RESUMO
UNLABELLED: Chronic hepatitis C virus (HCV) infection may progress to cirrhosis and hepatocellular carcinoma (HCC). Recently, two genetic variants, DEPDC5 rs1012068 and MICA rs2596542, were associated with the onset of HCC in Asian subjects with chronic HCV infection. The aim of the present study was to analyze whether DEPDC5 and MICA genetic variants were associated with liver disease progression in European subjects with chronic HCV infection. In a Northern Italian discovery cohort (n = 477), neither DEPDC5 rs1012068 nor MICA rs2596542 were associated with HCC (n = 150). However, DEPDC5 rs1012068 was independently associated with cirrhosis (n = 300; P = 0.049). The association of rs1012068 with moderate to severe fibrosis was confirmed in an independent cross-sectional German cohort (n = 415; P = 0.006). Furthermore, DEPDC5 rs1012068 predicted faster fibrosis progression in a prospective cohort (n = 247; P = 0.027). Next, we examined the distribution of nonsynonymous DEPDC5 variants in the overall cross-sectional cohort (n = 912). The presence of at least one variant increased the risk of moderate/severe fibrosis by 54% (P = 0.040). To understand the molecular mechanism underlying the genetic association of DEPDC5 variants with fibrosis progression, we performed in vitro studies on immortalized hepatic stellate cells (LX-2). In these cells, down-regulation of DEPDC5 resulted in increased expression of ß-catenin and production of its target matrix metallopeptidase 2 (MMP2), a secreted enzyme involved in fibrosis progression. CONCLUSION: DEPDC5 variants increase fibrosis progression in European subjects with chronic HCV infection. Our findings suggest that DEPDC5 down-regulation may contribute to HCV-related fibrosis by increasing MMP2 synthesis through the ß-catenin pathway.
Assuntos
Carcinoma Hepatocelular/etiologia , Progressão da Doença , Hepatite C Crônica/complicações , Hepatite C Crônica/genética , Cirrose Hepática/etiologia , Neoplasias Hepáticas/etiologia , Proteínas Repressoras/genética , Estudos Transversais , Feminino , Proteínas Ativadoras de GTPase , Variação Genética , Alemanha , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Suíça , População BrancaRESUMO
A lower bone mass accompanied by a higher bone fragility with increased risk of fracture are observed in individuals with type 1 diabetes mellitus. Low C-peptide levels are associated with low lumbar mineral density in postmenopausal woman. In this work, we investigated the role of C-peptide on the osteoblast cell biology in vitro. We examined intracellular pathways and we found that C peptide activates ERK1/2 in human osteoblast-like cells (Saos-2). We also observed that proinsulin C-peptide prevents a reduction of type I collagen expression and decreases, in combination with insulin, receptor activator of nuclear factor-κB (RANKL) levels. In this work we show for the first time that Cpeptide activates a specific intracellular pathway in osteoblasts and it modulates the expression of protein involved in bone remodeling. Our results suggest that both C-peptide may have a role in bone metabolism. Further studies are needing to fully clarify its role.
Assuntos
Peptídeo C/metabolismo , Colágeno Tipo I/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Osteoblastos/metabolismo , Ligante RANK/metabolismo , Remodelação Óssea/fisiologia , Linhagem Celular , Humanos , Insulina/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologiaRESUMO
The mechanisms underlying the change in phenotype from metabolically healthy to metabolically unhealthy obesity are still unclear. The aim of this study is to investigate whether a difference in fasting fat utilization exists between overweight/obese individuals with a favorable cardiovascular risk profile and those with Metabolic Syndrome and Type 2 diabetes. Furthermore, we sought to explore whether there is an association between fasting fat utilization and insulin resistance. In this cross-sectional study, 172 overweight/obese individuals underwent a nutritional assessment. Those with fasting glucose ≥ 126 mg/dL or antidiabetic treatment were considered to be diabetics. If at least three of the NCEP criteria were present, they had Metabolic Syndrome, while those with less criteria were considered to be healthy overweight/obese. An indirect calorimetry was performed to estimate Respiratory Quotient, an index of nutrient utilization. A lower Respiratory Quotient (i.e., higher fat utilization) was found in healthy overweight/obese individuals than in those with Metabolic Syndrome and Type 2 diabetes (0.85 ± 0.05; 0.87 ± 0.06; 0.88 ± 0.05 respectively, p = 0.04). The univariate and multivariable analysis showed a positive association between the Respiratory Quotient and HOMA-IR (slope in statistic (B) = 0.004; ß = 0.42; p = 0.005; 95% Confidence interval = 0.001-0.006). In this study, we find, for the first time, that the fasting Respiratory Quotient is significantly lower (fat utilization is higher) in individuals who are metabolically healthy overweight/obese than in those with metabolically unhealthy obesity. In addition, we demonstrated the association between fat utilization and HOMA-IR, an insulin resistance index.
