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Muhammad, R. N., L. A. Ahmed, R. M. Abdul Salam, K. A. Ahmed, and A. S. Attia, "Crosstalk Among NLRP3 Inflammasome, ETR Signaling, and miRNAs in Stress-Induced Depression-Like Behavior: a Modulatory Role for SGLT2 Inhibitors.", Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, vol. 18, issue 4, pp. 2664-2681, 2021. Abstract

Depression is an overwhelming health concern, and many patients fail to optimally respond to available standard therapies. Neuroplasticity and blood-brain barrier (BBB) integrity are the cornerstones of a well-functioning central nervous system, but they are vulnerable to an overly active NLRP3 inflammasome pathway that can also indirectly trigger the release of ET-1 and contribute to the ET system disturbance, which further damages stress resilience mechanisms. Here, the promising yet unexplored antidepressant potential of dapagliflozin (Dapa), a sodium-glucose co-transporter-2 inhibitor, was investigated by assessing its role in the modulation of the NLRP3 inflammasome pathway and ETR signal transduction, and their impact on neuroplasticity and BBB integrity in an animal model of depression. Dapa (1 mg/kg/day; p.o.) with and without BQ-788 (1 mg/kg/day; i.p.), a specific ETR blocker, were administered to adolescent male Wistar rats exposed to a 5-week chronic unpredictable stress protocol. The depressive animals demonstrated marked activation of the NLRP3 inflammasome pathway (NF-κB/NLRP3/caspase-1/IL/TNF-α), which was associated with both peripheral and central inflammatory responses. The ET system was disrupted, with noticeable reduction in miR-125a-5p and ETR gene expression. Cortical ZO-1 expression was downregulated under the influence of NLRP3/TNF-α/miR-501-3p signaling, along with a prominent reduction in hippocampal BDNF and synapsin-1. With ETR up-regulation being a cornerstone outcome, Dapa administration efficiently created an overall state of resilience, improved histopathological and behavioral variables, and preserved BBB function. These observations were further verified by the results obtained with BQ-788 co-administration. Thus, Dapa may exert its antidepressant action by reinforcing BBB integrity and promoting neuroplasticity through manipulation of the NLRP3/ET-1/ETR/BDNF/ZO-1 axis, with a significant role for ETR signaling. Graphical illustration for the proposed mechanisms of the anti-depressant potential of Dapa. Dapa suppressed NLRP3 inflammasome activation and assembly with subsequent inhibition of pro-inflammatory ILs. This results in attenuation of neuro-inflammation, BBB disruption, glial cell activation, TNF-α and ET-1 release, and the enhanced production of neurotrophins. The role of ETR signaling was emphasized; Dapa possibly augmented ETR expression, which is thought to boost neurotrophins production. The ETR blocker, BQ-788, suppressed most of the positive outcomes of Dapa. Finally, miR-125a-5p and miR-501-3p that played major roles in these pathological pathways were modulated by Dapa. It is not yet clear whether Dapa has a direct or rather indirect effect on their expression. BBB, blood-brain barrier; Dapa, dapagliflozin; ET-1, endothelin-1; ETR, endothelin B receptor; IL, interleukin; NF-κB, nuclear factor kappa B; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3; TNF-α, tumor necrosis factor-α. Created with BioRender.com.

Mohamed, Y. S., L. A. Ahmed, H. A. Salem, and A. M. Agha, "Role of nitric oxide and KATP channel in the protective effect mediated by nicorandil in bile duct ligation-induced liver fibrosis in rats.", Biochemical pharmacology, vol. 151, pp. 135-142, 2018 05. Abstract

Liver fibrosis is one of the most serious conditions affecting patients worldwide. In the present study, the role of nitric oxide and KATP channel was investigated for the first time in the possible protection mediated by nicorandil in bile duct ligation-induced liver fibrosis in rats. Nicorandil (3 mg/kg/day) was given orally 24 h after bile duct ligation for 14 days till the end of the experiment. Nicorandil group showed marked improvement in liver function tests, hepatic oxidative stress and inflammatory markers as well as inducible and endothelial nitric oxide synthase protein expressions. Furthermore, nicorandil administration led to significant decrement of phosphorylated protein kinase C, fibrosis and hepatic stellate cells activation as indicated by decreased alpha smooth muscle actin expression. Oral co-administration of glibenclamide (5 mg/kg/day) (a KATP channel blocker) with nicorandil mostly showed similar improvement though not reaching to that of nicorandil group. However, co-adminstration of L-NAME (15 mg/kg/day) (an inhibitor of nitric oxide synthase) completely abolished the protective effects of nicorandil and produced more or less similar results to that of untreated bile duct ligated group. In conclusion, nicorandil is an effective therapy against the development of bile duct ligation-induced liver fibrosis in rats where nitric oxide plays a more prominent role in the protective effect of nicorandil than KATP channel opening.

