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1.
J Hepatol ; 77(4): 991-1004, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35750136

RESUMO

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.


Assuntos
Colestase , Glicoproteínas de Membrana , Receptores Imunológicos , Ácido Ursodesoxicólico , Animais , Antibacterianos , Anti-Inflamatórios , Colestase/complicações , Inflamação , Interleucina-33 , Lipopolissacarídeos , Fígado , Glicoproteínas de Membrana/genética , Camundongos , Receptores Imunológicos/genética , Receptor Gatilho 1 Expresso em Células Mieloides , Ácido Ursodesoxicólico/farmacologia
2.
Gut ; 70(7): 1345-1361, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-32907830

RESUMO

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.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genética , Adulto , Idoso , Animais , Carcinogênese/genética , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Dietilnitrosamina , Feminino , Mutação com Ganho de Função , Expressão Gênica , Células Estreladas do Fígado/metabolismo , Hepatite/metabolismo , Hepatócitos/patologia , Hepatócitos/fisiologia , Humanos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Regeneração Hepática/genética , Regeneração Hepática/fisiologia , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Estresse Oxidativo , Fatores de Proteção , RNA/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Imunológicos/metabolismo , Esferoides Celulares , Regulação para Cima , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Proteína Wnt3/metabolismo
3.
Gut ; 68(3): 533-546, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29374630

RESUMO

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.


Assuntos
Cirrose Hepática/metabolismo , Fígado/metabolismo , Glicoproteínas de Membrana/fisiologia , Receptores Imunológicos/fisiologia , Acetaminofen , Idoso , Animais , Tetracloreto de Carbono , Estudos de Casos e Controles , Feminino , Células-Tronco Hematopoéticas/metabolismo , Hepatócitos/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Células de Kupffer/metabolismo , Peroxidação de Lipídeos/fisiologia , Cirrose Hepática/etiologia , Cirrose Hepática/imunologia , Cirrose Hepática Experimental/imunologia , Cirrose Hepática Experimental/metabolismo , Masculino , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos Knockout , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio/metabolismo , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Receptor 4 Toll-Like/fisiologia , Regulação para Cima/fisiologia
4.
Int J Mol Sci ; 19(7)2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-30018277

RESUMO

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.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Glucose/metabolismo , Lipogênese/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Estilbenos/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Tecido Adiposo/citologia , Adulto , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Transporte Biológico/efeitos dos fármacos , Células Cultivadas , Suplementos Nutricionais , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Estilbenos/administração & dosagem , Receptor fas/genética , Receptor fas/metabolismo
5.
Oncotarget ; 8(22): 35848-35862, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28415781

RESUMO

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.


Assuntos
Reparo do DNA/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo Genético , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Terapia Combinada , Feminino , Frequência do Gene , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Fenótipo , Risco , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/terapia
6.
Mol Nutr Food Res ; 61(1)2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27377854

RESUMO

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.


Assuntos
Fármacos Antiobesidade/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/dietoterapia , Obesidade/metabolismo , Estilbenos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Suplementos Nutricionais , Disbiose/dietoterapia , Ratos Zucker
7.
PLoS One ; 11(4): e0153084, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27078840

RESUMO

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.


Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco
8.
Oncotarget ; 7(4): 4379-84, 2016 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-26735890

RESUMO

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.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pravastatina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Idoso , Feminino , Seguimentos , Humanos , Masculino , Estadiamento de Neoplasias , Prognóstico , Neoplasias Gástricas/patologia , Taxa de Sobrevida
9.
Alcohol Alcohol ; 51(3): 258-67, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26447226

RESUMO

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.


Assuntos
Alcoolismo/etiologia , Alcoolismo/genética , Neurônios Dopaminérgicos/fisiologia , Predisposição Genética para Doença , Estilo de Vida , Monoaminoxidase/genética , Receptores de Dopamina D2/genética , Alcoolismo/fisiopatologia , Alcoolismo/psicologia , Alelos , Estudos de Casos e Controles , Catecol O-Metiltransferase/genética , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Receptores de Dopamina D1/genética , Receptores de Dopamina D3/genética , Recompensa , Caracteres Sexuais , Tirosina 3-Mono-Oxigenase/genética , Proteínas Vesiculares de Transporte de Monoamina/genética , População Branca/genética
10.
J Physiol Biochem ; 72(3): 555-66, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26660756

