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1.
J Hepatol ; 74(5): 1188-1199, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33278455

RESUMEN

BACKGROUND & AIMS: In advanced chronic liver disease (ACLD), deregulated hepatic necroinflammatory processes play a key role in the development of liver microvascular dysfunction, fibrogenesis, and increased hepatic vascular tone, resulting in progression of ACLD and portal hypertension. Given the current lack of an effective treatment, we aimed to characterise the effects of the pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist lanifibranor in 2 preclinical models of ACLD, as well as in liver cells from patients with ACLD. METHODS: Cirrhotic rats (thioacetamide or common bile duct ligation; TAA or cBDL) randomly received lanifibranor (100 mg/kg/day, po) or vehicle for 14 days (n = 12/group). PPAR expression, systemic and hepatic haemodynamics, presence of ascites, liver sinusoidal endothelial cell (LSEC) phenotype, hepatic stellate cell (HSC) activation, serum transaminases and albumin, hepatic macrophage infiltration, cytokine expression, and liver fibrosis were determined. Hepatic cells were isolated from the livers of patients with cirrhosis and their phenotype was evaluated after treatment with either lanifibranor or vehicle. RESULTS: TAA-cirrhotic rats receiving lanifibranor showed significantly lower portal pressure compared with vehicle-treated animals (-15%; p = 0.003) without decreasing portal blood flow, indicating improved hepatic vascular resistance. Moreover, lanifibranor-treated TAA-rats showed decreased ascites, improved LSEC and HSC phenotypes, ameliorated hepatic microvascular function, reduced hepatic inflammation, and significant fibrosis regression (-32%; p = 0.020). These findings were confirmed in the cBDL rat model as well as in human liver cells from patients with cirrhosis, which exhibited phenotypic improvement upon treatment with lanifibranor. CONCLUSIONS: Lanifibranor ameliorates fibrosis and portal hypertension in preclinical models of decompensated cirrhosis. Promising results in human hepatic cells further support its clinical evaluation for the treatment of ACLD. LAY SUMMARY: Advanced chronic liver disease (ACLD) constitutes a serious public health issue for which safe and effective treatments are lacking. This study shows that lanifibranor improves portal hypertension and liver fibrosis, 2 key elements of the pathophysiology of ACLD, in preclinical models of the disease. Evaluation of lanifibranor in liver cells from patients with ACLD further supports its beneficial effects.


Asunto(s)
Benzotiazoles/farmacología , Hipertensión Portal , Cirrosis Hepática , Receptores Activados del Proliferador del Peroxisoma/agonistas , Sulfonamidas/farmacología , Animales , Antiinflamatorios/farmacología , Antifibróticos/farmacología , Antihipertensivos/farmacología , Células Cultivadas , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Hipertensión Portal/tratamiento farmacológico , Hipertensión Portal/etiología , Hipertensión Portal/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Presión Portal/efectos de los fármacos , Ratas , Resistencia Vascular/efectos de los fármacos
2.
Nutrients ; 11(10)2019 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-31623374

RESUMEN

Inflammation and oxidative stress play a key role in the pathophysiology of advanced chronic liver disease (ACLD) and portal hypertension (PH). Considering the current lack of effective treatments, we evaluated an anti-inflammatory and antioxidant nutraceutical rich in docosahexaenoic acid (DHA) as a possible therapy for ACLD. We investigated the effects of two-week DHA supplementation (500 mg/kg) on hepatic fatty acids, PH, oxidative stress, inflammation, and hepatic stellate cell (HSC) phenotype in rats with ACLD. Additionally, the effects of DHA were evaluated in murine macrophages and human HSC. In contrast to vehicle-treated animals, cirrhotic rats receiving DHA reestablished a healthy hepatic fatty acid profile, which was associated with an improvement in PH. The mechanisms underlying this hemodynamic improvement included a reduction in oxidative stress and inflammation, as well as a marked HSC deactivation, confirmed in human HSC. Experiments with cultured macrophages showed that treatment with DHA protects against pro-inflammatory insults. The present preclinical study demonstrates that a nutraceutical rich in DHA significantly improves PH in chronic liver disease mainly by suppressing inflammation and oxidative stress-driven HSC activation, encouraging its evaluation as a new treatment for PH and cirrhosis.


