are common causes of liver fibrosis, sharing a similar pathogenesis with carbon tetrachloride (CCl₄) exposure. This process involves the activation of hepatic stellate cells (HSCs) into myofibroblasts. However, the detailed mechanism and effective treatment strategies require further investigation. In this study, we uncovered a negative correlation between VDR expression and YAP within HSCs. Subsequently, we demonstrated that VDR exerted a downregulatory influence on YAP transcriptional activity in HSCs. Intriguingly, activation VDR effectively inhibited the culture induced activation of primary HSCs by suppressing the transcriptional activity of early YAP. Furthermore, in vivo results manifested that hepatic-specific deletion of YAP/TAZ ameliorates CCl4-induced liver fibrosis, and nullified the antifibrotic efficacy of VDR. Importantly, a YAP inhibitor rescued the exacerbation of liver fibrosis induced by hepatic-specific VDR knockout. Moreover, the combined pharmacological of VDR agonist and YAP inhibitor demonstrated a synergistic effect in diminishing CCl4-induced liver fibrosis, primary HSCs activation and hepatic injury in vivo. These effects were underpinned by their collective ability to inhibit HSC activation through AMPK activation, consequently curbing ATP synthesis and HSCs proliferation. In conclusion, our results not only revealed the inhibition of VDR on YAP-activated liver stellate cells but also identified a synergistic effect of VDR agonist and YAP inhibitor in an AMPKα-dependent manner, providing a practical foundation for integration of multi-targeted drugs in the therapy of CCl4-induced hepatic fibrosis.
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  • 文章类型: Journal Article
    血吸虫病是由血吸虫侵染引起的人畜共患寄生虫病,吸虫的一个属。卵源外泌体中的microRNAs(miRNA)对于调节宿主的免疫反应和协调病理生理机制至关重要。尽管日本血吸虫分泌的外泌体含有丰富的miRNAs,这些miRNAs在血吸虫病肝纤维化发病机制中的具体作用尚待全面阐明。日本血吸虫卵外泌体分泌miRNA-30,一种新的miRNA。
    体外,通过用miRNA模拟物转染HSC来评估miRNA-30的效果。使用miRDB软件预测miRNA-30的靶基因生物特征。通过提高其在健康小鼠中的表达或通过施用表达miRNA-30或miRNA海绵的重组腺相关病毒血清型8载体抑制其在感染小鼠中的活性来评估miRNA-30在肝纤维化中的作用。
    这种新的miRNA可以激活肝星状细胞(HSC),肝纤维化的效应细胞,在体外,即,它显著增加纤维原因子Col1(α1),Col3(α1),和α-SMA在mRNA和蛋白质水平。此外,miRNA-30可能通过靶向宿主RORA基因激活HSC。此外,通过施用重组腺相关病毒载体以调节miRNA-30的表达水平进行体内实验。miRNA-30在健康小鼠中的过表达显著升高了Col1(α1)的表达,Col3(α1),和α-SMA在转录组和蛋白质组尺度上。这种过表达与肝羟脯氨酸含量的显着增加有关。相反,miRNA-30在感染小鼠体内的沉默导致肝肉芽肿的大小和胶原沉积的面积显著减少。因此,在体内,miRNA-30表达的调节可能在改善日本血吸虫小鼠肝纤维化的严重程度中起关键作用。
    研究结果表明,miRNA-30可能通过与宿主RORA的相互作用来增强血吸虫病诱导的肝纤维化。我们的研究可能会改善目前关于血吸虫病肝纤维化miRNA跨物种调控的理论框架。
    UNASSIGNED: Schistosomiasis is a zoonotic parasitic disorder induced by the infestation of schistosomes, a genus of trematodes. MicroRNAs (miRNAs) in egg-derived exosomes are crucial for modulating the host\'s immune responses and orchestrating the pathophysiological mechanisms. Although the exosomes secreted by S. japonicum contain abundant miRNAs, the specific roles of these miRNAs in the pathogenesis of schistosomiasis-induced hepatic fibrosis are yet to be comprehensively elucidated. The egg exosomes of S. japonicum secrete miRNA-30, a novel miRNA.
