RESUMEN

In this study, we evaluated the hepatoprotective effects of astaxanthin, a natural carotenoid, against the cholestatic liver fibrosis induced by bile duct ligation (BDL). Toward this end, male rats were subjected to BDL and treated with astaxanthin for 35 days. Afterwards, their serum and liver biochemical factors were assessed. Also, histopathological and immunohistochemical analyses were performed to determine the fibrosis and the expression levels of alpha-smooth muscle actin (α-SMA) and transforming growth factor beta (TGF-ß1) in the liver tissue. Based on the results, BDL caused a significant increase in liver enzyme levels, blood lipids, and bilirubin, while decreasing the activity of superoxide dismutase(SOD), catalase (CAT), and glutathione (GSH) enzymes. Also, in the BDL rats, hepatocyte necrosis, infiltration of inflammatory lymphocytes, and hyperplasia of bile ducts were detected, along with a significant increase in α-SMA and TGF-ß1 expression. Astaxanthin, however, significantly prevented the BDL's detrimental effects. In all, 10 mg/kg of this drug maintained the bilirubin and cholesterol serum levels of BDL rats at normal levels. It also reduced the liver enzymes' activity and serum lipids, while increasing the SOD, CAT, and GSH activity in BDL rats. The expression of α-SMA and TGF-ß1 in the BDL rats treated with 10 mg/kg of astaxanthin was moderate (in 34%-66% of cells) and no considerable cholestatic fibrosis was observed in this group. However, administrating the 20 mg/kg of astaxanthin was not effective in this regard. These findings showed that astaxanthin could considerably protect the liver from cholestatic damage by improving the biochemical features and regulating the expression of related proteins.

Asunto(s)

Conductos Biliares , Colestasis , Cirrosis Hepática , Ratas Wistar , Xantófilas , Animales , Xantófilas/farmacología , Xantófilas/uso terapéutico , Masculino , Ratas , Colestasis/patología , Colestasis/metabolismo , Colestasis/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Ligadura , Conductos Biliares/cirugía , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo

RESUMEN

BACKGROUND: Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality, but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis. Peroxisome proliferator activated receptor (PPAR) α and δ play a key role in lipid metabolism and intestinal barrier homeostasis, which are major contributors to the pathological progression of ALD. Meanwhile, elafibranor (EFN), which is a dual PPARα and PPARδ agonist, has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease and primary biliary cholangitis. However, the benefits of EFN for ALD treatment is unknown. AIM: To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model. METHODS: ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol (EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly (1 mL/kg) for 8 weeks. EFN (3 and 10 mg/kg/day) was orally administered during the experimental period. Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis, fibrosis, and intestinal barrier integrity. The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays. RESULTS: The hepatic steatosis, apoptosis, and fibrosis in the ALD mice model were significantly attenuated by EFN treatment. EFN promoted lipolysis and ß-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells, primarily through PPARα activation. Moreover, EFN inhibited the Kupffer cell-mediated inflammatory response, with blunted hepatic exposure to lipopolysaccharide (LPS) and toll like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling. EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses. The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation. CONCLUSION: EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis, enhancing hepatocyte autophagic and antioxidant capacities, and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.

Asunto(s)

Chalconas , Modelos Animales de Enfermedad , Mucosa Intestinal , Cirrosis Hepática , Hepatopatías Alcohólicas , Ratones Endogámicos C57BL , PPAR alfa , Animales , Ratones , Humanos , Femenino , Hepatopatías Alcohólicas/patología , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/prevención & control , Hepatopatías Alcohólicas/etiología , Hepatopatías Alcohólicas/tratamiento farmacológico , PPAR alfa/metabolismo , PPAR alfa/agonistas , Chalconas/farmacología , Cirrosis Hepática/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Células CACO-2 , Hígado/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Etanol/toxicidad , Apoptosis/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , PPAR delta/agonistas , PPAR delta/metabolismo , Transducción de Señal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Propionatos

RESUMEN

BACKGROUND/AIM: This study aimed to investigate the role of transient receptor potential vanilloid 2 (TRPV2) in a mouse model with non-alcoholic steatohepatitis (NASH) and to examine the effects of tranilast on TRPV2 and fibrosis-related cytokines. MATERIALS AND METHODS: C57BL/6N mice were fed a Gubra-Amylin NASH (GAN) diet for 20 weeks to induce NASH. The tranilast groups received oral administration of tranilast at doses of 300, 400 and 500 mg/kg/day, five days per week for 20 weeks, in addition to the GAN diet. The effects of tranilast were assessed based on the dosage of food intake, changes in body weight, liver weight, blood biochemical parameters, histopathological examination, and expression of TRPV2 and inflammatory cytokines. RESULTS: Hepatic expression of TRPV2 was observed in the GAN-fed NASH mouse model. The tranilast groups showed significantly suppressed increases in body and liver weights. The development of intrahepatic fat deposition and liver fibrosis, assessed histopathologically, was inhibited. Tranilast administration improved the expression of TRPV2 and inflammatory cytokines in the liver. Additionally, blood tests indicated a reduction in elevated liver enzyme levels. CONCLUSION: In GAN diet NASH models, TRPV2 was up-regulated in the liver and tranilast inhibited TRPV2 and suppressed fibrosis. Therefore, it might prevent the incidence of hepatocellular carcinoma associated with NASH.

