The aim of the present study was to evaluate the effects of monotherapies and combinations of drugs on insulin sensitivity, adipose tissue morphology, and pancreatic and hepatic remodelling in C57BL/6 mice fed on a very HF (high-fat) diet. Male C57BL/6 mice were fed on an HF (60% lipids) diet or SC (standard chow; 10% lipids) diet for 10 weeks, after which time the following drug treatments began: HF-T (HF diet treated with telmisartan; 5.2 mg x kg-1 of body weight x day-1), HF-S (HF diet treated with sitagliptin; 1.08 g x kg-1 of body weight.day-1), HF-M (HF diet treated with metformin; 310.0 mg x kg-1 of body weight x day-1), HF-TM (HF diet treated with telmisartan+metformin), HF-TS (HF diet treated with telmisartan+sitagliptin) and HF-SM (HF diet treated with sitagliptin+metformin). Treated groups also had free access to the HF diet, and treatments lasted for 6 weeks. Morphometry, stereological tools, immunostaining, ELISA, Western blot analysis and electron microscopy were used. The HF diet yielded an overweight phenotype, an increase in oral glucose intolerance, hyperinsulinaemia, hypertrophied islets and adipocytes, stage 2 steatosis (>33%), and reduced liver PPAR-alpha (peroxisome-proliferator-activated receptor-alpha) and GLUT-2 (glucose transporter-2) levels, concomitant with enhanced SREBP-1 (sterol-regulatory-element-binding protein-1) expression (P<0.0001). Conversely, all drug treatments resulted in significant weight loss, a reversal of insulin resistance, islet and adipocyte hypertrophy, and alleviated hepatic steatosis. Only the HF-T and HF-TS groups had body weights similar to the SC group at the end of the experiment, and the latter treatment reversed hepatic steatosis. Increased PPAR-alpha immunostaining in parallel with higher GLUT-2 and reduced SREBP-1 expression may explain the favourable hepatic outcomes. Restoration of adipocyte size was consistent with higher adiponectin levels and lower TNF-alpha (tumour necrosis factor-alpha) levels (P<0.0001) in the drug-treated groups. In conclusion, all of the drug treatments were effective in controlling the metabolic syndrome. The best results were achieved using telmisartan and sitagliptin as monotherapies or as a dual treatment, combining partial PPAR-gamma agonism and PPAR-alpha activation in the liver with extended incretin action.

Enzyme replacement therapy with α-galactosidase A has been used to treat Fabry disease since 2001. This article reviews the published evidence for clinical efficacy of the two available enzyme preparations. We focused on heart, kidney, and nervous system manifestations, which impact both quality of life and overall prognosis. A literature search was undertaken to identify prospective open or randomized controlled trials of enzyme replacement therapy in patients with Fabry disease published since 2001. To date, no definitive conclusion can be drawn from studies that have directly compared therapeutic responses between the two commercially available enzyme preparations. Significant clinical benefits of enzyme replacement therapy have been demonstrated, mainly in patients at an early phase of the disease, with beneficial effects on heart, kidneys, pain, and quality of life in treated patients. Incidence of antibodies against agalsidase alfa and agalsidase beta observed during major clinical studies suggests a greater antigenic response to agalsidase beta. Further studies are required to confirm the long-term clinical benefits of enzyme replacement therapy. More studies with female patients are needed as are investigations of early initiation of enzyme replacement therapy to determine the optimal time to start treatment to prevent irreversible organ damage. The value of adjunctive and supportive therapies should also be rigorously analyzed.

Cigarette smoke (CS) causes pulmonary emphysema in humans and elastin degradation plays a key role in its pathogenesis. Previous studies on CS-exposed animals have been equivocal and have not clearly demonstrated the progression of the disease. In this study, morphometry was used to assess lung modifications to alveolar septa, airspaces, elastic and collagen fibers, and alveolar macrophages. Male (n = 40) C57/BL6 mice were exposed 3 times/day, whole body, to CS from three cigarettes for 10, 20, 30, or 60 days. Control groups (n = 10) were sham-smoked or received no exposure (day 0, n = 10). Morphometry included measurements of volume fraction of alveolar septa and airspaces, elastic and collagen fibers, and surface fraction of elastic fibers and alveolar septa. Morphometrical differences in mice after 60 days of exposure were greater than those after 10, 20, or 30 days, suggesting a progression of the disease. Inflammatory lesions in the lungs of mice contained significantly more metalloelastase (MMP-12) in macrophages at 10, 20, and 30 days than in controls of mice exposed for 60 days. These results suggest that elastin degradation took place during development of pulmonary changes in mice exposed to CS, and activation of MMPs specific for elastin may be a determining factor for susceptibility to emphysema.

The aim of this study was to investigate the effect of a polyphenol-rich Açaí seed extract (ASE, 300 mg/kg-1d-1) on adiposity and hepatic steatosis in mice that were fed a high-fat (HF) diet and its underlying mechanisms based on hepatic lipid metabolism and oxidative stress. Four groups were studied: C57BL/6 mice that were fed with standard diet (10% fat, Control), 10% fat + ASE (ASE), 60% fat (HF), and 60% fat + ASE (HF + ASE) for 12 weeks. We evaluated the food intake, body weight gain, serum glucose and lipid profile, hepatic cholesterol and triacyglycerol (TG), hepatic expression of pAMPK, lipogenic proteins (SREBP-1c, pACC, ACC, HMG-CoA reductase) and cholesterol excretion transporters, ABCG5 and ABCG8. We also evaluated the steatosis in liver sections and oxidative stress. ASE reduced body weight gain, food intake, glucose levels, accumulation of cholesterol and TG in the liver, which was associated with a reduction of hepatic steatosis. The increased expressions of SREBP-1c and HMG-CoA reductase and reduced expressions of pAMPK and pACC/ACC in HF group were antagonized by ASE. The ABCG5 and ABCG8 transporters expressions were increased by the extract. The antioxidant effect of ASE was demonstrated in liver of HF mice by restoration of SOD, CAT and GPx activities and reduction of the increased levels of malondialdehyde and protein carbonylation. In conclusion, ASE substantially reduced the obesity and hepatic steatosis induced by HF diet by reducing lipogenesis, increasing cholesterol excretion and improving oxidative stress in the liver, providing a nutritional resource for prevention of obesity-related adiposity and hepatic steatosis.