    UNASSIGNED: In vitro, the effect of miRNA-30 was evaluated by transfecting HSCs with miRNA mimics. The target gene biosignature for miRNA-30 was predicted using the miRDB software. The effect of miRNA-30 in hepatic fibrosis was evaluated by either elevating its expression in healthy mice or by inhibiting its activity in infected mice by administration of recombinant adeno-associated virus serotype eight vectors expressing miRNA-30 or miRNA sponges.
    UNASSIGNED: This novel miRNA can activate hepatic stellate cells (HSCs), the prinary effector cells of hepatic fibrosis, in vitro, i.e., it significantly increases the fibrogenic factors Col1(α1), Col3(α1), and α-SMA at both mRNA and protein levels. In addition, miRNA-30 may activate HSCs by targeting the host RORA gene. In addition, in vivo experiments were conducted by administering a recombinant adeno-associated viral vector to modulate the expression levels of miRNA-30. The overexpression of miRNA-30 in healthy mice significantly elevated the expression of Col1(α1), Col3(α1), and α-SMA at both the transcriptomic and proteomic scales. This overexpression was coupled with a pronounced augmentation in the hepatic hydroxyproline content. Conversely, the in vivo silencing of miRNA-30 in infected mice induced a considerable reduction in the size of hepatic granulomas and areas of collagen deposition. Hence, in vivo, modulation of miRNA-30 expression may play a pivotal role in ameliorating the severity of hepatic fibrosis in mice afflicted with S. japonica.
    UNASSIGNED: The study results suggest that miRNA-30 may augment schistosomiasis-induced hepatic fibrosis through a probable interaction with the host RORA. Our study may improve the current theoretical framework regarding cross-species regulation by miRNAs of hepatic fibrosis in schistosomiasis.
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  • 文章类型: Journal Article
    肝星状细胞(HSC)活化是肝纤维化(LF)的重要病理进程。调节HSC活化和LF的分子机制尚不完全清楚。这里,我们探讨了转录因子SRY相关的高迁移率族蛋白7(SOX7)对HSC激活和LF的影响,以及潜在的分子机制。我们发现SOX7在人和小鼠纤维化肝脏中的表达水平降低,特别是在纤维化病灶。SOX7在原代活化的HSC和TGF-β1刺激的LX-2细胞中也下调。SOX7敲低可促进LX-2细胞的活化和增殖,同时抑制其凋亡。另一方面,SOX7的过表达抑制了HSC的活化和增殖。机械上,SOX7通过降低TGF-β1诱导的β-连环蛋白的表达和Smad2和Smad3的磷酸化来减弱HSC活化和LF。此外,使用AAV8-SOX7小鼠模型的SOX7的过表达改善了在体内响应于CCl4处理的LF的程度。总的来说,SOX7抑制HSC激活和LF。因此,以SOX7为目标,可能是一种潜在的新策略,以防止LF。
    Hepatic stellate cell (HSC) activation is the essential pathological process of liver fibrosis (LF). The molecular mechanisms regulating HSC activation and LF are incompletely understood. Here, we explored the effect of transcription factor SRY-related high mobility group box 7 (SOX7) on HSC activation and LF, and the underlying molecular mechanism. We found the expression levels of SOX7 were decreased in human and mouse fibrotic livers, particularly at the fibrotic foci. SOX7 was also downregulated in primary activated HSCs and TGF-β1 stimulated LX-2 cells. SOX7 knockdown promoted activation and proliferation of LX-2 cells while inhibiting their apoptosis. On the other hand, overexpression of SOX7 suppressed the activation and proliferation of HSCs. Mechanistically, SOX7 attenuates HSC activation and LF by decreasing the expression of β-catenin and phosphorylation of Smad2 and Smad3 induced by TGF-β1. Furthermore, overexpression of SOX7 using AAV8-SOX7 mouse models ameliorated the extent of LF in response to CCl4 treatment in vivo. Collectively, SOX7 suppressed HSC activation and LF. Targeting SOX7, therefore, could be a potential novel strategy to protect against LF.
