RESUMEN
OBJECTIVE: 28-55% of chronic hepatitis B (CHB) patients belong to the grey zone (GZ). By analyzing the pathological characteristics of the liver of patients in the GZ, this study clarified whether the patients in the GZ need anti-hepatitis B virus treatment. METHOD: We reviewed 324 cases of liver pathology that underwent liver biopsy between 2011 and 2022. According to the total score of inflammation G, 0-6 points are classified as mild, 7-12 points are classified as moderate, and 13-18 points are classified as severe. According to the total score of fibrosis F, 0-2 is mild, 3-4 is moderate, and 5-6 is severe. Significant histological diseases (SHD) are defined as the presence of inflammation G ≥ 6 and/or fibrosis F ≥ 2 in liver biopsy specimens. RESULT: 324 GZ patients were scored using the Ishak method, with G7-18 accounting for 9%, F3-6 accounting for 19.2%, and SHD accounting for 37%. The inflammation, fibrosis, and SHD in the HBeAg (+) group were more pronounced than those in the HBeAg (-) group. Among the GZ-A â¼ GZ-D subgroups, the highest proportion of SHD in the GZ-B group was 58.35%. CONCLUSION: More than 1/3 of the patients in GZ need anti-hepatitis B virus treatment. More than half of GZ-B patients need anti-hepatitis B virus treatment. It is very necessary to carry out rescue anti-hepatitis B virus treatment for patients in GZ as soon as possible.
Asunto(s)
Antivirales , Antígenos e de la Hepatitis B , Hepatitis B Crónica , Cirrosis Hepática , Hígado , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/patología , Hepatitis B Crónica/virología , Antivirales/uso terapéutico , Masculino , Femenino , Adulto , Hígado/patología , Persona de Mediana Edad , Cirrosis Hepática/virología , Cirrosis Hepática/patología , Cirrosis Hepática/tratamiento farmacológico , Antígenos e de la Hepatitis B/sangre , Biopsia , Virus de la Hepatitis B/efectos de los fármacos , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The immunomodulatory oligodeoxynucleotide (ODN) IMT504 might harbor antifibrotic properties within the liver. METHODS: Fibrosis models were induced in mice through thioacetamide (TAA) administration and bile-duct ligation. Cre-loxP mice were utilized to identify GLAST + Wnt1 + bone marrow stromal progenitors (BMSPs) and to examine their contribution with cells in the liver. In vivo and in vitro assays; flow-cytometry, immunohistochemistry, and qPCR were conducted. RESULTS: IMT504 demonstrated significant inhibition of liver fibrogenesis progression and reversal of established fibrosis. Early responses to IMT504 involved the suppression of profibrogenic and proinflammatory markers, coupled with an augmentation of hepatocyte proliferation. Additionally, this ODN stimulated the proliferation and mobilization of GLAST + Wnt1 + BMSPs, likely amplifying their contribution with endothelial- and hepatocytes-like cells. Moreover, IMT504 significantly modulated the expression levels of Wnt ligands and signaling pathway/target genes specifically within GLAST + Wnt1 + BMSPs, with minimal impact on other BMSPs. Intriguingly, both IMT504 and conditioned media from IMT504-pre-treated GLAST + Wnt1 + BMSPs shifted the phenotype of fibrotic macrophages, hepatic stellate cells, and hepatocytes, consistent with the potent antifibrotic effects observed. CONCLUSION: In summary, our findings identify IMT504 as a promising candidate molecule with potent antifibrotic properties, operating through both direct and indirect mechanisms, including the activation of GLAST + Wnt1 + BMSPs.
Asunto(s)
Cirrosis Hepática , Células Madre Mesenquimatosas , Proteína Wnt1 , Animales , Ratones , Cirrosis Hepática/patología , Cirrosis Hepática/tratamiento farmacológico , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Proteína Wnt1/metabolismo , Proteína Wnt1/genética , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Oligodesoxirribonucleótidos/farmacología , Masculino , Ratones Endogámicos C57BL , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , TioacetamidaRESUMEN
Hepatic fibrosis (HF) is a process that occurs during the progression of several chronic liver diseases, for which there is a lack of effective treatment options. Carthamus tinctorius L. (CTL) is often used in Chinese or Mongolian medicine to treat liver diseases. However, its mechanism of action remains unclear. In the present study, CTL was used to treat rats with CCl4induced HF. The histopathological, biochemical and HF markers of the livers of the rats were analyzed, and CTLinfused serum was used to treat hepatic stellate cells (HSCs) in order to detect the relevant markers of HSC activation. Protein expression pathways were detected both in vitro and in vivo. Histopathological results showed that CTL significantly improved CCl4induced liver injury, reduced aspartate aminotransferase and alanine aminotransferase levels, promoted Ecadherin expression, and decreased αsmooth muscle actin (SMA), SOX9, collagen I and hydroxyproline expression. Moreover, CTLinfused serum was found to decrease αSMA and collagen I expression in HSCs. Further studies showed that CTL inhibited the activity of the PI3K/Akt/mTOR pathway in the rat livers. Following the administration of the PI3K agonist 740YP to HSCs, the inhibitory effect of CTL on the PI3K/Akt//mTOR pathway was blocked. These results suggested that CTL can inhibit HF and HSC activation by inhibiting the PI3K/Akt/mTOR pathway.
