Publications by authors named "Mohamed El-Shafey"

17 Publications

  • Page 1 of 1

Ingestion of mannose ameliorates thioacetamide-induced intrahepatic oxidative stress, inflammation and fibrosis in rats.

Life Sci 2021 Oct 9:120040. Epub 2021 Oct 9.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address:

Background And Aims: The monosaccharide mannose has gained recent interest for its beneficial effect against certain inflammatory disorders. Nevertheless, the influence of mannose on experimentally-induced liver fibrosis and the ensued inflammation is still not fully clear to date.

Main Methods: The current study investigated the outcomes of treating rats with mannose (0.2 ml of 20% w/v, oral gavage) 30 min before the twice weekly intoxication with thioacetamide (TAA) (200 mg/kg, intraperitoneal) for a total period of 8 weeks.

Key Findings: The data indicated that mannose markedly dampened TAA-induced liver fibrosis, as indicated by lowering the fibrotic bridges shown by Masson's trichrome staining. This effect was consistent with reducing TAA-induced hepatocellular injury, as evidenced biochemically (serum ALT and AST activities) and pathologically (necroinflammation score). These hepatoprotective effects mediated by mannose were attributed to i) reversing TAA-induced rise in malondialdehyde (MDA) and decrease in reduced glutathione (GSH) expressions in the liver, ii) limiting TAA-induced release of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), iii) impairing TAA-induced activation of hepatic stellate cells by downregulating α-smooth muscle actin expression (α-SMA) and, and importantly, iv) dampening TAA-induced fibrogenesis driven by transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF).

Significance: Mannose may be an auspicious candidate for preventing oxidative stress, inflammation and fibrogenesis in the liver.
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http://dx.doi.org/10.1016/j.lfs.2021.120040DOI Listing
October 2021

Diacerein ameliorates testosterone-induced benign prostatic hyperplasia in rats: Effect on oxidative stress, inflammation and apoptosis.

Int Immunopharmacol 2021 Aug 24;100:108082. Epub 2021 Aug 24.

Biochemistry Department, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia. Electronic address:

Benign prostatic hypertrophy (BPH) is a serious medical condition among elderly male population. BPH pathogenesis has been linked to inflammation, cellular proliferation, oxidative stress and apoptosis. Diacerein (DIA) is a FDA approved anthraquinone drug that is used to treat joint diseases such as osteoarthritis. DIA has been studied for its potent anti-inflammatory and antioxidant effects, yet its role in managing BPH has not been investigated. In this study, DIA administration for two weeks at 50 mg/kg in testosterone-induced BPH rats significantly reduced prostate weight and index. Moreover, prostatic biochemical and structural features in BPH rats were significantly improved upon DIA treatment. Mechanistically, DIA treatment associated prostatic anti-hyperplastic effects were linked to downregulation of Nrf-2/HO-1 axis, downregulation of inflammatory TNF-a, IL-1β, IL-6, downregulation of the cell proliferative marker PCNA and upregulation of caspase-3 levels. In addition, DIA treatment upregulated prostatic antioxidant GSH, the enzymatic SOD and CAT activities and reduced prostatic lipid peroxidation levels. Altogether, the present study provides evidence that DIA treatment might limit BPH progression via its potent anti-oxidant, anti-inflammatory, anti-proliferative and apoptosis inducing effects.
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http://dx.doi.org/10.1016/j.intimp.2021.108082DOI Listing
August 2021

Effect of zinc oxide nanoparticles and ferulic acid on renal ischemia/reperfusion injury: possible underlying mechanisms.

Biomed Pharmacother 2021 Aug 17;140:111686. Epub 2021 May 17.

Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt; Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt.

Objectives: The present study examined the effects of ferulic acid (FA) and Zinc oxide nanoparticles (ZnO-NPs) and a combination of both on renal ischemia/reperfusion injury (IRI) in rats and their possible underlying mechanisms.

