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El-Sahar, A. E., N. A. Shiha, N. S. El Sayed, and L. A. Ahmed, "Alogliptin Attenuates Lipopolysaccharide-Induced Neuroinflammation in Mice Through Modulation of TLR4/MYD88/NF-κB and miRNA-155/SOCS-1 Signaling Pathways.", The international journal of neuropsychopharmacology, vol. 24, issue 2, pp. 158-169, 2021. Abstract

BACKGROUND: Endotoxin-induced neuroinflammation plays a crucial role in the pathogenesis and progression of various neurodegenerative diseases. A growing body of evidence supports that incretin-acting drugs possess various neuroprotective effects that can improve learning and memory impairments in Alzheimer's disease models. Thus, the present study aimed to investigate whether alogliptin, a dipeptidyl peptidase-4 inhibitor, has neuroprotective effects against lipopolysaccharide (LPS)-induced neuroinflammation and cognitive impairment in mice as well as the potential mechanisms underlying these effects.

METHODS: Mice were treated with alogliptin (20 mg/kg/d; p.o.) for 14 days, starting 1 day prior to intracerebroventricular LPS injection (8 μg/μL in 3 μL).

RESULTS: Alogliptin treatment alleviated LPS-induced cognitive impairment as assessed by Morris water maze and novel object recognition tests. Moreover, alogliptin reversed LPS-induced increases in toll-like receptor 4 and myeloid differentiation primary response 88 protein expression, nuclear factor-κB p65 content, and microRNA-155 gene expression. It also rescued LPS-induced decreases in suppressor of cytokine signaling gene expression, cyclic adenosine monophosphate (cAMP) content, and phosphorylated cAMP response element binding protein expression in the brain.

CONCLUSION: The present study sheds light on the potential neuroprotective effects of alogliptin against intracerebroventricular LPS-induced neuroinflammation and its associated memory impairment via inhibition of toll-like receptor 4/ myeloid differentiation primary response 88/ nuclear factor-κB signaling, modulation of microRNA-155/suppressor of cytokine signaling-1 expression, and enhancement of cAMP/phosphorylated cAMP response element binding protein signaling.

Ahmed, L. A., O. F. Hassan, O. Galal, D. I. N. A. F. Mansour, and A. El-Khatib, "Beneficial effects of benfotiamine, a NADPH oxidase inhibitor, in isoproterenol-induced myocardial infarction in rats.", PloS one, vol. 15, issue 5, pp. e0232413, 2020. Abstract

BACKGROUND: Acute myocardial infarction (AMI) remains the most common cause of morbidity and mortality worldwide. The present study was directed to investigate the beneficial effects of benfotiamine pre- and post-treatments in isoproterenol (ISO)-induced MI in rats.

METHODS: Myocardial heart damage was induced by subcutaneous injection of ISO (150 mg/kg) once daily for two consecutive days. Benfotiamine (100 mg/kg/day) was given orally for two weeks before or after ISO treatment.

RESULTS: ISO administration revealed significant changes in electrocardiographic recordings, elevation of levels of cardiac enzymes; creatinine kinase (CK-MB) and troponin-I (cTn-I), and perturbation of markers of oxidative stress; nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and glutathione peroxidase (GPx) and markers of inflammation; protein kinase C (PKC), nuclear factor-kappa B (NF-κB) and metalloproteinase-9 (MMP-9). The apoptotic markers (caspase-8 and p53) were also significantly elevated in ISO groups in addition to histological alterations. Groups treated with benfotiamine pre- and post-ISO administration showed significantly decreased cardiac enzymes levels and improved oxidative stress, inflammatory and apoptotic markers compared to the ISO groups.

CONCLUSION: The current study highlights the potential role of benfotiamine as a promising agent for prophylactic and therapeutic interventions in myocardial damage in several cardiovascular disorders via NADPH oxidase inhibition.