Asunto(s)
Carthamus tinctorius , Células Estrelladas Hepáticas , Cirrosis Hepática , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Carthamus tinctorius/química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Ratas , Masculino , Tetracloruro de Carbono , Ratas Sprague-Dawley , Extractos Vegetales/farmacología , Hígado/metabolismo , Hígado/patología , Hígado/efectos de los fármacosRESUMEN
OBJECTIVE: To analyze the core functional component groups (CFCG) in Yinchenhao Decoction (YCHD) and their possible pathways for treating hepatic fibrosis based on network pharmacology. METHODS: PPI data were extracted from DisGeNET, Genecards, CMGRN and PTHGRN to construct a weighted network using Cytoscape 3.9.1. The data of the chemical components in YCHD were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the potential active components and targets were selected using PreADMET Web server and SwissTargetPrediction. A fusion model was constructed to obtain the functional effect space and evaluate the effective proteins to identify the CFCG followed by GO and KEGG pathway enrichment analyses for all the targets. In cultured human hepatic stellate cells (LX-2 cells), the cytotoxicity of different compounds in YCHD was tested using CCK-8 assay; the effects of these compounds on collagen α1 (Col1a1) mRNA expression and the pathways in 20 ng/mL TGF-ß1-stimulated cells were analyzed using RT-qPCR and Western blotting. RESULTS: A total of 1005 pathogenic genes, 226 potential active components and 1529 potential targets in YCHD and 52 potential targets of CFCG were obtained. Benzyl acetate, vanillic acid, clorius, polydatin, lauric acid and ferulic acid were selected for CCK-8 verification, and they all showed minimal cytotoxicity below the concentration of 200 µmol/L. Clorius, polydatin, lauric acid and ferulic acid all effectively inhibited TGF-ß1-induced LX-2 cell activation. At the concentration of 200 µmol/L, all these 4 components inhibited PI3K, p-PI3K, AKT, p-AKT, ERK, p-ERK, P38 MAPK and p-P38 MAPK expressions in TGF-ß1-induced LX-2 cells. CONCLUSION: The therapeutic effect of YCHD on hepatic fibrosis is probably mediated by its core functional components including benzyl acetate, vanillic acid, clorius, polydatin, lauric acid and ferulic acid, which inhibit the PI3K-AKT and MAPK pathways in hepatic stellate cells.
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Medicamentos Herbarios Chinos , Células Estrelladas Hepáticas , Cirrosis Hepática , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Humanos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Medicina Tradicional China/métodos , Factor de Crecimiento Transformador beta1/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo I/genética , Ácidos Cumáricos/farmacología , Línea Celular , Transducción de Señal/efectos de los fármacos , Farmacología en Red , Cadena alfa 1 del Colágeno Tipo IRESUMEN
Chronic liver injuries often lead to hepatic fibrosis, a condition characterized by excessive extracellular matrix accumulation and abnormal connective tissue hyperplasia. Without effective treatment, hepatic fibrosis can progress to cirrhosis or hepatocellular carcinoma. Current treatments, including liver transplantation, are limited by donor shortages and high costs. As such, there is an urgent need for effective therapeutic strategies. This review focuses on the potential of plant-based therapeutics, particularly polyphenols, phenolic acids, and flavonoids, in treating hepatic fibrosis. These compounds have demonstrated anti-fibrotic activities through various signaling pathways, including TGF-ß/Smad, AMPK/mTOR, Wnt/ß-catenin, NF-κB, PI3K/AKT/mTOR, and hedgehog pathways. Additionally, this review highlights the advancements in nanoparticulate drug delivery systems that enhance the pharmacokinetics, bioavailability, and therapeutic efficacy of these bioactive compounds. Methodologically, this review synthesizes findings from recent studies, providing a comprehensive analysis of the mechanisms and benefits of these plant-based treatments. The integration of novel drug delivery systems with plant-based therapeutics holds significant promise for developing effective treatments for hepatic fibrosis.
