INTRODUCTION: Liver fibrosis results from chronic liver injury and inflammation, often leading to cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. Progress has been made in understanding the molecular mechanisms underlying hepatic fibrosis; however, translating this knowledge into effective therapies for disease regression remains a challenge, with considerably few interventions having entered clinical validation. The roles of exosomes during fibrogenesis and their potential as a therapeutic approach for reversing fibrosis have gained significant interest. This study aimed to investigate the association between microRNAs (miRNAs) derived from serum exosomes and liver fibrosis and to evaluate the effect of serum exosomes on fibrogenesis and fibrosis reversal, while identifying the underlying mechanism. METHODS: Using serum samples collected from healthy adults and paired histologic patients with advanced fibrosis or cirrhosis, we extracted human serum exosomes by ultrahigh-speed centrifugation. Transcriptomic analysis was conducted to identify dysregulated exosome-derived miRNAs. Liver fibrosis–related molecules were determined by qRT-PCR, Western blot, Masson staining, and immunohistochemical staining. In addition, we analyzed the importance of serum exosome–derived miRNA expression levels in 42 patients with advanced fibrosis or cirrhosis. RESULTS: Exosome-derived miR-193a-5p and miR-381-3p were associated with fibrogenesis, as determined by transcriptomic screening. Compared with healthy control group, the high expression of serum exosome–derived miR-193a-5p and miR-381-3 in chronic hepatitis B (n = 42) was closely associated with advanced liver fibrosis and cirrhosis. In vitro , exosome-derived miRNA-193a-5p and miR-381-3p upregulated the expression of α-smooth muscle actin, collagen 1a1, and tissue inhibitors of metalloproteinase 1 in the human hepatic stellate cell line at both mRNA and protein levels. DISCUSSION: Serum exosome–derived miR-193a-5p and miR-381-3p regulated the adenosine 5'-monophosphate–activated protein kinase/transforming growth factor beta/Smad2/3 signaling pathway and promoted fibrogenesis.
Excess acetaminophen(APAP) can be converted by the cytochrome P450 system to the toxic metabolite N-acetyl-p-benzoquinoneimine(NAPQI), which consumes glutathione(GSH). When GSH is depleted, NAPQI covalently binds with proteins, inducing mitochondrial dysfunction and oxidative stress and thereby leading to hepatotoxicity. Schisandrin C(SinC) is a dibenzocyclooctadiene derivative isolated from Schisandra chinensis. Although there is some evidence showing that SinC has hepatoprotective activity, its protective effect and mechanism on APAP-induced liver injury remain unclear. In this paper, an acute liver injury mouse model was established by intraperitoneal injection of APAP at a dose of 400 mg·kg~(-1) to evaluate the effect of SinC administration on the APAP-induced liver injury and its mechanism through an animal experiment. At the same time, a potential candidate drug was provi-ded for traditional Chinese medicine(TCM) prevention and treatment of overdose APAP-induced liver injury. In the APAP-induced liver injury mouse model, we found that SinC can relieve hepatic histopathological lesions and significantly reduce the activities of alanine aminotransferase(ALT), aspartate aminotransferase(AST) and alkaline phosphatase(ALP). It was also capable of increasing the content of GSH and superoxide dismutase(SOD) and decreasing the levels of total bilirubin(TBIL), direct bilirubin(DBIL), malondialdehyde(MDA), interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α). Further analysis showed that SinC decreased the content of CYP2 E1 in liver tissues at protein and mRNA levels and increased nuclear factor erythroid 2-related factor 2(Nrf2) and the expression of its downstream targets(including HO-1, NQO1 and GCLC). Taken together, the above results indicate that SinC can alleviate APAP-induced liver injury by reducing the expression of CYP2 E1, suppressing apoptosis, improving inflammatory response and activating the Nrf2 signaling pathway to inhibit oxidative stress.
