RESUMEN
BACKGROUND & AIMS: Inflammation, particularly that mediated by bacterial components translocating from the gut to the liver and binding to toll-like receptors (TLRs), is central to cholestatic liver injury. The triggering receptor expressed on myeloid cells-2 (TREM-2) inhibits TLR-mediated signaling and exerts a protective role in hepatocellular injury and carcinogenesis. This study aims to evaluate the role of TREM-2 in cholestasis. METHODS: TREM-2 expression was analyzed in the livers of patients with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC), and in mouse models of cholestasis. Wild-type (WT) and Trem-2 deficient (Trem-2-/-) mice were subjected to experimental cholestasis and gut sterilization. Primary cultured Kupffer cells were incubated with lipopolysaccharide and/or ursodeoxycholic acid (UDCA) and inflammatory responses were analyzed. RESULTS: TREM-2 expression was upregulated in the livers of patients with PBC or PSC, and in murine models of cholestasis. Compared to WT, the response to bile duct ligation (BDL)-induced obstructive cholestasis or alpha-naphtylisothiocyanate (ANIT)-induced cholestasis was exacerbated in Trem-2-/- mice. This was characterized by enhanced necroptotic cell death, inflammatory responses and biliary expansion. Antibiotic treatment partially abrogated the effects observed in Trem-2-/- mice after BDL. Experimental overexpression of TREM-2 in the liver of WT mice downregulated ANIT-induced IL-33 expression and neutrophil recruitment. UDCA regulated Trem-1 and Trem-2 expression in primary cultured mouse Kupffer cells and dampened inflammatory gene transcription via a TREM-2-dependent mechanism. CONCLUSIONS: TREM-2 acts as a negative regulator of inflammation during cholestasis, representing a novel potential therapeutic target. LAY SUMMARY: Cholestasis (the reduction or cessation of bile flow) causes liver injury. This injury is exacerbated when gut-derived bacterial components interact with receptors (specifically Toll-like receptors or TLRs) on liver-resident immune cells, promoting inflammation. Herein, we show that the anti-inflammatory receptor TREM-2 dampens TLR-mediated signaling and hence protects against cholestasis-induced liver injury. Thus, TREM-2 could be a potential therapeutic target in cholestasis.
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Colestasis , Glicoproteínas de Membrana , Receptores Inmunológicos , Ácido Ursodesoxicólico , Animales , Antibacterianos , Antiinflamatorios , Colestasis/complicaciones , Inflamación , Interleucina-33 , Lipopolisacáridos , Hígado , Glicoproteínas de Membrana/genética , Ratones , Receptores Inmunológicos/genética , Receptor Activador Expresado en Células Mieloides 1 , Ácido Ursodesoxicólico/farmacologíaRESUMEN
OBJECTIVE: Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer usually arising on a background of chronic liver injury involving inflammatory and hepatic regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM-2) is predominantly expressed in hepatic non-parenchymal cells and inhibits Toll-like receptor signalling, protecting the liver from various hepatotoxic injuries, yet its role in liver cancer is poorly defined. Here, we investigated the impact of TREM-2 on liver regeneration and hepatocarcinogenesis. DESIGN: TREM-2 expression was analysed in liver tissues of two independent cohorts of patients with HCC and compared with control liver samples. Experimental HCC and liver regeneration models in wild type and Trem-2-/- mice, and in vitro studies with hepatic stellate cells (HSCs) and HCC spheroids were conducted. RESULTS: TREM-2 expression was upregulated in human HCC tissue, in mouse models of liver regeneration and HCC. Trem-2-/- mice developed more liver tumours irrespective of size after diethylnitrosamine (DEN) administration, displayed exacerbated liver damage, inflammation, oxidative stress and hepatocyte proliferation. Administering an antioxidant diet blocked DEN-induced hepatocarcinogenesis in both genotypes. Similarly, Trem-2-/- animals developed more and larger tumours in fibrosis-associated HCC models. Trem-2-/- livers showed increased hepatocyte proliferation and inflammation after partial hepatectomy. Conditioned media from human HSCs overexpressing TREM-2 inhibited human HCC spheroid growth in vitro through attenuated Wnt ligand secretion. CONCLUSION: TREM-2 plays a protective role in hepatocarcinogenesis via different pleiotropic effects, suggesting that TREM-2 agonism should be investigated as it might beneficially impact HCC pathogenesis in a multifactorial manner.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Glicoproteínas de Membrana/genética , Receptores Inmunológicos/genética , Adulto , Anciano , Animales , Carcinogénesis/genética , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular , Dietilnitrosamina , Femenino , Mutación con Ganancia de Función , Expresión Génica , Células Estrelladas Hepáticas/metabolismo , Hepatitis/metabolismo , Hepatocitos/patología , Hepatocitos/fisiología , Humanos , Hígado/metabolismo , Cirrosis Hepática/metabolismo , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/patología , Regeneración Hepática/genética , Regeneración Hepática/fisiología , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Noqueados , Persona de Mediana Edad , Estrés Oxidativo , Factores Protectores , ARN/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores Inmunológicos/metabolismo , Esferoides Celulares , Regulación hacia Arriba , Proteínas Wnt/metabolismo , Vía de Señalización Wnt , Proteína Wnt3/metabolismoRESUMEN
Excessive fat accumulation within the liver is known as "simple hepatic steatosis", which is the most benign form of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to determine whether pterostilbene improves this hepatic alteration in Zucker (fa/fa) rats. Animals were distributed in two experimental groups (n = 10) and fed a standard laboratory diet. Rats in the pterostilbene group were given a dose of 30 mg/kg body weight/d for six weeks. After sacrifice, serum glucose, transaminase, and insulin concentrations were quantified and the liver triacylglycerol content and fatty acid profile was analyzed. Different pathways of triacylglycerol metabolism in liver were studied, including fatty acid synthesis and oxidation, triglyceride assembly, fatty acid uptake, and glucose uptake. With pterostilbene administration, a reduction in insulin concentrations (consequently in the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)) and hepatic triacylglycerol content were observed. No effects were observed in pterostilbene-treated rats in the activity of de novo lipogenesis enzymes. An improvement in the fatty acid profile was observed in pterostilbene-treated rats. In conclusion, pterostilbene is a useful molecule to reduce liver steatosis. Its delipidating effect is due, at least in part, to reduced fatty acid availability and triacylglycerol synthesis, as well as to an increased very low-density lipoprotein assembly and fatty acid oxidation.