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  • 文章类型: Journal Article
    肝纤维化是一个伤口愈合过程。它可以由各种慢性肝病引起。肝纤维化的特征是肝星状细胞(HSC)的激活,一个关键事件。然而,尚未开发出治愈或减轻肝纤维化引起的病理变化的有效治疗策略。中药(TCM)具有良好的抗纤维化作用,副作用少。龙胆汤,一种中医也叫龙胆泻干汤(LXT),用于在临床环境中清除肝脏。然而,LXT在预防肝纤维化中的作用和潜在的调节机制尚未被研究。这项研究表明,LXT治疗可以保护肝脏免受CCl4诱导的小鼠肝纤维化引起的损伤,并抑制HSC的活化。LXT组的小鼠表现出垫料胶原I和HSC激活标记α-平滑肌肌动蛋白(α-SMA)的表达。小鼠肝脏组织的转录组测序揭示了Parkin的水平,有丝分裂标记,减少CCl4诱导的肝纤维化。进一步的研究表明,经尾静脉注射Parkin过表达腺相关病毒(Parkin-AAV)可以减少小鼠CCl4诱导的肝纤维化发生。我们还进行了机械学研究,这表明LXT治疗通过上调Parkin的表达来抑制HSC的活化。因此,提示LXT通过激活Parkin信号通路抑制肝纤维化。
    Liver fibrosis is a wound-healing process. It can be induced by various chronic liver diseases. Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs), a key event. However, no effective treatment strategies to cure or alleviate liver fibrosis-induced pathologic changes have yet been developed. Traditional Chinese medicine (TCM) exhibits a good anti-fibrosis action, with few side effects. Gentiana decoction, a TCM also called Longdan Xiegan Tang (LXT), is used for purging the liver in clinical settings. However, the role of LXT in preventing liver fibrosis and the underlying regulatory mechanism have not yet been investigated. This study demonstrates that LXT treatment can protect the liver from the injuries resulting from CCl4-induced liver fibrosis in mice and suppress the activation of HSCs. The mice in the LXT group exhibit litter collagen I and HSC activation marker α-smooth muscle actin (α-SMA) expression. Transcriptome sequencing of the mouse liver tissue reveals that the level of Parkin, a mitophagy marker, decreased in CCl4-induced liver fibrosis. Further study shows that the injection of Parkin-overexpression adeno-associated virus (Parkin-AAV) via the tail vein can reduce CCl4-induced liver fibrogenesis in mice. We conducted a mechanistic study also, which suggests that LXT treatment suppresses the activation of HSCs by upregulating the expression of Parkin. Hence, it can be suggested that LXT inhibits liver fibrosis by activating the Parkin signaling pathway.
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  • 文章类型: Journal Article
    背景:肝纤维化主要由肝星状细胞(HSC)的激活驱动,其中涉及各种表观遗传修饰。
    目标:N6-甲基腺苷(m6A),真核细胞中最普遍的RNA修饰,影响许多生理和病理过程。然而,胰岛素样生长因子2mRNA结合蛋白3(IGF2BP3)的作用,介导m6A修饰的阅读器基因,肝纤维化仍不清楚。
    结果:这项研究表明,IGF2BP3敲除通过促进HSC铁凋亡(FPT)和灭活HSC来减少肝纤维化。多组学分析显示,HSC特异性IGF2BP3敲除降低了Jagged1(Jag1)中的m6A含量,Notch信号通路的关键组成部分。此外,IGF2BP3缺乏显著降低了split-1(Hes1)的毛状和增强子的表达,Notch/Jag1信号通路中的转录因子,mRNA水平下降到35%-62%,蛋白质水平下降到28%-35%。此外,它抑制了谷胱甘肽过氧化物酶4(GPX4)(降低至约31%-38%),FPT的负调节器,从而促进HSCFPT进展并减少促纤维化基因表达。
    结论:这些发现揭示了涉及HSCFPT的新型IGF2BP3/Notch/Jag1信号通路,提示改善肝纤维化的有希望的目标。
    IGF2BP3缺乏症使Jag1信号失活。IGF2BP3缺陷介导的m6A修饰促进HSC铁凋亡。IGF2BP3抑制通过Hes1/GPX4轴促进HSC中的铁凋亡。IGF2BP3缺乏使Jag1/Notch1/3/Hes1信号通路失活,导致GPX4的减少,这有助于HSC铁凋亡。
    BACKGROUND: Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), which involves various epigenetic modifications.
    OBJECTIVE: N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotic cells, influences numerous physiological and pathological processes. Nevertheless, the role of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader gene mediating m6A modifications, in liver fibrosis remains unclear.
