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Didamoony, M. A., A. M. Atwa, and L. A. Ahmed, "A novel mechanistic approach for the anti-fibrotic potential of rupatadine in rat liver via amendment of PAF/NF-ĸB p65/TGF-β1 and hedgehog/HIF-1α/VEGF trajectories.", Inflammopharmacology, vol. 31, issue 2, pp. 845-858, 2023. Abstract

Hepatic fibrosis is one of the major worldwide health concerns which requires tremendous research due to the limited outcomes of the current therapies. The present study was designed to assess, for the first time, the potential therapeutic effect of rupatadine (RUP) in diethylnitrosamine (DEN)-induced liver fibrosis and to explore its possible mechanistic actions. For the induction of hepatic fibrosis, rats were treated with DEN (100 mg/kg, i.p.) once weekly for 6 consecutive weeks, and on the 6th week, RUP (4 mg/kg/day, p.o.) was administered for 4 weeks. Treatment with RUP ameliorated changes in body weights, liver indices, liver function enzymes, and histopathological alterations induced by DEN. Besides, RUP amended oxidative stress, which led to the inhibition of PAF/NF-κB p65-induced inflammation, and, subsequently, prevention of TGF-β1 elevation and HSCs activation as indicated by reduced α-SMA expression and collagen deposition. Moreover, RUP exerted significant anti-fibrotic and anti-angiogenic effects by suppressing Hh and HIF-1α/VEGF signaling pathways. Our results highlight, for the first time, a promising anti-fibrotic potential of RUP in rat liver. The molecular mechanisms underlying this effect involve the attenuation of PAF/NF-κB p65/TGF-β1 and Hh pathways and, subsequently, the pathological angiogenesis (HIF-1α/VEGF).

Elgebaly, S. A., R. Todd, D. L. Kreutzer, R. Christenson, N. El-Khazragy, R. K. Arafa, M. A. Rabie, A. F. Mohamed, L. A. Ahmed, and N. S. El Sayed, "Nourin-Associated miRNAs: Novel Inflammatory Monitoring Markers for Cyclocreatine Phosphate Therapy in Heart Failure.", International journal of molecular sciences, vol. 22, issue 7, 2021. Abstract

BACKGROUND: Cyclocreatine phosphate (CCrP) is a potent bioenergetic cardioprotective compound known to preserve high levels of cellular adenosine triphosphate during ischemia. Using the standard Isoproterenol (ISO) rat model of heart failure (HF), we recently demonstrated that the administration of CCrP prevented the development of HF by markedly reducing cardiac remodeling (fibrosis and collagen deposition) and maintaining normal ejection fraction and heart weight, as well as physical activity. The novel inflammatory mediator, Nourin is a 3-KDa formyl peptide rapidly released by ischemic myocardium and is associated with post-ischemic cardiac inflammation. We reported that the Nourin-associated (marker of cell damage) and (marker of inflammation) are significantly upregulated in unstable angina patients and patients with acute myocardial infarction, but not in healthy subjects.

OBJECTIVES: To test the hypothesis that Nourin-associated and are upregulated in ISO-induced "HF rats" and that the administration of CCrP prevents myocardial injury (MI) and reduces Nourin gene expression in "non-HF rats".

METHODS: 25 male Wistar rats (180-220 g) were used: ISO/saline ( = 6), ISO/CCrP (0.8 g/kg/day) ( = 5), control/saline ( = 5), and control/CCrP (0.8 g/kg/day) ( = 4). In a limited study, CCrP at a lower dose of 0.4 g/kg/day ( = 3) and a higher dose of 1.2 g/kg/day ( = 2) were also tested. The Rats were injected SC with ISO for two consecutive days at doses of 85 and 170 mg/kg/day, respectively, then allowed to survive for an additional two weeks. CCrP and saline were injected IP (1 mL) 24 h and 1 h before first ISO administration, then daily for two weeks. Serum CK-MB (U/L) was measured 24 h after the second ISO injection to confirm myocardial injury. After 14 days, gene expression levels of and were measured in serum samples using quantitative real-time PCR (qPCR).