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Hígado Graso/prevención & control , Hígado/metabolismo , Obesidad/metabolismo , Estilbenos/uso terapéutico , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/enzimología , ARN/genética , ARN/metabolismo , Distribución Aleatoria , Ratas , Ratas Zucker , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estilbenos/administración & dosificaciónRESUMEN
OBJECTIVE: Liver injury impacts hepatic inflammation in part via Toll-like receptor (TLR) signalling. Triggering receptor expressed on myeloid cells 2 (TREM-2) modulates TLR4-mediated inflammation in bone marrow (BM)-derived macrophages but its function in liver injury is unknown. Here we hypothesised that the anti-inflammatory effects of TREM-2 on TLR signalling may limit hepatic injury. DESIGN: TREM-2 expression was analysed in livers of humans with various forms of liver injury compared with control individuals. Acute and chronic liver injury models were performed in wild type and Trem-2-/- mice. Primary liver cells from both genotypes of mice were isolated for in vitro experiments. RESULTS: TREM-2 was expressed on non-parenchymal hepatic cells and induced during liver injury in mice and man. Mice lacking TREM-2 exhibited heightened liver damage and inflammation during acute and repetitive carbon tetrachloride and acetaminophen (APAP) intoxication, the latter of which TREM-2 deficiency was remarkably associated with worsened survival. Liver damage in Trem-2-/- mice following chronic injury and APAP challenge was associated with elevated hepatic lipid peroxidation and macrophage content. BM transplantation experiments and cellular reactive oxygen species assays revealed effects of TREM-2 in the context of chronic injury depended on both immune and resident TREM-2 expression. Consistent with effects of TREM-2 on inflammation-associated injury, primary hepatic macrophages and hepatic stellate cells lacking TREM-2 exhibited augmented TLR4-driven proinflammatory responses. CONCLUSION: Our data indicate that by acting as a natural brake on inflammation during hepatocellular injury, TREM-2 is a critical regulator of diverse types of hepatotoxic injury.
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Cirrosis Hepática/metabolismo , Hígado/metabolismo , Glicoproteínas de Membrana/fisiología , Receptores Inmunológicos/fisiología , Acetaminofén , Anciano , Animales , Tetracloruro de Carbono , Estudios de Casos y Controles , Femenino , Células Madre Hematopoyéticas/metabolismo , Hepatocitos/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Macrófagos del Hígado/metabolismo , Peroxidación de Lípido/fisiología , Cirrosis Hepática/etiología , Cirrosis Hepática/inmunología , Cirrosis Hepática Experimental/inmunología , Cirrosis Hepática Experimental/metabolismo , Masculino , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones Noqueados , Persona de Mediana Edad , Especies Reactivas de Oxígeno/metabolismo , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Receptor Toll-Like 4/fisiología , Regulación hacia Arriba/fisiologíaRESUMEN
Phenolic compounds are among the most investigated herbal remedies, as is especially the case for resveratrol. Many reports have shown its anti-aging properties and the ability to reduce obesity and diabetes induced by high-fat diet in mice. However, such beneficial effects hardly translate from animal models to humans. The scientific community has therefore tested whether other plant phenolic compounds may surpass the effects of resveratrol. In this regard, it has been reported that piceatannol reproduces in rodents the anti-obesity actions of its parent polyphenol. However, the capacity of piceatannol to inhibit adipocyte differentiation in humans has not been characterized so far. Here, we investigated whether piceatannol was antiadipogenic and antilipogenic in human preadipocytes. Human mesenchymal stem cells (hMSC), isolated from adipose tissues of lean and obese individuals, were differentiated into mature adipocytes with or without piceatannol, and their functions were explored. Fifty µM of piceatannol deeply limited synthesis/accumulation of lipids in both murine and hMSC-derived adipocytes. Interestingly, this phenomenon occurred irrespective of being added at the earlier or later stages of adipocyte differentiation. Moreover, piceatannol lowered glucose transport into adipocytes and decreased the expression of key elements of the lipogenic pathway (PPARγ, FAS, and GLUT4). Thus, the confirmation of the antiadipogenic properties of piceatanol in vitro warrants the realization of clinical studies for the application of this compound in the treatment of the metabolic complications associated with obesity.