    RESULTS: This study demonstrated that IGF2BP3 knockout reduces liver fibrosis by promoting HSC ferroptosis (FPT) and inactivating HSCs. Multi-omics analysis revealed that HSC-specific IGF2BP3 knockout decreased m6A content in Jagged1 (Jag1), a key component of the Notch signalling pathway. Furthermore, IGF2BP3 deficiency significantly reduced the expression of hairy and enhancer of split-1 (Hes1), a transcription factor in the Notch/Jag1 signalling pathway, with mRNA levels declining to 35%-62% and protein levels to 28%-35%. Additionally, it suppressed glutathione peroxidase 4 (GPX4) (decreased to approximately 31%-38%), a negative regulator of FPT, thereby facilitating HSC FPT progression and reducing profibrotic gene expression.
    CONCLUSIONS: These findings uncover a novel IGF2BP3/Notch/Jag1 signalling pathway involving HSC FPT, suggesting promising targets for ameliorating liver fibrosis.
    UNASSIGNED: IGF2BP3 deficiency inactivates Jag1 signalling. IGF2BP3 deficiency-mediated m6A modifications promote HSC ferroptosis. IGF2BP3 inhibition facilitates ferroptosis in HSCs via the Hes1/GPX4 axis. IGF2BP3 deficiency inactivates Jag1/Notch1/3/Hes1 signalling pathway inactivation, leading to the decrease in GPX4, which contributes to HSC ferroptosis.
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  • 文章类型: Journal Article
    慢性乙型肝炎病毒(HBV)感染仍然是肝纤维化和终末期肝病在中国的一个突出原因,需要制定有效的治疗策略。这项研究调查了靶向TGR5通过阻止肝星状细胞(HSC)的激活来减轻肝纤维化的潜力,在纤维化进程中起关键作用。使用人肝星状细胞系LX-2过表达乙型肝炎病毒X蛋白(HBX),这项研究表明,通过INT-777激活TGR5抑制HBX诱导的LX-2细胞活化,从而改善肝纤维化,这与线粒体裂变的减弱有关,并在肝纤维化中引入了一种新的调节途径。使用线粒体裂变诱导剂和抑制剂的其他实验证实了线粒体动力学在TGR5介导的作用中的关键作用。使用TGR5敲除小鼠的体内研究证实了这些发现,证明在没有TGR5的情况下纤维化加剧,并且线粒体裂变抑制剂Mdivi-1减轻了纤维化。总的来说,本研究通过调节HSC的线粒体裂变,为TGR5介导的肝纤维化调节提供了见解,提示肝纤维化干预的潜在治疗策略。
    Chronic hepatitis B virus (HBV) infection continues to be a prominent cause of liver fibrosis and end-stage liver disease in China, necessitating the development of effective therapeutic strategies. This study investigated the potential of targeting TGR5 to alleviate liver fibrosis by impeding the activation of hepatic stellate cells (HSCs), which play a pivotal role in fibrotic progression. Using the human hepatic stellate cell line LX-2 overexpressing hepatitis B virus X protein (HBX), this study revealed that TGR5 activation through INT-777 inhibits HBX-induced LX-2 cell activation, thereby ameliorating liver fibrosis, which is associated with the attenuation of mitochondrial fission and introduces a novel regulatory pathway in liver fibrosis. Additional experiments with mitochondrial fission inducers and inhibitors confirm the crucial role of mitochondrial dynamics in TGR5-mediated effects. In vivo studies using TGR5 knockout mice substantiate these findings, demonstrating exacerbated fibrosis in the absence of TGR5 and its alleviation with the mitochondrial fission inhibitor Mdivi-1. Overall, this study provides insights into TGR5-mediated regulation of liver fibrosis through the modulation of mitochondrial fission in HSCs, suggesting potential therapeutic strategies for liver fibrosis intervention.
