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A
Attalla, D. M., L. A. Ahmed, H. F. Zaki, and M. M. Khattab, "Paradoxical effects of atorvastatin in isoproterenol-induced cardiotoxicity in rats: Role of oxidative stress and inflammation.", Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, vol. 104, pp. 542-549, 2018 Aug. Abstract

Atorvastatin (ATV) was previously shown to improve oxidative stress, inflammation and endothelial dysfunction in several experimental and clinical studies yet other studies have reported a pro-oxidant and damaging effect upon ATV administration. The present study was directed to investigate the effect of ATV pre- and post-treatment in isoproterenol (ISO)-induced cardiotoxicity in rats. Myocardial damage was induced by ISO (5 mg/kg/day, s.c.) for 1 week. ATV (10 mg/kg/day, p.o.) was given for 2 weeks starting 1 week before or after ISO administration. ISO-treated rats showed significant alterations in electrocardiographic recordings, serum creatine kinase-MB (CK-MB) level as well as oxidative stress and inflammatory biomarkers. Moreover, ISO administration resulted in endothelial dysfunction and significant histopathological damage. Pre-treatment with ATV aggravated ISO-induced cardiotoxicity. On the other hand, ATV post-treatment succeeded to significantly improve oxidative stress and inflammatory biomarkers, endothelial dysfunction and myocardial degeneration. These results suggest that ATV might produce a synergistic pro-oxidant effect if given before or along with another pro-oxidant (ISO). Thus, caution should be applied upon the use of statin as a prophylactic therapy for primary cardiovascular disease prevention.

E
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.

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.

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.

Essam, R. M., L. A. Ahmed, R. M. Abdelsalam, and A. S. El-Khatib, "Phosphodiestrase-1 and 4 inhibitors ameliorate liver fibrosis in rats: Modulation of cAMP/CREB/TLR4 inflammatory and fibrogenic pathways.", Life sciences, vol. 222, pp. 245-254, 2019. Abstract

BACKGROUND: Phosphodiestrase (PDE) enzymes are suggested to play a leading role in fibrogenesis of liver where studies showed the possible implication of PDE 1 & 4 in liver injury proposing them as possible targets for treating liver fibrosis.

AIM: The present study was designed to investigate, for the first time, the possible therapeutic effects of selective inhibitors of PDE-1 (vinpocetine) and PDE-4 (roflumilast) in liver fibrosis induced by diethylnitrosamine (DEN) in rats.

MAIN METHODS: Rats were given DEN (100 mg/kg, i.p.) once weekly for 6 weeks to induce liver fibrosis. Vinpocetine (10 mg/kg/day) or roflumilast (0.5 mg/kg/day) was then orally administered for 2 weeks.

KEY FINDINGS: Vinpocetine significantly suppressed the contents of hydroxyproline, transforming growth factor-beta 1 (TGF-β1), nuclear factor-kappa B (NF-κB) whereas roflumilast normalized them. Moreover, tumor necrosis factor-alpha (TNF-α) content and protein expressions of toll-like receptor 4 (TLR4) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly decreased whereas cAMP response element binding (CREB) protein expression was significantly elevated by both treatments. Additionally, vinpocetine and roflumilast up-regulated the gene expression of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) receptor where roflumilast showed better results. PDE1 and 4 activities were inhibited by vinpocetine and roflumilast, respectively. The superior results offered by roflumilast could be related to the higher cAMP level obtained relative to vinpocetine.

SIGNIFICANCE: Our study manifested the up-regulation of PDE enzymes (1 & 4) in liver fibrosis and addressed the therapeutic role of vinpocetine and roflumilast as PDEIs through a cAMP-mediated TLR4 inflammatory and fibrogenic signaling pathways.

K
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.

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.

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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.

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.

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Rasheed, N. A. O., L. A. Ahmed, D. M. Abdallah, and B. M. El-Sayeh, "Paradoxical cardiotoxicity of intraperitoneally-injected epigallocatechin gallate preparation in diabetic mice", Scientific reports, vol. 8, pp. 7880, 1979 Oct, 2018. Abstract

It has been found that NADPH-dependent hydroxylation of dimethylaniline, aniline, p- and o-nitroanisol and lipid peroxidation is inhibited by the tyrosine-copper (II) complex (low molecular weight analog of superoxide dismutase), which is indicative of a possibility of superoxide radicals formation in these reactions. The inhibition of the above-mentioned reactions with Tyr2-Cu2+ is less pronounced or absent, if cumole hydroperoxide is used as cosubstrate instead of NADPH. Differences in the Tyr2-Cu2+ complex effects on the cumule hydroperoxide-dependent xenobiotics hydroxylation and lipid peroxidation catalyzed by various forms of cytochrome P-450, e. g. microsomal, soluble and incorporated into liposomes, have been found. The data obtained suggest that the efficiency of the inhibitory effect of the Tyr2-Cu2+ complex depends on the type of cosubstrates (NADPH, cumole hydroperoxide) and substrates used as well as on the form of cytochrome P-450.

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.
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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.

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