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Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Glucosa/metabolismo , Lipogénesis/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Estilbenos/farmacología , Células 3T3-L1 , Adipocitos/citología , Adipocitos/metabolismo , Tejido Adiposo/citología , Adulto , Animales , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Transporte Biológico/efectos de los fármacos , Células Cultivadas , Suplementos Dietéticos , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Humanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , PPAR gamma/genética , PPAR gamma/metabolismo , Estilbenos/administración & dosificación , Receptor fas/genética , Receptor fas/metabolismoRESUMEN
Variations in DNA repair genes have been reported as key factors in gastric cancer (GC) susceptibility but results among studies are inconsistent. We aimed to assess the relevance of DNA repair gene polymorphisms and environmental factors to GC risk and phenotype in a Caucasian population in Spain. Genomic DNA from 603 patients with primary GC and 603 healthy controls was typed for 123 single nucleotide polymorphisms in DNA repair genes using the Illumina platform. Helicobacter pylori infection with CagA strains (odds ratio (OR): 1.99; 95% confidence interval (CI): 1.55-2.54), tobacco smoking (OR: 1.77; 95% CI: 1.22-2.57), and family history of GC (OR: 2.87; 95% CI: 1.85-4.45) were identified as independent risk factors for GC. By contrast, the TP53 rs9894946A (OR: 0.73; 95% CI: 0.56-0.96), TP53 rs1042522C (OR: 0.76; 95% CI: 0.56-0.96), and BRIP1 rs4986764T (OR: 0.55; 95% CI: 0.38-0.78) variants were associated with lower GC risk. Significant associations with specific anatomopathological GC subtypes were also observed, most notably in the ERCC4 gene with the rs1799801C, rs2238463G, and rs3136038T variants being inversely associated with cardia GC risk. Moreover, the XRCC3 rs861528 allele A was significantly increased in the patient subgroup with diffuse GC (OR: 1.75; 95% CI: 1.30-2.37). Our data show that specific TP53, BRIP1, ERCC4, and XRCC3 polymorphisms are relevant in susceptibility to GC risk and specific subtypes in Caucasians.
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Reparación del ADN/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , Terapia Combinada , Femenino , Frecuencia de los Genes , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Oportunidad Relativa , Fenotipo , Riesgo , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/terapiaRESUMEN
SCOPE: Nutritional interventions based on the use of natural bioactive compounds might offer new possibilities for reshaping obesity-associated bacterial dysregulation or dysbiosis and improving health. We evaluated whether pterostilbene supplementation could induce changes in gut microbiota composition and whether these modifications were associated with improvements in metabolic variables. METHODS AND RESULTS: Zucker (fa/fa) rats were given a standard diet supplemented (n = 10) or not (n = 9) with pterostilbene (15 mg/kg body weight/day) by oral gavage for 6 weeks. Faucal samples at the beginning and at the end of the intervention period were analyzed by Illumina Mi-Seq sequencing approach. Pterostilbene exerted protective antiobesity effects, improved metabolic function (insulin sensitivity), and induced structural changes in gut microbiota composition. A decrease in the levels of Firmicutes and an increase in Verrucomicrobia phyla were detected in the pterostilbene-treated group. Bacterial species belonging to genera Akkermansia and Odoribacter were also increased. A strong inverse correlation between Akkermansia muciniphila and body weight was evidenced. Odoribacter splanchnicus showed a negative correlation with adiposity. CONCLUSION: Pterostilbene modifies intestinal bacteria composition toward a healthier microbial profile and suggests that the antiobesity effects induced in Zucker rats could be associated with an enrichment of the mucin-degrading bacterial members, namely Akkermansia and Odoribacter genus.
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Fármacos Antiobesidad/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Obesidad/dietoterapia , Obesidad/metabolismo , Estilbenos/farmacología , Animales , Peso Corporal/efectos de los fármacos , Suplementos Dietéticos , Disbiosis/dietoterapia , Ratas ZuckerRESUMEN
BACKGROUND: Common low-penetrance genetic variants have been consistently associated with colorectal cancer risk. AIM: To determine if these genetic variants are associated also with adenoma susceptibility and may improve selection of patients with increased risk for advanced adenomas and/or multiplicity (≥ 3 adenomas). METHODS: We selected 1,326 patients with increased risk for advanced adenomas and/or multiplicity and 1,252 controls with normal colonoscopy from population-based colorectal cancer screening programs. We conducted a case-control association study analyzing 30 colorectal cancer susceptibility variants in order to investigate the contribution of these variants to the development of subsequent advanced neoplasia and/or multiplicity. RESULTS: We found that 14 of the analyzed genetic variants showed a statistically significant association with advanced adenomas and/or multiplicity: the probability of developing these lesions increased with the number of risk alleles reaching a 2.3-fold risk increment in individuals with ≥ 17 risk alleles. CONCLUSIONS: Nearly half of the genetic variants associated with colorectal cancer risk are also related to advanced adenoma and/or multiplicity predisposition. Assessing the number of risk alleles in individuals within colorectal cancer screening programs may help to identify better a subgroup with increased risk for advanced neoplasia and/or multiplicity in the general population.
