Metabolic associated fatty liver disease (MAFLD) is a hepatic manifestation of metabolic syndrome and usually associated with obesity and diabetes. Our aim is to characterize the pathophysiological mechanism involved in MAFLD development in Black Tan and brachyuric (BTBR) insulin-resistant mice in combination with leptin deficiency (ob/ob). We studied liver morphology and biochemistry on our diabetic and obese mice model (BTBR ob/ob) as well as a diabetic non-obese control (BTBR + streptozotocin) and non-diabetic control mice (BTBR wild type) from 4–22 weeks. Lipid composition was assessed, and lipid related pathways were studied at transcriptional and protein level. Microvesicular steatosis was evident in BTBR ob/ob from week 6, progressing to macrovesicular in the following weeks. At 12th week, inflammatory clusters, activation of STAT3 and Nrf2 signaling pathways, and hepatocellular ballooning. At 22 weeks, the histopathological features previously observed were maintained and no signs of fibrosis were detected. Lipidomic analysis showed profiles associated with de novo lipogenesis (DNL). BTBR ob/ob mice develop MAFLD profile that resemble pathological features observed in humans, with overactivation of inflammatory response, oxidative stress and DNL signaling pathways. Therefore, BTBR ob/ob mouse is an excellent model for the study of the steatosis to steatohepatitis transition.
In diabetes, chronic hyperglycemia, dyslipidemia, inflammation and oxidative stress contribute to the progression of macro/microvascular complications. Recently, benefits of the use of flavonoids in these conditions have been established. This study investigates, in two different mouse models of diabetes, the vasculoprotective effects of the synthetic flavonoid hidrosmin on endothelial dysfunction and atherogenesis. In a type 2 diabetes model of leptin-receptor-deficient (db/db) mice, orally administered hidrosmin (600 mg/kg/day) for 16 weeks markedly improved vascular function in aorta and mesenteric arteries without affecting vascular structural properties, as assessed by wire and pressure myography. In streptozotocin-induced type 1 diabetic apolipoprotein E-deficient mice, hidrosmin treatment for 7 weeks reduced atherosclerotic plaque size and lipid content; increased markers of plaque stability; and decreased markers of inflammation, senescence and oxidative stress in aorta. Hidrosmin showed cardiovascular safety, as neither functional nor structural abnormalities were noted in diabetic hearts. Ex vivo, hidrosmin induced vascular relaxation that was blocked by nitric oxide synthase (NOS) inhibition. In vitro, hidrosmin stimulated endothelial NOS activity and NO production and downregulated hyperglycemia-induced inflammatory and oxidant genes in vascular smooth muscle cells. Our results highlight hidrosmin as a potential add-on therapy in the treatment of macrovascular complications of diabetes.
Excitotoxic cell death due to the massive release of glutamate and ATP contributes to the secondary extension of cellular and tissue loss following traumatic spinal cord injury (SCI). Evidence from blockage experiments suggests that overexpression and activation of purinergic receptors, especially P2X7, causes excitotoxicity in neurodegenerative diseases and traumatisms of the central nervous system. We hypothesize that the downregulation of specific miRNAs after the SCI contributes to the overexpression of P2X7 and that restorative strategies can be used to reduce excitotoxic response. In the present study, we have employed bioinformatic analyses to identify microRNAs whose dowregulation following SCI can be responsible for P2X7 overexpression and excitotoxic activity. Additional luciferase assays validated microRNA-135a-5p (miR-135a) as a posttranscriptional modulator of P2X7. Moreover, gene expression analysis in spinal cord samples from a rat SCI model confirmed that the decrease in miR-135a expression correlates with P2X7 overexpression after injury. Transfection of cultures of Neuro-2a neuronal cell line with a miR-135a inhibitory sequences (antagomiR-135a), simulating the reduction of miR-135a observed after SCI, resulted in the increase of P2X7 expression and the subsequent ATP-dependent rise in intracellular calcium concentration. Conversely, a restorative strategy employing miR-135a mimics reduced P2X7expression attenuating the increase in intracellular calcium concentration that depends on this receptor and protecting cells from excitotoxic death. Therefore, we conclude that miR-135a is a potential therapeutic target for SCI and that restoration of its expression may reduce the deleterious effects of ATP-dependent excitotoxicity induced after a traumatic spinal cord injury.
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