Assuntos
Índice de Massa Corporal , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gorduras/metabolismo , Síndrome Metabólica/metabolismo , Obesidade Metabolicamente Benigna/metabolismo , Obesidade/complicações , Idoso , Glicemia/metabolismo , Calorimetria Indireta , Doenças Cardiovasculares/etiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/etiologia , Metabolismo Energético , Feminino , Humanos , Insulina/sangue , Resistência à Insulina , Metabolismo dos Lipídeos , Masculino , Síndrome Metabólica/etiologia , Pessoa de Meia-Idade , Obesidade/metabolismo , Sobrepeso , Valores de Referência , Fatores de RiscoRESUMO
BACKGROUND: Inflammatory bowel diseases (IBD) are characterized by chronic relapsing inflammation of the gastrointestinal tract and encompass Crohn's disease and ulcerative colitis. IBD are often associated with extraintestinal manifestations affecting multiple organs including the liver. Increased levels of serum aminotransferases, possibly related to nonalcoholic fatty liver disease, constitute one of the most frequently described IBD-related liver diseases. The PNPLA3 I148M substitution is a major common genetic determinant of hepatic fat content and progression to chronic liver disease. The aim of this study was to investigate whether carriers of PNPLA3 148M allele with IBD have higher risk of liver steatosis and increase in transaminases levels. METHODS: The PNPLA3 I148M (rs738409) genotype was performed by Taqman assays in 158 individuals from Southern Italy (namely, Catanzaro cohort) and in 207 individuals from Northern Italy (namely, Milan cohort) with a definite diagnosis of IBD. Demographic and clinical data and also alanine transaminase levels were collected for both cohorts. The Catanzaro cohort underwent liver evaluation by sonography and liver stiffness and controlled attenuation parameter measurements by transient elastography. RESULTS: Here, we show for the first time that carriers of the PNPLA3 148M allele with IBD have a greater risk of hepatic steatosis (odds ratio, 2.9, and confidence interval, 1.1-7.8), higher controlled attenuation parameter values (P = 0.029), and increased circulating alanine transaminase (P = 0.035) in the Catanzaro cohort. We further confirm the higher alanine transaminase levels in the Milan cohort (P < 0.001). CONCLUSIONS: Our results show that PNPLA3 148M carriers with IBD have higher susceptibility to hepatic steatosis and liver damage.
Assuntos
Alanina Transaminase/sangue , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/complicações , Lipase/genética , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Alelos , Aspartato Aminotransferases/sangue , Biomarcadores/análise , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Genótipo , Heterozigoto , Humanos , Doenças Inflamatórias Intestinais/genética , Itália , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , Reação em Cadeia da Polimerase , Prognóstico , Fatores de RiscoRESUMO
Environmental pollutants are known to have adverse effects on human health. However, the link between chemical exposure and osteoarthritis remains little investigated. This study sought to assess in vitro the effect of several non-dioxin-like polychlorinated biphenyls (NDL-PCBs) on chondrocytes viability and apoptosis induction. Murine chondrogenic ATDC-5 cell line and human T/C-28a2 immortalized chondrocytes were exposed to NDL-PCBs 101, 153 and 180. Cell viability was examined using MTT assay. Necrosis was evaluated by LDH assay. Expression of apoptotic related proteins, such as caspase-3, Bcl-2 and Bax was assessed by Western blot analysis. Finally, oxidative stress was evaluated by malondialdehyde (MDA) assay and the Oxidative Stress Index. In vitro exposure to NDL-PCBs caused strong reduction of cell viability in a concentration-dependent manner. Data from LDH assay showed cellular necrosis induction. Caspase-3 activation, as well as, altered Bcl2/Bax ratio and p38 MAP-kinase phosphorylation also suggested apoptosis induction. Finally, MDA levels and Oxidative Stress Index revealed that PCBs drive chondrocyte death via increase of oxidative stress. The viability of murine and human chondrocytes was reduced in presence of PCBs. The activity of PCBs on cell viability is likely to be mediated by complex alterations involving regulation mechanisms of apoptosis, necrosis and oxidative stress.
Assuntos
Condrócitos/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Osteoartrite/etiologia , Estresse Oxidativo/efeitos dos fármacos , Bifenilos Policlorados/toxicidade , Animais , Caspase 3/análise , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/metabolismo , Humanos , L-Lactato Desidrogenase/análise , Malondialdeído/análise , Camundongos , Proteína X Associada a bcl-2/análise , Proteínas Quinases p38 Ativadas por Mitógeno/análiseRESUMO
The metabolic syndrome (MetS) is a cluster of cardiometabolic disorders that result from the increasing prevalence of obesity. The major components of MetS include insulin resistance, central obesity, dyslipidemia, and hypertension. MetS identifies the central obesity with increased risk for cardiovascular diseases (CVDs) and type-2 diabetes mellitus (T2DM). Patients with rheumatic diseases, such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis, have increased prevalence of CVDs. Moreover, CVD risk is increased when obesity is present in these patients. However, traditional cardiovascular risk factors do not completely explain the enhanced cardiovascular risk in this population. Thus, MetS and the altered secretion patterns of proinflammatory adipokines present in obesity could be the link between CVDs and rheumatic diseases. Furthermore, adipokines have been linked to the pathogenesis of MetS and its comorbidities through their effects on vascular function and inflammation. In the present paper, we review recent evidence of the role played by adipokines in the modulation of MetS in the general population, and in patients with rheumatic diseases.