Asunto(s)
Antiinflamatorios/administración & dosificación , Antioxidantes/administración & dosificación , Suplementos Dietéticos/análisis , Ácidos Docosahexaenoicos/administración & dosificación , Hipertensión Portal/tratamiento farmacológico , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/análisis , Ácidos Grasos/análisis , Ácidos Grasos Omega-3/análisis , Hígado Graso/tratamiento farmacológico , Células Estrelladas Hepáticas/efectos de los fármacos , Humanos , Hígado/química , Hepatopatías/fisiopatología , Macrófagos/efectos de los fármacos , Masculino , Ratones , Células RAW 264.7 , Ratas , Ratas Sprague-Dawley
3.
Food Chem ; 165: 14-20, 2014 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-25038643

RESUMEN

The ingestion of dietary lipids leads to oxidative stress. This postprandial oxidative stress may potentiate the adverse effects of postprandial hyperlipidaemia. Proanthocyanidins have been shown to alleviate oxidative stress and hypertriglyceridaemia associated with the postprandial state. Additionally, omega-3 polyunsaturated fatty acids (PUFAs) also have beneficial effects on lipoprotein metabolism and oxidative stress. The present study was designed to investigate the possible additive effects in liver of an acute dose of grape seed proanthocyanidins extract (GSPE) and oil rich in docosahexaenoic acid (DHA-OR) on lipidic postprandial oxidative stress in Wistar rats. GSPE+DHA-OR modifies the hepatic antioxidant enzymatic activities (GST and GPx), clearly showing that this combination increases the detoxification of postprandial xenobiotics via the GST action mediated hepatic GSH conjugation. In conclusion, this study provides evidence that the combination of GSPE and DHA-OR ameliorate the transient imbalance between the lipid hydroperoxide level and antioxidant status related to a lipidic postprandial state.


Asunto(s)
Ácidos Docosahexaenoicos/metabolismo , Extracto de Semillas de Uva/química , Hígado/metabolismo , Estrés Oxidativo/efectos de los fármacos , Proantocianidinas/química , Animales , Antioxidantes/farmacología , Masculino , Periodo Posprandial , Ratas , Ratas Wistar
4.
Mol Nutr Food Res ; 58(4): 727-37, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24338985

RESUMEN

SCOPE: Increased oxidative stress may play an important role in metabolic syndrome and related manifestations, including obesity, atherosclerosis, hypertension, and insulin resistance. Its relation to obesity is due to increased reactive oxygen species and/or decreased glutathione (GSH) antioxidant metabolism. Consequently, the activation of glutathione metabolism appears to be a central defense response to prevent oxidative stress. In this sense, dietary supplements with natural antioxidant molecules, including proanthocyanidins, may present a useful strategy of controlling and reducing complications of obesity, including hepatic steatosis. MATERIALS AND RESULTS: We assessed the grape seed proanthocyanidin extract (GSPE) effect on oxidative alterations related to genetically obese rats (Zucker rats) and, more specifically, to hepatic GSH metabolism. We demonstrate that the administration of GSPE reduced the oxidized glutathione accumulation increasing the total GSH/oxidized glutathione hepatic ratio and consequently decreasing the activation of antioxidant enzymes, including glutathione peroxidase, glutathione reductase, and glutathione S-transferase, and increasing the total antioxidant capacity of the cell. CONCLUSION: In Zucker rats, the obesity-induced oxidative stress related to liver glutathione alteration was mitigated by GSPE administration.


Asunto(s)
Glutatión/metabolismo , Extracto de Semillas de Uva/farmacología , Hígado/efectos de los fármacos , Obesidad/tratamiento farmacológico , Proantocianidinas/farmacología , Animales , Suplementos Dietéticos , Femenino , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Obesidad/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Zucker , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/genética , Triglicéridos/metabolismo
5.
Food Chem Toxicol ; 62: 750-7, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24140970

RESUMEN

The excessive production of reactive oxygen species has been implicated in several pathologies, such as atherosclerosis, obesity, hypertension and insulin resistance. Docosahexaenoic acid (DHA) may protect against the above mentioned diseases, but paradoxically the main DHA treated pathologies are also associated with increased ROS levels. Therefore, the aim of this study was to explore if in vitro DHA supplementation may increase the sensitivity of cells to tert-BHP induced oxidative stress, and if the green tea polyphenol epigallocatechin-3-gallate (EGCG) is able to correct such detrimental effect. We found that DHA-enriched cells exacerbate ROS generation, decrease cell viability and increase Nrf2 nuclear translocation and HO-1 expression. Interestingly, cellular EGCG is able to counteract oxidative damage from either tert-BHP or DHA-enriched cells. In consequence, our results suggest that in a ROS enriched environment DHA could not always be beneficial for cells and can be considered a double-edged sword in terms of its benefits vs. risks. In this sense, our results propose that the supplementation with potent antioxidant molecules could be an appropriate strategy to reduce the risks related with the DHA supplementation in an oxidative stress-associated condition.