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Cirrosis Hepática , Humanos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Animales , Sistema de Administración de Fármacos con Nanopartículas , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/química , Transducción de Señal/efectos de los fármacos , Flavonoides/uso terapéutico , Flavonoides/administración & dosificación , Flavonoides/farmacocinética , Polifenoles/uso terapéutico , Polifenoles/administración & dosificación , Polifenoles/químicaRESUMEN
Aberrant activation of the NLRP3 inflammasome is recognized to induce a chronic inflammatory response in the liver, ultimately leading to hepatic fibrosis. HSP90 is suggested to regulate NLRP3 activation and its downstream signaling. This study is the first to explore the potential therapeutic role of pimitespib in mitigating liver fibrosis in rats. The results of the study revealed that pimitespib effectively suppressed hepatic inflammation and fibrogenesis by modulating HSP90's control over the NFκB/NLRP3/caspase-1 axis. In vitro experiments demonstrated that pimitespib reduced LDH levels and increased hepatocyte survival, whereas in vivo, it prolonged the survival of rats with hepatic fibrosis. Additionally, pimitespib exhibited improvements in the function and microscopic characteristics of rat livers. Pimitespib effectively inhibited NFκB, which serves as the priming signal for NLRP3 activation. Pimitespib's inhibitory effect on NLRP3, identified as an HSP90 client protein, plays a central role in the observed anti-fibrotic effect. The simultaneous inhibition of both priming and activation signals of NLRP3 by pimitespib led to a reduction in caspase-1 activity and subsequent suppression of the N-terminal fragment of gasdermin D, ultimately constraining hepatocyte pyroptotic cell death. These diverse effects were associated with a decrease in the transcription of inflammatory mediators IL-1ß, IL-18, and TNF-α, as well as the fibrogenic mediators TGF-ß, TIMP-1, PDGF-BB, and Col1a1. Moreover, pimitespib induced the expression of HSP70, which could further contribute to the repression of fibrosis development. In summary, our findings provide an evolutionary perspective on managing liver fibrosis, positioning pimitespib as a promising candidate for anti-inflammatory and antifibrotic therapy.
Asunto(s)
Caspasa 1 , Proteínas HSP90 de Choque Térmico , Cirrosis Hepática , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/tratamiento farmacológico , Proteínas HSP90 de Choque Térmico/metabolismo , FN-kappa B/metabolismo , Masculino , Caspasa 1/metabolismo , Transducción de Señal , Ratas Sprague-Dawley , Inflamasomas/metabolismo , Sulfonamidas/farmacología , Hepatocitos/metabolismo , Hepatocitos/patología , Hepatocitos/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ligustrum lucidum W.T. Aiton is a traditional Chinese medicine that has long been used with high hepatoprotective therapeutic and condition value. Specnuezhenide (SP), the standard prominent secoiridoid compound of Fructus Ligustri Lucidi may ameliorate hepatic inflammation in chronic liver diseases. AIM OF THE STUDY: Regulating inflammation through SIRT6-P2X7R axis has caused the emergence of novel molecular mechanism strategies for reversing hepatic fibrosis. This study focused on the mechanism of SP in modulating the liver inflammatory microenvironment in hepatic fibrosis. MATERIALS AND METHODS: C57BL/6 mice with hepatic fibrosis were stimulated with thioacetamide (TAA) prior to administration of SP. Hepatic stellate cells (HSCs) or normal mouse primary hepatocytes were exposed to transforming growth factor-ß (TGF-ß) treatment. Meanwhile, normal mouse bone marrow-derived macrophages (BMDMs) were treated with lipopolysaccharide/adenosine triphosphate (LPS/ATP), aiming to obtain the conditioned medium. HSCs and hepatocytes were transfected with SIRT6 knockdown vector (siRNA-SIRT6) to estimate the impact of SP on the SIRT6-P2X7R/NLRP3 signaling pathway. RESULTS: SP suppressed the HSCs extracellular matrix (ECM) deposition as well as pro-inflammatory cytokine levels induced by the medium of BMDMs or TGF-ß. In addition, SP also significantly up-regulated SIRT6, inhibited P2X7R-NLRP3 inflammasome in HSCs and hepatocytes, and functioned as MDL-800 (a SIRT6 agonist). SP reduced the hepatocytes pyroptosis and further prevented the occurrence of inflammatory response in the liver. SP could inhibit the activation of BMDMs and impede IL-1ß and IL-18 from entering extracellular regions. Moreover, deficiency of SIRT6 in HSCs or hepatocytes reduced SP's regulation of P2X7R suppression. For TAA-treated mice, SP mitigated histopathological changes, ECM accumulation, EMT process, and NETs formation in hepatic fibrosis. CONCLUSIONS: Therefore, SP decreased inflammatory response via SIRT6-P2X7R/NLRP3 pathway and suppressed fibrillogenesis. These findings supported SP as the novel candidate to treat hepatic fibrosis.
Asunto(s)
Cirrosis Hepática , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Transducción de Señal , Sirtuinas , Animales , Sirtuinas/metabolismo , Sirtuinas/genética , Transducción de Señal/efectos de los fármacos , Ratones , Masculino , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Tioacetamida/toxicidad , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Antiinflamatorios/farmacologíaRESUMEN
Liver cirrhosis is a chronic condition of the liver and is the 14th most common cause of death around the world; yet it remains an incurable disease. Probiotics have gained significant popularity as a potential treatment option for liver cirrhosis. METHODS: A systematic review and meta-analysis was conducted to assess the effects of probiotics on liver cirrhosis. PubMed, Scopus, Cochrane Central Register for Controlled Trials (CENTRAL) and ProQuest Dissertation and Thesis were searched from 2000 to January 2024 for studies that evaluated the effects of probiotics on a variety of outcomes of liver disease. RESULTS: A total of 22 randomised controlled trial studies were included in the meta-analysis. Probiotics significantly decreased Gamma-glutamyl transferase (effect size: 0.307, p = 0.024, 95% CI [-0.572, -0.040]) and Aspartate aminotransferase (p = 0.013, 95% CI [-17.927, -2.128]). Significant reduction in serum ammonia levels (effect size = -1.093, p = 0.000, 95% CI [-1.764, -0.423]) and endotoxin levels (effect size = -0.961, p = 0.000, 95% CI [-1.537, -0.385]) were also found. SUMMARY: Overall probiotics could be recommended as a potential adjunct therapy for patients with cirrhosis, as they appear to have some benefit in improving liver function, and are well tolerated with minimal adverse effects. More comprehensive research with larger sample sizes is recommended to understand more about the widespread effects of probiotic use.