Asunto(s)

Modelos Animales de Enfermedad , Cirrosis Hepática , Enfermedad del Hígado Graso no Alcohólico , Canales Catiónicos TRPV , Aumento de Peso , ortoaminobenzoatos , Animales , Canales Catiónicos TRPV/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , ortoaminobenzoatos/farmacología , Ratones , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/prevención & control , Aumento de Peso/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Progresión de la Enfermedad , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Citocinas/metabolismo , Canales de Calcio

RESUMEN

BACKGROUND: The involvement of gut microbiota in carcinogenesis has gradually been highlighted in past decades. Bacteria could play its role by the secretion of extracellular vesicles (EVs); however, interrelationship between bacterial EVs and hepatocellular carcinoma (HCC) development has not been investigated much. METHODS: Diethylnitrosamine (DEN) was utilized to produce HCC model in mice, of which fecal was collected for detecting Bifidobacterium longum (B.longum) with real-time polymerase chain reaction (PCR). EV isolated from B.longum (B.longum-EV) with ultracentrifugation were stained with PKH26 to investigate the cellular uptake of murine hepatocytes (AML12). After treatment with B.longum-EV, TGF-ß1-induced AML12 cells were subjected to morphological observation, fibrosis- and apoptosis-related marker detection with western blot, apoptotic ratio and reactive oxygen species (ROS) level analysis with flow cytometry, and oxidative stress biomarker assessment with enzyme-linked immunosorbent assay (ELISA); meanwhile, animal studies including liver function, tumor formation rate, and histological analysis, were also performed to investigate the role of B.longum-EV in the fibrosis, apoptosis, oxidative stress, and carcinogenesis of the liver in vivo. RESULTS: The levels of B.longum were significantly reduced in HCC model mice. B.longum-EV could enter AML12 cells and effectively attenuate TGF-ß1-induced fibrosis, apoptosis, and oxidative stress in AML12 cells. In vivo studies showed that B.longum-EV administration alleviated DEN-induced liver fibrosis, apoptosis, and oxidative stress at the early stage. Moreover, B.longum-EV administration also effectively reduced the tumor formation rate and liver function injury in DEN-induced mice and down-regulated TGF-ß1 expression and Smad3 phosphorylation of mouse liver. CONCLUSIONS: B.longum-EVs protect hepatocytes against fibrosis, apoptosis, and oxidative damage, which exert a potential of preventing HCC development.

Asunto(s)

Apoptosis , Bifidobacterium longum , Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Vesículas Extracelulares/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/prevención & control , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/inducido químicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/patología , Ratones , Bifidobacterium longum/metabolismo , Apoptosis/efectos de los fármacos , Estrés Oxidativo , Masculino , Dietilnitrosamina/toxicidad , Proteínas Smad/metabolismo , Hepatocitos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/prevención & control , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología

RESUMEN

Objective To better understand drivers of disease progression in non-alcoholic steatohepatitis (NASH), we assessed clinical and sociodemographic markers of fibrosis progression in adults with NASH.Patients and methodsPhysician-reported patient demographics and clinical characteristics were utilised from the real-world Global Assessment of the Impact of NASH (GAIN) study. Factors associated with likelihood of fibrosis progression since NASH diagnosis were identified using a logistic regression model.ResultsOverall, 2349 patients in Europe from the GAIN study were included; mean age was 54.6 years and 41% were women. Significant covariates included age, years since diagnosis, employment status, fibrosis stage at diagnosis, type 2 diabetes mellitus, hypertension, liver transplant and liver biopsy at diagnosis. Risk of progression was 1.16 (95% confidence interval 1.12–1.20; p<0.001) times higher for each additional year since NASH diagnosis and 5.43 (2.68–11.37; p<0.001) times higher when physicians proposed a liver transplant at diagnosis. Compared with full-time employed patients, risk of progression was 1.77 (1.19–2.60; p=0.004) times higher for unemployed patients and 3.16 (1.30–7.63; p=0.010) times higher for those unable to work due to NASH.ConclusionsDisease duration, NASH severity and presence of other metabolic comorbidities could help to assess risk of progression in patients with NASH. (AU)

