Background & AimsOestrogen and oestrogen‐mediated signalling protect from hepatitis C virus through incompletely understood mechanisms. We aimed to ascertain which phase(s) of hepatitis C virus life cycle is/are affected by oestrogens.MethodsHuh7 cells infected with the JFH1 virus (genotype 2a) were exposed to dehydroepiandrosterone, testosterone, progesterone and 17β‐estradiol (tested with/without its receptor antagonist fulvestrant). Dose–response curves were established to calculate half maximal inhibitory concentration values. To dissect how 17β‐estradiol interferes with phases of hepatitis C virus life cycle, its effects were measured on the hepatitis C virus pseudo‐particle system (viral entry), the subgenomic replicon N17/JFH1 and the replicon cell line Huh7‐J17 (viral replication). Finally, in a dual‐step infection model, infectious supernatants, collected from infected cells exposed to hormones, were used to infect naïve cells.ResultsProgesterone and testosterone showed no inhibitory effect on hepatitis C virus; dehydroepiandrosterone was only mildly inhibitory. In contrast, 17β‐estradiol inhibited infection by 64%‐67% (IC 50 values 140‐160 nmol/L). Fulvestrant reverted the inhibition by 17β‐estradiol in a dose‐dependent manner. 17β‐estradiol exerted only a slight inhibition (<20%) on hepatitis C virus pseudo‐particles, and had no effect on cells either transiently or stably (Huh7‐J17 cells) expressing the N17/JFH1 replicon. In the dual‐step infection model, a significant half maximal inhibitory concentration decline occurred between primary (134 nmol/L) and secondary (100 nmol/L) infections (P=.02), with extracellular hepatitis C virus RNA and infectivity being reduced to a higher degree in comparison to its intracellular counterpart.Conclusions17β‐estradiol inhibits hepatitis C virus acting through its intracellular receptors, mainly interfering with late phases (assembly/release) of the hepatitis C virus life cycle.
The proinflammatory state of metabolic disorders encompasses the alterations in leukocyte counts and acute-phase reactants, and thus, predisposes to acute and chronic cardiovascular events linked to fat accumulation. Leptin is a marker of adiposity and also yields regulatory effects on innate and adaptive immunity; however, its role on the immune function of obese subjects remains to be elucidated. The aim of this study is to determine the influence of obesity and the role of leptin concentrations on lymphocyte counts and immunoglobulin levels as broad markers of immune function. Cross-sectional analysis in 147 obese (64 M, BMI 43 ± 8.1 kg/m(2)) and 111 age- and sex-matched controls (36 M, BMI 22.5 ± 2.6 kg/m(2)) by assessment of peripheral leukocyte counts, immunoglobulin (Ig) A, G, M levels, leptin, glucose and lipid homeostasis, and acute-phase reactants. Compared to controls, all the leukocyte components were significantly increased in obesity (p < 0.0001 for all) except for basophils and eosinophils. While IgA and IgG levels were similar between groups, IgM levels were lower (p < 0.001) in obese individuals. A significant relationship was evident between leptin and leukocyte counts (p < 0.001), with this latter being correlated to insulin resistance, adiposity, and lipid profile. At the stepwise multiple regression analysis, leukocytes were best predicted by leptin (β = 0.43, p < 0.0001) and male gender (β = 0.15, p < 0.05), yet when obesity entered the equation, it acted as an independent predictor of leukocytes (β = 0.51, p < 0.0001). Leptin also acted as a predictor of IgA levels (β = 0.20, p < 0.01). Current results show that IgM levels are significantly decreased in patients with obesity in association to significant increments in leukocyte counts. These latter are markedly correlated to leptin levels, insulin resistance, lipid profile, and adiposity. This circumstance, and the significant correlation seen between leptin and IgA levels, may suggest an indirect intervention of leptin in the immunologic alterations consequent to obesity and related to its cardiovascular risk.
Background:Cirrhotic cardiomyopathy is characterized by a set of cardiovascular modifications observed in advanced chronic liver disease. The aim of this study was to investigate cardiovascular alterations in chronic liver disease with different stages of fibrosis and to correlate cardiac involvement with endoscopic complications of portal hypertension.Methods:Seventy patients with chronic hepatitis C-related chronic liver disease and 20 sex- and age-matched controls underwent clinical evaluation, hepatic transient elastography, and echocardiography. Forty-nine of the 70 patients underwent an esophagogastroduodenoscopy for screening of esophageal and gastric varices.Results:According to the value of liver stiffness (LS), patients were divided in 2 groups: non-cirrhotics (LS<12.5 kPa; n=30; median LS=8.1 kPa, 95% confidence interval [CI] 6.4-9.2 kPa) and cirrhotics (LS>12.5 kPa; n=40; median LS=19.4 kPa, 95%CI 17-22 kPa). Compared to non-cirrhotics, cirrhotics showed a significant dilatation of the left atrium (P=0.007 and P=0.003 for area and volume index, respectively). In patients with chronic liver disease, peak systolic wave velocity (S¢) measured by tissue Doppler imaging (TDI) was lower (P=0.004), but ejection fraction was not reduced. Left atrial volume, left ventricular mass index and TDI S¢-wave velocity, but not liver stiffness, correlated with endoscopic signs of portal hypertension.Conclusions:Left atrial enlargement and peak S¢-wave systolic velocities are echocardiographic markers of diastolic and systolic dysfunction in liver cirrhosis. Cardiac alterations closely correlate to endoscopic portal hypertension; further studies could elucidate the potential role of echocardiography in the early identification of cirrhotic patients at higher risk for endoscopic complications of portal hypertension.
In the early postoperative period of liver transplantation, interferon-stimulated gene activation is dependent on hepatitis C recurrence (the main factor responsible for early fibrosis progression) and donor age, and is related to the risk of acute cellular rejection.
We found no evidence that CXCL-10, IL-12 or IL-21 were associated with HBeAg seroconversion following HBV-active cART. Other immunological determinants should be explored in this setting.
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