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Cirrosis Hepática , Probióticos , Ensayos Clínicos Controlados Aleatorios como Asunto , Probióticos/uso terapéutico , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Resultado del Tratamiento , Amoníaco/sangre , Aspartato Aminotransferasas/sangre , gamma-Glutamiltransferasa/sangreRESUMEN
Liver fibrosis is a pathological process that endangers human health, for which effective treatments remain elusive to date. Paeoniflorin (PAE), a pineane-type monoter penoid compound from the traditional Chinese medicine PaeoniaeRubra Radix, and metformin (MET), an oral biguanide hypoglycemic agent, both demonstrate anti-inflammatory and hepatoprotective effects. In current work, we first discovered that the combined treatment of PAE and MET synergistically inhibited the progression of liver fibrosis in two different animal models: therapeutic and preventive. This therapeutic effect is evidenced by a reduction in the expression levels of liver fibrosis markers and an improvement in histopathological characteristics. Mechanistic exploration further revealed that this combination therapy downregulated the expression of TGF-ß1 and p-Smad2, while upregulating Smad7 expression in both models. Importantly, we also found that this combinatorial approach significantly reduced hepatotoxicity and nephrotoxicity in both models. Our findings suggest an effective combination therapy for liver fibrosis and provide the possibility of therapeutic improvement for patients with liver fibrosis.
Asunto(s)
Sinergismo Farmacológico , Glucósidos , Cirrosis Hepática , Metformina , Monoterpenos , Animales , Monoterpenos/farmacología , Monoterpenos/uso terapéutico , Monoterpenos/administración & dosificación , Glucósidos/farmacología , Glucósidos/uso terapéutico , Glucósidos/administración & dosificación , Metformina/farmacología , Metformina/uso terapéutico , Metformina/administración & dosificación , Ratones , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Masculino , Progresión de la Enfermedad , Ratones Endogámicos C57BL , Quimioterapia Combinada , Factor de Crecimiento Transformador beta1/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Proteína Smad2/metabolismo , Modelos Animales de EnfermedadRESUMEN
This study aimed to investigate the effects of corn gluten-derived soluble epoxide hydrolase (sEH) inhibitory peptides on nonalcoholic fatty liver fibrosis induced by a high-fat diet and carbon tetrachloride in mice. Mice treated with corn peptides at doses of 500 or 1000 mg/kg/d for 4 weeks exhibited reduced sEH activity in serum and liver, enhanced lipid metabolism, and decreased lipid accumulation and oxidative stress. Corn peptides effectively downregulated the mRNA levels of Pro-IL-1ß, Pro-IL-18, NOD-like receptor protein 3 (NLRP3), ASC, Pro-caspase-1, Caspase-1, and GSDMD in the liver. This hepatoprotective effect of corn peptides by inhibiting NLRP3 inflammasome activation was further validated in H2O2-induced HepG2 cells. Moreover, corn peptides restored the composition of the gut microbiota and promoted short-chain fatty acid production. This study provides evidence that corn-derived sEH inhibitory peptides have hepatoprotective activity against nonalcoholic fatty liver fibrosis by suppressing NLRP3 inflammasome activation and modulating gut microbiota.