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Objetivo Para comprender mejor los factores que impulsan la progresión de la enfermedad en la esteatohepatitis no alcohólica (NASH), evaluamos los marcadores clínicos y sociodemográficos de la progresión de la fibrosis en adultos con NASH.Pacientes y métodosSe utilizaron las características demográficas y clínicas de los pacientes informadas por los médicos del estudio de Evaluación Global del Impacto de NASH (GAIN) del mundo real. Los factores asociados con la probabilidad de progresión de la fibrosis desde el diagnóstico de EHNA se identificaron mediante un modelo de regresión logística.ResultadosEn total, se incluyeron 2.349 pacientes en Europa del estudio GAIN; la edad media fue 54,6 años y el 41% eran mujeres. Las covariables significativas incluyeron edad, años desde el diagnóstico, situación laboral, estadio de fibrosis en el momento del diagnóstico, diabetes mellitus tipo 2, hipertensión, trasplante de hígado y biopsia de hígado en el momento del diagnóstico. El riesgo de progresión fue 1,16 (intervalo de confianza del 95% 1,12-1,20; p < 0,001) veces mayor por cada año adicional desde el diagnóstico de EHNA y 5,43 (2,68-11,37; p < 0,001) veces mayor cuando los médicos propusieron un trasplante de hígado. en el momento del diagnóstico. En comparación con los pacientes empleados a tiempo completo, el riesgo de progresión fue 1,77 (1,19-2,60; p = 0,004) veces mayor para los pacientes desempleados y 3,16 (1,30-7,63; p = 0,010) veces mayor para aquellos que no podían trabajar debido a a NASH.ConclusionesLa duración de la enfermedad, la gravedad de NASH y la presencia de otras comorbilidades metabólicas podrían ayudar a evaluar el riesgo de progresión en pacientes con NASH. (AU)

Asunto(s)

Humanos , Masculino , Femenino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Hepatopatías/prevención & control , Cirrosis Hepática/prevención & control , Cirrosis Hepática/terapia , Biopsia , Factores de Riesgo

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent progressive liver disease. Currently, there is only one drug for NAFLD treatment, and the options are limited. Phosphodiesterase-4 (PDE-4) inhibitors have potential in treating NAFLD. Therefore, this study aims to investigate the effect of roflumilast on NAFLD. Here, we fed ob/ob mice to induce the NAFLD model by GAN diet. Roflumilast (1 mg/kg) was administered orally once daily. Semaglutide (20 nmol/kg), used as a positive control, was injected subcutaneously once daily. Our findings showed that roflumilast has beneficial effects on NAFLD. Roflumilast prevented body weight gain and improved lipid metabolism in ob/ob-GAN NAFLD mice. In addition, roflumilast decreased hepatic steatosis by down-regulating the expression of hepatic fatty acid synthesis genes (SREBP1c, FASN, and CD36) and improving oxidative stress. Roflumilast not only reduced liver injury by decreasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, but also ameliorated hepatic inflammation by reducing the gene expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6). Roflumilast lessened liver fibrosis by inhibiting the expression of fibrosis mRNA (TGFß1, α-SMA, COL1a1, and TIMP-1). Collectively, roflumilast could ameliorate NAFLD, especially in reducing hepatic steatosis and fibrosis. Our findings suggested a PDE-4 inhibitor roflumilast could be a potential drug for NAFLD.

Asunto(s)

Aminopiridinas , Benzamidas , Ciclopropanos , Cirrosis Hepática , Enfermedad del Hígado Graso no Alcohólico , Inhibidores de Fosfodiesterasa 4 , Animales , Ciclopropanos/farmacología , Ciclopropanos/uso terapéutico , Aminopiridinas/farmacología , Aminopiridinas/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/etiología , Benzamidas/farmacología , Benzamidas/uso terapéutico , Masculino , Ratones , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/prevención & control , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Ratones Endogámicos C57BL , Metabolismo de los Lípidos/efectos de los fármacos , Ratones Obesos , Estrés Oxidativo/efectos de los fármacos , Dieta

RESUMEN

Liver fibrosis is a key pathological stage in the progression of chronic liver disease. If the disease is mistreated, it can further deteriorate into liver failure, which seriously affects the quality of life of patients and brings heavy medical costs. Hepatic stellate cell(HSC) activation triggers extracellular matrix(ECM) deposition, which plays an important driving role in liver fibrosis, and ferroptosis is an effective strategy to clear or reverse the activation of HSCs into a deactivated phenotype. Therefore, inhibiting the activation and proliferation of HSCs by regulating ferroptosis is the key to the treatment of this disease, so as to derive the prospect of inducing ferroptosis of HSCs(including RNA-binding proteins, non-coding RNA, chemicals, and active components of traditional Chinese medicine) to intervene in liver fibrosis. On this basis, this paper started from the activation of HSCs to induce ECM deposition and focused on summarizing the mechanism of inducing HSC ferroptosis in delaying the progression of liver fibrosis, so as to continuously enrich the clinical practice of liver fibrosis and provide a reference for subsequent basic research.

