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Background and rationale for the study. Bacterial translocation is an important triggering factor of infection and mortality in cirrhosis. In a rat model using bile duct ligation (BDL), bacterial translocation appears within 24 h after ligation. The dynamic between TH1/TH2/TH17 cytokines and the integrity of the colonic mucosa in the context of cirrhosis is little known. This study aims to determine the link between bacterial translocation and intestinal inflammation in a cholestasis model. Additionally, alterations of the colonic mucus layer and the bacterial load were also addressed. RESULTS: Bacterial translocation detected by microbiological cultures and MALDI-TOF showed that Escherichia coli predominates in mesenteric lymph nodes of BDL rats. Intestinal bacterial load analyzed by qPCR indicates a dramatic Escherichia/Shigella overgrowth at 8 and 30 days post-BDL. IFN-γ, IL-4, and IL-17 evaluated by Western blotting were increased at 8 and 30 days in the small intestine. In the colon, in contrast, only IFN-γ was significantly increased. The colonic mucus layer and mucin-2 expression determined by Alcian blue staining and immunohistochemistry surprisingly showed an increase in the mucus layer thickness related to increased mucin-2 expression during the entire process of liver damage. Hepatic enzymes, as well as collagen I, collagen III, TNF-α, and IL-6 liver gene expression were increased. In conclusion, bacterial overgrowth associated with bacterial translocation is linked to the over-expression of IFN-γ, IL-4, IL-17 and mucin-2. These molecules might facilitate the intestinal permeability through exacerbating the inflammatory process and disturbing tight junctions, leading to the perpetuation of the liver damage.
Assuntos
Translocação Bacteriana , Colestase/metabolismo , Colestase/microbiologia , Microbioma Gastrointestinal , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Intestinos/microbiologia , Mucina-2/metabolismo , Animais , Colestase/patologia , Modelos Animais de Doenças , Hepatite/metabolismo , Hepatite/microbiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Intestinos/patologia , Fígado/metabolismo , Fígado/microbiologia , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/microbiologia , Linfonodos/metabolismo , Linfonodos/microbiologia , Linfonodos/patologia , Masculino , Permeabilidade , Ratos Wistar , Fatores de Tempo , Regulação para CimaRESUMO
INTRODUCTION: Obesity is the world's most important public health problem. Adipose tissue contributes significantly to increase pro-inflammatory mediators whose cascade begins with the union of TLR4 to its microbial ligands (TLR: Toll Like Receptors). It has been reported recently that NEFAs (Non-Esterified Fatty Acids) bind to this receptor as agonists. The purpose of our study was to determine the levels of expression of TLR4-CD14, the pro-inflammatory cytokines, the metabolic markers and the NEFAs in a group of adult, non-diabetic obese Mexicans. METHOD: A group of 210 adult middle-class Mexican non-diabetic obese patients was evaluated: 105 normal weight individuals, and 105 non-diabetic obese. On both groups, the following was tested in each patient: TLR4-CD14 receptors on monocytes in peripheral blood, inflammatory profile, HOMA-IR (Homeostasis Model Assessment-Insulin Resistance), NEFAs and each individual's anthropometric profile. RESULTS: Obesity is strongly associated with the expression of TLR4 (77%, MFI (Mean Fluorescence Index) 7.70) and CD14 (86% MFI 1.61) with 66% double positives (p = 0.000). These figures contrast with those for the normal weight individuals that constituted the control group: TLR4 (70% MFI 6.41) and CD14 (84% MFI 1.25) with 59% double positives. As for cytokine concentration, non- diabetic obese individuals vs the normal weight/thin, the numbers were: IL-1ß = 2.0 vs 2.5 pg/ml (p = NS), IL-6 = 36 vs 28 pg/ml (p = 0.030), IL-8 = 27 vs 27 pg/ml (p = NS), IL-10 = 8.4 vs 6.8 pg/ml (p = NS), TNF-α =31 vs 15 pg/ml (p = 0.000) respectively. Insulin levels were 12.1 vs 19.7 mcU/ml (p = 0.000) and the NEFAs were much higher in the obese vs normal weight/thin individuals (p = 0.000). CONCLUSION: Adipose tissue used to be thought of as mere storage of fats and energy, but it has been revealed to be an important neuro-immune-endocrine organ. Immune cells, stimulated by NEFAs, produce pro-inflammatory cytokines, which have a direct effect on oxidating radicals that directly target the release of noradrenalin. This in turn, reactivates the vicious cycle of low-grade chronic inflammation, as is now described in obesity.
