Raltegravir (RAL) has been shown to be virologically effective in both treatment naive and triple class resistant patients. A more favourable metabolic profile associated with RAL in comparison with other antiretroviral drugs has also been observed. The aim of this study was to investigate the molecular mechanisms that could explain the lack of toxicity of this drug in metabolism. Thus, the effects of RAL on adipogenesis and adipocyte metabolism were analyzed using 3T3-L1 cells, a very adequate and convenient cell culture model for the investigation of adipose differentiation and metabolism. The effects of RAL on adipogenesis were evaluated by the Oil Red O staining after 8 days of induction of differentiation. Several adipogenic genes (C/EBP, PPAR, Pref-1 and AP2) were analyzed by real time PCR. Fully differentiated adipocytes were also incubated with RAL for 24 hours and glucose utilization, lactate production and glycerol release were analyzed. Thus, minimal effects of RAL on murine adipocyte differentiation were observed. Basal glucose uptake and lactate production were not affected by RAL at any of the concentrations used. No effects were also found on the percentage of glucose that is metabolized to lactate. Lipolysis was only slightly inhibited by Raltegravir (-10%) at the highest concentration used (50 µM), while no effects were observed with lower doses. Our results suggest that the absence of significant actions of RAL on adipogenesis and glucose and lipid metabolism in adipocytes could explain, at least in part, the neutral metabolic effects of RAL in clinical studies.
IntroductionSeveral factors such as duration of infection, age, male gender, consumption of alcohol, HIV infection and low CD4 count have been associated with fibrosis progression rate. However, it is relatively scarce, the knowledge about the liver fibrosis progression rate in HIV-infected patients with undetectable HIV viral load (VL). For this reason, we performed the present study.Materials and MethodsObservational and multicenter study (2008–2012) conducted in four hospitals of the northern Spain. HIV/HCV (hepatitis c) virus coinfected patients ≥18 years on stable combination antiretroviral therapy (cART) (≥6 months) and with a HIV VL <50 copies/mL were selected to analyze their liver fibrosis progression. Fibrosis progression was assessed using a Fibroscan® (502 STEP 3 model) and measuring a basal test and a second one at least 12 months apart from baseline. This evolution was compared with different variables such as duration of HIV/HCV coinfection, gender, age, previous treatment for HCV, HCV genotype, CD4 lymphocyte counts and the cART employed at the basal test.ResultsA total of 608 patients were included (median age 29.4 years, 71.7% men). Of these, 463 patients met the inclusion criteria. In these patients, the liver fibrosis progression was nearly flat and the only variables related to a higher liver fibrosis progression were the increasing age of the patients (p=0.02) and the duration of the coinfection (p=0.001). CD4 lymphocyte counts showed a tendency to improved liver fibrosis (p=0.056).ConclusionsIn HIV/HCV coinfected patients on stable cART and HIV undetectable VL, the increase in liver fibrosis rate progression was nearly flat, although it was significantly associated with the duration of the coinfection and the age of the patient. The beneficial effects of the cART were independent of the antiretroviral drug employed. A tendency to a lower fibrosis progression was observed in those patients with a higher CD4 count.
Background: Cellular senescence and low-grade inflammation favor the acceleration of aging. The liver is an essential metabolic organ because changes related to its function are related to age-related diseases. The objective of this study was to evaluate the effects of maraviroc (MVC) and/or rapamycin (RAPA) on liver tissue in an experimental model of aging in mice.Materials and methods: Eighty male homozygous IL10KO mice were randomly assigned to one of 4 groups (n= 20): i) IL10KO group (IL10KO); ii) IL10KO mice that received MVC in drinking water (MVC group), iii) IL10KO mice that received RAPA in drinking water (RAPA group), and iv) MVC-RAPA group that received MVC and RAPA in drinking water. Liver samples were analyzed. Gene expression quantification, western blotting and histopathological analyses were also performed.Results: The proinflammatory cytokines IL-6 and IL-18 were decreased in the MVC and MVC/RAPA groups, and TNF-α was decreased in all therapeutic groups. Galactosidase beta-1, a senescence biomarker, was also significantly reduced in all therapeutic groups, as were NK-kB1 and NF-kB2. In all groups, mTOR and CCL5 were significantly reduced. CCR5 expression was decreased in the MVC and MVC/RAPA groups.Conclusions: MVC and RAPA may protect against some factors involved in liver aging. More studies will be necessary to verify their clinical applications.
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