Asunto(s)

Ferroptosis , Células Estrelladas Hepáticas , Cirrosis Hepática , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Humanos , Ferroptosis/efectos de los fármacos , Cirrosis Hepática/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Animales , Matriz Extracelular/metabolismo

RESUMEN

Liver fibrosis is a common pathological process in the progression of several chronic liver diseases to cirrhosis and hepatocellular carcinoma. Therefore, the development of medications that can repress the progress of liver fibrosis is essential. We discovered that initially, 12ß-(m-methyl-benzoyl)-11,12-dihydro oleanolic acid (12d-OA), a farnesoid X receptor (FXR) modulator, possessed potential anti-fibrotic properties. Through an in-depth study, we revealed that 12d-OA not only inhibited the expression of fibrogenic markers in the LX-2 cells and HSC-T6 cells but also exhibited significant protective effects against liver injury and liver fibrosis in bile duct ligation (BDL) rats. Further exploration of its molecular mechanism indicated that 12d-OA exerted antifibrotic activity by inhibiting the extracellular signal-regulated kinase (ERK)/stress-activated protein kinase (p38) signaling pathways. Consequently, the great effects of 12d-OA in vitro and in vivo suggest that it may be a good candidate for liver fibrosis.

Asunto(s)

Cirrosis Hepática , Ácido Oleanólico , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/agonistas , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Masculino , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/prevención & control , Humanos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Línea Celular , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ratas , Antifibróticos/farmacología , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo

RESUMEN

Chronic liver injury due to various etiological factors results in excess secretion and accumulation of extracellular matrix proteins, leading to scarring of liver tissue and ultimately to hepatic fibrosis. If left untreated, fibrosis might progress to cirrhosis and even hepatocellular carcinoma. Thymoquinone (TQ), an active compound of Nigella sativa, has been reported to exhibit antioxidant, anti-inflammatory and anticancer activities. Therefore, the effect of TQ against thioacetamide (TAA)-induced liver fibrosis was assessed in rats. Fibrosis was induced with intraperitoneal administration of TAA (250 mg/kg b.w.) twice a week for 5 weeks. TQ (20 mg/kg b.w.) and silymarin (50 mg/kg b.w.) were orally administered daily for 5 weeks separately in TAA administered groups. Liver dysfunction was reported by elevated liver enzymes, increased oxidative stress, inflammation and fibrosis upon TAA administration. Our study demonstrated that TQ inhibited the elevation of liver marker enzymes in serum. TQ administration significantly increased antioxidant markers, such as superoxide dismutase, catalase, glutathione, glutathione peroxidase and glutathione reductase in the liver tissue of rats. Further, TQ significantly attenuated liver fibrosis, as illustrated by the downregulation of TAA-induced interleukin-ß, tumour necrosis factor-α, inducible nitric oxide synthase and fibrosis markers like transforming growth factor-ß (TGF-ß), α-smooth muscle actin, collagen-1, Smad3 and 7. Therefore, these findings suggest that TQ has a promising hepatoprotective property, as indicated by its potential to effectively suppress TAA-induced liver fibrosis in rats by inhibiting oxidative stress and inflammation via TGF-ß/Smad signaling.

Asunto(s)

Benzoquinonas , Neoplasias Hepáticas , Factor de Crecimiento Transformador beta1 , Ratas , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Tioacetamida/toxicidad , Antioxidantes/metabolismo , Hígado/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Factor de Crecimiento Transformador beta/metabolismo , Inflamación/metabolismo , Estrés Oxidativo , Neoplasias Hepáticas/metabolismo

RESUMEN

The effects of SGLT2 inhibitors on hepatic fibrosis in diabetes remain unclear. This study aimed to investigate the effects of empagliflozin on liver fibrosis in high-fat diet/streptozotocin-induced mice and the correlation with gut microbiota. After the application of empagliflozin for 6 weeks, we performed oral glucose tolerance and intraperitoneal insulin tolerance tests to assess glucose tolerance and insulin resistance, and stained liver sections to evaluate histochemical and hepatic pathological markers of liver fibrosis. Moreover, 16S rRNA amplicon sequencing was performed on stool samples to explore changes in the composition of intestinal bacteria. We finally analysed the correlation between gut microbiome and liver fibrosis scores or indicators of glucose metabolism. The results showed that empagliflozin intervention improved glucose metabolism and liver function with reduced liver fibrosis, which might be related to changes in intestinal microbiota. In addition, the abundance of intestinal probiotic Lactobacillus increased, while Ruminococcus and Adlercreutzia decreased after empagliflozin treatment, and correlation analysis showed that the changes in microbiota were positively correlated with liver fibrosis and glucose metabolism. Overall, considering the contribution of the gut microbiota in metabolism, empagliflozin might have improved the beneficial balance of intestinal bacteria composition. The present study provides evidence and indicates the involvement of the gut-liver axis by SGLT2 inhibitors in T2DM with liver fibrosis.

