Non-alcoholic fatty liver disease (NAFLD) is characterized by liver steatosis, oxidative stress, and drastic depletion of n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA), namely, eicosapentaenoic acid (C20:5 n-3, EPA) and docosahexaenoic acid (C22:6 n-3, DHA), which trigger lipolysis stimulation and lipogenesis inhibition. Extra virgin olive oil (EVOO) has important antioxidant effects. This study evaluated the anti-steatotic effects of n-3 LCPUFA plus EVOO in the liver of male C57BL/6J mice subjected to a control diet (CD) (10% fat, 20% protein, 70% carbohydrate) or high fat diet (HFD) (60% fat, 20% protein, 20% carbohydrate), without and with supplementation with n-3 LCPUFA (100 mg per kg per day) plus EVOO (100 mg per kg per day) for 12 weeks. HFD induced (i) liver steatosis (increased total fat, triacylglycerols, and free fatty acid total contents), (ii) higher fasting serum glucose and insulin levels and HOMA index, total cholesterol, triacylglycerols and TNF-α and IL-6, (iii) liver and plasma oxidative stress enhancement, (iv) depletion of the n-3 LCPUFA hepatic content, and (v) increment in lipogenic enzyme activity and reduction in lipolytic enzyme activity. These changes were either reduced (p < 0.05) or normalized to control the values in animals subjected to HFD supplemented with n-3 LCPUFA plus EVOO. In conclusion, n-3 LCPUFA plus EVOO intervention exerts anti-steatotic effects underlying antioxidant and anti-inflammatory responses, improved insulin sensitivity, and recovery of the lipolytic/lipogenic status of the liver altered by HFD, and supports the potential therapeutic use of n-3 LCPUFA plus EVOO supplementation in the treatment of human liver steatosis induced by nutritional factors or other etiologies.
During allograft rejection, several immune cell types, including dendritic cells, CD4(+) and CD8(+) T cells among others, recirculate between the graft and the nearest draining lymph node, resulting in immunity against the 'foreign' tissue. Regulatory CD4(+) T cells are critical for controlling the magnitude of the immune response and may act to promote or maintain tolerance. They are characterized by the expression of CD25 and Foxp3, and more recently, Neuropilin-1 (Nrp1). The role of these suppressor cells during allograft rejection is not well understood. Our work shows that during graft rejection, there is an increase in the frequency of total CD4(+) T cells expressing Nrp1, but the expression of this molecule is downregulated in the regulatory CD4(+) T-cell compartment. Interestingly, the expression of the transcription factor Eos, which renders cell function stability, is also reduced. In adoptive transfer experiments, we observed that during allograft rejection: (i) natural regulatory CD4(+) T cells maintain high levels of Nrp1 expression, (ii) effector CD4(+) T cells (Nrp1(-)) become Nrp1(+)Eos(+) and (iii) the transfer of regulatory CD4(+) T cells (Nrp1(+)) can promote allograft survival, and also enhance the gain of Nrp1 and Eos on T-effector cells. Together, these data suggest that rejection occurs, at least in part, through the loss of Nrp1 expression on regulatory CD4(+) T cells, their stability or both. Additionally, the transfer of regulatory CD4(+) T cells (based on Nrp1 expression) permits the acceptance of the allograft, placing Nrp1 as a new target for immune therapy.
Harmful algae blooms (HABs) are the main source of marine toxins in the aquatic environment surrounding the austral fjords in Chile. Huichas Island (Aysén) has an history of HABs spanning more than 30 years, but there is limited investigation of the bioaccumulation of marine toxins in the bivalves and gastropods from the Region of Aysén. In this study, bivalves (Mytilus chilenses, Choromytilus chorus, Aulacomya ater, Gari solida, Tagelus dombeii and Venus antiqua) and carnivorous gastropods (Argobuccinum ranelliformes and Concholepas concholepas) were collected from 28 sites. Researchers analysed the accumulation of STX-group toxins using a LC with a derivatisation post column (LC-PCOX), while lipophilic toxins (OA-group, azapiracids, pectenotoxins and yessotoxins) were analysed using LC-MS/MS with electrospray ionisation (+/-) in visceral (hepatopancreas) and non-visceral tissues (mantle, adductor muscle, gills and foot). Levels of STX-group and OA-group toxins varied among individuals from the same site. Among all tissue samples, the highest concentrations of STX-group toxins were noted in the hepatopancreas in V. antiqua (95 ± 0.1 μg STX-eq 100 g(-1)), T. dombeii (148 ± 1.4 μg STX-eq 100 g(-1)) and G. solida (3232 ± 5.2 μg STX-eq 100 g(-1); p < 0.05); in the adductor muscle in M. chilensis (2495 ± 6.4 μg STX-eq 100 g(-1); p < 0.05) and in the foot in C. concholepas (81 ± 0.7 μg STX-eq 100 g(-1)) and T. dombeii (114 ± 1.2 μg STX-eq 100 g(-1)). The highest variability of toxins was detected in G. solida, where high levels of carbamate derivatives were identified (GTXs, neoSTX and STX). In addition to the detected hydrophilic toxins, OA-group toxins were detected (OA and DTX-1) with an average ratio of ≈1:1. The highest levels of OA-group toxins were in the foot of C. concholepas, with levels of 400.3 ± 3.6 μg OA eq kg(-1) (p < 0.05) and with a toxic profile composed of 90% OA. A wide range of OA-group toxins was detected in M. chilensis with a toxicity < 80 μg OA eq kg(-1), but with 74% of those toxins detected in the adductor muscle. In all evaluated species, there was no detection of lipophilic toxins associated with biotransformation in molluscs and carnivorous gastropods. In addition, the STX-group and OA-group toxin concentrations in shellfish was not associated with the presence of HAB. The ranking of toxin concentration in the tissues of most species was: digestive glands > mantle > adductor muscle for the STX-group toxins and foot > digestive gland for the OA-group toxins. These results gave a better understanding of the variability and compartmentalisation of STX-group and OA-group toxins in different bivalve and gastropod species from the south of Chile, and the analyses determined that tissues could play an important role in the biotransformation of STX-group toxins and the retention of OA-group toxins.
To assess the relationship between the length of (GT)n repeats in HO-1 gene promoter and heme oxygenase (HO) enzymatic activity in mononuclear cells with iron (Fe) stores in type 2 diabetic mellitus (DM2) patients and metabolic syndrome (MS) subjects, we studied 163 patients with DM2, 185 with MS, and 120 controls subjects. We evaluated iron status (hemoglobin and serum Fe, ferritin, and transferrin receptor), and we determined the length of (GT)n repeats in HO-1 gene promoter by capillary electrophoresis and HO enzymatic activity in mononuclear cells and assessed the relationship between these results and Fe stores. Only 1/163, 6/185, and 7/120 had iron deficiency anemia in DM2 patients, MS subjects, and controls, respectively. No iron overload (ferritin>200 μg/L) was detected in all the subjects studied. DM2 patients had higher iron deposits, total body iron, and heme oxygenase activity (a suggestion of high oxidative stress condition) than MS subjects and controls. In DM2, we found a positive association between serum iron and HO activity. There were no difference in allelic frequency between the three groups; however, among DM2 and MS patients, the frequency of short/medium (SM) genotype of (GT)n repetition was increased and medium/medium (MM) genotype of (GT)n repetition was lower than controls. These results imply that DM2 patients and individuals with MS carrying SM repeats might have higher susceptibility to develop diabetes consequences. This increased susceptibility could be Fe-mediated oxidative stress.
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