Arab, H. H., A. H. Eid, A. M. Mahmoud, and M. A. Senousy, "Linagliptin mitigates experimental inflammatory bowel disease in rats by targeting inflammatory and redox signaling.", Life sciences, vol. 273, pp. 119295, 2021. Abstract

AIMS: Dipeptidyl peptidase-4 (DPP-4) has been involved in the pathogenesis of inflammatory bowel diseases (IBD), yet the underlying mechanisms remain inconclusive. The present study aimed to investigate the potential of linagliptin, a potent/selective DPP-4 inhibitor with marked anti-inflammatory actions, to attenuate trinitrobenzene sulfonic acid (TNBS)-evoked colitis in rats; an experimental model of IBD, and the implicated molecular mechanisms. This may add to the clinical utility of linagliptin for the management of patients with coexisting IBD and diabetes mellitus. Notably, no former studies have linked JAK2/STAT3, HMGB1/NF-κB, and Nrf2/HO-1 signaling in TNBS-evoked colitis.

MATERIALS AND METHODS: Western blotting and ELISA were used to determine the levels of target signals.

KEY FINDINGS: Administration of linagliptin (1.5 mg/kg; p.o.) mitigated the colitis severity via diminishing the disease activity index, colon weight/length ratio, and macroscopic scores. Linagliptin also lowered the colonic histologic scores and leukocyte invasion. Notably, linagliptin inhibited the colonic DPP-4 activity and upregulated the expression of intestinotrophic GLP-2 without incurring hypoglycemia in animals. Linagliptin curbed inflammation through the suppression of colonic IL-6, TNF-α, and myeloperoxidase and upregulation of IL-10. It also inhibited the IL-6/JAK2/STAT3 pathway via downregulating p-JAK2/JAK2 and p-STAT3/STAT3 protein expression and HMGB1/RAGE/NF-κB cascade through lowering HMGB1, RAGE, and p-NF-κB p65/NF-κB p65 protein expression. In the context of mucosal oxidative stress, linagliptin diminished lipid peroxides and augmented GSH, GPx, and total antioxidant capacity. It also activated Nrf2/HO-1 pathway via upregulating Nrf2 and HO-1 protein expression.

SIGNIFICANCE: Linagliptin shows a promise for the management of IBD via targeting IL-6/JAK2/STAT3, HMGB1/RAGE/NF-κB, and Nrf2/HO-1 pathways.

Arab, H. H., A. H. Eid, A. M. Mahmoud, and M. A. Senousy, "Linagliptin mitigates experimental inflammatory bowel disease in rats by targeting inflammatory and redox signaling.", Life sciences, vol. 273, pp. 119295, 2021. Abstract

AIMS: Dipeptidyl peptidase-4 (DPP-4) has been involved in the pathogenesis of inflammatory bowel diseases (IBD), yet the underlying mechanisms remain inconclusive. The present study aimed to investigate the potential of linagliptin, a potent/selective DPP-4 inhibitor with marked anti-inflammatory actions, to attenuate trinitrobenzene sulfonic acid (TNBS)-evoked colitis in rats; an experimental model of IBD, and the implicated molecular mechanisms. This may add to the clinical utility of linagliptin for the management of patients with coexisting IBD and diabetes mellitus. Notably, no former studies have linked JAK2/STAT3, HMGB1/NF-κB, and Nrf2/HO-1 signaling in TNBS-evoked colitis.

MATERIALS AND METHODS: Western blotting and ELISA were used to determine the levels of target signals.

KEY FINDINGS: Administration of linagliptin (1.5 mg/kg; p.o.) mitigated the colitis severity via diminishing the disease activity index, colon weight/length ratio, and macroscopic scores. Linagliptin also lowered the colonic histologic scores and leukocyte invasion. Notably, linagliptin inhibited the colonic DPP-4 activity and upregulated the expression of intestinotrophic GLP-2 without incurring hypoglycemia in animals. Linagliptin curbed inflammation through the suppression of colonic IL-6, TNF-α, and myeloperoxidase and upregulation of IL-10. It also inhibited the IL-6/JAK2/STAT3 pathway via downregulating p-JAK2/JAK2 and p-STAT3/STAT3 protein expression and HMGB1/RAGE/NF-κB cascade through lowering HMGB1, RAGE, and p-NF-κB p65/NF-κB p65 protein expression. In the context of mucosal oxidative stress, linagliptin diminished lipid peroxides and augmented GSH, GPx, and total antioxidant capacity. It also activated Nrf2/HO-1 pathway via upregulating Nrf2 and HO-1 protein expression.