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Adenoma/genética , Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple , Anciano , Alelos , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Factores de RiesgoRESUMEN
OBJECTIVES: A fluoropyrimidine plus cisplatin combined with surgery is standard first-line treatment for advanced gastric cancer. We evaluated the effect of pravastatin on overall survival in patients with advanced gastric cancer in a prospective cohort study. METHODS: At the time of surgery, we assigned 60 patients with advanced gastric cancer (stage III or IV) to receive standard first-line treatment (control group) or standard first-line treatment plus pravastatin at a dose of 40 mg once daily (pravastatin group). The minimum follow-up period was 4 years and the maximum of 6 years. RESULTS: The mean of age was 66 years and the TNM stage was III and IV in 65% and 35% of patients, respectively. There was no significant difference between the two groups (control vs pravastatin) in median overall survival (15 vs 14 months; P = 0.8). Predictors of survival were the stage (hazard ratio of death stage IV (III stage as reference): 4.4; 95% CI: 2-9.7; p < 0.05) and older age (hazard ratio of death ≥ 65 years (< 65 years as reference): 2.8; 95% CI: 1.3-6; p < 0.05). CONCLUSIONS: Pravastatin did not improve outcome in patients with advanced gastric cancer.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Pravastatina/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estadificación de Neoplasias , Pronóstico , Neoplasias Gástricas/patología , Tasa de SupervivenciaRESUMEN
In recent years, much attention has been paid by the scientific community to phenolic compounds as active biomolecules naturally present in foods. Pterostilbene is a resveratrol dimethylether derivative which shows higher bioavailability. The aim of the present study was to analyze the effect of pterostilbene on brown adipose tissue thermogenic markers in a model of genetic obesity, which shows reduced thermogenesis. The experiment was conducted with 30 Zucker (fa/fa) rats that were distributed in three experimental groups: control and two groups orally administered with pterostilbene at 15 and 30 mg/kg body weight/day for 6 weeks. Gene expression of uncoupling protein 1 (Ucp1), peroxisome proliferator-activated receptor γ co-activator 1 α (Pgc-1α), carnitine palmitoyl transferase 1b (Cpt1b), peroxisome proliferator-activated receptor α (Pparα), nuclear respiratory factor 1 (Nfr1), and cyclooxygenase-2 (Cox-2); protein expression of PPARα, PGC-1α, p38 mitogen-activated protein kinase (p38 MAPK), UCP1 and glucose transporter (GLUT4); and enzyme activity of CPT 1b and citrate synthase (CS) were assessed in interscapular brown adipose tissue. With the exception of Pgc-1α expression, all these parameters were significantly increased by pterostilbene administration. These results show for the first time that pterostilbene increases thermogenic and oxidative capacity of brown adipose tissue in obese rats. Whether these effects effectively contribute to the antiobesity properties of these compound needs further research.
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Tejido Adiposo Pardo/efectos de los fármacos , Fármacos Antiobesidad/farmacología , Obesidad/tratamiento farmacológico , Estilbenos/farmacología , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/patología , Tejido Adiposo Blanco/patología , Animales , Fármacos Antiobesidad/uso terapéutico , Evaluación Preclínica de Medicamentos , Ingestión de Energía , Expresión Génica , Masculino , Obesidad/metabolismo , Obesidad/patología , Tamaño de los Órganos , Ratas Zucker , Estilbenos/uso terapéutico , TermogénesisRESUMEN
AIMS: To examine the role of genetic and environmental factors in the pathogenesis of alcohol dependence in a Spanish cohort of women and men. METHODS: We analyzed the relationship between 56 genetic variants in 7 genes associated with the dopaminergic reward pathway and excessive alcohol consumption. The study sample (N = 1533, of which 746 were women) consisted of 653 heavy consumers and 880 very low consumers from the Spanish subcohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Single nucleotide polymorphisms (SNPs) were genotyped using a customized array. Lifestyle variables were also examined to assess associations between genetic and environmental factors. RESULTS: No statistically significant differences were found between cases and controls for the allele frequencies in five genes: TH, SLC18A2, DRD1, DRD3 and COMT. Conversely, some alleles of the 12 SNPs from the DRD2 locus and the 5 from the MAOA locus showed significant associations with excessive alcohol consumption. Namely, rs10891556 (DRD2) proved to be the only SNP positively correlated with excessive alcohol consumption in both sexes. DRD2 rs1800497 and rs877138 were significantly associated in men, whereas DRD2 rs17601612 and rs4936271 and MAOA rs5906898 were associated with excessive alcohol consumption in women. A correspondence analysis provided an overall lifestyle profile of excessive drinkers, who were predominantly men who smoked, had large intakes of meat, small intakes of fruit and vegetables, whose jobs did not require high education levels and who engaged in little physical activity. CONCLUSIONS: It has shown the influence of dopaminergic pathway in the genetics of alcohol dependence with differences between men and women and providing a lifestyle profile of excessive drinkers.