RESUMO

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.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Suplementos Nutricionais , Rim/fisiopatologia , Obesidade/dietoterapia , Insuficiência Renal/prevenção & controle , Estilbenos/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Antioxidantes/administração & dosagem , Biomarcadores/metabolismo , Biomarcadores/urina , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/urina , Fibrose , Rim/imunologia , Rim/metabolismo , Rim/patologia , Peroxidação de Lipídeos , Masculino , Obesidade/imunologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Tamanho do Órgão , Estresse Oxidativo , Distribuição Aleatória , Ratos Zucker , Insuficiência Renal/etiologia , Insuficiência Renal/fisiopatologia , Índice de Gravidade de Doença , Estilbenos/administração & dosagem , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
11.
J Hepatol ; 63(4): 952-61, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26044126

RESUMO

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.


Assuntos
Apoptose , Cistos/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Fígado/patologia , Ácido Ursodesoxicólico/farmacologia , Animais , Ácidos e Sais Biliares/metabolismo , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Cálcio/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colagogos e Coleréticos/farmacologia , Cistos/metabolismo , Cistos/patologia , Modelos Animais de Doenças , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/metabolismo , Hepatopatias/patologia , Ratos , Espectrometria de Massas em Tandem
12.
Int J Cancer ; 137(6): 1362-73, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25721731

RESUMO

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.


Assuntos
Antígenos de Neoplasias/genética , Úlcera Duodenal/genética , Predisposição Genética para Doença/genética , Proteínas de Neoplasias/genética , Polimorfismo Genético/genética , Neoplasias Gástricas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Úlcera Duodenal/microbiologia , Úlcera Duodenal/patologia , Feminino , Proteínas Ligadas por GPI/genética , Estudo de Associação Genômica Ampla/métodos , Infecções por Helicobacter/genética , Infecções por Helicobacter/patologia , Helicobacter pylori , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Risco , Fatores de Risco , Espanha , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia , População Branca/genética , Adulto Jovem
13.
BMC Med ; 12: 137, 2014 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-25164060

RESUMO

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.


Assuntos
Imageamento por Ressonância Magnética/métodos , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade , Triglicerídeos/metabolismo , Cirurgia Bariátrica , Estudos Transversais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Índice de Gravidade de Doença
14.
World J Gastroenterol ; 20(23): 7366-80, 2014 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-24966607

RESUMO

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.


Assuntos
Hipolipemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Polifenóis/uso terapêutico , Estilbenos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Fitoterapia , Plantas Medicinais , Quercetina/uso terapêutico , Resveratrol , Resultado do Tratamento
15.
Clin Gastroenterol Hepatol ; 12(10): 1708-16.e4, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24681078

RESUMO

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.


Assuntos
Colo/patologia , Neoplasias do Colo/diagnóstico , Fezes/química , Imuno-Histoquímica/métodos , Sigmoidoscopia/métodos , Idoso , Análise Custo-Benefício , Feminino , Humanos , Imuno-Histoquímica/economia , Masculino , Programas de Rastreamento/economia , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Sigmoidoscopia/economia , Reino Unido
16.
Gut ; 63(10): 1658-67, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24436140

RESUMO

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.


Assuntos
Ductos Biliares/enzimologia , Cistos/prevenção & controle , Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/farmacologia , Hepatopatias/prevenção & controle , Metaloendopeptidases/antagonistas & inibidores , Animais , Ductos Biliares/patologia , Western Blotting , Técnicas de Cultura de Células , Cistos/enzimologia , Citocinas/metabolismo , Citofotometria , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Humanos , Imuno-Histoquímica , Fígado/patologia , Hepatopatias/enzimologia , Masculino , Ratos , Reação em Cadeia da Polimerase em Tempo Real
17.
Biosens Bioelectron ; 54: 499-505, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24316452

RESUMO

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.


Assuntos
Técnicas Analíticas Microfluídicas/instrumentação , Sistemas Automatizados de Assistência Junto ao Leito , Fator de Necrose Tumoral alfa/sangue , Técnicas Biossensoriais/instrumentação , Desenho de Equipamento , Humanos , Limite de Detecção , Reação em Cadeia da Polimerase em Tempo Real/instrumentação
18.
Nutrition ; 29(11-12): 1374-80, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24012391