Asunto(s)
Catequina/análogos & derivados , Ácidos Docosahexaenoicos/farmacología , terc-Butilhidroperóxido/toxicidad , Animales , Catalasa/metabolismo , Catequina/farmacología , Línea Celular Tumoral/efectos de los fármacos , Suplementos Dietéticos , Ácidos Docosahexaenoicos/toxicidad , Glutatión/metabolismo , Hemo-Oxigenasa 1/metabolismo , Malondialdehído/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Transporte de Proteínas/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Té/química
6.
Free Radic Biol Med ; 60: 107-14, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23439188

RESUMEN

Acute inflammation is a response to injury, infection, tissue damage, or shock. Bacterial lipopolysaccharide (LPS) is an endotoxin implicated in triggering sepsis and septic shock, and LPS promotes the inflammatory response, resulting in the secretion of proinflammatory and anti-inflammatory cytokines such as the interleukins (IL-6, IL-1ß, and IL-10) and tumor necrosis factor-α by the immune cells. Furthermore, nitric oxide and reactive oxygen species levels increase rapidly, which is partially due to the activation of inducible nitric oxide synthase in several tissues in response to inflammatory stimuli. Previous studies have shown that procyanidins, polyphenols present in foods such as apples, grapes, cocoa, and berries, have several beneficial properties against inflammation and oxidative stress using several in vitro and in vivo models. In this study, the anti-inflammatory and antioxidant effects of two physiological doses and two pharmaceutical doses of grape seed procyanidin extract (GSPE) were analyzed using a rat model of septic shock by the intraperitoneal injection of LPS derived from Escherichia coli. The high nutritional (75mg/kg/day) and the high pharmacological doses (200mg/kg/day) of GSPE showed anti-inflammatory effects by decreasing the proinflammatory marker NOx in the plasma, red blood cells, spleen, and liver. Moreover, the high pharmacological dose also downregulated the genes Il-6 and iNos; and the high nutritional dose decreased the glutathione ratio (GSSG/total glutathione), further illustrating the antioxidant capability of GSPE. In conclusion, several doses of GSPE can alleviate acute inflammation triggered by LPS in rats at the systemic and local levels when administered for as few as 15 days before the injection of endotoxin.


Asunto(s)
Biflavonoides/administración & dosificación , Catequina/administración & dosificación , Extracto de Semillas de Uva/administración & dosificación , Inflamación/tratamiento farmacológico , Lipopolisacáridos/toxicidad , Proantocianidinas/administración & dosificación , Animales , Inflamación/inducido químicamente , Inflamación/patología , Interleucinas/metabolismo , Lipopolisacáridos/farmacología , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Choque Séptico/inducido químicamente , Choque Séptico/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/metabolismo
7.
Br J Nutr ; 108(2): 208-17, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22011563

RESUMEN

Proanthocyanidins have been shown to improve postprandial hypertriacylglycerolaemia. The present study aims to determine the actual contribution of chylomicrons (CM) and VLDL in the hypotriacylglycerolaemic action of grape seed proanthocyanidin extract (GSPE) in the postprandial state and to characterise the mechanisms by which the GSPE treatment reduces TAG-rich lipoproteins in vivo. A plasma lipid tolerance test was performed on rats fasted for 14 h and orally loaded with lard containing either GSPE or not. GSPE (250 mg/kg body weight) markedly blocked the increase in plasma TAG induced by lard, with a statistically significant reduction of 22 % in the area under the curve. The VLDL-rich fraction was the major contributor (72 %) after 1 h, whereas the CM-rich fraction was the major contributor (85 %) after 3 h. At 5 and 7 h after treatment, CM-rich and VLDL-rich fractions showed a similar influence. Plasma post-heparin lipoprotein lipase (LPL) activity and LPL mRNA levels in white adipose tissue and muscle were not affected by GSPE. On the contrary, GSPE treatment significantly repressed (30 %) the secretion of VLDL-TAG. In the liver, GSPE treatment induced different effects on the expression of acyl-coenzyme A synthetase long-chain family member 1, Apoc3 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase at 1 h and Cd36 at 5 h, compared to those induced by lard. Furthermore, GSPE treatment significantly increased the activity of carnitine palmitoyltransferase 1a at 1 h. In conclusion, both CM-rich and VLDL-rich fractions contributed to the hypotriacylglycerolaemic action of GSPE, but their influence depended on time. GSPE induces hypotriacylglycerolaemic actions by repressing lipoprotein secretion and not by increasing LPL activity.


Asunto(s)
Quilomicrones/sangre , Suplementos Dietéticos , Extracto de Semillas de Uva/uso terapéutico , Hipertrigliceridemia/prevención & control , Hipolipemiantes/uso terapéutico , Lipoproteínas VLDL/sangre , Proantocianidinas/uso terapéutico , Triglicéridos/sangre , Ácido 3-Hidroxibutírico/sangre , Animales , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Quilomicrones/química , Ácidos Grasos no Esterificados/sangre , Regulación Enzimológica de la Expresión Génica , Hipertrigliceridemia/sangre , Hipertrigliceridemia/metabolismo , Mucosa Intestinal/enzimología , Mucosa Intestinal/metabolismo , Grasa Intraabdominal/enzimología , Grasa Intraabdominal/metabolismo , Lipoproteína Lipasa/sangre , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/metabolismo , Lipoproteínas VLDL/química , Lipoproteínas VLDL/metabolismo , Hígado/enzimología , Hígado/metabolismo , Masculino , Especificidad de Órganos , Periodo Posprandial , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Triglicéridos/efectos adversos , Triglicéridos/metabolismo
8.
Br J Nutr ; 107(2): 170-8, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21733324