RESULTS: While high levels of CK-MB were detected after 24 h in the ISO/saline rats indicative of MI, the ISO/CCrP rats showed normal CK-MB levels, supporting prevention of MI by CCrP. After 14 days, gene expression profiles showed significant upregulation of and by 8.6-fold and 8.7-fold increase, respectively, in the ISO/saline rats, "HF rats," compared to the control/saline group. On the contrary, CCrP treatment at 0.8 g/kg/day markedly reduced gene expression of miR-137 by 75% and of by 44% in the ISO/CCrP rats, "non-HF rats," compared to the ISO/Saline rats, "HF rats." Additionally, healthy rats treated with CCrP for 14 days showed no toxicity in heart, liver, and renal function.

CONCLUSIONS: Results suggest a role of Nourin-associated and in the pathogenesis of HF and that CCrP treatment prevented ischemic injury in "non-HF rats" and significantly reduced Nourin gene expression levels in a dose-response manner. The Nourin gene-based mRNAs may, therefore, potentially be used as monitoring markers of drug therapy response in HF, and CCrP-as a novel preventive therapy of HF due to ischemia.

Ahmed, L. A., "Nicorandil: A drug with ongoing benefits and different mechanisms in various diseased conditions.", Indian journal of pharmacology, vol. 51, issue 5, pp. 296-301, 2019. Abstract

Nicorandil is a well-known antianginal agent, which has been recommended as one of the second-line treatments for chronic stable angina as justified by the European guidelines. It shows an efficacy equivalent to that of classic antianginal agents. Nicorandil has also been applied clinically in various cardiovascular diseases such as variant or unstable angina and reperfusion-induced damage following coronary angioplasty or thrombolysis. Different mechanisms have been involved in the protective effects of nicorandil in various diseases through either opening of adenosine triphosphate-sensitive potassium (KATP) channel or donation of nitric oxide (NO). The predominance or participation of any of these proposed mechanisms depends on the dose of nicorandil used, the location of diseased conditions, and if this mechanism is still functioning or not. The protection afforded by nicorandil has been shown to be mainly attributed to KATP channel opening in experimental models of myocardial and pulmonary fibrosis as well as renal injury or glomerulonephritis, whereas NO donation predominates as a mechanism of protection in hepatic fibrosis and inflammatory bowel diseases. Therefore, in different diseased conditions, it is important to know which mechanism plays the major role in nicorandil-induced curative or protective effects. This can bring new insights into the proper use of selected medication and its recommended dose for targeting certain disease.

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.

Ahmed, L. A., and S. A. EL-Maraghy, "Nicorandil ameliorates mitochondrial dysfunction in doxorubicin-induced heart failure in rats: possible mechanism of cardioprotection.", Biochemical pharmacology, vol. 86, issue 9, pp. 1301-10, 2013 Nov 01. Abstract

Despite of its known cardiotoxicity, doxorubicin is still a highly effective anti-neoplastic agent in the treatment of several cancers. In the present study, the cardioprotective effect of nicorandil was investigated on hemodynamic alterations and mitochondrial dysfunction induced by cumulative administration of doxorubicin in rats. Doxorubicin was injected i.p. over 2 weeks to obtain a cumulative dose of 18 mg/kg. Nicorandil (3 mg/kg/day) was given orally with or without doxorubicin treatment. Heart rate and aortic blood flow were recorded 24 h after receiving the last dose of doxorubicin. Rats were then sacrificed and hearts were rapidly excised for estimation of caspase-3 activity, phosphocreatine and adenine nucleotides contents in addition to cytochrome c, Bcl2, Bax and caspase 3 expression. Moreover, mitochondrial oxidative phosphorylation capacity, creatine kinase activity and oxidative stress markers were measured together with the examination of DNA fragmentation and ultrastructural changes. Nicorandil was effective in alleviating the decrement of heart rate and aortic blood flow and the state of mitochondrial oxidative stress induced by doxorubicin cardiotoxicity. Nicorandil also preserved phosphocreatine and adenine nucleotides contents by restoring mitochondrial oxidative phosphorylation capacity and creatine kinase activity. Moreover, nicorandil provided a significant cardioprotection via inhibition of apoptotic signaling pathway, DNA fragmentation and mitochondrial ultrastructural changes. Interestingly, nicorandil did not interfere with cytotoxic effect of doxorubicin against the growth of solid Ehrlich carcinoma. In conclusion, nicorandil was effective against the development of doxorubicin-induced heart failure in rats as indicated by improvement of hemodynamic perturbations, mitochondrial dysfunction and ultrastructural changes without affecting its antitumor activity.