Asunto(s)
Microbioma Gastrointestinal , Inflamasomas , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Enfermedad del Hígado Graso no Alcohólico , Péptidos , Zea mays , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/inmunología , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Inflamasomas/metabolismo , Inflamasomas/genética , Masculino , Humanos , Zea mays/química , Péptidos/farmacología , Péptidos/administración & dosificación , Hígado/metabolismo , Hígado/efectos de los fármacos , Bacterias/clasificación , Bacterias/genética , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Células Hep G2 , Epóxido Hidrolasas/genética , Epóxido Hidrolasas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Yajieshaba (YJSB), approved by the Yunnan Provincial Food and Drug Administration in 2008, are known for their anti-inflammatory, antiviral, and pro-apoptotic properties, effectively treating Hepatic fibrosis (HF). However, its mechanism of action remains unclear. AIM OF THE STUDY: The objective of this investigation is to explore how YJSB influences the TGF-ß1/Smad signaling pathway as a strategy for reducing HF. METHODS: The establishment of a HF model in mice involved ligation of the common bile duct, followed by administration of YJSB. Body and liver weights were measured, and the liver index calculated. Serum levels of ALT, AST, ALP, TBA, and TBIL were assessed using colorimetric methods. Additionally, liver homogenates were analyzed for PIIINP, Col-IV, LN, HA, and Hyp, as well as TGF-ß1 activity, using ELISA. Histological analyses of liver sections, stained with H&E, Ag, and Masson's trichrome, were performed to examine inflammation and the accumulation of collagen and reticular fibers. These studies aimed to elucidate the pharmacodynamic effects of YJSB on HF in mice with bile duct obstruction. The target pathways of YJSB were preliminarily identified through immunofluorescence detection of TGF-ß1, P-Smad2L, P-Smad2C, P-Smad3L, P-Smad3C, and Smad4 proteins. In vitro experiments included the induction of hepatic stellate cell (HSC-T6) activation by H2O2. A cell injury model was established for HSC-T6, and the CCK-8 assay was used to determine the optimal YJSB concentration and treatment duration. After pirfenidone (PFD) administration, which inhibits the TGF-ß1/Smad pathway, the effects of YJSB on HSC-T6 cell proliferation were observed. ELISA assays quantified Col-III, α-SMA, and Col-I in cell lysates to assess YJSB's impact on collagen synthesis in HSC-T6 cells. Western blot analysis was performed to assess the protein levels within the TGF-ß1/Smad signaling cascade. RESULTS: In the HF mouse model, administration of YJSB notably augmented the body weight and reduced the liver index. Concurrently, there was an elevation in serum concentrations of ALP, AST, ALT, TBA, and TBIL. Similarly, in the liver homogenates of HF mice, increases were observed in the levels of HA, PIIINP, Col-IV, LN, Hyp, and TGF-ß1. Histological assessments using H&E, Ag, and Masson stains indicated a substantial diminution in liver tissue damage. Through immunofluorescence analysis, it was discerned that YJSB modulated the expression of TGF-ß1, P-Smad2L, P-Smad2C, and P-Smad3L downwards, while elevating P-Smad3C and Smad4 protein expressions. Additional investigations revealed a significant reduction in α-SMA, Col-I, and Col-III levels in cell culture fluids, suggesting a decrease in collagen synthesis and a protective role against cellular damage. Western blot analyses demonstrated that the TGF-ß1/Smad pathway inhibitor, PFD, acted in synergy with YJSB, enhancing its regulatory effects on this pathway, decreasing levels of TGF-ß1, P-Smad2L, P-Smad2C, P-Smad3L, and promoting the expression of P-Smad3C. CONCLUSIONS: YJSB demonstrates a pharmacodynamic effect against HF, enhancing liver functionality and effectively mitigating the damage associated with bile duct obstruction. The proposed action mechanism of YJSB involves modulation of the TGF-ß1/Smad signaling pathway. Research indicates that YJSB might play a role in suppressing the movement, programmed cell death, and activation of HSC-T6, potentially decelerating the advancement of hepatic fibrosis.
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Colestasis , Células Estrelladas Hepáticas , Peróxido de Hidrógeno , Cirrosis Hepática , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Animales , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Factor de Crecimiento Transformador beta1/metabolismo , Ratones , Masculino , Peróxido de Hidrógeno/metabolismo , Colestasis/metabolismo , Colestasis/patología , Colestasis/tratamiento farmacológico , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Transducción de Señal/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Línea Celular , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Proteínas Smad/metabolismo , Ratones Endogámicos C57BL , Proteína Smad2/metabolismoRESUMEN
Liver fibrosis, characterized by excessive extracellular matrix deposition, is driven by activated hepatic stellate cells (HSCs). Due to the limited availability of anti-fibrotic drugs, the research on therapeutic agents continues. Here we have investigated Moringa oleifera Lam. (MO), known for its various bioactive properties, for anti-fibrotic effects. This study has focused on 1-phenyl-2-pentanol (1-PHE), a compound derived from MO leaves, and its effects on LX-2 human hepatic stellate cell activation. TGF-ß1-stimulated LX-2 cells were treated with MO extract or 1-PHE, and the changes in liver fibrosis markers were assessed at both gene and protein levels. Proteomic analysis and molecular docking were employed to identify potential protein targets and signaling pathways affected by 1-PHE. Treatment with 1-PHE downregulated fibrosis markers, including collagen type I alpha 1 chain (COL1A1), collagen type IV alpha 1 chain (COL4A1), mothers against decapentaplegic homologs 2 and 3 (SMAD2/3), and matrix metalloproteinase-2 (MMP2), and reduced the secretion of matrix metalloproteinase-9 (MMP-9). Proteomic analysis data showed that 1-PHE modulates the Wnt/ß-catenin pathway, providing a possible mechanism for its effects. Our results suggest that 1-PHE inhibits the TGF-ß1 and Wnt/ß-catenin signaling pathways and HSC activation, indicating its potential as an anti-liver-fibrosis agent.