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Alcoholismo/etiología , Alcoholismo/genética , Neuronas Dopaminérgicas/fisiología , Predisposición Genética a la Enfermedad , Estilo de Vida , Monoaminooxidasa/genética , Receptores de Dopamina D2/genética , Alcoholismo/fisiopatología , Alcoholismo/psicología , Alelos , Estudios de Casos y Controles , Catecol O-Metiltransferasa/genética , Femenino , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Receptores de Dopamina D1/genética , Receptores de Dopamina D3/genética , Recompensa , Caracteres Sexuales , Tirosina 3-Monooxigenasa/genética , Proteínas de Transporte Vesicular de Monoaminas/genética , Población Blanca/genéticaRESUMEN
Obesity-associated nephropathy is considered to be a leading cause of end-stage renal disease. Resveratrol supplementation represents a promising therapy to attenuate kidney injury, but the poor solubility and limited bioavailability of this polyphenol limits its use in dietary intervention. Piceatannol, a resveratrol analogue, has been suggested as a better option. In this study, we aimed to provide evidence of a preventive action of piceatannol in very early stages of obesity-associated nephropathy. Thirty obese Zucker rats were divided into three experimental groups: one control and two groups orally treated for 6 weeks with 15 and 45 mg piceatannol/kg body weight/day. Enzyme-linked immunosorbent assays (ELISA) were used to determine renal and urinary kidney injury molecule-1 (Kim-1), renal fibrosis markers (transforming growth factor ß1 and fibronectin) and renal sirtuin-1 protein. Oxidative stress was assessed in the kidney by measuring lipid peroxidation and nitrosative stress (thiobarbituric acid reactive substrates and 3-nitrotyrosine levels, respectively) together with the activity of the antioxidant enzyme superoxide dismutase. Renal fatty acids profile analysis was performed by thin-layer and gas chromatography. Piceatannol-treated rats displayed lower levels of urinary and renal Kim-1. Renal fibrosis biomarkers and lipid peroxidation exhibited a tendency to decrease in the piceatannol-treated groups. Piceatannol treatment did not modify superoxide dismutase activity or sirtuin-1 protein levels, while it seemed to increase the levels of polyunsaturated and omega-6 polyunsaturated fatty acids in the kidneys. Our findings suggest a mild renoprotective effect of piceatannol in obese Zucker rats and the need of intervention at early stages of renal damage.
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Antiinflamatorios no Esteroideos/uso terapéutico , Antioxidantes/uso terapéutico , Suplementos Dietéticos , Riñón/fisiopatología , Obesidad/dietoterapia , Insuficiencia Renal/prevención & control , Estilbenos/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antioxidantes/administración & dosificación , Biomarcadores/metabolismo , Biomarcadores/orina , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/orina , Fibrosis , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Peroxidación de Lípido , Masculino , Obesidad/inmunología , Obesidad/metabolismo , Obesidad/fisiopatología , Tamaño de los Órganos , Estrés Oxidativo , Distribución Aleatoria , Ratas Zucker , Insuficiencia Renal/etiología , Insuficiencia Renal/fisiopatología , Índice de Severidad de la Enfermedad , Estilbenos/administración & dosificación , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
BACKGROUND & AIMS: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive biliary cystogenesis. Current therapies show short-term and/or modest beneficial effects. Cystic cholangiocytes hyperproliferate as a consequence of diminished intracellular calcium levels ([Ca(2+)]i). Here, the therapeutic value of ursodeoxycholic acid (UDCA) was investigated. METHODS: Effect of UDCA was examined in vitro and in polycystic (PCK) rats. Hepatic cystogenesis and fibrosis, and the bile acid (BA) content were evaluated from the liver, bile, serum, and kidneys by HPLC-MS/MS. RESULTS: Chronic treatment of PCK rats with UDCA inhibits hepatic cystogenesis and fibrosis, and improves their motor behaviour. As compared to wild-type animals, PCK rats show increased BA concentration ([BA]) in liver, similar hepatic Cyp7a1 mRNA levels, and diminished [BA] in bile. Likewise, [BA] is increased in cystic fluid of PLD patients compared to their matched serum levels. In PCK rats, UDCA decreases the intrahepatic accumulation of cytotoxic BA, normalizes their diminished [BA] in bile, increases the BA secretion in bile and diminishes the increased [BA] in kidneys. In vitro, UDCA inhibits the hyperproliferation of polycystic human cholangiocytes via a PI3K/AKT/MEK/ERK1/2-dependent mechanism without affecting apoptosis. Finally, the presence of glycodeoxycholic acid promotes the proliferation of polycystic human cholangiocytes, which is inhibited by both UDCA and tauro-UDCA. CONCLUSIONS: UDCA was able to halt the liver disease of a rat model of PLD through inhibiting cystic cholangiocyte hyperproliferation and decreasing the levels of cytotoxic BA species in the liver, which suggests the use of UDCA as a potential therapeutic tool for PLD patients.
