Flavonoids and Related Compounds in Non-Alcoholic Fatty Liver Disease Therapy

P. 2991-3012Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, is one of the most common chronic liver diseases, which may progress to fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD is characterized by the accumulation of lipids in the liver arising from multiple factors: increased fatty acid uptake, increased de novo lipogenesis, reduced fatty acid oxidation and very low density lipoproteins (VLDL) secretion. Most therapeutic approaches for this disease are often directed at reducing body mass index and improving insulin resistance through lifestyle modifications, bariatric surgery and pharmacological treatments. Nevertheless, there is increasing evidence that the use of natural compounds, as polyphenols, exert multiple benefits on the disorders associated with NAFLD. These molecules seem to be able to regulate the expression of genes mainly involved in de novo lipogenesis and fatty acid oxidation, which contributes to their lipid-lowering effect in the liver. Their antioxidant, anti-inflammatory, antifibrogenic and antilipogenic properties seem to confer on them a great potential as strategy for preventing NAFLD progression. In this review, we summarized the effects of these compounds, especially flavonoids, and their mechanisms of action, that have been reported in several studies carried out in in vitro and in vivo models of NAFL

Intestinal microbiota transplantation to germ-free mice in a in vivo model of nafld associated with a quercetin treatment

15 p.To select mice donors for intestinal microbiota transplantation based on its metabolic phenotype in response to a high fat diet (HFD) and quercetin treatment (Q). Intestinal microbiota. Resumen de un trabajo resultado del proyecto de investigación financiado por la Consejería de Educación de la Junta de Castilla y León (referencia LE063U16)S

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

60 p.Gut microbiota is involved in obesity, metabolic syndrome and the progression of nonalcoholic fatty liver disease (NAFLD). It has been recently suggested that the flavonoid quercetin may have the ability to modulate the intestinal microbiota composition, suggesting a prebiotic capacity which highlights a great therapeutic potential in NAFLD. The present study aims to investigate benefits of experimental treatment with quercetin on gut microbial balance and related gut-liver axis activation in a nutritional animal model of NAFLD associated to obesity. C57BL/6J mice were challenged with high fat diet (HFD) supplemented or not with quercetin for 16 weeks. HFD induced obesity, metabolic syndrome and the development of hepatic steatosis as main hepatic histological finding. Increased accumulation of intrahepatic lipids was associated with altered gene expression related to lipid metabolism, as a result of deregulation of their major modulators. Quercetin supplementation decreased insulin resistance and NAFLD activity score, by reducing the intrahepatic lipid accumulation through its ability to modulate lipid metabolism gene expression, cytochrome P450 2E1 (CYP2E1)-dependent lipoperoxidation and related lipotoxicity. Microbiota composition was determined via 16S ribosomal RNA Illumina next-generation sequencing. Metagenomic studies revealed HFD-dependent differences at phylum, class and genus levels leading to dysbiosis, characterized by an increase in Firmicutes/Bacteroidetes ratio and in Gram-negative bacteria, and a dramatically increased detection of Helicobacter genus. Dysbiosis was accompanied by endotoxemia, intestinal barrier dysfunction and gut-liver axis alteration and subsequent inflammatory gene overexpression. Dysbiosis-mediated toll-like receptor 4 (TLR-4)-NF-B signaling pathway activation was associated with inflammasome initiation response and reticulum stress pathway induction. Quercetin reverted gut microbiota imbalance and related endotoxemia-mediated TLR-4 pathway induction, with subsequent inhibition of inflammasome response and reticulum stress pathway activation, leading to the blockage of lipid metabolism gene expression deregulation. Our results support the suitability of quercetin as a therapeutic approach for obesity-associated NAFLD via its anti-inflammatory, antioxidant and prebiotic integrative response.Gut microbiota is involved in obesity, metabolic syndrome and the progression of nonalcoholic fatty liver disease (NAFLD). It has been recently suggested that the flavonoid quercetin may have the ability to modulate the intestinal microbiota composition, suggesting a prebiotic capacity which highlights a great therapeutic potential in NAFLD. The present study aims to investigate benefits of experimental treatment with quercetin on gut microbial balance and related gut-liver axis activation in a nutritional animal model of NAFLD associated to obesity. C57BL/6J mice were challenged with high fat diet (HFD) supplemented or not with quercetin for 16 weeks. HFD induced obesity, metabolic syndrome and the development of hepatic steatosis as main hepatic histological finding. Increased accumulation of intrahepatic lipids was associated with altered gene expression related to lipid metabolism, as a result of deregulation of their major modulators. Quercetin supplementation decreased insulin resistance and NAFLD activity score, by reducing the intrahepatic lipid accumulation through its ability to modulate lipid metabolism gene expression, cytochrome P450 2E1 (CYP2E1)-dependent lipoperoxidation and related lipotoxicity. Microbiota composition was determined via 16S ribosomal RNA Illumina next-generation sequencing. Metagenomic studies revealed HFD-dependent differences at phylum, class and genus levels leading to dysbiosis, characterized by an increase in Firmicutes/Bacteroidetes ratio and in Gram-negative bacteria, and a dramatically increased detection of Helicobacter genus. Dysbiosis was accompanied by endotoxemia, intestinal barrier dysfunction and gut-liver axis alteration and subsequent inflammatory gene overexpression. Dysbiosis-mediated toll-like receptor 4 (TLR-4)-NF-B signaling pathway activation was associated with inflammasome initiation response and reticulum stress pathway induction. Quercetin reverted gut microbiota imbalance and related endotoxemia-mediated TLR-4 pathway induction, with subsequent inhibition of inflammasome response and reticulum stress pathway activation, leading to the blockage of lipid metabolism gene expression deregulation. Our results support the suitability of quercetin as a therapeutic approach for obesity-associated NAFLD via its anti-inflammatory, antioxidant and prebiotic integrative respons