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  • 文章类型: Journal Article
    背景:肝纤维化(HF)是不同慢性肝病进展为肝硬化甚至肝细胞癌的重要阶段。肝星状细胞(HSC)的激活在HF的进展中起着至关重要的作用。IFN-γ/Smad7通路可抑制HSCs活化,而TGF-β1/CUGBP1通路可抑制IFN-γ/Smad7通路的转导,促进HSCs的活化。因此,抑制TGF-β1/CUGBP1途径和激活IFN-γ/Smad7途径逆转HSCs活化并抑制HF。加味桃河承气汤(JTCD)源自古代中医著作《伤寒论》中的桃河承气汤。我们在JTCD中发现了几种抗HF成分,包括人参皂苷Rb1等,但JTCD中抗HF的具体机制尚不清楚。
    目的:阐明JTCD通过抑制HSC活化逆转HF的具体机制,并建立中医药治疗HF的科学基础。
    方法:我们构建了CCl4诱导的小鼠HF模型,并在体外激活了TGF-β1的人肝星状细胞系(LX-2),之后他们用JTCD和相应的抑制剂治疗。我们通过免疫荧光染色检查了上述两种途径中关键分子的表达,Western印迹和RT-PCR。
    结果:JTCD减轻了小鼠的肝损伤并降低了血清ALT和AST水平。此外,JTCD通过降低α-SMA的表达减弱CCl4诱导的HF,COL1A1等标志HSCs在小鼠肝组织中活化。此外,JTCD能有效抑制TGF-β1、p-Smad3、p-p38MAPK,p-ATF2和CUGBP1在体内和体外上调IFN-γ的水平,p-STAT1和Smad7。机械上,在体外使用两种途径的抑制剂后,我们发现JTCD通过恢复TGF-β1/CUGBP1和IFN-γ/Smad7通路的平衡来抑制HSC的活化。
    结论:我们证明JTCD通过抑制TGF-β1/CUGBP1信号通路和上调IFN-γ/Smad7信号通路抑制HSCs活化并逆转HF。此外,我们已经确定了JTCD干扰两种途径以抑制HSC活化的特定联系。JTCD是临床治疗HF的有效候选药物。
    BACKGROUND: Hepatic fibrosis (HF) is an essential stage in the progression of different chronic liver conditions to cirrhosis and even hepatocellular carcinoma. The activation of hepatic stellate cells (HSCs) plays a crucial role in the progression of HF. IFN- γ/Smad7 pathway can inhibit HSCs activation, while TGF-β1/CUGBP1 pathway can inhibit IFN-γ/Smad7 pathway transduction and promote HSCs activation. Thus, inhibiting the TGF-β1/CUGBP1 pathway and activating the IFN-γ/Smad7 pathway reverses HSCs activation and inhibits HF. Jiawei Taohe Chengqi Decoction (JTCD) was derived from the Taohe Chengqi Tang in the ancient Chinese medical text titled \"Treatise on Febrile Diseases\". We found several anti-HF components in JTCD including ginsenoside Rb1 and others, but the specific mechanism of anti-HF in JTCD is not clear.
    OBJECTIVE: To elucidate the specific mechanism by which JTCD reverses HF by inhibiting the activation of HSCs, and to establish a scientific foundation for treating HF with Traditional Chinese medicine (TCM).
    METHODS: We constructed a CCl4-induced mice HF model in vivo and activated human hepatic stellate cell line (LX-2) with TGF-β1 in vitro, after which they were treated with JTCD and the corresponding inhibitors. We examined the expression of pivotal molecules in the two pathways mentioned above by immunofluorescence staining, Western blotting and RT-PCR.
    RESULTS: JTCD attenuated liver injury and reduced serum ALT and AST levels in mice. In addition, JTCD attenuated CCl4-induced HF by decreasing the expression of α-SMA, COL1A1 and other markers of HSCs activation in mice liver tissue. Moreover, JTCD effectively suppressed the levels of TGF-β1, p-Smad3, p-p38MAPK, p-ATF2, and CUGBP1 in vivo and in vitro and upregulated the levels of IFN-γ, p-STAT1, and Smad7. Mechanically, after using the inhibitors of both pathways in vitro, we found that JTCD inhibited the activation of HSCs by restoring the balance of the TGF-β1/CUGBP1 and IFN-γ/Smad7 pathways.
    CONCLUSIONS: We demonstrated that JTCD inhibited HSCs activation and reversed HF by inhibiting the TGF-β1/CUGBP1 signalling pathway and upregulating the IFN-γ/Smad7 signalling pathway. Moreover, we have identified specific links where JTCD interferes with both pathways to inhibit HSCs activation. JTCD is an effective candidate for the clinical treatment of HF.