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Apoptosis , Quistes/tratamiento farmacológico , Hepatopatías/tratamiento farmacológico , Hígado/patología , Ácido Ursodesoxicólico/farmacología , Animales , Ácidos y Sales Biliares/metabolismo , Conductos Biliares/metabolismo , Conductos Biliares/patología , Calcio/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Colagogos y Coleréticos/farmacología , Quistes/metabolismo , Quistes/patología , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Hígado/metabolismo , Hepatopatías/metabolismo , Hepatopatías/patología , Ratas , Espectrometría de Masas en TándemRESUMEN
Two recent genome-wide association studies in Asians have reported the association between the PSCA (prostate stem cell antigen) rs2294008C>T gene polymorphism and two Helicobacter pylori infection-related diseases such as gastric cancer (GC) and duodenal ulcer (DU). Since rs2294008 allele frequencies differ notably among ethnicities, we aimed to assess the role of rs2294008 on the susceptibility to GC and DU in a Caucasian population in Spain. Moreover, the relevance of rs2294008 on GC prognosis was evaluated. Genomic DNA from 603 Spanish patients with primary GC, 139 with DU and 675 healthy controls was typed for the PSCA rs2294008C>T polymorphism by PCR-TaqMan assays. H. pylori infection [odds ratio (OR): 8.27; 95% confidence interval (CI): 3.45-15.33] and nonsteroidal anti-inflammatory drugs (OR: 6.54; 95% CI: 3.19-12.43) were identified as independent risk factors for DU whereas the rs2294008T allele was associated with reduced risk of developing the disease (OR: 0.52; 95% CI: 0.33-0.82). Infection with CagA strains (OR: 2.10; 95% CI: 1.63-2.34), smoking (OR: 1.93; 95% CI: 1.54-2.61), family history of GC (OR: 2.83; 95% CI: 2.01-3.83), and the rs2294008T allele (OR: 1.46; 95% CI: 1.07-1.99) were associated with increased risk of GC. Interestingly, the association with the rs2294008T allele was restricted to noncardia GC (OR: 1.43; 95% CI: 1.12-1.82), particularly of the diffuse histotype (OR: 1.59; 95% CI: 1.16-1.92). Finally, Cox regression analysis identified the rs2294008T variant as a prognosis factor associated with worse overall survival in patients with diffuse-type GC (hazard ratio: 1.85; 95% CI: 1.12-3.06). From these results we conclude that the PSCA rs2294008 polymorphism is involved in the susceptibility to GC and DU, as well as in the prognosis of the diffuse-type of GC in Caucasians.
Asunto(s)
Antígenos de Neoplasias/genética , Úlcera Duodenal/genética , Predisposición Genética a la Enfermedad/genética , Proteínas de Neoplasias/genética , Polimorfismo Genético/genética , Neoplasias Gástricas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , Úlcera Duodenal/microbiología , Úlcera Duodenal/patología , Femenino , Proteínas Ligadas a GPI/genética , Estudio de Asociación del Genoma Completo/métodos , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/patología , Helicobacter pylori , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Pronóstico , Riesgo , Factores de Riesgo , España , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Población Blanca/genética , Adulto JovenRESUMEN
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is caused by abnormal accumulation of lipids within liver cells. Its prevalence is increasing in developed countries in association with obesity, and it represents a risk factor for non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. Since NAFLD is usually asymptomatic at diagnosis, new non-invasive approaches are needed to determine the hepatic lipid content in terms of diagnosis, treatment and control of disease progression. Here, we investigated the potential of magnetic resonance imaging (MRI) to quantitate and monitor the hepatic triglyceride concentration in humans. METHODS: A prospective study of diagnostic accuracy was conducted among 129 consecutive adult patients (97 obesity and 32 non-obese) to compare multi-echo MRI fat fraction, grade of steatosis estimated by histopathology, and biochemical measurement of hepatic triglyceride concentration (that is, Folch value). RESULTS: MRI fat fraction positively correlates with the grade of steatosis estimated on a 0 to 3 scale by histopathology. However, this correlation value was stronger when MRI fat fraction was linked to the Folch value, resulting in a novel equation to predict the hepatic triglyceride concentration (mg of triglycerides/g of liver tissue = 5.082 + (432.104 * multi-echo MRI fat fraction)). Validation of this formula in 31 additional patients (24 obese and 7 controls) resulted in robust correlation between the measured and estimated Folch values. Multivariate analysis showed that none of the variables investigated improves the Folch prediction capacity of the equation. Obese patients show increased steatosis compared to controls using MRI fat fraction and Folch value. Bariatric surgery improved MRI fat fraction values and the Folch value estimated in obese patients one year after surgery. CONCLUSIONS: Multi-echo MRI is an accurate approach to determine the hepatic lipid concentration by using our novel equation, representing an economic non-invasive method to diagnose and monitor steatosis in humans.
