RESUMO
Recently, some preclinical and clinical studies have demonstrated the ability of brown seaweeds in reducing the risk factors for metabolic syndrome. Here, we analyzed the beneficial effect of a nutraceutical formulation containing a phytocomplex extracted from seaweeds and chromium picolinate in animal models of liver steatosis of differing severities (rats with non-alcoholic fatty liver disease (NAFLD) and its complication, non-alcoholic steatohepatitis (NASH)). This treatment led to a significant drop in hepatic fat deposition in both models (p < 0.01 vs. untreated animals), accompanied by a reduction in plasma inflammatory cytokines, such as interleukin 6, tumor necrosis factor α, and C reactive protein, and myeloperoxidase expression in liver tissue. Furthermore, a modulation of the molecular pathways involved in lipid metabolism and storage was demonstrated, since we observed the significant reduction of the mRNA levels of fatty acid synthase, diacylglycerol acyltransferases, the sterol-binding protein SREBP-1, and the lipid transporter perilipin-2, in both treated NAFLD and NASH rats in comparison to untreated ones. In conclusion, this nutraceutical product was effective in reducing liver steatosis and showed further beneficial effects on hepatic inflammation and glycemic control, which were particularly evident in rats characterized by a more severe condition, thus representing a therapeutic option for the treatment of NAFLD and NASH patients.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Phaeophyceae , Alga Marinha , Animais , Proteína C-Reativa/metabolismo , Suplementos Nutricionais , Diglicerídeos/metabolismo , Ácido Graxo Sintases , Inflamação/metabolismo , Interleucina-6/metabolismo , Metabolismo dos Lipídeos , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Modelos Teóricos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Perilipina-2/metabolismo , Peroxidase/metabolismo , Phaeophyceae/metabolismo , RNA Mensageiro/metabolismo , Ratos , Alga Marinha/química , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Esteróis/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
INTRODUCTION: Inflammatory bowel diseases (IBD) are complex multi-factorial diseases with increasing incidence worldwide but their treatment is far from satisfactory. Unconventional strategies have consequently been investigated, proposing the use of cells as an effective alternative approach to IBD. In the present study we examined the protective potential of exogenously administered human umbilical cord derived mesenchymal stem cells (UCMSCs) against Dextran Sulfate Sodium (DSS) induced acute colitis in immunodeficient NOD.CB17-Prkdc (scid)/J mice with particular attention to endoplasmic reticulum (ER) stress. METHODS: UCMSCs were injected in NOD.CB17-Prkdc (scid)/J via the tail vein at day 1 and 4 after DSS administration. To verify attenuation of DSS induced damage by UCMSCs, Disease Activity Index (DAI) and body weight changes was monitored daily. Moreover, colon length, histological changes, myeloperoxidase and catalase activities, metalloproteinase (MMP) 2 and 9 expression and endoplasmic reticulum (ER) stress related proteins were evaluated on day 7. RESULTS: UCMSCs administration to immunodeficient NOD.CB17-Prkdc (scid)/J mice after DSS damage significantly reduced DAI (1.45 ± 0.16 vs 2.08 ± 0.18, p < 0.05), attenuating the presence of bloody stools, weight loss, colon shortening (8.95 ± 0.33 cm vs 6.8 ± 0.20 cm, p < 0.01) and histological score (1.97 ± 0.13 vs 3.27 ± 0.13, p < 0.001). Decrease in neutrophil infiltration was evident from lower MPO levels (78.2 ± 9.7 vs 168.9 ± 18.2 U/g, p < 0.01). DSS treatment enhanced MMP2 and MMP9 activities (>3-fold), which were significantly reduced in mice receiving UCMSCs. Moreover, positive modulation in ER stress related proteins was observed after UCMSCs administration. CONCLUSIONS: Our results demonstrated that UCMSCs are able to prevent DSS-induced colitis in immunodeficient mice. Using these mice we demonstrated that our UCMSCs have a direct preventive effect other than the T-cell immunomodulatory properties which are already known. Moreover we demonstrated a key function of MMPs and ER stress in the establishment of colitis suggesting them to be potential therapeutic targets in IBD treatment.