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Background/Aims: Extracellular vesicles (EVs) are promising as a biomarker of metabolic dysfunction associated steatotic liver disease (MASLD). The objective is to study EVs and their involvement in MASLD concerning the disease's pathogenesis and progression characteristics. Methods: Male adult Sprague Dawley rats were randomly assigned into two experimental models of MASLD: MASLD-16 and MASLD-28, animals received a choline-deficient high-fat diet (CHFD) and Control-16 and Control-28, animals received a standard diet (SD) for 16 and 28 weeks, respectively. Biological samples from these animal models were used, as well as previously registered variables. EVs from hepatic tissue were characterized using confocal microscopy. EVs were isolated through differential ultracentrifugation from serum and characterized using NanoSight. The data from the EVs were correlated with biochemical, molecular, and histopathological parameters. Results: Liver EVs were identified through the flotillin-1 protein. EVs were isolated from the serum of all groups. There was a decrease of EVs concentration in MASLD-28 in comparison with Control-28 (P < 0.001) and a significant increase in EVs concentration in Control-28 compared with Control-16 (P < 0.001). There was a strong correlation between serum EVs concentration with hepatic gene expression of interleukin (Il)6 (r2 = 0.685, P < 0.05), Il1b (r2 = 0.697, P < 0.05) and tumor necrosis factor-alpha (Tnfa; r2 = 0.636, P < 0.05) in MASLD-16. Moreover, there was a strong correlation between serum EVs size and Il10 in MASLD-28 (r2 = 0.762, P < 0.05). Conclusion: The concentration and size of EVs correlated with inflammatory markers, suggesting their involvement in the systemic circulation, cellular communication, and development and progression of MASLD, demonstrating that EVs have the potential to serve as noninvasive biomarkers for MASLD diagnosis and prognosis.
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Dieta Alta en Grasa , Modelos Animales de Enfermedad , Vesículas Extracelulares , Ratas Sprague-Dawley , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patología , Animales , Masculino , Ratas , Hígado/metabolismo , Hígado/patología , Biomarcadores/sangre , Biomarcadores/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/etiología , Hígado Graso/patología , Hígado Graso/metabolismo , Hígado Graso/etiología , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/sangre , Inflamación/patología , Inflamación/metabolismo , Deficiencia de Colina/complicacionesRESUMEN
BACKGROUND: Prevalence of hepatocellular carcinoma (HCC) is increasing, especially in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). AIM: To investigate rifaximin (RIF) effects on epigenetic/autophagy markers in animals. METHODS: Adult Sprague-Dawley rats were randomly assigned (n = 8, each) and treated from 5-16 wk: Control [standard diet, water plus gavage with vehicle (Veh)], HCC [high-fat choline deficient diet (HFCD), diethylnitrosamine (DEN) in drinking water and Veh gavage], and RIF [HFCD, DEN and RIF (50 mg/kg/d) gavage]. Gene expression of epigenetic/autophagy markers and circulating miRNAs were obtained. RESULTS: All HCC and RIF animals developed metabolic-dysfunction associated steatohepatitis fibrosis, and cirrhosis, but three RIF-group did not develop HCC. Comparing animals who developed HCC with those who did not, miR-122, miR-34a, tubulin alpha-1c (Tuba-1c), metalloproteinases-2 (Mmp2), and metalloproteinases-9 (Mmp9) were significantly higher in the HCC-group. The opposite occurred with Becn1, coactivator associated arginine methyltransferase-1 (Carm1), enhancer of zeste homolog-2 (Ezh2), autophagy-related factor LC3A/B (Map1 Lc3b), and p62/sequestosome-1 (p62/SQSTM1)-protein. Comparing with controls, Map1 Lc3b, Becn1 and Ezh2 were lower in HCC and RIF-groups (P < 0.05). Carm1 was lower in HCC compared to RIF (P < 0.05). Hepatic expression of Mmp9 was higher in HCC in relation to the control; the opposite was observed for p62/Sqstm1 (P < 0.05). Expression of p62/SQSTM1 protein was lower in the RIF-group compared to the control (P = 0.024). There was no difference among groups for Tuba-1c, Aldolase-B, alpha-fetoprotein, and Mmp2 (P > 0.05). miR-122 was higher in HCC, and miR-34a in RIF compared to controls (P < 0.05). miR-26b was lower in HCC compared to RIF, and the inverse was observed for miR-224 (P < 0.05). There was no difference among groups regarding miR-33a, miR-143, miR-155, miR-375 and miR-21 (P > 0.05). CONCLUSION: RIF might have a possible beneficial effect on preventing/delaying liver carcinogenesis through epigenetic modulation in a rat model of MASLD-HCC.