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  • 文章类型: Journal Article
    背景:肝纤维化(HF)贯穿肝脏疾病的多个阶段,并促进这些疾病的进展。Oxysophoridine(OSR),来源于苦豆子,是一种生物活性生物碱,据报道可拮抗酒精性肝损伤。然而,OSR是否抑制HF和Nrf2涉及的机制仍然未知。
    目的:由于炎症和氧化应激的失调是导致肝脏细胞外基质(ECM)过度积累和纤维化的原因。我们假设OSR可以通过激活Nrf2信号抑制炎症和氧化应激来减弱HF。
    方法:在本研究中,我们使用LPS刺激的HSC-T6细胞,RAW264.7细胞,和CCl4诱导的C57BL/6小鼠纤维化模型,以评估其抑制炎症和氧化应激,以及纤维化。
    结果:结果表明,OSR在10μM的低剂量下在体外和在50mg/kg的剂量下在体内显着降低α-SMA和TGF-β1,与水飞蓟素相当,唯一的中草药活性成分已上市抗肝纤维化。此外,OSR有效抑制10μM剂量的iNOS和40μM剂量的COX-2的表达,分别。此外,OSR对IL-1β有抑制作用,体外IL-6和TNF-α以及体内几乎消除的细胞因子风暴。OSR通过减少MDA和增加GSH表现出抗氧化作用,从而保护细胞膜免受氧化损伤并减少LDH释放。此外,OSR有效上调Nrf2,HO-1和p62的蛋白水平,但降低p-NF-κBp65,p-IκBα,Keap1或者,参与Nrf2的机制通过siNrf2干扰得到验证,siNrf2干扰表明OSR的抗纤维化作用归因于其对Nrf2的激活。
    结论:本研究为参与Nrf2激活和NF-κB阻断的HF提供了有效的候选药物,这在出版的作品中没有报道。本研究为HF新药开发的鉴定提供了新的见解。
    BACKGROUND: Hepatic fibrosis (HF) runs through multiple stages of liver diseases and promotes these diseases progression. Oxysophoridine (OSR), derived from Sophora alopecuroides l., is a bioactive alkaloid that has been reported to antagonize alcoholic hepatic injury. However, whether OSR suppresses HF and the mechanisms involved in Nrf2 remain unknown.
    OBJECTIVE: Since the dysregulation of inflammation and oxidative stress is responsible for the excessive accumulation of extracellular matrix (ECM) and fibrosis in the liver. We hypothesized that OSR may attenuate HF by inhibiting inflammation and oxidative stress through activating Nrf2 signaling.
    METHODS: In this study, we employed LPS-stimulated HSC-T6 cells, RAW264.7 cells, and a CCl4-induced C57BL/6 mouse fibrotic model to evaluate its suppressing inflammation and oxidative stress, as well as fibrosis.
    RESULTS: The result showed that OSR significantly reduced α-SMA and TGF-β1 at a low dose of 10 μM in vitro and at a dose of 50 mg/kg in vivo, which is comparable to Silymarin, the only Chinese herbal active ingredient that has been marketed for anti-liver fibrosis. Moreover, OSR effectively suppressed the expression of iNOS at a dose of 10 μM and COX-2 at a dose of 40 μM, respectively. Furthermore, OSR demonstrated inhibitory effects on the IL-1β, IL-6, and TNF-α in vitro and almost extinguished cytokine storm in vivo. OSR exhibited antioxidative effects by reducing MDA and increasing GSH, thereby protecting the cell membrane against oxidative damage and reducing LDH release. Moreover, OSR effectively upregulated the protein levels of Nrf2, HO-1, and p62, but decreased p-NF-κB p65, p-IκBα, and Keap1. Alternatively, mechanisms involved in Nrf2 were verified by siNrf2 interference, siNrf2 interference revealed that the anti-fibrotic effect of OSR was attributed to its activation of Nrf2.
    CONCLUSIONS: The present study provided an effective candidate for HF involved in both activation of Nrf2 and blockage of NF-κB, which has not been reported in the published work. The present study provides new insights for the identification of novel drug development for HF.
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  • 文章类型: Journal Article
    肝纤维化的特征在于慢性炎症反应和进行性纤维瘢痕形成。巨噬细胞通过重建免疫微环境在肝纤维化的发病机制中起着核心作用。黄连苷II(PICII),从苦参中提取,已经证明了治疗各种肝损伤的潜力。然而,巨噬细胞极化启动免疫级联反应并促进肝纤维化发展的机制,以及这个过程是否会受到PICII的影响,仍然不清楚。在目前的研究中,RNA测序和多种分子方法被用来探索PICII对抗多药耐药蛋白2敲除(Mdr2-/-)小鼠肝纤维化的潜在机制。我们的发现表明,PICII激活M1极化的巨噬细胞招募自然杀伤细胞(NK细胞),可能通过CXCL16-CXCR6轴。此外,PICII促进活化肝星状细胞(aHSC)的凋亡,增强NK细胞的细胞毒作用,同时也减少了中性粒细胞胞外陷阱(NET)的形成。值得注意的是,Mdr2-/-小鼠的巨噬细胞耗竭在很大程度上逆转了与PICII相关的抗肝纤维化作用.总的来说,我们的研究表明,PICII是阻止肝纤维化进展的潜在候选者.