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Células Estrelladas Hepáticas , Cirrosis Hepática , Moringa oleifera , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Humanos , Moringa oleifera/química , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Línea Celular , Proteómica/métodos , Simulación del Acoplamiento Molecular , Extractos Vegetales/farmacología , Extractos Vegetales/química , Antifibróticos/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Hepatic fibrosis is a reversible pathological phenomenon caused by the abnormal proliferation of connective tissues in the liver for self-repair after persistent liver injury. Among these tissues, the activation status of hepatic stellate cells (HSCs) is crucial. Glycyrrhizic acid (GA) agents have been proven to have excellent anti-fibrosis effects, but their targets are unclear. PURPOSE: To investigate the anti-hepatic fibrosis effect of GA and its target in activated HSCs. METHODS: A mouse model of hepatic fibrosis was prepared with 20 % carbon tetrachloride (CCl4) and GA was administered continuously for 4 weeks. Subsequently, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), type â ¢ procollagen peptide (P III P), laminin (LN), hyaluronic acid (HA), and type â £ collagen (Col â £) were measured. Liver tissues were subjected to hematoxylin and eosin (HE), Masson, and Sirius red staining and proteome sequencing analysis. Based on LX-2 cells, activity-based protein profiling (ABPP) was used to investigate the potential targets of GA, which was further validated by the cellular thermal shift assay (CETSA), immunofluorescence co-localization, molecular docking, small interfering RNA (siRNA) and western blot (WB) assays. RESULTS: In vivo, GA significantly reduced serum ALT, AST, HA, P III P, Col IV, and LN levels. HE, Masson, and Sirius red staining showed that GA significantly ameliorated hepatic inflammatory response and collagen deposition in CCl4-treated mice. Proteome sequencing results showed that GA mainly regulated glutathione S-transferase family members involved in glutathione metabolism. In vitro, GA significantly inhibited LX-2 cell proliferation and reduced reactive oxygen species accumulation. ABPP suggested that aldo-keto reductase family 7 member A2 (AKR7A2) was the major binding protein of GA in LX-2 cells. CETSA, fluorescence co-localization, molecular docking, and surface plasmon resonance further validated GA binding to AKR7A2. The WB results showed that GA up-regulated AKR7A2 expression both in vitro and in vivo and was corroborated by siRNA experiments. CONCLUSION: GA targeted AKR7A2 in LX-2 cells to defend against sustained oxidative stress injury, thereby inhibiting the proliferation of activated HSCs and reversing hepatic fibrosis.
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Tetracloruro de Carbono , Ácido Glicirrínico , Células Estrelladas Hepáticas , Cirrosis Hepática , Estrés Oxidativo , Animales , Ácido Glicirrínico/farmacología , Estrés Oxidativo/efectos de los fármacos , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Ratones , Masculino , Cirrosis Hepática/tratamiento farmacológico , Humanos , Ratones Endogámicos C57BL , Hígado/efectos de los fármacos , Línea Celular , Alanina Transaminasa/sangre , Simulación del Acoplamiento Molecular , Modelos Animales de Enfermedad , Aspartato Aminotransferasas/sangreRESUMEN
BACKGROUND: Hepatic fibrosis is a pathophysiological process of extracellular matrix abnormal deposition induced by multiple pathogenic factors. Currently, there is still a lack of effective and non-toxic drugs for treating fibrosis in clinic. Flavonoids are polyphenolic compounds synthesized in plants and modern pharmacological studies confirmed flavonoids exhibit potent hepatoprotective effect. PURPOSE: Summarize literature to elaborate the mechanism of HF and evaluate the potential of flavonoids in HF, aiming to provide a new perspective for future research. METHODS: The literatures about hepatic fibrosis and flavonoids are collected via a series of scientific search engines including Google Scholar, Elsevier, PubMed, CNKI, WanFang, SciFinder and Web of Science database. The key words are "flavonoids", "hepatic fibrosis", "pharmacokinetic", "toxicity", "pathogenesis" "traditional Chinese medicine" and "mechanism" as well as combination application. RESULTS: Phytochemical and pharmacological studies revealed that about 86 natural flavonoids extracted from Chinese herbal medicines possess significantly anti-fibrosis effect and the mechanisms maybe through anti-inflammatory, antioxidant, inhibiting hepatic stellate cells activation and clearing activated hepatic stellate cells. CONCLUSIONS: This review summarizes the flavonoids which are effective in HF and the mechanisms in vivo and in vitro. However, fewer studies are focused on the pharmacokinetics of flavonoids in HF model and most studies are limited to preclinical studies, therefore there is no reliable data from clinical trials for the development of new drugs. Further in-depth research related it can be conducted to improve the bioavailability of flavonoids and serve the development of new drugs.