Protective effect of quercetin treatment on HFD-induced intestinal dysbiosis and barrier dysfunction in an in vivo model of non-alcoholic fatty liver disease

1 p.Gut microbiota is involved in obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). Quercetin may have the ability to modulate the intestinal microbiota composition, suggesting therapeutic potential in NAFLD. The present study aims to investigate the beneficial effect of quercetin treatment on dysbiosis, intestinal barrier dysfunction and gut-liver axis alteration in high-fat diet (HFD)-fed mice. Resumen de un trabajo resultado del proyecto de investigación financiado por la Consejería de Educación de la Junta de Castilla y León (referencia LE063U16)S

Quercetin ameliorates dysregulation of lipid metabolism genes via the PI3K/AKT pathway in a diet-induced mouse model of non-alcoholic fatty liver disease

P. 879-893Flavonoids and related compounds seem to have favorable effects on nonalcoholic fatty liver disease (NAFLD) progression, although the exact mechanisms implicated are poorly understood. In this study, we aimed to investigate the effect of the flanovol quercetin on gene expression deregulation involved in the development of NAFLD, as well as the possible implication of phosphatidylinositol 3-kinase (PI3K)/AKT pathway modulatio

Protective Effect of Quercetin Treatment on Gut Microbiota Imbalance in Obesity-Associated NAFLD in Patients and in HFD-FED Mice

2 p.Gut microbiota is involved in obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). Quercetin may modulate the intestinal microbiota composition, suggesting therapeutic potential in NAFLD. The present study aims to establish the role of gut microbiota imbalance in obesity-related NAFLD development in patients and in an in vivo model and to investigate benefits of experimental treatment with quercetin. Resumen de un trabajo resultado del proyecto de investigación financiado por la Consejería de Educación de la Junta de Castilla y León (referencia LE063U16)S

Efecto modulador de la quercetina sobre la disbiosis intestinal en un modelo animal de NAFLD asociada a obesidad

2 p.El estudio pretende investigar, en un modelo in vivo de NAFLD, el efecto beneficioso del tratamiento con quercetina sobre la disbiosis, la disfunción de la barrera intestinal y la alteración del eje intestinohígado inducido por una dieta rica en grasa (HFD). Resumen de un trabajo resultado del proyecto de investigación financiado por la Consejería de Educación de la Junta de Castilla y León (referencia LE063U16)S