Asunto(s)

Compuestos de Bencidrilo , Microbioma Gastrointestinal , Glucósidos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Ratones , Animales , Estreptozocina/metabolismo , Estreptozocina/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Dieta Alta en Grasa/efectos adversos , ARN Ribosómico 16S/metabolismo , Hígado/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Glucosa/metabolismo , Ratones Endogámicos C57BL

RESUMEN

Metabolic dysfunction-associated steatohepatitis (MASH) is always accompanied with hepatic fibrosis that could potentially progress to liver cirrhosis and hepatocellular carcinoma. Employing a rat model, we evaluated the role of human placental extract (HPE) to arrest the progression of hepatic fibrosis to cirrhosis in patients with MASH. SHRSP5/Dmcr rats were fed with a high-fat and high-cholesterol diet for 4 weeks and evaluated for the development of steatosis. The animals were divided into control and treated groups and received either saline or HPE (3.6 ml/kg body weight) subcutaneously thrice a week. A set of animals were killed at the end of 6th, 8th, and 12th weeks from the beginning of the experiment. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), hepatic malondialdehyde (MDA), and glutathione content were measured. Immunohistochemical staining was performed for α-smooth muscle actin (α-SMA), 4-hydroxy-2-nonenal (4-HNE), collagen type I, and type III. Control rats depicted progression of liver fibrosis at 6 weeks, advanced fibrosis and bridging at 8 weeks, and cirrhosis at 12 weeks, which were significantly decreased in HPE-treated animals. Treatment with HPE maintained normal levels of MDA and glutathione in the liver. There was marked decrease in the staining intensity of α-SMA, 4-HNE, and collagen type I and type III in HPE treated rats compared with control animals. The results of the present study indicated that HPE treatment mediates immunotropic, anti-inflammatory, and antioxidant responses and attenuates hepatic fibrosis and early cirrhosis. HPE depicts therapeutic potential to arrest the progression of MASH towards cirrhosis.

Asunto(s)

Hígado Graso , Enfermedad del Hígado Graso no Alcohólico , Extractos Placentarios , Humanos , Embarazo , Ratas , Femenino , Animales , Extractos Placentarios/metabolismo , Extractos Placentarios/uso terapéutico , Colágeno Tipo I/metabolismo , Placenta/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Hígado Graso/tratamiento farmacológico , Hígado Graso/prevención & control , Hígado/metabolismo , Fibrosis , Glutatión/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Dieta Alta en Grasa

RESUMEN

Liver cirrhosis is the consequence of chronicisation and of the evolution of untreated liver diseases. The complexity of the disease and the complications it can cause have been and are still intensively researched, aiming to discover new therapies or improve existing ones for the effective management of liver cirrhosis. Currently, the treatment used is directed against the cause that caused the disease, if it is known; in advanced cases, liver transplantation is the only valid therapeutic option. Hepatoprotectors that are currently on the market are numerous, having as common properties the antioxidant, anti-inflammatory, stabilizing properties of the hepatocytic membrane; A few examples: the ethanolic extract of Curcuma longa, the extract from the plant called Sophora flavescens, the extract of Glycyrrhiza glabra, silymarin (extracted from Sylibum marianum), the extract of Ganoderma lucidum, etc. Liver cirrhosis is accompanied by generalized hypovitaminosis, so supplementing the diet with hydro- and liposoluble vitamins is mandatory. Protein-caloric malnutrition can be prevented by a hyperprotein diet, especially beneficial being the supplementation with branched-chain amino acids, which are also applicable in the prophylaxis and treatment of hepatic encephalopathy. Nanoparticles are a state-of-the-art therapeutic option, proving increased bioavailability, for example polydopamine nanoparticles loaded with l-arginine have been tested as therapy in liver cirrhosis. Among the innovative treatment directions in liver cirrhosis are hybrid products (e.g. hybrid polymer nanoparticles loaded with caffeic acid), cell cultures and artificial or bioartificial liver support.

Asunto(s)

Cirrosis Hepática , Silimarina , Humanos , Cirrosis Hepática/prevención & control , Antioxidantes/uso terapéutico , Silimarina/uso terapéutico

RESUMEN

PURPOSE OF REVIEW: The liver is an important digestive gland in the body. Lifestyle and dietary habits are increasingly damaging our liver, leading to various diseases and health problems. Non-alcoholic fatty liver disease (NAFLD) has become one of the most serious liver disease problems in the world. Diet is one of the important factors in maintaining liver health. Functional foods and their components have been identified as novel sources of potential preventive agents in the prevention and treatment of liver disease in daily life. However, the effects of functional components derived from small molecules in food on different types of liver diseases have not been systematically summarized. RECENT FINDINGS: The components and related mechanisms in functional foods play a significant role in the development and progression of NAFLD and liver fibrosis. A variety of structural components are found to treat and prevent NAFLD and liver fibrosis through different mechanisms, including flavonoids, alkaloids, polyphenols, polysaccharides, unsaturated fatty acids, and peptides. On the other hand, the relevant mechanisms include oxidative stress, inflammation, and immune regulation, and a large number of literature studies have confirmed a close relationship between the mechanisms. The purpose of this article is to examine the current literature related to functional foods and functional components used for the treatment and protection against NAFLD and hepatic fibrosis, focusing on chemical properties, health benefits, mechanisms of action, and application in vitro and in vivo. The roles of different components in the biological processes of NAFLD and liver fibrosis were also discussed.

