Chagas disease is caused by infection with the intracellular protozoan parasite Trypanosoma cruzi. At present, nifurtimox and benznidazole, both compounds developed empirically over four decades ago, represent the chemotherapeutic arsenal for treating this highly neglected disease. However, both drugs present variable efficacy depending on the geographical area and the occurrence of natural resistance, and are poorly effective against the later chronic stage. As a part of a search for new therapeutic opportunities to treat chagasic patients, pre-clinical studies were performed to characterize the activity of a novel arylimidamide (AIA - DB1831 (hydrochloride salt) and DB1965 (mesylate salt)) against T.cruzi. These AIAs displayed a high trypanocidal effect in vitro against both relevant forms in mammalian hosts, exhibiting a high selectivity index and a very high efficacy (IC50 value/48 h of 5–40 nM) against intracellular parasites. DB1965 shows high activity in vivo in acute experimental models (mouse) of T.cruzi, showing a similar effect to benznidazole (Bz) when compared under a scheme of 10 daily consecutive doses with 12.5 mg/kg. Although no parasitological cure was observed after treating with 20 daily consecutive doses, a combined dosage of DB1965 (5 mg/kg) with Bz (50 mg/kg) resulted in parasitaemia clearance and 100% animal survival. In summary, our present data confirmed that aryimidamides represent promising new chemical entities against T.cruzi in therapeutic schemes using the AIA alone or in combination with other drugs, like benznidazole.
BackgroundThis study aimed to investigate the pathophysiology of hepatic microcirculatory dysfunction in non-alcoholic fatty liver disease (NAFLD).MethodsIn Wistar rats, NAFLD model was induced by 20 weeks of high-fat diet (HFD) feeding. Rolling and adhesion of leukocytes and tissue perfusion in hepatic microcirculation were examined using in vivo microscopic and laser speckle contrast imaging (LSCI), respectively. Oxidative stress and inflamatory parameters were analysed by TBARs, catalase enzyme activity, RT-PCR and ELISA. The participation of advanced glycation end-products (AGE) and its receptor RAGE was evaluated by the measurement of gene and protein expression of RAGE by RT-PCR and Western-blot, respectively and by liver and serum quantification of fluorescent AGEs.ResultsWistar rats fed high-fat diet (HFD) showed increase in epididymal and abdominal fat content, systolic arterial blood pressure, fasting blood glucose levels, hepatic triglycerides and cholesterol, and impairment of glucose and insulin metabolisms. Liver histology confirmed the presence of steatosis and ultrasound analysis revealed increased liver size and parenchymal echogenicity in HFD-fed rats. HFD causes significant increases in leukocyte rolling and adhesion on hepatic microcirculation and decrease in liver microvascular blood flow. Liver tissue presented increase in oxidative stress and inflammtion. At 20 weeks, there was a significantly increase in AGE content in the liver and serum of HFD-fed rats and an increase in RAGE gene expression in the liver.ConclusionThe increase in liver AGE levels and microcirculatory disturbances could play a role in the pathogenesis of liver injury and are key components of NAFLD.
Chagas disease, which is caused by the intracellular parasite
ObjectiveWe investigated the protective effects of pyridoxamine against metabolic and microcirculatory complications in nonalcoholic fatty liver disease.MethodsNonalcoholic fatty liver disease was established by a high‐fat diet administration over 28 weeks. Pyridoxamine was administered between weeks 20 and 28. The recruitment of leukocytes and the number of vitamin A‐positive hepatic stellate cells were examined by in vivo microscopy. Laser speckle contrast imaging was used to evaluate microcirculatory hepatic perfusion. Thiobarbituric acid reactive substances measurement and RT‐PCR were used for oxidative stress and inflammatory parameters. advanced glycation end products were evaluated by fluorescence spectroscopy.ResultsThe increase in body, liver, and fat weights, together with steatosis and impairment in glucose metabolism observed in the nonalcoholic fatty liver disease group were attenuated by pyridoxamine treatment. Regarding the hepatic microcirculatory parameters, rats with high‐fat diet‐induced nonalcoholic fatty liver disease showed increased rolling and adhesion of leukocytes, increased hepatic stellate cells activation, and decreased tissue perfusion, which were reverted by pyridoxamine. Pyridoxamine protected against the increased hepatic lipid peroxidation observed in the nonalcoholic fatty liver disease group. Pyridoxamine treatment was associated with increased levels of tumor necrosis factor alpha (TNF‐α) mRNA transcripts in the liver.ConclusionPyridoxamine modulates oxidative stress, advanced glycation end products, TNF‐α transcripts levels, and metabolic disturbances, being a potential treatment for nonalcoholic fatty liver disease‐associated microcirculatory and metabolic complications.
Introduction: Combined antiretroviral therapy (cART) used to treat acquired immunodeficiency virus (HIV) induces a number of adverse effects, such as insulin resistance and dyslipidemia, which ultimately increases the cardiovascular risk. Advanced glycation end products (AGEs) have been implicated in the etiology of cardiovascular diseases, diabetes and other chronic diseases. It is known that physical exercise improves the lipid profile, insulin resistance and reduces the risk of cardiovascular diseases. However, the impact of physical exercise on AGE levels in HIV-infected patients has not been so far investigated. Therefore, this study compared AGEs levels in people with and without HIV and verified the effect of physical training on serum AGE levels.Methods: Participants were initially assigned into three groups: healthy control (CTL, n = 35), physically inactive HIV-infected (In-HIV, n = 33) and physically active HIV-infected (Ac-HIV, n = 19). The In-HIV group underwent physical training for 3 months, consisting of 60-min sessions of multimodal supervised exercise (aerobic, resistance and flexibility) with moderate intensity (50–80% heart rate reserve), performed 3 times/week. AGEs were measured in serum by fluorescence spectrometry.Results: At baseline, serum AGEs fluorescence level was significantly higher in inactive HIV-patients when compared to controls or active HIV-patients (In-HIV: 0.93 ± 0.08 vs. controls: 0.68 ± 0.13 and Ac-HIV: 0.59 ± 0.04 A.U.; P < 0.001). Triglycerides were also higher in In-HIV than CTL (182.8 ± 102 vs. 132.8 ± 52.3 mg/dL; P < 0.05). Waist circumference was lower in Ac-HIV, compared to In-HIV and controls (83.9 ± 10.4 vs. 92.9 ± 13.5 and 98.3 ± 12.4, respectively; P < 0.05). Body mass, fasting blood glucose, LDL, HDL, and total cholesterol were similar between groups. After training, AGE levels decreased (Baseline: 0.93 ± 0.08 vs. 3 months follow-up: 0.59 ± 0.04 AU; P < 0.001), no further difference being detected vs. CTL or Ac-HIV. Conclusion: HIV-infected patients under cART exhibited elevated AGEs levels compared to healthy individuals and physically active patients. Short-term aerobic training of moderate intensity counteracted this condition.
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