SIGNIFICANCE: Linagliptin shows a promise for the management of IBD via targeting IL-6/JAK2/STAT3, HMGB1/RAGE/NF-κB, and Nrf2/HO-1 pathways.

Fathi, D., A. I. Abulsoud, M. A. Saad, N. N. Nassar, M. M. Maksimos, S. M. Rizk, and M. A. Senousy, "Agomelatine attenuates alcohol craving and withdrawal symptoms by modulating the Notch1 signaling pathway in rats.", Life sciences, vol. 284, pp. 119904, 2021. Abstract

AIM: Alcohol abuse is a significant causative factor of death worldwide. The Notch1 signaling pathway is involved in alcohol tolerance, withdrawal and dependence. Agomelatine is a known antidepressant acting as a melatonin receptor (MT1/2) agonist and a 5-hydroxytryptamine receptor-2C antagonist. However, its effects on alcohol cravings and alcohol withdrawal symptoms have not been investigated. In this study, we assessed the possibility of using agomelatine for the treatment of these symptoms in a rat model of alcoholism and the possible role of Notch1 signaling.

MAIN METHODS: We induced alcoholism in rats using a free-choice drinking model for 60 days. From day 61, free-choice was continued until day 82 for the craving model, whereas only water was offered in the withdrawal model. Meanwhile, the treated groups for both models received agomelatine (50 mg/kg/day) orally from day 61 to 82, followed by behavioral, histopathological and biochemical assessment.

KEY FINDINGS: Agomelatine treatment caused significant decrease in alcohol consumption with a positive effect on anxiety-like behavior in the open field, memory in the Morris water maze and immobility in the forced swim test. Moreover, agomelatine induced the expression of Notch1 pathway markers, including Notch1, NICD, CREB, CCNE-2, Hes-1, both total and phosphorylated ERK1/2, MMP9, Per2and RGS-2 in the hippocampal formation. By contrast, NMDAR expression was reduced. Furthermore, agomelatine normalized the serum levels of BDNF, cortisol, dopamine and glutamate which were disrupted by alcohol consumption.

SIGNIFICANCE: Based on these findings, agomelatine reversed alcohol cravings and withdrawal symptoms associated with alcohol dependence by modulating the Notch1 signaling pathway.

Senousy, M. A., A. M. El-Abd, R. R. Abdel-Malek, and S. M. Rizk, "Circulating long non-coding RNAs HOTAIR, Linc-p21, GAS5 and XIST expression profiles in diffuse large B-cell lymphoma: association with R-CHOP responsiveness.", Scientific reports, vol. 11, issue 1, pp. 2095, 2021. Abstract

The reliable identification of diffuse large B-cell lymphoma (DLBCL)-specific targets owns huge implications for its diagnosis and treatment. Long non-coding RNAs (lncRNAs) are implicated in DLBCL pathogenesis; however, circulating DLBCL-related lncRNAs are barely investigated. We investigated plasma lncRNAs; HOTAIR, Linc-p21, GAS5 and XIST as biomarkers for DLBCL diagnosis and responsiveness to R-CHOP therapy. Eighty-four DLBCL patients and thirty-three healthy controls were included. Only plasma HOTAIR, XIST and GAS5 were differentially expressed in DLBCL patients compared to controls. Pretreatment plasma HOTAIR was higher, whereas GAS5 was lower in non-responders than responders to R-CHOP. Plasma GAS5 demonstrated superior diagnostic accuracy (AUC = 0.97) whereas a panel of HOTAIR + GAS5 superiorly discriminated responders from non-responders by ROC analysis. In multivariate analysis, HOTAIR was an independent predictor of non-response. Among patients, plasma HOTAIR, Linc-p21 and XIST were correlated. Plasma GAS5 negatively correlated with International Prognostic Index, whereas HOTAIR positively correlated with performance status, denoting their prognostic potential. We constructed the lncRNAs-related protein-protein interaction networks linked to drug response via bioinformatics analysis. In conclusion, we introduce plasma HOTAIR, GAS5 and XIST as potential non-invasive diagnostic tools for DLBCL, and pretreatment HOTAIR and GAS5 as candidates for evaluating therapy response, with HOTAIR as a predictor of R-CHOP failure. We provide novel surrogates for future predictive studies in personalized medicine.