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Intestinal fungi play an important role in the health-disease process. We observed that in liver diseases, fungal infections lead to high mortality. In this review, we were able to gather and evaluate the available scientific evidence on intestinal mycobiota and liver diseases. We searched PubMed and Embase, using a combination of several entry terms. Only studies in adults ≥ 18 years old with liver disease and published after 2010 were included. We observed that individuals with liver disease have an altered intestinal mycobioma, which accompanies the progression of these diseases. In cirrhotic patients, there are a high number of Candida sp. strains, especially Candida albicans. In early chronic liver disease, there is an increase in alpha diversity at the expense of Candida sp. and conversely, in advanced liver disease, there is a negative correlation between alpha diversity and model for end-stage liver disease score. On the other hand, patients with non-alcoholic fatty liver disease demonstrate greater diversity compared to controls. Our study concluded that the evidence on the subject is sparse, with few studies and a lack of standardization of outcome measures and reporting, and it was not possible to perform a meta-analysis capable of synthesizing relevant parameters of the human mycobiotic profile. However, certain fungal genera such as Candida play an important role in the context of liver disease and that adults with liver disease have a distinct gut mycobiotic profile from healthy controls.
In people with end-stage liver disease, there is a high mortality from fungal infections. In this context, the genus Candida plays an important role in the context of liver disease, and adults with liver disease have a distinct gut mycobiota profile from healthy controls.
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Enfermedad Hepática en Estado Terminal , Microbioma Gastrointestinal , Hepatopatías , Micobioma , Humanos , Animales , Hongos , Enfermedad Hepática en Estado Terminal/veterinaria , Índice de Severidad de la Enfermedad , Candida albicans , Hepatopatías/veterinariaRESUMEN
OBJECTIVES: No specific therapy is available for metabolic dysfunction-associated fatty liver disease. We investigated nicotinamide riboside (NR) and dietary restriction (DR) effects in liver lipids, inflammation, histology, intestinal permeability, and gut microbiota in a cafeteria diet (CAFD)-induced obesity model. METHODS: Adult male Wistar rats were randomly assigned to standard diet (SD) or CAFD. After 6 wk, they were subdivided into six groups-SD + vehicle (Veh) (distilled water), SD + NR (400 mg/kg), DR + Veh, DR + NR, CAFD + Veh, and CAFD + NR-for 4 wk more until euthanasia. RESULTS: CAFD increased the hepatic content of lipids, triacylglycerols, and total cholesterol and promoted hepatomegaly, steatosis, steatohepatitis, and liver fibrosis. DR intervention successfully delayed the onset of CAFD-induced liver abnormalities except for steatosis and fibrosis. CAFD suppressed Sirt1 expression in the liver and DR increased Sirt3 expression. CAFD did not affect hepatic inflammatory genes but DR enhanced Il10 expression while decreasing Il1ß expression. CAFD reduced Firmicutes and increased Bacteroidetes and Cyanobacteria, with no changes in intestinal permeability. Gut microbiota patterns in animals exposed to DR were similar to those of animals in SD. NR, specifically in CAFD, reduced hepatic triacylglycerols and total cholesterol deposition and collagen fiber accumulation in the liver and limited the colonization of CAFD-induced Cyanobacteria. NR combined with DR decreased the liver's relative weight and Tnfα expression and suppressed Sirt1 and Sirt3 hepatic expression. CONCLUSIONS: This study suggests that NR can be a potential adjuvant to metabolic dysfunction-associated fatty liver disease therapy, encouraging further research in this field.