Association of long non-coding RNAs and ABO blood groups with acute lymphoblastic leukemia in Egyptian children.

Acute lymphoblastic leukemia (ALL) is the most prevailing cancer among children. Despite extensive studies, ALL etiology is still an unsolved puzzle. Long non-coding RNAs (lncRNAs) emerged as key mediators in cancer etiology. Several lncRNAs are dysregulated in ALL, leading to oncogenic or tumor-suppressive activities. Additionally, a relation between ABO blood groups and hematological malignancies was proposed. The current study intended to explore the association of lncRNAs, ANRIL and LINC-PINT, and their downstream targets, CDKN2A and heme oxygenase-1 (HMOX1), with the incidence of ALL and treatment response, and to determine the distribution of blood groups across different childhood ALL phenotypes. Blood samples were taken from 66 ALL patients (at diagnosis and at the end of remission induction phase) and 39 healthy children. Whole blood was used for blood group typing. Expression of ANRIL, LINC-PINT and CDKN2A was analyzed in plasma by qRT-PCR. Serum HMOX1 was measured using ELISA. ANRIL and CDKN2A were upregulated, while LINC-PINT and HMOX1 were downregulated in newly diagnosed patients. All of which showed remarkable diagnostic performance, where HMOX1 was superior. HMOX1 was independent predictor of ALL as well. LINC-PINT and HMOX1 were significantly upregulated after treatment. Notably, ANRIL and LINC-PINT were associated with poor outcome. No significant difference in the distribution of ABO blood groups was observed between patients and controls. In conclusion, our results suggested an association of ANRIL and LINC-PINT with childhood ALL predisposition, at least in part, through altering CDKN2A and HMOX1 production. Furthermore, the impact of remission induction treatment was newly revealed.

Mechanistic insights into the protective role of eugenol against stress-induced reproductive dysfunction in female rat model.

The challenging and highly demanding life rhythm nowadays subjects people to unavoidable chronic stress. Chronic stress is associated with a wide array of serious health complications including neuroendocrine dysregulations. Women are more prone to chronic stress-related hormonal disturbances and their physical and psychological consequences, especially reproductive impairment. Eugenol is a natural phenolic anti-oxidant that has several beneficial biological activities. The current study intended to scrutinize the potential protective effect of eugenol in female Wistar rats exposed to chronic unpredictable mild stress (CUMS). Rats were randomly allocated into 4 groups; group 1 received olive oil, group 2 received eugenol in olive oil, groups 3 and 4 were subjected to CUMS protocol for 8 weeks, with pre- and concomitant treatment with eugenol (50 mg/kg/day; p.o.) in group 4. The results showed that CUMS exposure led to weight loss and depressive-like behaviours. CUMS induced hypothalamic-pituitary-adrenal axis activation with subsequent elevation of serum corticosterone level which, in turn, caused decline in ovarian release of estradiol and antimullerian hormones together with an increased production of follicle-stimulating and luteinizing hormones by the anterior pituitary, leading to reproductive disturbances. In ovaries, CUMS imposed oxidative stress, insulin resistance and molecular damage. Intriguingly, all these adverse effects were significantly mitigated by the administration of eugenol that improved animals' behaviours, corrected corticosterone upsurge, tempered hormonal disturbances, and amended ovarian damage. All biochemical results were further confirmed by hippocampal and ovarian histopathological examinations. In conclusion, the current study highlights the prophylactic role of eugenol against reproductive disturbances induced by chronic stress in female rats.

Naringenin affords protection against lipopolysaccharide/D-galactosamine-induced acute liver failure: Role of autophagy.

Acute liver failure (ALF) is considered a fatal clinical disorder and novel therapeutic interventions are mandatory. Naringenin is a flavonoid with anti-inflammatory, antioxidant and antiapoptotic effects that have displayed beneficial effects in different animal models of ALF. The current study aimed at investigating the hepatoprotective effect and the possible underlying molecular mechanisms of naringenin in lipopolysaccharide (LPS)/D-galactosamine (D-Gal) mouse model of ALF. Interestingly, naringenin pretreatment substantially alleviated LPS/D-Gal-induced liver injury, enhanced survival, improved liver function and ameliorated histopathological liver changes. Importantly, naringenin potently activated autophagy as evidenced by the increased Beclin-1 expression and LC3 II/LC3 I ratio. Furthermore, results demonstrated that naringenin alleviated oxidative stress by inducing nuclear factor-erythroid 2-related factor 2 (Nrf2) and increasing hepatic SOD activity and GSH level as well as ameliorated endoplasmic reticulum (ER) stress. Likewise, naringenin mitigated LPS/D-Gal-triggered inflammation by suppressing NF-κB and NLRP3 pathways. Accordingly, apoptotic cell death provoked by LPS/D-Gal challenge was markedly attenuated as depicted by the decrease in caspase-3 and p53 in naringenin-treated mice. To investigate the contribution of autophagy to naringenin-conferred hepatoprotection, autophagy was inhibited using 3-methyladenine (3 MA). Strikingly, 3 MA co-treatment abolished the hepatoprotective effect of naringenin, a finding that strongly suggests that naringenin-afforded protection is, at least in part, attributed to autophagy. Taken together, the present study revealed that naringenin exerted a prominent hepatoprotective effect by promoting autophagy with consequent attenuation of inflammatory responses, oxidative stress, ER stress and apoptosis. Our results provide evidence that naringenin use holds a promise as a potential therapeutic agent for ALF management.

Long Noncoding RNAs MALAT1 and ANRIL Gene Variants and the Risk of Cerebral Ischemic Stroke: An Association Study.

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.

LncRNA GAS5 and miR-137 Polymorphisms and Expression are Associated with Multiple Sclerosis Risk: Mechanistic Insights and Potential Clinical Impact.

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 Attenuates Huntington's Disease through Activation of GLP-1 Receptor/PI3K/Akt/BDNF Pathway in 3-Nitropropionic Acid Rat Model.

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.