Mona Kortam

This study aimed to uncover the protective potentiality of resveratrol and dimethyl fumarate (DMF) in the liver of a chronic unpredictable mild stress (CUMS)-induced depression animal model. Resveratrol and DMF significantly alleviated CUMS-induced behavioral abnormalities in stressed rats through improving sucrose preference in sucrose preference test and decreasing immobility time in a forced swimming test. They also mitigated serum corticosterone levels and elevated serum serotonin levels, which were formerly disturbed in CUMS rats. The hepatoprotective effect is evidenced by improvement in hepatic histopathological examinations, as well as normalized serum alanine aminotransferase and aspartate aminotransferase activities. Molecular signaling of resveratrol and DMF was estimated by diminishing hepatic expression of phosphorylated p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK). Consequently, they improved the hepatic antioxidant and anti-inflammatory activities as elaborated by the normalization of total antioxidant capacity, glutathione, malondialdehyde, nuclear factor-κB, tumor necrosis factor-α, and myeloperoxidase levels. In addition, they inhibited hepatocyte apoptosis as evidenced by the increased expression of B-cell lymphoma 2, the decreased expression of Bax, as well as the suppressed activity of caspase-3. In conclusion, resveratrol and DMF purveyed a significant anti-depressant effect, which may be mediated, at least in part, via inhibiting the MAPK/ERK/JNK pathway in the CUMS rat model.

Cerebral ischemic stroke (CIS) is one of the primary causes of death worldwide and a major cause of long-term disability. Long noncoding RNAs (lncRNAs) have emerged as crucial mediators in the pathology of CIS; however, their potential importance is yet to be discovered. Herein, we examined the association of four single-nucleotide polymorphisms (SNPs) with the risk of CIS, their correlation with the lncRNAs, MALAT1 and ANRIL, expression, and the potential of serum MALAT1 and ANRIL as biomarkers for CIS. A total of 100 CIS patients and 100 healthy controls were recruited in the study. Genotyping and expression analysis of MALAT1 and ANRIL SNPs were carried out by qPCR. The present results showed that serum MALAT1 was downregulated, while serum ANRIL was overexpressed in CIS patients, relative to controls. MALAT1 downregulation discriminated CIS patients from controls by receiver-operating-characteristic analysis. Moreover, serum ANRIL denoted good diagnostic accuracy. MALAT1 rs619586 AA and rs3200401 CT, TT were associated with increased CIS risk, whereas ANRIL rs10965215 GG was found to be protective. The studied ANRIL rs10738605 polymorphism was not associated with CIS susceptibility. Notably, the G variant of MALAT1 rs619586 demonstrated a higher serum MALAT1 expression level. Multivariate logistic regression analysis revealed serum MALAT1 as well as MALAT1 rs3200401 CT + TT as independent predictors of CIS. Additionally, a negative association was found between the serum MALAT1 level and the National Institutes of Health Stroke Scale score. In conclusion, MALAT1 rs619586 and rs3200401 and ANRIL rs10965215 are novel prospective noninvasive diagnostic biomarkers for CIS predisposition.

The pathogenesis of multiple sclerosis (MS) is influenced by the interaction of genetic and epigenetic mechanisms. The long noncoding RNA GAS5 acts as a competing endogenous RNA for microRNA-137 and is involved in demyelination. We investigated the association of GAS5 and miR-137 expression and their polymorphisms with MS susceptibility. One hundred and eight MS patients and 104 healthy controls were included. Expression analysis and genotyping of GAS5-rs2067079 and miR-137-rs1625579 single nucleotide polymorphisms were performed by qPCR. Serum GAS5 was upregulated, while serum miR-137 was downregulated in MS compared with the controls. Serum miR-137 was an excellent discriminator of MS patients from the controls (AUC = 0.97) and a negative independent predictor of MS in multivariate logistic analysis. Serum GAS5 expression was positively correlated with the expanded disability status scale scores in the relapsing-remitting MS patients. The rs2067079TT minor homozygote genotype was associated with an increased MS risk, while the rs1625579G minor allele was protective. rs1625579 showed an age-specific effect, while the rs2067079 affected the MS risk in gender- and age-specific manners. In MS patients, rs2067079TT was associated with a higher serum GAS5 than other genotypes, while serum miR-137 did not differ between rs1625579 genotypes. Our results suggest serum GAS5 and miR-137 as MS biomarkers, with miR-137 as a negative predictor of MS risk and GAS5 as a marker of MS severity. We propose rs2067079 and rs1625579 as novel genetic markers of MS susceptibility, and at least, rs2067079 possibly impacts the crosstalk between GAS5 and miR-137.