Ahmed, L. A., A. F. Mohamed, E. A. Abd El-Haleim, and D. M. El-Tanbouly, "Boosting Akt Pathway by Rupatadine Modulates Th17/Tregs Balance for Attenuation of Isoproterenol-Induced Heart Failure in Rats.", Frontiers in pharmacology, vol. 12, pp. 651150, 2021. Abstract

Disruption of Th17/Tregs homeostasis plays a crucial role in governing the immune response during myocardial fibrosis and its progression to heart failure. The present study aimed to assess for the first time the possible protection afforded by rupatadine against isoproterenol-induced heart failure in rats. It also explored the role of PI3k/Akt as a possible mechanistic pathway, through which rupatadine could modulate Th17/Tregs balance to display its effect. Isoproterenol (85 and 170 mg/kg/day) was injected subcutaneously for 2 successive days, respectively and rupatadine (4 mg/kg/day) was then given orally for 14 days with or without wortmannin (PI3K/Akt inhibitor). Rupatadine succeeded to completely ameliorate isoproterenol-induced cardiac dysfunction as demonstrated by improvements of electrocardiographic and echocardiographic measurements. Moreover, rupatadine prevented the marked elevation of PAF and oxidative stress in addition to Th17 promoting cytokines (IL-6, IL-23, and TGF-β). Accordingly, rupatadine prevented Th17 stimulation or expansion as indicated by increased Foxp3/RORγt ratio and decreased production of its pro-inflammatory cytokine (IL-17). Rupatadine treatment mitigated isoproterenol-induced activation of STAT-3 signaling and the imbalance in -Akt/total Akt ratio affording marked decrease in atrogin-1 and apoptotic biomarkers. Finally, this therapy was effective in averting cardiac troponin loss and reverting the histological alterations as assessed by myocardial fibrosis and hypertrophy grading. Contrariwise, co-administration of wortmannin mostly attenuated the protective effects of rupatadine affording more or less similar results to that of isoproterenol-untreated rats. In conclusion, rupatadine could be an effective therapy against the development of isoproterenol-induced heart failure where PI3K/Akt pathway seems to play a crucial role in its protective effect.

Ahmed, L. A., F. Y. Abdou, A. A. Elfiky, E. A. Shaaban, and A. A. Ain-Shoka, "Bradykinin-Potentiating Activity of a Gamma-Irradiated Bioactive Fraction Isolated from Scorpion (Leiurus quinquestriatus) Venom in Rats with Doxorubicin-Induced Acute Cardiotoxicity:", Cardiovascular toxicology, vol. 21, issue 2, pp. 127-141, 2021. Abstract

Although doxorubicin (Dox) is a backbone of chemotherapy, the search for an effective and safe therapy to revoke Dox-induced acute cardiotoxicity remains a critical matter in cardiology and oncology. The current study was the first to explore the probable protective effects of native and gamma-irradiated fractions with bradykinin-potentiating activity (BPA) isolated from scorpion (Leiurus quinquestriatus) venom against Dox-induced acute cardiotoxicity in rats. Native or irradiated fractions (1 μg/g) were administered intraperitoneally (i.p.) twice per week for 3 weeks, and Dox (15 mg/kg, i.p.) was administered on day 21 at 1 h after the last native or irradiated fraction treatment. Electrocardiographic (ECG) aberrations were ameliorated in the Dox-treated rats pretreated with the native fraction, and the irradiated fraction provided greater amelioration of ECG changes than that of the native fraction. The group pretreated with native protein with BPA also exhibited significant improvements in the levels of oxidative stress-related, inflammatory, angiogenic, fibrogenic, and apoptotic markers compared with those of the Dox group. Notably, the irradiated fraction restored these biomarkers to their normal levels. Additionally, the irradiated fraction ameliorated Dox-induced histological changes and alleviated the severity of cardiac injury to a greater extent than that of the native fraction. In conclusion, the gamma-irradiated detoxified fraction of scorpion venom elicited a better cardioprotective effect than that of the native fraction against Dox-induced acute cardiotoxicity in rats.