BackgroundThe interest in the mechanisms involved in Toxoplasma gondii lipid acquisition has steadily increased during the past few decades, but it remains not completely understood. Here, we investigated the biogenesis and the fate of lipid droplets (LD) of skeletal muscle cells (SkMC) during their interaction with T. gondii by confocal and electron microscopy. We also evaluated whether infected SkMC modulates the production of prostaglandin E2 (PGE2), cytokines interleukin-12 (IL-12) and interferon-gamma (INF-g), and also the cyclooxygenase-2 (COX-2) gene induction.MethodsPrimary culture of skeletal muscle cells were infected with tachyzoites of T. gondii and analysed by confocal microscopy for observation of LD. Ultrastructural cytochemistry was also used for lipid and sarcoplasmatic reticulum (SR) detection. Dosage of cytokines (IL-12 and INF-g) by ELISA technique and enzyme-linked immunoassay (EIA) for PGE2 measurement were employed. The COX-2 gene expression analysis was performed by real time reverse transcriptase polymerase chain reaction (qRT-PCR).ResultsWe demonstrated that T. gondii infection of SkMC leads to increase in LD number and area in a time course dependent manner. Moreover, the ultrastructural analysis demonstrated that SR and LD are in direct contact with parasitophorous vacuole membrane (PVM), within the vacuolar matrix, around it and interacting directly with the membrane of parasite, indicating that LD are recruited and deliver their content inside the parasitophorous vacuole (PV) in T. gondii-infected SkMC. We also observed a positive modulation of the production of IL-12 and IFN-g, increase of COX-2 mRNA levels in the first hour of T. gondii-SkMC interaction and an increase of prostaglandin E2 (PGE2) synthesis from 6 h up to 48 h of infection.ConclusionsTaken together, the close association between SR and LD with PV could represent a source of lipids as well as other nutrients for the parasite survival, and together with the increased levels of IL-12, INF-g and inflammatory indicators PGE2 and COX-2 might contribute to the establishment and maintenance of chronic phase of the T. gondii infection in muscle cell.

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Alpinia zerumbet (K. Schum), a medicinal plant originated from West Asia, is used in the northeast and southeast of Brazil as infusions or decoctions as a diuretic, antihypertensive, and antiulcerogenic. Experiments were undertaken to determine whether a hydroalcoholic extract obtained from leaves of Alpinia zerumbet (AZE) induces vasodilation in the mesenteric vascular bed (MVB), and an antihypertensive effect was also assessed in rats with DOCA-salt hypertension. In MVB precontracted with norepinephrine, AZE induces a long-lasting endothelium-dependent vasodilation that is not reduced by indomethacin. Inhibition of NO synthase by NG-nitro-L-arginine methyl ester (L-NAME) and guanylyl cyclase by 1H-[1,2,3]oxadiazolo [4,4-a]quinoxalin-1-one (ODQ) reduces the vasodilator effect of AZE. In vessels precontracted with norepinephrine, the vasodilator effect of AZE was not changed by 4-aminopyridine, glibenclamide, or by charybdotoxin plus apamin. Concentrations of atropine, pyrilamine, and yohimbine that significantly reduced the vasodilator effect of acetylcholine, histamine, and clonidine, respectively, did not change the vasodilator effect of AZE. HOE 140, which significantly reduced the vasodilator effect of bradykinin, induced a slight but significant reduction on the vasodilator effect of AZE. Chronic oral administration of AZE induced a significant reduction in systolic, mean, and diastolic arterial pressure in rats with DOCA-salt hypertension. Probably the vasodilator effect of AZE is dependent on the activation of the NO-cGMP pathway and independent of activation of ATP-dependent, voltage-dependent, and calcium-dependent K+ channels. Bradykinin receptors may also participate in the vasodilator effect of AZE. Finally, the vasodilator and antihypertensive effects of AZE demonstrated in the present study provide experimental support for the indication of Alpinia zerumbet as an antihypertensive medicinal plant.

Purpose: Fabry disease is a progressive multiorgan, multisystem disorder that is caused by a deficiency in the lysosomal enzyme ␣-galactosidase A. Serious renal, cardiac, and cerebrovascular involvement are responsible for much of the morbidity and premature mortality associated with Fabry disease, and neuropathic pain, gastrointestinal problems, and hypohidrosis negatively affect quality of life of patients with Fabry disease. Fabry disease is X-linked, but women are often symptomatic and may be as severely affected as men. Methods: We propose a series of therapeutic and symptomatic goals for use in setting the expectations of enzyme replacement therapy and for assessing the response to enzyme replacement therapy in the treatment of Fabry disease. Results: Enzyme replacement therapy has been available since 2001 and has been associated with benefit in clinical trials, including stabilization of kidney function, improvement of cardiac structure and function, reduction in severity of neuropathic pain, and improvement in gastrointestinal involvement. Conclusions: The presentation of these therapeutic goals will aid in the evaluation of response to enzyme replacement therapy and be useful in establishing an overall management plan for individual patients. Genet Med 2010:12(11):713-720.