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Flavonoides , Células Estrelladas Hepáticas , Cirrosis Hepática , Flavonoides/farmacología , Flavonoides/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Humanos , Animales , Células Estrelladas Hepáticas/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Medicina Tradicional China/métodosRESUMEN
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-ß1/CUGBP1 pathway can inhibit IFN-γ/Smad7 pathway transduction and promote HSCs activation. Thus, inhibiting the TGF-ß1/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. PURPOSE: 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-ß1 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-ß1, 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-ß1/CUGBP1 and IFN-γ/Smad7 pathways. CONCLUSION: We demonstrated that JTCD inhibited HSCs activation and reversed HF by inhibiting the TGF-ß1/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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Tetracloruro de Carbono , Medicamentos Herbarios Chinos , Células Estrelladas Hepáticas , Interferón gamma , Cirrosis Hepática , Transducción de Señal , Proteína smad7 , Factor de Crecimiento Transformador beta1 , Animales , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Medicamentos Herbarios Chinos/farmacología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/inducido químicamente , Factor de Crecimiento Transformador beta1/metabolismo , Masculino , Proteína smad7/metabolismo , Interferón gamma/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , HumanosRESUMEN
PURPOSE: We performed animal and organoid study to evaluate the anti-fibrotic effect of steroid on biliary atresia (BA) and the underlying patho-mechanism. METHODS: BA animal models were created by inoculation of mice on post-natal day 1 with rhesus rotavirus (RRV). They received either 20 µl phosphate-buffered saline (PBS) or steroid from day 21 to day 34. On day 34, their serum samples were collected for hormonal markers. Necrosis, fibrosis and CK 19 expression in the liver were evaluated. Liver organoids were developed and their morphology as well as bulk RNA sequencing data were analyzed. RESULTS: Twenty-four mice developed BA features after RRV injection and were equally divided into steroid and PBS groups. On day 34, the weight gain of steroid group increased significantly than PBS group (p < 0.0001). All mice in the PBS group developed liver fibrosis but only one mouse in the steroid group did. Serum bilirubin and liver parenchymal enzymes were significantly lower in steroid group. The morphology of liver organoids were different between the two groups. A total of 6359 differentially expressed genes were found between steroid group and PBS group. CONCLUSION: Based on our findings obtained from RRV-induced BA animal and organoid models, steroid has the potential to mitigate liver fibrosis in BA.
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Atresia Biliar , Modelos Animales de Enfermedad , Cirrosis Hepática , Organoides , Animales , Ratones , Organoides/efectos de los fármacos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Hígado/patología , Hígado/efectos de los fármacosRESUMEN
Hepatocellular carcinoma (HCC) is the most common liver cancer and is among the leading causes of cancer-related death worldwide. There is no reliable biomarker for the early diagnosis of HCC. Circulating microRNAs (miRNAs) have attracted attention as potential biomarkers of disease. By small-RNA next-generation sequencing, the analysis of serum miRNAs led to the identification of molecular signatures able to discriminate advanced HCC from early HCC (n = 246); advanced HCC from CIRRHOSIS (n = 299); advanced HCC from HEALTHY (n = 320); HEALTHY from early HCC (n = 343); and HEALTHY from CIRRHOSIS (n = 414). Cirrhotic patients and early HCC patients exhibited similar serum miRNA profiles, yet a small number of miRNAs (n = 57) were able to distinguish these two classes of patients. A second objective of the study was to identify serum miRNAs capable of predicting the response to therapy in patients with advanced HCC. All patients were treated with sorafenib as first-line therapy: 24 were nonresponsive and 24 responsive. Analysis of circulating miRNAs revealed a 54 miRNAs signature able to separate the two subgroups. This study suggested that circulating miRNAs could be useful biomarkers for monitoring patients with liver diseases ranging from cirrhosis to advanced HCC and possibly predicting susceptibility to first-line treatment based on sorafenib.
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Biomarcadores de Tumor , Carcinoma Hepatocelular , MicroARN Circulante , Progresión de la Enfermedad , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/diagnóstico , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , MicroARN Circulante/sangre , MicroARN Circulante/genética , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/genética , Cirrosis Hepática/tratamiento farmacológico , Sorafenib/uso terapéutico , MicroARNs/sangre , MicroARNs/genética , AdultoRESUMEN
Hepatic fibrosis is intricately associated with dysregulation of gut microbiota and host metabolomes. Our previous studies have demonstrated that matrine can effectively reduce hepatosteatosis and associated disorders. However, it is poorly understood whether the gut microbiota involved in the attenuation of liver fibrosis by matrine. Herein we explored a novel mechanism of how oral administration of matrine alleviates liver fibrosis by modulating gut microbiota. Administration of matrine not only potently ameliorated liver fibrosis in carbon tetrachloride (CCl4)-induced mice, but also significantly preserved hepatic heat shock protein 72 (HSP72) in vivo and in vitro. Matrine was failed to reduce liver fibrosis when HSP72 upregulation was blocked by the HSP72 antagonist VER-155008. Also, consumption of matrine significantly alleviated gut dysbiosis and fecal metabonomic changes in CCl4-treated mice. Transplanted the faces of matrine-treated mice induced a remarkable upregulation of HSP72 and remission of fibrosis in liver in CCl4-exposed mice and inhibition of TGF-ß1-induced inflammatory response and epithelial-mesenchymal transition (EMT) in AML-12 cells. Furthermore, deficiency of HSP72 partly reversed the intestinal microbial composition that prevented matrine from reducing CCl4-induced liver fibrosis in mice. This study reveals the "gut microbiota-hepatic HSP72" axis as a key mechanism of matrine in reducing liver fibrosis and suggest that this axis may be targeted for developing other new therapies for liver fibrosis.