Ahmed, L. A., H. A. Salem, M. N. Mawsouf, A. S. Attia, and A. M. Agha, "Cardioprotective effects of ozone oxidative preconditioning in an in vivo model of ischemia/reperfusion injury in rats.", Scandinavian journal of clinical and laboratory investigation, vol. 72, issue 5, pp. 345-54, 2012 Sep. Abstract

BACKGROUND: Several studies have demonstrated the beneficial effects of ozone oxidative preconditioning in several pathologies characterized by cellular oxidative and inflammatory burden. The present study was designed to investigate the cardioprotective effects of oxidative preconditioning in ischemia/reperfusion (I/R) injury.

METHODS: Rats were randomly assigned into five groups. Groups 1 and 2 were normal and I/R groups, respectively. Two of the other groups received two different doses of ozone therapies by rectal insufflations. The last group received vehicle (oxygen). Rats were subjected to myocardial I/R (40 min/10 min). Heart rate and ventricular arrhythmias were recorded during I/R progress. At the end of reperfusion, plasma creatine kinase-MB (CK-MB) activity and total nitrate/nitrite (NO(x)) were determined. In addition, lactate, adenine nucleotides, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and myeloperoxidase (MPO) activity were estimated in the heart left ventricle. Histological examination was also performed to visualize the protective cellular effects.

RESULTS: Both doses of ozone therapy were equally protective in reducing CK-MB release. However, the higher dose was more effective in reducing oxidative stress, lactate accumulation, elevated MPO activity and plasma NO(x) as well as preserving myocardial adenine nucleotides. Histological examination also revealed better improvement with a higher dose of ozone therapy compared to the I/R group.

CONCLUSION: Ozone therapy can afford significant cardioprotection against biochemical and histological changes associated with I/R injury.

Abd El Aal, H. A., L. A. Ahmed, W. A. Hassan, H. M. Fawzy, and H. Moawad, "Combination of carvacrol with simvastatin improves the lipid-lowering efficacy and alleviates simvastatin side effects.", Journal of biochemical and molecular toxicology, vol. 31, issue 12, 2017 Dec. Abstract

The present investigation was designed to examine the possible additive hypolipidemic effect of carvacrol (CARV) in combination with simvastatin (SIM) on poloxamer 407 (P407)-induced hyperlipidemia. Rats were injected with P407, (500 mg/ kg; i.p.), twice a week, for 30 days. Treatment was carried out by administration of SIM (20 mg/kg/day; p.o.) or CARV (50 mg/kg/day; p.o.) or combination of them. Treatment with CARV significantly decreased total cholesterol, triglycerides, low-density lipoprotein, atherogenic index, leptin, and increased high-density lipoprotein and adiponectin. Moreover, CARV potentiated the hypolipidemic effect of SIM. Both SIM and CARV alleviated the oxidative stress induced by P407. Interestingly, CARV, when combined with SIM, significantly ameliorated SIM-induced liver and muscle injury by reducing the level of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and myoglobin and restoring the normal histological picture of both liver and muscle as well as apoptosis.

Ahmed, L. A., H. A. Salem, A. S. Attia, and A. M. Agha, "Comparative study of the cardioprotective effects of local and remote preconditioning in ischemia/reperfusion injury.", Life sciences, vol. 90, issue 7-8, pp. 249-56, 2012 Feb 13. Abstract

AIMS: Though the cardioprotective effects of local or remote preconditioning have been estimated, it is still unclear which of them is more reliable and provides more cardioprotection. The present investigation was directed to compare, in one study, the cardioprotective effects of different cycles of local or remote preconditioning in ischemia/reperfusion (I/R)-induced electrophysiological, biochemical and histological changes in rats.

MAIN METHODS: Rats were randomly assigned into 10 groups. Groups 1 and 2 were normal and I/R groups, respectively. Other groups were subjected to 1, 2, 3, 4 cycles of local or remote preconditioning before myocardial I/R (40 min/10 min). Heart rate and ventricular arrhythmias were recorded during I/R progress. At the end of reperfusion, plasma creatine kinase-MB (CK-MB) activity and total nitrate/nitrite (NO(x)) were determined. In addition, lactate, adenine nucleotides, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and myeloperoxidase (MPO) activity were estimated in the heart left ventricle. Histological examination was also performed to visualize the protective cellular effects of the effective cycle of local or remote preconditioning.