Asunto(s)

Ingredientes Alimentarios , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Alimentos Funcionales , Cirrosis Hepática/prevención & control

RESUMEN

OBJECTIVES: Detailed simulation models are needed to assess strategies for prevention and treatment of hepatitis B virus (HBV) infection, the world's leading cause of liver disease. We sought to develop and validate a simulation model of chronic HBV that incorporates virological, serological and clinical outcomes. METHODS: We developed a novel Monte Carlo simulation model (the HEPA-B Model) detailing the natural history of chronic HBV. We parameterised the model with epidemiological data from the Western Pacific and sub-Saharan Africa. We simulated the evolution of HBV DNA, 'e' antigen (HBeAg) and surface antigen (HBsAg). We projected incidence of HBeAg loss, HBsAg loss, cirrhosis, hepatocellular carcinoma (HCC) and death over 10-year and lifetime horizons. We stratified outcomes by five HBV DNA categories at the time of HBeAg loss, ranging from HBV DNA<300 copies/mL to >106 copies/mL. We tested goodness of fit using intraclass coefficients (ICC). RESULTS: Model-projected incidence of HBeAg loss was 5.18% per year over lifetime (ICC, 0.969 (95% CI: 0.728 to 0.990)). For people in HBeAg-negative phases of infection, model-projected HBsAg loss ranged from 0.78% to 3.34% per year depending on HBV DNA level (ICC, 0.889 (95% CI: 0.542 to 0.959)). Model-projected incidence of cirrhosis was 0.29-2.09% per year (ICC, 0.965 (95% CI: 0.942 to 0.979)) and HCC incidence was 0.06-1.65% per year (ICC, 0.977 (95% CI: 0.962 to 0.986)). Over a lifetime simulation of HBV disease, mortality rates were higher for people with older age, higher HBV DNA level and liver-related complications, consistent with observational studies. CONCLUSIONS: We simulated HBV DNA-stratified clinical outcomes with the novel HEPA-B Model and validated them to observational data. This model can be used to examine strategies of HBV prevention and management.

Asunto(s)

Carcinoma Hepatocelular , Hepatitis B Crónica , Hepatitis B , Neoplasias Hepáticas , Humanos , Hepatitis B Crónica/complicaciones , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/prevención & control , Carcinoma Hepatocelular/etiología , Antígenos de Superficie de la Hepatitis B , Antígenos e de la Hepatitis B , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , ADN Viral , Virus de la Hepatitis B/genética , Hepatitis B/complicaciones , Cirrosis Hepática/epidemiología , Cirrosis Hepática/prevención & control , Cirrosis Hepática/complicaciones

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is increasing globally, and seeking therapeutic molecule targets is urgent. Several studies have demonstrated that IL-33 plays an important role in the progression of Non-alcoholic steatohepatitis (NASH) with fibrosis and the proliferation of hepatocellular carcinoma (HCC). However, whether the inhibition of IL-33 signaling prevents NAFLD from progressing to NASH and HCC has not been clarified. We investigated the effects of a novel antibody, IL-33RAb, and luseogliflozin, a SGLT2 inhibitor, when administered to a model mouse for NASH and HCC, and their effects were compared to investigate the mechanisms of how IL-33 is involved in the pathogenesis of NASH progression. Compared with the positive control of luseogliflozin, inhibition of IL-33 signaling ameliorated decreasing hepatic fibrosis via decreasingαSMA and MCP-1, and also partially suppressed the progression of the HCC cell line in in vitro experiments. These findings suggest that inhibition of IL-33 possibly prevents progression from NASH to HCC, and their effect may be a newly arrived therapeutic agent.

Asunto(s)

Carcinoma Hepatocelular , Diabetes Mellitus , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Sorbitol , Animales , Ratones , Carcinoma Hepatocelular/prevención & control , Diabetes Mellitus/tratamiento farmacológico , Modelos Animales de Enfermedad , Interleucina-33/metabolismo , Interleucina-33/uso terapéutico , Hígado/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/etiología , Cirrosis Hepática/prevención & control , Neoplasias Hepáticas/prevención & control , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Sorbitol/análogos & derivados