Idiosyncratic drug-induced liver injury (IDILI) is an infrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs. Epimedii Folium (EF), the widely used herbal medicine, has shown to cause idiosyncratic liver injury, but the underlying mechanisms are poorly understood. Increasing evidence has indicated that most cases of IDILI are immune mediated. Here, we report that icariside Ⅱ (ICS Ⅱ), the major active and metabolic constituent of EF, causes idiosyncratic liver injury by promoting NLRP3 inflammasome activation. ICS Ⅱ exacerbates NLRP3 inflammasome activation triggered by adenosine triphosphate (ATP) and nigericin, but not silicon dioxide (SiO2), monosodium urate (MSU) crystal or cytosolic lipopolysaccharide (LPS). Additionally, the activation of NLRC4 and AIM2 inflammasomes is not affected by ICS Ⅱ. Mechanistically, synergistic induction of mitochondrial reactive oxygen species (mtROS) is a crucial contributor to the enhancing effect of ICS Ⅱ on ATP- or nigericin-induced NLRP3 inflammasome activation. Importantly, in vivo data show that a combination of non-hepatotoxic doses of LPS and ICS Ⅱ causes the increase of aminotransferase activity, hepatic inflammation and pyroptosis, which is attenuated by Nlrp3 deficiency or pretreatment with MCC950 (a specific NLRP3 inflammasome inhibitor). In conclusion, these findings demonstrate that ICS Ⅱ causes idiosyncratic liver injury through enhancing NLRP3 inflammasome activation and suggest that ICS Ⅱ may be a risk factor and responsible for EF-induced liver injury.
Abstract Background HBV infection can result in severe liver diseases and is one of the primary causes of liver cell carcinoma-related mortality. Liuwei Wuling tablet (LWWL) is a traditional Chinese medicine formula, with a protecting liver and decreasing enzyme activity, usually used to treat chronic hepatitis B with NAs in clinic. However, its main active ingredients and mechanism of action have not been fully investigated. Hence, we aimed to screen the active ingredient and effective ingredient combinations from Liuwei Wuling tablet to explore the anti-herpatitis B virus activity and mechanism. Methods Analysis and screening of effective antiviral components in LWWL by network pharmacology, luteolin (Lut) may be a compound with significant antiviral activity. The mechanism of antiviral action of Lut was also found by real-time PCR detection and western blotting. Meanwhile, we established a co-culture model to investigate the antiviral mechanism of Schisandrin C (SC), one of the main active components of Schisandra chinensis fructus (the sovereign drug of LWWL). Next, HBV-infected mice were established by tail vein injection of pAAV-HBV1.2 plasmid and administered continuously for 20 days. And their antiviral capacity was evaluated by checking serum levels of HBsAg, HBeAg, levels of HBV DNA, and liver levels of HBcAg. Results In this study, we conducted network pharmacology analysis on LWWL, and through in vitro experimental validation and data analysis, we found that luteolin (Lut) possessed obviously anti-HBV activity, inhibiting HBV replication by downregulating hepatocyte nuclear factor 4α (HNF4α) via the ERK pathway. Additionally, we established a co-culture system and proved that SC promoted activation of cGAS-STINIG pathway and IFN-β production in THP-1 cells to inhibit HBV replication in HepG2.2.15 cells. Moreover, we found the combination of SC and Lut shows a greater effect in inhibiting HBV compared to SC or Lut alone in HBV-infected mice. Conclusion Taken together, our study suggests that combination of SC and Lut may be potential candidate drug for the prevention and treatment of chronic hepatitis B.
Epimedii Folium (EF) is commonly used for treating bone fractures and joint diseases, but the potential hepatotoxicity of EF limits its clinical application. Our previous study confirms that EF could lead to idiosyncratic drug-induced liver injury (IDILI) and hepatocyte apoptosis, but the mechanism remains unknown. Studies have shown that NLRP3 inflammasome plays an important role in the development of various inflammatory diseases such as IDILI. Specific stimulus-induced NLRP3 inflammasome activation may has been a key strategy for lead to liver injury. Therefore, main compounds derived from EF were chosen to test whether the ingredients in EF could activate the NLRP3 inflammasome and to induce IDILI.
With the advancing comprehension of immunology, an increasing number of immunotherapies are being explored and implemented in the field of cancer treatment. The cGAS-STING pathway, a crucial element of the innate immune response, has been identified as pivotal in cancer immunotherapy. We evaluated the antitumor effects of
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