KEY FINDINGS: In general, local preconditioning was more effective than remote preconditioning in reducing ventricular arrhythmias, CK-MB release, lactate accumulation and elevated MPO activity as well as preserving adenine nucleotides. Concerning the most effective group in each therapy, 3 cycles of local preconditioning provided more cardioprotection than that of remote preconditioning in the histological examination.

SIGNIFICANCE: Despite being invasive, local preconditioning provided more effective cardioprotection than remote preconditioning in ameliorating the overall electrophysiological, biochemical and histological changes.

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.

Ahmed, L. A., R. H. Abd El-Rhman, A. M. Gad, S. K. Hassaneen, and M. F. El-Yamany, "Dibenzazepine combats acute liver injury in rats via amendments of Notch signaling and activation of autophagy.", Naunyn-Schmiedeberg's archives of pharmacology, vol. 394, issue 2, pp. 337-348, 2021. Abstract

Paracetamol is a commonly used over-the-counter analgesic and antipyretic drug. Nevertheless, an overdose of paracetamol leads to hepatic necrosis that can be lethal. This study aimed to assess the potential hepatoprotective effects of dibenzazepine, a Notch inhibitor, against acute liver injury in rats via interfering with oxidative stress, inflammation, apoptosis, autophagy, and Notch signaling. Silymarin (200 mg/kg, p.o.) or dibenzazepine (2 mg/kg, i.p.) were administered to rats for 5 days before a single hepatotoxic dose of paracetamol (800 mg/kg, i.p.). Pretreatment with silymarin and dibenzazepine significantly mitigated oxidative stress, inflammatory and apoptotic markers induced by paracetamol hepatotoxicity where dibenzazepine showed greater repression of inflammation. Furthermore, dibenzazepine was found to be significantly more efficacious than silymarin in inhibiting Notch signaling as represented by expression of Notch-1 and Hes-1. A significantly greater response was also demonstrated with dibenzazepine pretreatment with regard to the expression of autophagic proteins, Beclin-1 and LC-3. The aforementioned biochemical results were confirmed by histopathological examination. Autophagy and Notch signaling seem to play a significant role in protection provided by dibenzazepine for paracetamol-induced hepatotoxicity in rats, which could explain its superior results relative to silymarin. Graphical abstract.

Ahmed, L. A., and K. F. Al-Massri, "Directions for Enhancement of the Therapeutic Efficacy of Mesenchymal Stem Cells in Different Neurodegenerative and Cardiovascular Diseases: Current Status and Future Perspectives.", Current stem cell research & therapy, vol. 16, issue 7, pp. 858-876, 2021. Abstract

Mesenchymal stem cells (MSCs) have shown promising therapeutic effects in a wide variety of medical conditions, including neurodegenerative disorders and cardiovascular diseases. Although preliminary research has emphasized the ability of MSCs to engraft at sites of injury, several studies have revealed that MSCs mediate their effects through the release of various paracrine factors and through their antioxidant, anti-inflammatory, immunomodulatory, and anti-apoptotic effects. The clinical implications of MSCs application are limited due to their low survival rate in conditions of inflammation, oxidative stress, and nutrient restriction in damaged areas. Furthermore, the function of isolated MSCs is usually affected by the patient's health. Therefore, it is necessary to develop new methods to enhance the therapeutic efficacy of MSCs under pathophysiological conditions. This review provides an overview of the general properties of MSCs, their therapeutic potential in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease, as well as cardiovascular diseases such as myocardial infarction, diabetic cardiomyopathy, and dilated cardiomyopathy, and their related mechanisms. In addition, this review also discusses potential problems and side effects, as well as current and future directions for improvement of MSCs therapy and their implications and applications.