RESUMEN

The effect of long term exposure to low concentrations of environmental pollutants on hepatic disorders is a major public health concern worldwide. Polycyclic aromatic hydrocarbons (PAHs) are a class of persistent organic pollutants. In recent years, an increasing number of studies have focused on the deleterious effects of low concentrations of PAHs in the initiation or exacerbation of the progression of chronic liver disease. However, the underlying molecular mechanisms and effective intervention methods remain unclear. Here, we found that in hepatocytes, a low concentration of benzo(a)pyrene (B[a]P, an indicator of PAHs) chronic exposure continuously activated 14-3-3η via an epigenetic accumulation of DNA demethylation. As a "switch like" factor, 14-3-3η activated its downstream PI3K/Akt signal, which in turn promoted vascular endothelial growth factor (VEGF) production and secretion. As the characteristic fibrogenic paracrine factor regulated by B[a]P/14-3-3η, VEGF significantly induced the neovascularization and activation of hepatic stellate cells, leading to the development of hepatic fibrosis. Importantly, targeted 14-3-3η by using its specific inhibitor invented by our lab could prevent B[a]P-induced hepatic fibrosis, and could even reverse existent hepatic fibrosis caused by B[a]P. The present study not only revealed novel mechanisms, but also proposed an innovative approach for the targeted reversion/prevention of the harmful effects of exposure to PAHs on chronic liver disease.

Asunto(s)

Hepatopatías , Hidrocarburos Policíclicos Aromáticos , Humanos , Benzo(a)pireno/toxicidad , Benzo(a)pireno/metabolismo , Factor A de Crecimiento Endotelial Vascular , Fosfatidilinositol 3-Quinasas , Hidrocarburos Policíclicos Aromáticos/toxicidad , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/prevención & control

RESUMEN

In a preliminary study, live biotherapeutic products (LBPs) Lactobacillus plantarum LC27 and Bifidobacterium longum LC67 inhibited the secretion of alanine transaminase (ALT) and aspartate transaminase (AST) in LPS-stimulated HepG2 cells, while Escherichia coli K1 (Ec) increased ALT and ALT secretion. Therefore, we examined the effects of LC27 and LC67 on LPS-induced liver injury and fibrosis in mice and the correlation between their biomarkers in cell and animal experiments. Orally administered LC27 or LC67 significantly decreased blood ALT, AST, γ-glutamyl transferase (γGTP), TNF-α, triglyceride (TG), total cholesterol (TCh), total bile acid, and LPS levels, liver TNF-α, toll-like receptor-4 gene (Tlr4), α-smooth muscle actin (αSMA), and collagen-1 expression and αSMA+GFAP+ and NF-κB+F4/80+ cell populations, and colonic Tlr4, TNF-α, and IL-6 expression and NF-κB-positive cell population in LPS-treated mice. Furthermore, they increased AMPKa phosphorylation in the liver and colon. However, Ec increased the expression of TNF-α and IL-6 in blood, liver, and colon. The suppression of LPS-stimulated ALT and AST secretion in HepG2 cells by LBPs was positively correlated with their ameliorating effects on LPS-induced blood γGTP, ALT, and AST levels and liver αSMA and collagen-1 expression in mice. Based on these findings, LC27 and LC67 may improve liver injury and fibrosis by regulating NF-κB and AMPK signaling pathway and a protocol that can assay the inhibitory activity of LBPs on LPS-induced ALT and AST secretion in HepG2 may be useful for guessing their antihepatitic effects in the in vivo experiments.

Asunto(s)

Bifidobacterium longum , Lactobacillus plantarum , Ratones , Animales , FN-kappa B/metabolismo , Lactobacillus plantarum/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Lipopolisacáridos/farmacología , Interleucina-6/metabolismo , Bifidobacterium longum/fisiología , Receptor Toll-Like 4/metabolismo , Hígado , Transducción de Señal , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/prevención & control , Colágeno/metabolismo

RESUMEN

Desde fines de 2023, la denominación hígado graso no alcohólico cambió por esteatosis hepática asociada a disfunción metabólica (MASLD, por sus iniciales en inglés), ya que el nombre anterior era considerado estigmatizante para los pacientes. No está recomendado rastrear esta entidad en la población general. Sin embargo, si por algún motivo se solicitó una ecografía y esta informa esteatosis hepática, se recomienda evaluar el riesgo de progresión a fibrosis hepática mediante el puntaje FIB-4. Los pacientes con puntaje mayor a 1,3 requieren mayor evaluación y se les solicita una elastografía transicional (Fibroscan®). El tratamiento de esta entidad apunta, en general, al descenso de peso mediante la actividad física y la dieta hipocalórica. (AU)

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Since the end of 2023, the name non-alcoholic fatty liver has been changed to metabolic dysfunction-associated steatotic liver disease (MASLD), as the former denomination was considered stigmatizing for patients. It is not recommended to screen for this entity in the general population. However, if for some reason an ultrasound was performed and it reports hepatic steatosis, it is recommended to evaluate the risk of progression to liver fibrosis using the FIB-4 score. Patients with a score greater than 1.3 require further evaluation, and a transient elastography (FibroScan®) is requested. Treatment in general aims at weight loss through physical activity and a low-calorie diet. (AU)

Asunto(s)