Ahmed, L. A., and K. Al-Massri, "New Approaches for Enhancement of the Efficacy of Mesenchymal Stem Cell-Derived Exosomes in Cardiovascular Diseases.", Tissue engineering and regenerative medicine, 2022. Abstract

Cardiovascular diseases (CVDs) remain a major health concern worldwide, where mesenchymal stem cells (MSCs) therapy gives great promise in their management through their regenerative and paracrine actions. In recent years, many studies have shifted from the use of transplanted stem cells to their secreted exosomes for the management of various CVDs and cardiovascular-related diseases including atherosclerosis, stroke, myocardial infarction, heart failure, peripheral arterial diseases, and pulmonary hypertension. In different models, MSC-derived exosomes have shown beneficial outcomes similar to cell therapy concerning regenerative and neovascular actions in addition to their anti-apoptotic, anti-remodeling, and anti-inflammatory actions. Compared with their parent cells, exosomes have also demonstrated several advantages, including lower immunogenicity and no risk of tumor formation. However, the maintenance of stability and efficacy of exosomes after in vivo transplantation is still a major concern in their clinical application. Recently, new approaches have been developed to enhance their efficacy and stability including their preconditioning before transplantation, use of genetically modified MSC-derived exosomes, or their utilization as a targeted drug delivery system. Herein, we summarized the use of MSC-derived exosomes as therapies in different CVDs in addition to recent advances for the enhancement of their efficacy in these conditions.

Rasheed, N. A. O., L. A. Ahmed, D. M. Abdallah, and B. M. El-Sayeh, "Nephro-toxic effects of intraperitoneally injected EGCG in diabetic mice: involvement of oxidative stress, inflammation and apoptosis", scientific reports, vol. 7, pp. 40617 , 2017.
Ahmed, L. A., A. A. Z. Obaid, H. F. Zaki, and A. M. Agha, "Naringenin adds to the protective effect of L-arginine in monocrotaline-induced pulmonary hypertension in rats: favorable modulation of oxidative stress, inflammation and nitric oxide.", European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, vol. 62, pp. 161-70, 2014 Oct 01. Abstract

The present study was directed to investigate the possible modulatory effect of naringenin when co-administered with L-arginine in monocrotaline-induced pulmonary hypertension in rats. Pulmonary hypertension was induced by a single subcutaneous injection of monocrotaline (60 mg/kg). L-arginine (500 mg/kg) and naringenin (50 mg/kg) were orally administered daily, alone and in combination, for 3 weeks. Mean arterial blood pressure, electrocardiography and echocardiography were then recorded and rats were sacrificed and serum was separated for determination of total nitrate/nitrite level. Right ventricles and lungs were isolated for estimation of oxidative stress markers, tumor necrosis factor-alpha, total nitrate/nitrite and transforming growth factor-beta. Myeloperoxidase and caspase-3 activities in addition to endothelial and inducible nitric oxide synthase protein expression were also determined. Moreover, histological analysis of pulmonary arteries and cardiomyocyte cross-sectional area was performed. Combined therapy provided a significant improvement in L-arginine protective effect toward preserving hemodynamic changes and alleviating oxidative stress, inflammatory and apoptotic markers induced by monocrotaline treatment. Furthermore, combined therapy prevented monocrotaline-induced changes in endothelial and inducible nitric oxide synthase protein expression as well as histological analysis compared with either treatment alone. In conclusion, naringenin significantly adds to the protective effect of L-arginine in pulmonary hypertension induced by monocrotaline in rats.

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