RESUMEN

The present study aims to determine the effects of grape seed proanthocyanidin extract (GSPE) on brown adipose tissue (BAT) mitochondrial function in a state of obesity induced by diet. Wistar male rats were fed with a cafeteria diet (Cd) for 4 months; during the last 21 d, two groups were treated with doses of 25 and 50 mg GSPE/kg body weight. In the BAT, enzymatic activities of citrate synthase, cytochrome c oxidase (COX) and ATPase were determined and gene expression was analysed by real-time PCR. The mitochondrial function of BAT was determined in fresh mitochondria by high-resolution respirometry using both pyruvate and carnitine-palmitoyl-CoA as substrates. The results show that the Cd causes an important decrease in the gene expression of sirtuin 1, nuclear respiratory factor 1, isocitrate dehydrogenase 3γ and COX5α and, what is more telling, decreases the levels of mitochondrial respiration both with pyruvate and canitine-palmitoyl-CoA. Most of these parameters, which are indicative of mitochondrial dysfunction due to diet-induced obesity, are improved by chronic supplementation of GSPE. The beneficial effects caused by the administration of GSPE are exhibited as a protection against weight gain, in spite of the Cd the rats were fed. These data indicate that chronic consumption of a moderate dose of GSPE can correct an energy imbalance in a situation of diet-induced obesity, thereby improving the mitochondrial function and thermogenic capacity of the BAT.


Asunto(s)
Tejido Adiposo Pardo/metabolismo , Fármacos Antiobesidad/uso terapéutico , Suplementos Dietéticos , Extracto de Semillas de Uva/uso terapéutico , Enfermedades Mitocondriales/dietoterapia , Obesidad/dietoterapia , Obesidad/metabolismo , Proantocianidinas/uso terapéutico , Animales , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/efectos adversos , Peso Corporal , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos/efectos adversos , Regulación Enzimológica de la Expresión Génica , Extracto de Semillas de Uva/administración & dosificación , Extracto de Semillas de Uva/efectos adversos , Masculino , Mitocondrias/enzimología , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/fisiopatología , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Obesidad/fisiopatología , Fosforilación Oxidativa , Proantocianidinas/administración & dosificación , Proantocianidinas/efectos adversos , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Distribución Aleatoria , Ratas , Ratas Wistar , Termogénesis
9.
J Agric Food Chem ; 59(15): 8491-8, 2011 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-21726097

RESUMEN

The aim of this study was to determine the effect of chronic dietary supplementation of a grape seed proanthocyanidin extract (GSPE) at a dose of 35 mg/kg body weight on energy metabolism and mitochondrial function in the skeletal muscle of Zucker obese rats. Three groups of 10 animals each were used: lean Fa/fa lean group (LG) rats, a control fa/fa obese group (OG) of rats, and an obese supplemented fa/fa proanthocyanidins obese group (POG) of rats, which were supplemented with a dose of 35 mg GSPE/kg of body weight/day during the 68 days of experimentation. Skeletal muscle energy metabolism was evaluated by determining enzyme activities, key metabolic gene expression, and immunoblotting of oxidative phosphorylation complexes. Mitochondrial function was analyzed by high-resolution respirometry using both a glycosidic and a lipid substrate. In muscle, chronic GSPE administration decreased citrate synthase activity, the amount of oxidative phosphorylation complexes I and II, and Nrf1 gene expression, without any effects on the mitochondrial oxidative capacity. This situation was associated with lower reactive oxygen species (ROS) generation. Additionally, GSPE administration enhanced the ability to oxidize pyruvate, and it also increased the activity of enzymes involved in oxidative phosphorylation including cytochrome c oxidase. There is strong evidence to suggest that GSPE administration stimulates mitochondrial function in skeletal muscle specifically by increasing the capacity to oxidize pyruvate and contributes to reduced muscle ROS generation in obese Zucker rats.


Asunto(s)
Suplementos Dietéticos/análisis , Extracto de Semillas de Uva/administración & dosificación , Mitocondrias/metabolismo , Obesidad/tratamiento farmacológico , Proantocianidinas/administración & dosificación , Animales , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Femenino , Humanos , Mitocondrias/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Obesidad/genética , Obesidad/metabolismo , Oxidación-Reducción , Fosforilación Oxidativa , Ratas , Ratas Transgénicas , Ratas Zucker
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