Circulating microRNAs (miRNAs) play a role in modulating the prevalence of fibrosis and have been a target of the cardiac anti-fibrotic effect of Carvedilol. However, the impact of miRNAs on the hepatoprotective effect of this non-selective β-blocker has not been yet elucidated. Hence, the current goal is to evaluate the potential role of circulating miR-200a in the hepatic anti-fibrotic pathway of Carvedilol. Male Wistar rats were randomized into normal, CCl4 (2 ml/kg, i.p, twice weekly for 8 weeks), and CCl4 + Carvedilol (10 mg/kg, p.o, daily). Carvedilol over-expressed the circulating miR-200a to modulate epithelial mesenchymal transition (EMT) markers (vimentin, E-Cadherin). In turn, Carvedilol increased SMAD7 gene expression and protein content to attenuate the pro-fibrogenic marker transforming growth factor β1 (TGF-β1) and the inflammatory markers (p-38 MAPK and p-S536-NF-κB p65). The anti-fibrotic potential was reflected on the decreased expression of the mesenchymal product and EMT marker α-SMA, besides the improved histopathological examination, and the fibrosis scores/collagen quantification to enhance liver functions (AST, ALT, ALP, and AST/platelet ratio index; APRI). In conclusion, circulating miR-200a/SMAD7/TGF-β1/EMT/MAPK axis is crucial in the hepatic anti-fibrotic mechanism of Carvedilol.

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Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by progressive motor, psychiatric, and cognitive abnormalities. The antidiabetic drug liraglutide possesses a neuroprotective potential against several neurodegenerative disorders; however, its role in Huntington’s disease (HD) and the possible mechanisms/trajectories remain elusive, which is the aim of this work. Liraglutide (200 μg/kg, s.c) was administered to rats intoxicated with 3-nitropropionic acid (3-NP) for 4 weeks post HD model induction. Liraglutide abated the 3-NP-induced neurobehavioral deficits (open field and elevated plus maze tests) and histopathological changes. Liraglutide downregulated the striatal mRNA expression of HSP 27, PBR, and GFAP, while it upregulated that of DARPP32. On the molecular level, liraglutide enhanced striatal miR-130a gene expression and TrKB protein expression and its ligand BDNF, while it reduced the striatal protein content and mRNA expression of the death receptors sortilin and p75NTR, respectively. It enhanced the neuroprotective molecules cAMP, p-PI3K, p-Akt, and p-CREB, besides modulating the p-GSK-3β/p-β-catenin axis. Liraglutide enhanced the antioxidant transcription factor Nrf2, abrogated TBARS, upregulated both Bcl2 and Bcl-XL, and downregulated Bax along with decreasing caspase-3 activity. Therefore, liraglutide exerts a neurotherapeutic effect on 3-NP-treated rats that is, besides the upturn of behavioral and structural findings, it at least partially, increased miR-130a and modulated PI3K/Akt/CREB/BDNF/TrKB, sortilin, and p75NTR, and Akt/GSK-3β/p-β-catenin trajectories besides its capacity to decrease apoptosis and oxidative stress, as well as its neurotrophic activity.

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BackgroundIn practice, there is increasing recognition of the importance of hypothalamic pituitary adrenal axis in the cardiovascular disease progression. The association of brain natriuretic peptide with obesity and characteristics of the metabolic syndrome in adults and aged patients is well established, but that in pediatrics needs thorough elucidation.AimThe aim of this study was to assess the association of hypothalamic pituitary adrenal axis mediators (cortisol and aldosterone) with plasma NT-pro β-type natriuretic peptide (NT-proBNP) levels on metabolic, immune-inflammatory and endothelial markers in young obese pediatric patients.MethodsThis is achieved by recruitment of 60 young (13–17 years) obese pediatric cohorts who are further subclassified according to their stage of hypertension; normotensive, prehypertensive and hypertensive patients.ResultsThe study showed significant differences in the metabolic parameters (glucose, insulin and HOMA-index) among the three obese young patient groups. Levels of cortisol and aldosterone, as well as NT-proBNP levels are positively associated with characteristics of the metabolic syndrome; blood pressure, BMI, HOMA index in all three obese groups. However, their association to the lipid profile was insignificant. These increases aligned harmonically with the assessed immune-inflammatory markers; CRP, TNF-α, and IL-23, as well as levels of sICAM, sVCAM and p-selectin, reflecting the involvement of mast cells and inflammatory effects on the vascular endothelium. ROC analysis revealed their beneficial addition as promising biomarkers for a better prognostic profile of hypertension-induced cardiovascular risk.ConclusionEarly detection of NT-proBNP, cortisol and aldosterone levels in pre-hypertension stage added to the immune-inflammatory mediators may improve the coronary risk assessment in young Egyptian patients.

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