Humanos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/terapia , Cirrosis Hepática/prevención & control , Atención Primaria de Salud , Piridazinas/uso terapéutico , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Biopsia , Ejercicio Físico , Pérdida de Peso , Tamizaje Masivo , Ultrasonografía , Restricción Calórica , Diagnóstico Diferencial , Diagnóstico por Imagen de Elasticidad , Consumo Excesivo de Bebidas Alcohólicas/prevención & control , Enfermedad del Hígado Graso no Alcohólico/clasificación , Cirrosis Hepática/diagnóstico

RESUMEN

AIM: Men are more susceptible to liver fibrosis (LF) than women. However, the underlying molecular mechanism, especially the role of estrogen/estrogen receptor (ER) activation in this sexual dimorphism is unclear. Therefore, the aim of the current study was to investigate the impact and the underlying molecular mechanisms of estrogen/ER activation on diethyl nitrosamine (DEN)-induced LF. MAIN METHODS: Thirty ovariectomized (OVX) female rats were randomly allocated into five groups (n = 6), and received no treatment, diethyl nitrosamine (DEN), DEN/fulvestrant, DEN/silymarin or DEN/estradiol benzoate (EB). In addition, three sham groups received no treatment, DEN or DEN/fulvestrant, and one control group that neither ovariectomized nor treated. Directly after treatment, liver injury biomarkers were measured. In addition, hepatic tissue hydroxyproline, TNF- α, TGF- ß, and IL-10 were evaluated. Expression of NF-kß, CD68 (a marker for macrophage infiltration), ER-ß and TLR-4 were measured. Finally, liver tissue histopathology was assessed. KEY FINDINGS: Ovariectomy aggravates DEN-induced LF, as it significantly elevated all liver tissue injury biomarkers. This effect has become even worse after blocking ER by fulvestrant, indicating a protective role of estrogen/ER activation against DEN-induced LF. Inhibition of TLR-4/NF-kß signaling pathway contributed to this protective effect, as estrogen deprivation or blocking of ER significantly activates this pathway during the onset of LF. While administration of EB or silymarin (selective ER-ß activator) improved LF indices and deactivated this pathway. SIGNIFICANCE: These results provide new insight into the pivotal role of estrogen/ER activation via modulation of TLR-4/NF-kß, in the alleviation of LF pathogenesis.

Asunto(s)

Nitrosaminas , Silimarina , Humanos , Masculino , Ratas , Femenino , Animales , Receptor Toll-Like 4 , Fulvestrant/farmacología , Estrógenos/farmacología , Estradiol/farmacología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/prevención & control , Receptor beta de Estrógeno/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/farmacología , Biomarcadores , Silimarina/farmacología , Nitrosaminas/farmacología , Ovariectomía , Receptor alfa de Estrógeno/metabolismo

RESUMEN

OBJECTIVE: Fine particulate matter (PM2.5) is a source of pollution worldwide, that causes inflammation and liver fibrosis. Melatonin, as the predominant hormone secreted by the pineal gland, can inhibit PM2.5-induced lung injury by activating nuclear factor erythroid 2-related factor 2 (Nrf2) to inhibit ferroptosis. However, the possible role of melatonin in PM2.5-induced liver damage remains unclear. EXPERIMENTAL APPROACH: In vitro, the effects of melatonin on PM2.5-induced oxidative stress and LX-2 cell activation were examined. In vivo, a PM2.5-induced inflammation and liver fibrosis mouse model was used to evaluate the hepatoprotective effect of melatonin. RESULTS: In vitro, melatonin induced the expression of Nrf2 and its downstream genes and inhibited PM2.5-induced reactive oxygen species (ROS) production and mitochondrial damage. Melatonin also ameliorated the PM2.5-induced oxidative stress and fibrogenic marker upregulation. However, the antifibrotic effect of melatonin was abolished in siNrf2-treated LX-2 cells. In vivo, we observed mitochondrial abnormalities and mitochondrial fragmentation, which were accompanied by increased PTEN-induced kinase 1 (PINK1) and Parkin expression, in PM2.5-treated mouse hepatocytes. These changes were partially reversed by melatonin. In addition, melatonin activated the Nrf2 signaling pathway and protected against PM2.5-induced oxidative stress. Furthermore, melatonin alleviated inflammation and liver fibrosis. Moreover, Nrf2-KO mice exhibited more severe inflammation and liver fibrosis after PM2.5 exposure than wild-type mice, and the protective effect of melatonin on PM2.5- treated Nrf2-KO mice was greatly compromised. CONCLUSION: These data suggest that melatonin effectively inhibits PM2.5-induced liver fibrosis by activating Nrf2 and inhibiting ROS-mediated mitophagy and inflammation.

Asunto(s)

Melatonina , Material Particulado , Animales , Ratones , Inflamación/tratamiento farmacológico , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Melatonina/metabolismo , Melatonina/farmacología , Mitofagia , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Material Particulado/toxicidad , Especies Reactivas de Oxígeno/metabolismo