Mohamed, S. S., N. F. Abdeltawab, W. Wadie, L. A. Ahmed, R. M. Ammar, S. Rabini, H. Abdel-Aziz, and M. T. Khayyal, "Effect of the standard herbal preparation, STW5, treatment on dysbiosis induced by dextran sodium sulfate in experimental colitis.", BMC complementary medicine and therapies, vol. 21, issue 1, pp. 168, 2021. Abstract

BACKGROUND: The standardized herbal preparation, STW 5, is effective clinically in functional gastrointestinal disorders and experimentally in ulcerative colitis (UC). The present study explores whether the beneficial effect of STW 5 involves influencing the intestinal microbiota.

METHODS: UC was induced in Wistar rats by feeding them 5% dextran sodium sulfate (DSS) in drinking water for 7 days. Rats were treated concurrently with STW 5 and sacrificed 24 h after last drug administration. Fecal samples were used to determine changes in the abundance of selected microbial phyla and genera using real-time PCR.

RESULTS: Induction of UC led to dysbiosis and changes in the gut microbiota. The changes included an increase in some genera of the Firmicutes, namely Enterococcus, and a decrease in others, namely Blautia, Clostridium, and Lactobacillus. DSS further induced a marked increase in the abundance of Bacteroidetes and Proteobacteria as well as in the relative abundance of Actinobacteria and its genus Bifidobacterium. Methanobrevibacter levels (phylum Euryarchaeota) were also increased. Microbial dysbiosis was associated with changes in various parameters of colonic inflammation. STW 5 effectively guarded against those changes and significantly affected the indices of edema and inflammation in the UC model. Changes in colon length, colon mass index, inflammatory and apoptotic markers, and histological changes induced by DSS were also prevented.

CONCLUSIONS: Dysbiosis plays a contributing role in the development of DSS-induced UC. Derangements in the microbial flora and associated inflammatory processes were largely prevented by STW 5, suggesting that this effect might contribute towards its beneficial usefulness in this condition.

Mohamed, S. S., L. A. Ahmed, W. A. Attia, and M. M. Khattab, "Nicorandil enhances the efficacy of mesenchymal stem cell therapy in isoproterenol-induced heart failure in rats.", Biochemical pharmacology, vol. 98, issue 3, pp. 403-11, 2015 Dec 01. Abstract

Stem cell transplantation has emerged as a promising technique for regenerative medicine in cardiovascular therapeutics. However, the results have been less than optimal. The aim of the present study was to investigate whether nicorandil could offer an additional benefit over bone marrow-derived mesenchymal stem cell therapy in isoproterenol-induced myocardial damage and its progression to heart failure in rats. Isoproterenol was injected subcutaneously for 2 consecutive days at doses of 85 and 170 mg/kg/day, respectively. Nicorandil (3 mg/kg/day) was then given orally with or without a single intravenous bone marrow-derived mesenchymal stem cell administration. Electrocardiography and echocardiography were recorded 2 weeks after the beginning of treatment. Rats were then sacrificed and the ventricle was isolated for estimation of tumor necrosis factor-alpha, vascular endothelial growth factor and transforming growth factor-beta. Moreover, protein expressions of caspase-3, connexin-43 as well as endothelial and inducible nitric oxide synthases were evaluated. Finally, histological studies of myocardial fibrosis and blood vessel density were performed and cryosections were done for estimation cell homing. Combined nicorandil/bone marrow-derived mesenchymal stem cell therapy provided an additional improvement compared to cell therapy alone toward reducing isoproterenol-induced cardiac hypertrophy, fibrosis and inflammation. Notably, combined therapy induced significant increase in angiogenesis and cell homing and prevented isoproterenol-induced changes in contractility and apoptotic markers. In conclusion, combined nicorandil/bone marrow-derived mesenchymal stem cell therapy was superior to cell therapy alone toward preventing isoproterenol-induced heart failure in rats through creation of a supportive environment for mesenchymal stem cells.