Seif El-Din, S. H., M. B. Salem, N. M. El-Lakkany, O. A. Hammam, S. M. Nasr, H. Okasha, L. A. Ahmed, S. Saleh, and S. S. Botros, "Early intervention with probiotics and metformin alleviates liver injury in NAFLD rats via targeting gut microbiota dysbiosis and p-AKT/mTOR/LC-3II pathways.", Human & experimental toxicology, vol. 40, issue 9, pp. 1496-1509, 2021. Abstract

Non-alcoholic fatty liver disease (NAFLD) constitutes a major health problem worldwide and intimately links with obesity and diabetes. This study aimed to explore the therapeutic impact of early treatment with metformin (MTF) alone or in combination with DSM 17938 () + metronidazole (MTZ) in male Sprague Dawley rats with high-fat diet (HFD)-induced NAFLD. Hepatic steatosis was induced by feeding rats HFD for 6 weeks. MTF (150 mg/kg/day) or (2 × 10 colony forming unit/day) were given orally for 4 weeks; meanwhile, MTZ (15 mg/kg/day, p.o.) was administered for 1 week. Administration of + MTZ in combination with MTF produced a superior effect concerning insulin resistance (IR), lipid profile, liver function, oxidative stress, inflammatory and autophagic markers than using each treatment alone. Besides, this combination resulted in disappearance of steatosis, inflammation and vacuolation within hepatic architecture. Moreover, it normalized short chain fatty acids (SCFAs) as well as faecal contents. In conclusion, early treatment with MTZ in combination with MTF could prevent NAFLD progression and liver injury through targeting gut dysbiosis, inflammation and autophagic pathways.

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.

Ahmed, L. A., H. A. Salem, A. S. Attia, and M. E. El-Sayed, "Enhancement of amlodipine cardioprotection by quercetin in ischaemia/reperfusion injury in rats.", The Journal of pharmacy and pharmacology, vol. 61, issue 9, pp. 1233-41, 2009 Sep. Abstract

OBJECTIVES: To investigate the possible modification of the cardioprotective effect of amlodipine when co-administered with quercetin in myocardial ischaemia/reperfusion-induced functional, metabolic and cellular alterations in rats.

METHODS: Oral doses of amlodipine (15 mg/kg) and quercetin (5 mg/kg), alone or in combination, were administered once daily for 1 week. Rats were then subjected to myocardial ischaemia/reperfusion (35(min)/10(min)). Heart rates and ventricular arrhythmias were recorded during ischaemia/reperfusion progress. At the end of reperfusion, activities of plasma creatine kinase (CK) and cardiac myeloperoxidase were determined. In addition, cardiac contents of lactate, ATP, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total nitrate/nitrite (NO(x)) were estimated. Finally, histological examination was performed to visualize the protective cellular effects of different pretreatments.

KEY FINDINGS: Combined therapy provided significant improvement in the amlodipine effect toward preserving cardiac electrophysiologic functions, ATP and GSH contents as well as reducing the elevated plasma CK, cardiac TBARS and NO(x) contents.

CONCLUSION: Quercetin could add benefits to the cardioprotective effect of amlodipine against injury induced in the heart by ischaemia/reperfusion.

Ahmed, L. A., N. A. Shiha, and A. S. Attia, "Escitalopram Ameliorates Cardiomyopathy in Type 2 Diabetic Rats via Modulation of Receptor for Advanced Glycation End Products and Its Downstream Signaling Cascades.", Frontiers in pharmacology, vol. 11, pp. 579206, 2020. Abstract