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Obesity is a world health problem that increases the risk for developing type 2 diabetes, cardiovascular disease, fatty liver, and some types of cancer. In postmenopausal women, it represents an important risk factor for the development of breast cancer (BC). Leptin is an adipokine that is secreted by fatty tissue, and high leptin levels are observed both in mouse models of obesity and in obese subjects. High levels of leptin promote the proliferation and progression of various types of cancer, including BC. This review provides a general overview of the biology of leptin, important laboratory studies, and animal and clinical models that have provided evidence for an active role of leptin in the proliferation, progression, and survival of mammary tumors. Finally, this review addresses the most recent studies on the use of leptin receptor antagonists as a novel therapeutic treatment for BC.
Assuntos
Neoplasias da Mama/metabolismo , Leptina/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Modelos Animais de Doenças , Metabolismo Energético , Feminino , Homeostase , Humanos , Leptina/genética , Camundongos , Terapia de Alvo Molecular , Receptores para Leptina/antagonistas & inibidores , Receptores para Leptina/química , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Fatores de Risco , Transdução de SinaisRESUMO
Hypertriglyceridemia and dietary lipids have been suggested to modulate the severity of alcoholic liver disease and the progression to alcoholic cirrhosis (AC). The intestinal fatty acid binding protein (IFABP) is the main transporter of dietary fatty acids into the enterocyte and has a genetic polymorphism, FABP2 A54T that has been associated with hypertriglyceridemia. We determined the frequency of the FABP2 gene polymorphism using PCR-RFLP and measured serum triglycerides, HDL, LDL, total lipids and cholesterol in 67 patients with AC and in 124 unrelated healthy individuals. Frequencies of genotypes and alleles were similar between the two groups. The healthy subjects, who were homozygous for the Thr54 genotype had significantly higher mean triglyceride serum concentrations than those homozygous for the Ala54 genotype (P<0.05). However, AC patients who were homozygous for the Thr54 genotype, had lower mean triglyceride serum concentrations (P<0.01), and had a significantly longer period of continued alcohol abuse prior to the diagnosis of liver cirrhosis compared to the AC patients homozygous for the Ala54 genotype (P<0.05). Our data suggests that the polymorphism Thr54 of the FABP2 gene is associated with a later onset of AC in the lower economic status Mexican population studied.
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Objetivo. Estudiar prospectivamente las características demográficas y epidemiológicas de los pacientes con cirrosis hepática en el Hospital Civil de Guadalajara en un periodo de un año. Material y métodos. Se estudiaron 157 pacientes (48 mujeres y 109 hombres), de los servicios de Medicina Interna, Gastroenterología y Clínica de Hígado con diagnóstico de cirrosis hepática el cual se hizo con base en la información clínica, bioquímica o histopatológica; asimismo, se les aplicó un cuestionario especializado en enfermedades hepáticas. Resultados. La principal causa de la cirrosis fue el alcoholismo (38 por ciento en mujeres y 95 por ciento en hombres), seguida de la etiología viral. Las bebidas más frecuentes fueron el tequila y el alcohol de 96º G.L. El grado de insuficiencia hepática más frecuentemente observado fue el de Child-Pugh "B" en mujeres y "C" en los hombres. Las complicaciones más frecuentes fueron hemorragia de tubo digestivo, ascitis y encefalopatía hepática. Se observaron diferencias en varias características relacionadas con el sexo de los pacientes. Conclusiones. El alcoholismo fue la primera causa de cirrosis hepática. En mujeres la segunda causa fue la viral (16.7 por ciento). Se propone un comité nacional de vigilancia de enfermedades del hígado, para generar una información más completa y detallada acerca de la epidemiología de la cirrosis hepática