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Imagen por Resonancia Magnética/métodos , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad , Triglicéridos/metabolismo , Cirugía Bariátrica , Estudios Transversales , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
Non-alcoholic fatty liver disease covers a wide spectrum of liver pathologies which range from simple steatosis to non-alcoholic steatohepatitis. Polyphenols are members of a very large family of plant-derived compounds that can have beneficial effects on human health, and thus their study has become an increasingly important area of human nutrition research. The aim of the present review is to compile published data concerning the effects of both isolated polyphenols as well as polyphenol extracts, on hepatocyte and liver fat accumulation under different steatosis-inducing conditions. The results reported clearly show that this group of biomolecules is able to reduce fat accumulation, but further studies are needed to establish the optimal dose and treatment period length. With regard to the potential mechanisms of action, there is a good consensus. The anti-lipidogenic effect of polyphenols is mainly due to reduced fatty acid and triacylglycerol synthesis, increased in fatty acid oxidation, and reduced of oxidative stress and inflammation. As a general conclusion, it can be stated that polyphenols are biomolecules which produce hepatoprotective effects. To date, these beneficial effects have been demonstrated in cultured cells and animal models. Thus, studies performed in humans are needed before these molecules can be considered as truly useful tools in the prevention of liver steatosis.
Asunto(s)
Hipolipemiantes/uso terapéutico , Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Polifenoles/uso terapéutico , Estilbenos/uso terapéutico , Animales , Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hígado/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Fitoterapia , Plantas Medicinales , Quercetina/uso terapéutico , Resveratrol , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: We compared the ability of biennial fecal immunochemical testing (FIT) and one-time sigmoidoscopy to detect colon side-specific advanced neoplasms in a population-based, multicenter, nationwide, randomized controlled trial. METHODS: We identified asymptomatic men and women, 50-69 years old, through community health registries and randomly assigned them to groups that received a single colonoscopy examination or biennial FIT. Sigmoidoscopy yield was simulated from results obtained from the colonoscopy group, according to the criteria proposed in the UK Flexible Sigmoidoscopy Trial for colonoscopy referral. Patients who underwent FIT and were found to have ≥75 ng hemoglobin/mL were referred for colonoscopy. Data were analyzed from 5059 subjects in the colonoscopy group and 10,507 in the FIT group. The main outcome was rate of detection of any advanced neoplasm proximal to the splenic flexure. RESULTS: Advanced neoplasms were detected in 317 subjects (6.3%) in the sigmoidoscopy simulation group compared with 288 (2.7%) in the FIT group (odds ratio for sigmoidoscopy, 2.29; 95% confidence interval, 1.93-2.70; P = .0001). Sigmoidoscopy also detected advanced distal neoplasia in a higher percentage of patients than FIT (odds ratio, 2.61; 95% confidence interval, 2.20-3.10; P = .0001). The methods did not differ significantly in identifying patients with advanced proximal neoplasms (odds ratio, 1.17; 95% confidence interval, 0.78-1.76; P = .44). This was probably due to the lower performance of both strategies in detecting patients with proximal lesions (sigmoidoscopy detected these in 19.1% of patients and FIT in 14.9% of patients) vs distal ones (sigmoidoscopy detected these in 86.8% of patients and FIT in 33.5% of patients). Sigmoidoscopy, but not FIT, detected proximal lesions in lower percentages of women (especially those 50-59 years old) than men. CONCLUSIONS: Sigmoidoscopy and FIT have similar limitations in detecting advanced proximal neoplasms, which depend on patients' characteristics; sigmoidoscopy underperforms for women 50-59 years old. Screening strategies should be designed on the basis of target population to increase effectiveness and cost-effectiveness. ClinicalTrials.gov number: NCT00906997.