Predictive Power of the "Trigger Tool" for the detection of adverse events in general surgery: a multicenter observational validation study

Background In spite of the global implementation of standardized surgical safety checklists and evidence-based practices, general surgery remains associated with a high residual risk of preventable perioperative complications and adverse events. This study was designed to validate the hypothesis that a new “Trigger Tool” represents a sensitive predictor of adverse events in general surgery. Methods An observational multicenter validation study was performed among 31 hospitals in Spain. The previously described “Trigger Tool” based on 40 specific triggers was applied to validate the predictive power of predicting adverse events in the perioperative care of surgical patients. A prediction model was used by means of a binary logistic regression analysis. Results The prevalence of adverse events among a total of 1,132 surgical cases included in this study was 31.53%. The “Trigger Tool” had a sensitivity and specificity of 86.27% and 79.55% respectively for predicting these adverse events. A total of 12 selected triggers of overall 40 triggers were identified for optimizing the predictive power of the “Trigger Tool”. Conclusions The “Trigger Tool” has a high predictive capacity for predicting adverse events in surgical procedures. We recommend a revision of the original 40 triggers to 12 selected triggers to optimize the predictive power of this tool, which will have to be validated in future studies

Estudio de los mecanismos patogénicos de la hepatitis C y su relación con el desarrollo de esteatosis. Efecto de un tratamiento antioxidante con flavonoides = Study of the mechanisms involved in the development of steatosis associated to hepatitis C. Effects of antioxidant treatment with flavonoids

200 p.La hepatitis C es una enfermedad infecciosa que supone uno de los problemas de salud más graves, debido a la propagación del virus de la hepatitis C (VHC) en todo el mundo, a la existencia de varias vías de transmisión y a la falta de una terapia realmente eficiente. El VHC posee la habilidad de activar varias respuestas celulares que pueden participar en el desarrollo de enfermedades hepáticas asociadas a la patogénesis del VHC, por ejemplo alterando el metabolismo lipídico o activando la vía de señalización oncogénica. Aproximadamente el 50% de los pacientes infectados con VHC tienen esteatosis, pudiendo evolucionar a esteatohepatitis y fibrosis e incluso progresar a cirrosis y carcinoma hepatocelular. La infección con el VHC es única en su dependencia y modificación del metabolismo lipídico del hospedador. De hecho, el acúmulo intrahepatocitario de lípidos inducido por el virus contribuye a una peor respuesta al tratamiento. Por ello, incluir terapias moduladoras del metabolismo lipídico junto con los agentes antivirales puede incrementar la efectividad del tratamiento. Se ha descrito la existencia de numerosos compuestos naturales que afectan al metabolismo lipídico y presentan actividad antiviral. Entre éstos se encuentra la quercetina, un componente perteneciente a la familia de los flavonoides, con actividad frente al VHC y capaz de reducir la acumulación de grasa en el hígado, disminuyendo tanto el estrés oxidativo como la expresión de genes relacionados con el desarrollo de esteatosi

Lysosomotropic Drugs: Pharmacological Tools to Study Lysosomal Function

Background: Lysosomotropic molecules are taken up into lysosomes in vitro and in vivo. Many drugs approved for clinical medicine are lysosomotropic agents, characterized by promoting particular effects including cytoplasmic vacuolization, increase in number and size of lysosomes, inhibition of their enzymes and accumulation of undegraded material, leading mainly to phospholipidosis. Despite lysosomotropism has been extensively described and studied, the pathophysiological significance of this process is still not well understood. Objetive: In this review, we focus on what is known about the effects of lysosomotropic drugs on specific lysosomal functions and their similarities with the phenotypic features of lysosomal storage disorders (LSDs). Conclusion: Some effects of lysosomotropic drugs are very similar to pathologic features of human genetic diseases affecting lysosomal function, and therefore these drugs can be used as tools to understand the mechanisms underlying such patho-pathways as well as to create pharmacologically-induced models of LSDs