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Alcaloides , Tetracloruro de Carbono , Microbioma Gastrointestinal , Proteínas del Choque Térmico HSP72 , Cirrosis Hepática , Matrinas , Quinolizinas , Animales , Masculino , Ratones , Administración Oral , Alcaloides/farmacología , Línea Celular , Disbiosis , Transición Epitelial-Mesenquimal/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Proteínas del Choque Térmico HSP72/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/inducido químicamente , Ratones Endogámicos C57BL , Quinolizinas/farmacología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND: Cirrhosis leads to portal hypertension (PHT), affecting survival with limited treatment options. This study investigated Imperatorin (IMP), a furanocoumarin with anti-inflammatory and hypotensive properties, for its therapeutic role and mechanisms in cirrhotic PHT. METHODS: Hepatic stellate cells (HSCs) inhibition by IMP was evaluated using LX-2 cell line. Rat cirrhosis was induced via CCl4 for 16 weeks. Experimental group were orally administered IMP (15/25 mg/kg/day) for 4 weeks. We subsequently examined portal pressure (PP), cirrhosis, inflammation, angiogenesis, and vascular remodeling. Network pharmacology was employed for mechanistic insights. RESULTS: IMP significantly inhibited the fibrogenesis in HSCs and suppressed cell viability. CCl4 exposure induced cirrhosis, inflammation, angiogenesis, vascular remodeling and PHT. IMP significantly reduced PP from 22.85 ± 3.88 mmHg to 6.67 ± 0.6 mmHg, diminished collagen deposition and pro-fibrotic factor expression, alleviated inflammation, and improved liver function. Vessel wall thickness in superior mesenteric arteries was restored, and intra-/extrahepatic angiogenesis was inhibited via VEGF and vWF. Furthermore, IMP induced sinusoidal vasodilation by upregulating eNOS and GCH1. Enrichment analysis indicated that IMP was involved in various biological processes associated with cirrhosis, such as the regulation of blood pressure, tissue remodeling, response to inflammation, and regulation of angiogenesis, etc. Additionally, IMP suppressed hepatic expression of TGF-ß both in vitro and in vivo, which was further supported by KEGG analysis. CONCLUSION: Our research demonstrated that IMP significantly mitigated cirrhosis PHT by reducing hepatic fibrosis and inflammation, curbing angiogenesis and vascular remodeling, and promoting vasodilation. This protective mechanism appears to be facilitated through the downregulation of TGF-ß.
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Tetracloruro de Carbono , Furocumarinas , Células Estrelladas Hepáticas , Hipertensión Portal , Cirrosis Hepática , Remodelación Vascular , Furocumarinas/farmacología , Furocumarinas/uso terapéutico , Animales , Hipertensión Portal/tratamiento farmacológico , Hipertensión Portal/fisiopatología , Remodelación Vascular/efectos de los fármacos , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Masculino , Ratas , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/inducido químicamente , Humanos , Ratas Sprague-Dawley , Línea Celular , Transducción de Señal/efectos de los fármacos , Farmacología en Red , Neovascularización Patológica/tratamiento farmacológico , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Hígado/irrigación sanguíneaRESUMEN
Infection with Schistosoma japonicum (S. japonicum) is an important zoonotic parasitic disease that causes liver fibrosis in both human and domestic animals. The activation of hepatic stellate cells (HSCs) is a crucial phase in the development of liver fibrosis, and inhibiting their activation can alleviate this progression. Total flavonoids of litchi seed (TFL) is a naturally extracted drug, and modern pharmacological studies have shown its anti-fibrotic and liver-protective effects. However, the role of TFL in schistosomiasis liver fibrosis is still unclear. This study investigated the therapeutic effects of TFL on liver fibrosis in S. japonicum infected mice and explored its potential mechanisms. Animal study results showed that TFL significantly reduced the levels of Interleukin-1ß (IL-1ß), Tumor Necrosis Factor-α (TNF-α), Interleukin-4 (IL-4), and Interleukin-6 (IL-6) in the serum of S. japonicum infected mice. TFL reduced the spleen index of mice and markedly improved the pathological changes in liver tissues induced by S. japonicum infection, decreasing the expression of alpha-smooth muscle actin (α-SMA), Collagen I and Collagen III protein in liver tissues. In vitro studies indicated that TFL also inhibited the activation of HCSs induced by Transforming Growth Factor-ß1 (TGF-ß1) and reduced the levels of α-SMA. Gut microbes metagenomics study revealed that the composition, abundance, and functions of the mice gut microbiomes changed significantly after S. japonicum infection, and TLF treatment reversed these changes. Therefore, our study indicated that TFL alleviated granulomatous lesions and improved S. japonicum induced liver fibrosis in mice by inhibiting the activation of HSCs and by improving the gut microbiomes.