Type 2 diabetes mellitus (T2DM) has been recognized as a known risk factor for cardiovascular diseases. Additionally, studies have shown the prevalence of depression among people with diabetes. Thus, the current study aimed to investigate the possible beneficial effects of escitalopram, a selective serotonin reuptake inhibitor, on metabolic changes and cardiac complications in type 2 diabetic rats. Diabetes was induced by feeding the rats high fat-high fructose diet (HFFD) for 8 weeks followed by a subdiabetogenic dose of streptozotocin (STZ) (35 mg/kg, i. p.). Treatment with escitalopram (10 mg/kg/day; p. o.) was then initiated for 4 weeks. At the end of the experiment, electrocardiography was performed and blood samples were collected for determination of glycemic and lipid profiles. Animals were then euthanized and heart samples were collected for biochemical and histopathological examinations. Escitalopram alleviated the HFFD/STZ-induced metabolic and cardiac derangements as evident by improvement of oxidative stress, inflammatory, fibrogenic and apoptotic markers in addition to hypertrophy and impaired conduction. These results could be secondary to its beneficial effects on the glycemic control and hence the reduction of receptor for advanced glycation end products content as revealed in the present study. In conclusion, escitalopram could be considered a favorable antidepressant medication in diabetic patients as it seems to positively impact the glycemic control in diabetes in addition to prevention of its associated cardiovascular complications.

El-Sawalhi, M. M., and L. A. Ahmed, "Exploring the protective role of apocynin, a specific NADPH oxidase inhibitor, in cisplatin-induced cardiotoxicity in rats.", Chemico-biological interactions, vol. 207, pp. 58-66, 2014 Jan 25. Abstract

Despite the clinical reports, few studies have focused on reducing the cardiotoxicity of cisplatin. In the present study, cardiotoxicity was examined after a single ip injection of cisplatin (7mg/kg) in rats. Apocynin was given in drinking water (600mg/L) for five successive days before and after cisplatin injection. At the end of the experiment, hemodynamic parameters were recorded, animals were sacrificed and serum creatine kinase-MB activity was determined. The whole ventricle was isolated for estimation of tumor necrosis factor-alpha (TNF-α) content, NADPH oxidase, myeloperoxidase and caspase-3 activities in addition to nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and nuclear factor kappa B (NF-κB) gene expressions. Furthermore, oxidative stress markers and antioxidant enzymes were measured in postmitochondrial and mitochondrial fractions. Mitochondrial membrane potential, nuclear DNA fragmentation and cardiomyocyte cross-sectional area were also evaluated. Apocynin was effective against cisplatin-induced decrement in heart rate and blood pressure. Moreover, pretreatment with apocynin notably ameliorated the state of oxidative stress, mitigated inflammation and preserved mitochondrial membrane potential. Apocynin provided also a significant cardioprotection as revealed by alleviating the overexpression of Nrf2, HO-1 and NF-κB, the elevation of caspase-3 activity, the prominent nuclear DNA fragmentation and the decreased cardiomyocyte cross-sectional area. This study highlights the potential role of apocynin in inhibiting cisplatin-induced hemodynamic changes, postmitochondrial and mitochondrial damage as indicated by improvement in the state of oxidative stress, inflammation and apoptosis.

Ahmed, L. A., M. B. Salem, S. H. Seif El-Din, N. M. El-Lakkany, H. O. Ahmed, S. M. Nasr, O. A. Hammam, S. S. Botros, and S. Saleh, "Gut microbiota modulation as a promising therapy with metformin in rats with non-alcoholic steatohepatitis: Role of LPS/TLR4 and autophagy pathways.", European journal of pharmacology, vol. 887, pp. 173461, 2020. Abstract

Gut microbiota is a crucial factor in pathogenesis of non-alcoholic steatohepatitis (NASH). Therefore, targeting the gut-liver axis might be a novel therapeutic approach to treat NASH. This study aimed to investigate the therapeutic effects of a probiotic (Lactobacillus reuteri) and metronidazole (MTZ) (an antibiotic against Bacteroidetes) either alone or in combination with metformin (MTF) in experimentally-induced NASH. NASH was induced by feeding rats high fat diet (HFD) for 12 weeks. MTF (150 mg/kg/day) or L. reuteri (2x10 colony forming unit/day) were given orally for 8 weeks; meanwhile, MTZ (15 mg/kg/day, p.o.) was administered for 1 week. Treatment with L. reuteri and MTZ in combination with MTF showed additional benefit compared to MTF alone concerning lipid profile, liver function, oxidative stress, inflammatory and autophagic markers. Furthermore, combined regimen succeeded to modulate acetate: propionate: butyrate ratios as well as Firmicutes and Bacteroidetes fecal contents with improvement of insulin resistance (IR). Yet, the administration of MTF alone failed to normalize Bacteriodetes and acetate contents which could be the reason for its moderate effect. In conclusion, gut microbiota modulation may be an attractive therapeutic avenue against NASH. More attention should be paid to deciphering the crosstalk mechanisms linking gut microbiota to non-alcoholic fatty liver disease (NAFLD) to identify new therapeutic targets for this disease.