RESUMO

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.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Inflamação/metabolismo , Obesidade/metabolismo , Estilbenos/farmacologia , Acetil-CoA Carboxilase/metabolismo , Adiponectina/sangue , Tecido Adiposo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Proteína C-Reativa/metabolismo , Quimiocina CCL2/sangue , Ácidos Graxos/administração & dosagem , Ácidos Graxos/farmacocinética , Glucosefosfato Desidrogenase/metabolismo , Inflamação/sangue , Inflamação/etiologia , Interleucina-6/sangue , Lipólise/efeitos dos fármacos , Masculino , NF-kappa B/metabolismo , Obesidade/complicações , Ratos , Ratos Zucker , Resveratrol , Fator de Necrose Tumoral alfa/sangue
19.
World J Gastroenterol ; 19(5): 638-47, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23429423

RESUMO

Although the association between alcohol and pancreatic diseases has been recognized for a long time, the impact of alcohol consumption on pancreatitis and pancreatic cancer (PC) remains poorly defined. Nowadays there is not consensus about the epidemiology and the beverage type, dose and duration of alcohol consumption causing these diseases. The objective of this study was to review the epidemiology described in the literature for pancreatic diseases as a consequence of alcoholic behavior trying to understand the association between dose, type and frequency of alcohol consumption and risk of pancreatitis and PC. The majority of the studies conclude that high alcohol intake was associated with a higher risk of pancreatitis (around 2.5%-3% between heavy drinkers and 1.3% between non drinkers). About 70% of pancreatitis are due to chronic heavy alcohol consumption. Although this incidence rate differs between countries, it is clear that the risk of developing pancreatitis increases with increasing doses of alcohol and the average of alcohol consumption vary since 80 to 150 g/d for 10-15 years. With regard to PC, the role of alcohol consumption remains less clear, and low to moderate alcohol consumption do not appear to be associated with PC risk, and only chronic heavy drinking increase the risk compared with lightly drinkers. In a population of 10%-15% of heavy drinkers, 2%-5% of all PC cases could be attributed to alcohol consumption. However, as only a minority (less than 10% for pancreatitis and 5% for PC) of heavily drinkers develops these pancreatic diseases, there are other predisposing factors besides alcohol involved. Genetic variability and environmental exposures such as smoking and diet modify the risk and should be considered for further investigations.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Etanol/efeitos adversos , Neoplasias Pancreáticas/epidemiologia , Pancreatite Alcoólica/epidemiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/prevenção & controle , Dieta/efeitos adversos , Relação Dose-Resposta a Droga , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Incidência , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/prevenção & controle , Pancreatite Alcoólica/genética , Pancreatite Alcoólica/prevenção & controle , Fatores de Risco , Comportamento de Redução do Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Fatores de Tempo
20.
PLoS One ; 8(1): e51810, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23300952

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the second most common cause of death from cancer in both men and women in the majority of developed countries. Molecular tests of blood could potentially provide this ideal screening tool. AIM: Our objective was to assess the usefulness of serum markers and mRNA expression levels in the diagnosis of CRC. METHODS: In a prospective study, we measured mRNA expression levels of 13 markers (carbonic anhydrase, guanylyl cyclase C, plasminogen activator inhibitor, matrix metalloproteinase 7 (MMP7), urokinase-type plasminogen activator receptor (uPAR), urokinase-type plasminogen activator, survivin, tetranectin, vascular endothelial growth factor (VEGF), cytokeratin 20, thymidylate synthase, cyclooxygenase 2 (COX-2), and CD44) and three proteins in serum (alpha 1 antitrypsin, carcinoembryonic antigen (CEA) and activated C3 in 42 patients with CRC and 33 with normal colonoscopy results. RESULTS: Alpha 1-antitrypsin was the serum marker that was most useful for CRC diagnosis (1.79 ± 0.25 in the CRC group vs 1.27 ± 0.25 in the control group, P<0.0005). The area under the ROC curve for alpha 1-antitrypsin was 0.88 (0.79-0.96). The mRNA expression levels of five markers were statistically different between CRC cases and controls: those for which the ROC area was over 75% were MMP7 (0.81) and tetranectin (0.80), COX-2 (0.78), uPAR (0.78) and carbonic anhydrase (0.77). The markers which identified early stage CRC (Stages I and II) were alpha 1-antitrypsin, uPAR, COX-2 and MMP7. CONCLUSIONS: Serum alpha 1-antitrypsin and the levels of mRNA expression of MMP7, COX-2 and uPAR have good diagnostic accuracy for CRC, even in the early stages.


Assuntos
Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico , Ciclo-Oxigenase 2/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , alfa 1-Antitripsina/sangue , Idoso , Biomarcadores Tumorais/sangue , Colonoscopia/métodos , Primers do DNA/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Mensageiro/metabolismo , Curva ROC
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