Radwan, A. F., O. G. Shaker, N. A. El-Boghdady, and M. A. Senousy, "Association of MALAT1 and PVT1 Variants, Expression Profiles and Target miRNA-101 and miRNA-186 with Colorectal Cancer: Correlation with Epithelial-Mesenchymal Transition.", International journal of molecular sciences, vol. 22, issue 11, 2021. Abstract

The influence of and variants on colorectal cancer (CRC) susceptibility and their impact on //epithelial-mesenchymal transition (EMT) and //EMT axes in CRC are unknown. We investigated the influence of and on the risk of CRC and adenomatous polyps (AP), their impact on the long noncoding RNAs and expression and their target , /E-cadherin pathways, along with their potential as early CRC biomarkers. Overall, 280 individuals were recruited: 140 patients with CRC, 40 patients with AP, and 100 healthy volunteers. Genotyping and serum expression profiles were assessed using qPCR. The EMT biomarker, E-cadherin, was measured by ELISA. was associated with increased CRC risk, whereas was protective. Serum and were upregulated in CRC and AP patients versus healthy controls, whereas, , and E-cadherin were downregulated in CRC versus non-CRC groups. showed superior diagnostic potential for CRC and predicted CRC risk among non-CRC groups in the multivariate logistic analysis. , , and levels were correlated with E-cadherin, tumor stage, lymph node and distant metastasis. E-cadherin was lost in metastatic vs. non-metastatic CRC. genotype carriers showed higher E-cadherin levels than carriers. was correlated with lymph node status. For the first time, and are potential genetic CRC predisposition markers, with possibly impacting the EMT process. Serum , , and are novel non-invasive diagnostic biomarkers that could improve the clinical outcome of CRC.

Motawi, T. K., O. G. Shaker, S. O. Hassanin, S. G. Ibrahim, and M. A. Senousy, "Genetic and epigenetic control on clock genes in multiple sclerosis.", Journal of genetics and genomics = Yi chuan xue bao, vol. 49, issue 1, pp. 74-76, 2022.
Abdelazim, S. A., O. G. Shaker, Y. A. H. Aly, and M. A. Senousy, "Uncovering serum placental-related non-coding RNAs as possible biomarkers of preeclampsia risk, onset and severity revealed MALAT-1, miR-363 and miR-17", Scientific Reports, vol. 12, issue 1, pp. 1249, 2022.
Helmy, H. T. S., M. A. Senousy, A. E. El-Sahar, R. H. Sayed, M. A. Saad, and E. M. Elbaz, "Aberrations of miR-126-3p, miR-181a and sirtuin1 network mediate Di-(2-ethylhexyl) phthalate-induced testicular damage in rats: The protective role of hesperidin.", Toxicology, vol. 433-434, pp. 152406, 2020. Abstract

Recently, oxidative stress was implicated in the environmental contaminant Di-(2-ethylhexyl) phthalate (DEHP)-induced testicular toxicity, however the mechanism is unclear. We investigated the role of oxidative stress-responsive microRNAs in DEHP-induced aberrations and the protective effect of the citrus flavonoid, hesperidin (HSP). Male Wistar rats were randomly allocated into four groups as vehicle-treated control, DEHP-alone group (500 mg/kg/day) for 30 days, and HSP (25 or 50 mg/kg) for 60 days; testicular damage was triggered by oral administration of DEHP (500 mg/kg/day) after thirty days of oral administration of HSP (25 or 50 mg/kg). DEHP administration reduced testis weight coefficient, serum testosterone, testicular 3β-hydroxysteroid dehydrogenase and antioxidant enzyme activities, and elevated serum fatty acid-binding protein-9, testicular malondialdehyde, and Bax/Bcl2 ratio. Aberrant testicular miR-126-3p and miR-181a expression was observed, along with decreased expression of sirtuin1 (SIRT1) and its targets; nuclear factor-erythroid 2-related factor2, haeme oxygenase-1, and superoxide dismutase2. HSP administration significantly ameliorated these changes and restored testicular function in a dose-dependent manner. We highlight a novel role of oxidative stress-miR-126/miR-181a-SIRT1 network in mediating DEHP-induced changes which were reversed by the antioxidant HSP.

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