KANDIL, E. S. R. A. A. A., R. H. Sayed, L. A. Ahmed, M. A. Abd El Fattah, and B. M. El-Sayeh, "Hypoxia-inducible factor 1 alpha and nuclear-related receptor 1 as targets for neuroprotection by albendazole in a rat rotenone model of Parkinson's disease.", Clinical and experimental pharmacology & physiology, vol. 46, issue 12, pp. 1141-1150, 2019. Abstract

Hypoxia-inducible factor-1 alpha (HIF-1α) and nuclear receptor related-1 (Nurr1) play pivotal roles in the development and survival of dopaminergic neurons, and deficiencies in these genes may be involved in Parkinson's disease (PD) pathogenesis. Recently, anthelminthic benzimidazoles were shown to promote HIF-1α transcription in vitro and were proposed to activate Nurr1 via their benzimidazole group. Therefore, the aim of this study was to explore the neuroprotective effects of albendazole (ABZ), an anthelminthic benzimidazole, in a rotenone model of Parkinson's disease (PD). Rotenone (1.5 mg/kg) was subcutaneously injected into rats every other day for a period of 21 days, resulting in the development of the essential features of PD. In addition to rotenone, ABZ (10 mg/kg) was administered orally starting from the 11th day. Treatment of rats with ABZ markedly mitigated rotenone-induced histological alterations in substantia nigra (SN), restored striatal dopamine (DA) level and motor functions and decreased the expression of α-synuclein (a disease marker protein). ABZ also enhanced expression of Hypoxia-inducible factor-1 alpha (HIF-1α) in the SN along with its downstream target, vascular endothelial growth factor, promoting neuronal survival. Similarly, ABZ augmented nuclear receptor related-1 (Nurr1) expression in the SN and increased transcriptional activation of Nurr1-controlled genes, which are essential for regulation of DA synthesis; additionally, expression of neurotoxic proinflammatory cytokines that induce neuronal death was suppressed. In conclusion, the present study suggests that ABZ exerts a neuroprotective effect in a rotenone-induced PD model associated with HIF-1α and Nurr1 activation and thus may be a viable candidate for treating PD.

Al-Massri, K. F., L. A. Ahmed, and H. S. El-Abhar, "Mesenchymal stem cells in chemotherapy-induced peripheral neuropathy: A new challenging approach that requires further investigations.", Journal of tissue engineering and regenerative medicine, vol. 14, issue 1, pp. 108-122, 2020. Abstract

Chemotherapeutic drugs may disrupt the nervous system and cause chemotherapy-induced peripheral neuropathy (CIPN) as side effects. There are no completely successful medications for the prevention or treatment of CIPN. Many drugs such as tricyclic antidepressants and anticonvulsants have been used for symptomatic treatment of CIPN. Unfortunately, these drugs often give only partial relief or have dose-limiting side effects. Thus, the treatment of CIPN becomes a challenge because of failure to regenerate and repair the injured neurons. Mesenchymal stem cell (MSC) therapy is a new attractive approach for CIPN. Evidence has demonstrated that MSCs play important roles in reducing oxidative stress, neuroinflammation, and apoptosis, as well as mediating axon regeneration after nerve damage in several experimental studies and some clinical trials. We will briefly review the pathogenesis of CIPN, traditional therapies used and their drawbacks as well as therapeutic effects of MSCs, their related mechanisms, future challenges for their clinical application, and the additional benefit of their combination with pharmacological agents. MSCs-based therapies may provide a new therapeutic strategy for patients suffering from CIPN where further investigations are required for studying their exact mechanisms. Combined therapy with pharmacological agents can provide another promising option for enhancing MSC therapy success while limiting its adverse effects.