Vildagliptin (Vilda), a dipeptidyl peptidase-4 (DPP-4) inhibitor, has been highlighted as a promising therapeutic agent for neurodegenerative diseases as Alzheimer's and Parkinson's diseases. Vilda's effect is mostly linked to PI3K/Akt signaling in CNS. Moreover, PI3K/Akt activation reportedly enhanced survival and dampened progression of Huntington's disease (HD). However, Vilda's role in HD is yet to be elucidated. Thus, the aim of the study is to uncover the potentiality of Vilda in HD and unfold its link with PI3K/Akt pathway in 3-nitropropionic acid (3NP) rat model. Rats were randomly assigned into 4 groups; group 1 received saline, whereas, groups 2, 3 and 4 received 3NP (10 mg/kg/day; i.p.) for 14 days, concomitantly with Vilda (5 mg/kg/day; p.o.) in groups 3 and 4, and wortmannin (WM), a PI3K inhibitor, (15 μg/kg/day; i.v.) in group 4. Vilda improved cognitive and motor perturbations induced by 3NP, as confirmed by striatal histopathological specimens and immunohistochemical examination of GFAP. The molecular signaling of Vilda was estimated by elevation of GLP-1 level and protein expressions of survival proteins; p85/p55 (pY458/199)-PI3K, pS473-Akt. Together, it boosted striatal neurotrophic factors and receptor; pS133-CREB, BDNF, pY515-TrKB, which subsequently maintained mitochondrial integrity, as indicated by enhancing both SDH and COX activities, and the redox modulators; Sirt1, Nrf2. Such neuroprotection restored imbalance of neurotransmitters through increasing GABA and suppressing glutamate as well PDE10A. These effects were reversed by WM pre-administration. In conclusion, Vilda purveyed significant anti-Huntington effect which may be mediated, at least in part, via activation of GLP-1/PI3K/Akt pathway in 3NP rat model.

Dysregulation of miRNAs has been described in systemic lupus erythematosis (SLE), however the clinical relevance of using miRNAs as biomarkers for SLE or predictors of disease progression is poorly investigated. This study investigated the expression signature of plasma miR-21, miR-181a and miR-196a among seventy SLE patients with different systemic lupus erythematosis disease activity index (SLEDAI) scores and thirty healthy controls using quantitative real-time PCR. Plasma IL-10 level was also measured in patients and control groups. The expression levels of all selected miRNAs were significantly increased in SLE patients as compared to healthy controls. MiR-196a was superior to differentiate patients from controls, whereas miR-21 was superior to discriminate mild from severe patients. Multivariate logistic analysis revealed miR-196a as independent predictor SLE diagnosis, it also suggest the strength of miR-21 and miR-196a as predictive biomarkers for development of SLE from mild severe form. Plasma IL-10 level was higher in SLE patients than in controls but it was not correlated with disease activity however; it showed a significant correlation with miR-21 expression. These miRNAs represent potential biomarkers in SLE. MiR-21 could serve as predictor of disease progression, while MiR-196a emerges as a novel valuable biomarker to predict both SLE risk and progression, this would be a critical tool for personalizing therapy and to avoid irreversible organ damage associated with SLE.