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Colon/patología , Neoplasias del Colon/diagnóstico , Heces/química , Inmunohistoquímica/métodos , Sigmoidoscopía/métodos , Anciano , Análisis Costo-Beneficio , Femenino , Humanos , Inmunohistoquímica/economía , Masculino , Tamizaje Masivo/economía , Tamizaje Masivo/métodos , Persona de Mediana Edad , Sigmoidoscopía/economía , Reino UnidoRESUMEN
OBJECTIVE: Polycystic liver diseases (PCLDs) are genetic disorders characterised by progressive bile duct dilatation and/or cyst development. Their pathogenesis is a consequence of hyperproliferation, hypersecretion and microRNA alterations in cholangiocytes. Here we evaluate the role of matrix metalloproteases (MMPs) in the hepatic cystogenesis of PCLDs. DESIGN: Metalloprotease activity was measured by microfluorimetric assays in normal and polycystic cholangiocyte cultures from humans and rats, and gene expression by real time quantitative PCR. The role of cytokines, oestrogens and growth factors present in the cystic fluid of PCLD patients was evaluated for MMP activity. The MMP inhibitor marimastat was examined for cystic expansion in vitro and in polycystic kidney (PCK) rats. RESULTS: Polycystic human and rat cholangiocytes displayed increased MMP activity, which was associated with increased mRNA levels of different MMPs. Interleukin (IL)-6 and IL-8, and 17ß-oestradiol, all stimulated MMP activity in human cholangiocytes. The presence of antibodies against IL-6 and/or IL-8 receptor/s inhibited baseline MMP hyperactivity of polycystic human cholangiocytes but had no effect on normal human cholangiocytes. MMP-3 was overexpressed in cystic cholangiocytes from PCLD human and PCK rat livers by immunohistochemistry. Marimastat reduced MMP hyperactivity of polycystic human and rat cholangiocytes and blocked the cystic expansion of PCK cholangiocytes cultured in three-dimensions. Chronic treatment of 8-week-old PCK rats with marimastat inhibited hepatic cystogenesis and fibrosis. CONCLUSIONS: PCLDs are associated with cholangiocyte MMP hyperactivity resulting from autocrine/paracrine stimulation by IL-6 and IL-8. Inhibition of this MMP hyperactivity with marimastat decreased hepatic cystogenesis in vitro and in an animal model of PCLD, offering a potential therapeutic tool.
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Conductos Biliares/enzimología , Quistes/prevención & control , Inhibidores Enzimáticos/farmacología , Ácidos Hidroxámicos/farmacología , Hepatopatías/prevención & control , Metaloendopeptidasas/antagonistas & inhibidores , Animales , Conductos Biliares/patología , Western Blotting , Técnicas de Cultivo de Célula , Quistes/enzimología , Citocinas/metabolismo , Citofotometría , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Hígado/patología , Hepatopatías/enzimología , Masculino , Ratas , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
There is a general need in healthcare systems all around the world to reduce costs in terms of time and money without compromising patients outcome. Point-of-Care Testing (POCT) is currently being used in some applications (e.g. POC coagulation devices) as an alternative to already established standard central laboratory tests to overcome sample transportation and long turnaround times. The main objective of this investigation was to quantify Tumour Necrosis Factor-alpha (TNF-α) on-chip within the clinical relevant range of 5-100 pg/mL in human pooled plasma. The novel solid-phase assay developed in this study was a magnetic bead-based proximity ligation assay (PLA) in which one of the assay proximity probes was directly immobilised onto streptavidin-coated magnetic beads. The portable device was based on a disposable and single-use cyclo-olefin polymer (COP) microfluidic chip interfaced with a quantitative real-time polymerase chain reaction (qPCR) device previously developed in-house. Sample volume was 10 µL and total assay time under 3 h. The POC device and assay developed offer portability, smaller reagent and sample consumption, and faster time-to-results compared with standard ELISAs. Determination and monitoring of TNF-α therapy at the point-of-care will help to improve clinical and/or economical outcome in governmental healthcare budgets.
Asunto(s)
Técnicas Analíticas Microfluídicas/instrumentación , Sistemas de Atención de Punto , Factor de Necrosis Tumoral alfa/sangre , Técnicas Biosensibles/instrumentación , Diseño de Equipo , Humanos , Límite de Detección , Reacción en Cadena en Tiempo Real de la Polimerasa/instrumentaciónRESUMEN
OBJECTIVE: The aim of this study was to examine whether resveratrol might represent a promising therapeutic tool with which to combat adipose tissue chronic inflammation in a model of genetic obesity and to link its anti-inflammatory activity with its effect on body fat reduction. METHODS: Twenty 6-wk-old male Zucker (fa/fa) rats were randomly distributed into two experimental groups. Resveratrol (RSV) was given orally (15 mg/kg body weight/d in RSV group) by means of an orogastric catheter for 6 wk. Enzyme activities were measured spectrophotometrically or fluorimetrically. Gene and protein expressions were analyzed by reverse transcriptase polymerase chain reaction and Western blot respectively. Cytokine concentrations and the activity of nuclear factor κ-light-chain-enhancer of activated ß cells (NF-κB) were measured by using commercial kits. RESULTS: RSV reduced the weight of internal adipose tissues. In epididymal depot glucose-6P-dehydrogenase, acetyl-CoA carboxylase activities, as well as lipoprotein lipase expression and activity were reduced by RSV. The expression of hormone-sensitive lipase was increased, and that of the cluster of differentiation 36 was reduced. Serum concentrations of tumor necrosis factor-α, monocyte chemoattractant protein 1, and C-reactive protein were lower in the RSV-treated group than in the control group. Protein expression of interleukin-6 and the activity of NF-κB, were decreased by RSV. CONCLUSION: The present results provide evidence that fatty acid uptake and lipolysis are metabolic pathways involved in the response of adipose tissue to RSV. This polyphenol modulates plasma cytokine levels partially by reducing macrophage infiltration in adipose tissue and inhibiting NF-κB activity.