Al-Massri, K. F., L. A. Ahmed, and H. S. El-Abhar, "Mesenchymal stem cells therapy enhances the efficacy of pregabalin and prevents its motor impairment in paclitaxel-induced neuropathy in rats: Role of Notch1 receptor and JAK/STAT signaling pathway.", Behavioural brain research, vol. 360, pp. 303-311, 2019. Abstract

Peripheral neuropathy is a common adverse effect observed during the use of paclitaxel (PTX) as chemotherapy. The present investigation was directed to estimate the modulatory effect of bone marrow derived mesenchymal stem cells (BM-MSCs) on pregabalin (PGB) treatment in PTX-induced peripheral neuropathy. Neuropathic pain was induced in rats by injecting PTX (2 mg/kg, i.p) 4 times every other day. Rats were then treated with PGB (30 mg/kg/day, p.o.) for 21 days with or without a single intravenous administration of BM-MSCs. At the end of experiment, behavioral and motor abnormalities were assessed. Animals were then sacrificed for measurement of total antioxidant capacity (TAC), nerve growth factor (NGF), nuclear factor kappa B p65 (NF-κB p65), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and active caspase-3 in the sciatic nerve. Moreover, protein expressions of Notch1 receptor, phosphorylated Janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and phosphorylated p38 mitogen-activated protein kinase (p-p38-MAPK) were estimated. Finally, histological examinations were performed to assess severity of sciatic nerve damage and for estimation of BM-MSCs homing. Combined PGB/BM-MSCs therapy provided an additional improvement toward reducing PTX-induced oxidative stress, neuro-inflammation, and apoptotic markers. Interestingly, BM-MSCs therapy effectively prevented motor impairment observed by PGB treatment. Combined therapy also induced a significant increase in cell homing and prevented PTX-induced sciatic nerve damage in histological examination. The present study highlights a significant role for BM-MSCs in enhancing treatment potential of PGB and reducing its motor side effects when used as therapy in the management of peripheral neuropathy.

KANDIL, E. S. R. A. A. A., R. H. Sayed, L. A. Ahmed, M. A. Abd El Fattah, and B. M. El-Sayeh, "Modulatory Role of Nurr1 Activation and Thrombin Inhibition in the Neuroprotective Effects of Dabigatran Etexilate in Rotenone-Induced Parkinson's Disease in Rats.", Molecular neurobiology, vol. 55, issue 5, pp. 4078-4089, 2018. Abstract

Recently, it has been shown that both decreased nuclear receptor-related 1 (Nurr1) expression and thrombin accumulation are involved in the degeneration of dopaminergic neurons in Parkinson's disease (PD). The new anticoagulant dabigatran etexilate (DE) is a direct thrombin inhibitor that owns benzimidazole group, which has been proposed to activate Nurr1. In the present study, we examined the neuroprotective effects of DE in rotenone model of PD. Rotenone was injected subcutaneously at a dose of 1.5 mg/kg every other day for 21 days. An oral regimen of DE (15 mg/kg) was started after the 5th rotenone injection following the manifestations of PD. Treatment of PD rats with DE mitigated rotenone-induced neuronal degeneration and restored striatal dopamine level with motor recovery. As well, DE enhanced Nurr1 expression in substantia nigra along with increasing transcriptional activation of Nurr1-controlled genes namely tyrosine hydroxylase, vascular monoamine transporter, glial cell line-derived neurotrophic factor, and its receptor gene c-Ret, which are critical for development and maintenance of dopaminergic neurons. DE also suppressed thrombin accumulation in substantia nigra. Both effects probably contributed to repressing neurotoxic proinflammatory cytokines, which was manifested by decreased level of nuclear factor kappa beta and tumor necrosis factor alpha. In conclusion, the present results suggest that DE could possess significant neuroprotective and regenerative effects in a rotenone-induced PD animal model as consequence of Nurr1 activation and thrombin inhibition.

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.

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., 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.

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.

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.