    Liver fibrosis is characterized by chronic inflammatory responses and progressive fibrous scar formation. Macrophages play a central role in the pathogenesis of hepatic fibrosis by reconstructing the immune microenvironment. Picroside II (PIC II), extracted from Picrorhizae Rhizoma, has demonstrated therapeutic potential for various liver damage. However, the mechanisms by which macrophage polarization initiates immune cascades and contributes to the development of liver fibrosis, and whether this process can be influenced by PIC II, remain unclear. In the current study, RNA sequencing and multiple molecular approaches were utilized to explore the underlying mechanisms of PIC II against liver fibrosis in multidrug-resistance protein 2 knockout (Mdr2-/-) mice. Our findings indicate that PIC II activates M1-polarized macrophages to recruit natural killer cells (NK cells), potentially via the CXCL16-CXCR6 axis. Additionally, PIC II promotes the apoptosis of activated hepatic stellate cells (aHSCs) and enhances the cytotoxic effects of NK cells, while also reducing the formation of neutrophil extracellular traps (NETs). Notably, the anti-hepatic fibrosis effects associated with PIC II were largely reversed by macrophage depletion in Mdr2-/- mice. Collectively, our research suggests that PIC II is a potential candidate for halting the progression of liver fibrosis.
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  • 文章类型: Journal Article
    代谢功能障碍相关脂肪性肝炎(MASH)受肝脏中巨噬细胞和周围细胞之间复杂的相互作用调节。这里,我们表明,Atf3调节葡萄糖-脂肪酸循环在巨噬细胞减弱肝细胞脂肪变性,和肝星状细胞(HSC)中的纤维发生。巨噬细胞中Atf3的过表达可以防止西方饮食喂养小鼠中MASH的发展,而Atf3消融具有相反的效果。机械上,Atf3通过叉头盒O1(FoxO1)和Cd36促进葡萄糖诱导的脂肪酸氧化还原。Atf3通过阻断Hdac1介导的FoxO1在K242、K245和K262的脱乙酰化作用来抑制FoxO1活性,并增加Zdhhc4/5介导的CD36在C3、C7、C464和C466的棕榈酰化作用;巨噬细胞Atf3通过视黄醇结合蛋白4(Rbp4)降低肝细胞脂肪生成和HSC活化。抗Rbp4可以防止巨噬细胞中Atf3缺乏诱导的MASH进展。这项研究确定Atf3是葡萄糖-脂肪酸循环的调节剂。靶向巨噬细胞Atf3或Rbp4可能是MASH的合理治疗策略。
    Metabolic dysfunction-associated steatohepatitis (MASH) is regulated by complex interplay between the macrophages and surrounding cells in the liver. Here, we show that Atf3 regulates glucose-fatty acid cycle in macrophages attenuates hepatocyte steatosis, and fibrogenesis in hepatic stellate cells (HSCs). Overexpression of Atf3 in macrophages protects against the development of MASH in Western diet-fed mice, whereas Atf3 ablation has the opposite effect. Mechanistically, Atf3 improves the reduction of fatty acid oxidation induced by glucose via forkhead box O1 (FoxO1) and Cd36. Atf3 inhibits FoxO1 activity via blocking Hdac1-mediated FoxO1 deacetylation at K242, K245, and K262 and increases Zdhhc4/5-mediated CD36 palmitoylation at C3, C7, C464, and C466; furthermore, macrophage Atf3 decreases hepatocytes lipogenesis and HSCs activation via retinol binding protein 4 (Rbp4). Anti-Rbp4 can prevent MASH progression that is induced by Atf3 deficiency in macrophages. This study identifies Atf3 as a regulator of glucose-fatty acid cycle. Targeting macrophage Atf3 or Rbp4 may be a plausible therapeutic strategy for MASH.
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