Methods: two-hundreds male Sprague Dawley rats were randomly allocated into the 5 groups; i) sham group, ii) control (IRI) group (occlusion of the left renal pedicle for 45 min), iii) FA group as IRI group with FA (100 mg/Kg oral 24 hrs before ischemia), iv) ZnO-NPs group as IRI group with ZnO-NPs single 5 mg/Kg i.p. 2 hrs before ischemia and v) FA + ZnO-NPs group as IRI group with both FA and ZnO-NPs in the same previous doses. According to the reperfusion times, each group was further subdivided into 4 hr, 24 hr, 48 hr and 7 days reperfusion subgroups.

Results: administration of either FA or ZnO-NPs caused significant improvement in the elevated serum creatinine and BUN and malondialdehyde (MDA) concentrations and expression of TNF-α, Bax, caspase-3 in kidney tissues with significant rise in the creatinine clearance, the activities of catalase (CAT) and superoxide dismutase (SOD) and the expression of HO-1, HIF-1α genes and proliferation marker (ki67) in kidney tissues compared to IRI group (p < 0.05). Moreover, a combination of both agents produced more significant improvement in the studied parameters than each agent did alone (p < 0.05).

Conclusions: Both FA and ZnO-NPs exerted cytoprotective effects against ischemic kidney injury and a combination of both exhibited more powerful renoprotective effect. This renoprotective effect might be due to suppression of oxidative stress, enhancement of cell proliferation (ki67), upregulation of antioxidant genes (Nrf2, HO-1 and HIF-1α) and downregulation of inflammatory cytokine (TNF-α) and apoptotic genes (caspase-3 and Bax).
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http://dx.doi.org/10.1016/j.biopha.2021.111686DOI Listing
August 2021

Leflunomide Induces Dose-Dependent Lung Injury in Mice via Stimulating Vimentin and NLRP3 Inflammasome Production.

Front Pharmacol 2021 23;12:631216. Epub 2021 Apr 23.

Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

Recently, the therapeutic importance of the anti-rheumatic drug, leflunomide, has been increased after the involvement of leflunomide in treating other autoimmune diseases and its promising role in retarding human malignancies. Few studies have focused on the safety in human or animals without clear outlining of the pathologic features on target organs. One clinical study related leflunomide with significant pulmonary complications in predisposed individuals. The current study examined the dose-dependent lung injury produced by leflunomide in healthy mice. Albino mice were allocated into four different groups. Group (1): Vehicle control group, Group (2-4): mice received leflunomide (2.5, 5 or 10 mg/kg), respectively, for 8 weeks and then lungs were dissected from the mice for histopathological examination and fibrosis evaluation (Masson's trichrome staining and α-smooth muscle actin immunohistochemistry). Enzyme linked immunosorbent assay was used to assess the vimentin and other inflammatory factors in the lung homogenate whereas Western blot analysis was employed to assess α-smooth muscle actin, vimentin and collagen 1. Results indicated that leflunomide induced dose-dependent pulmonary injury and the high dose and increased the vimentin, inflammatory markers (NLRP3 and interlukin-1β). Histologic examination showed distorted architecture, marked inflammatory cells infiltrate and increase collagen content. The findings were supported by Western blotting and the immunohistochemical study which showed greater pulmonary α-smooth muscle actin and vimentin content. In conclusion, the current results highlighted that leflunomide produced dose-dependent pulmonary toxicities that requires further investigation of the nature of injury.
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http://dx.doi.org/10.3389/fphar.2021.631216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115235PMC
April 2021

Protective effect of metformin on rat diabetic retinopathy involves suppression of toll-like receptor 4/nuclear factor-k B expression and glutamate excitotoxicity.

Int Immunopharmacol 2021 Jan 25;90:107193. Epub 2020 Nov 25.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia. Electronic address:

Microvascular complications of diabetes mellitus are progressively significant reasons for mortality. Metformin (MET) is considered as the first-line therapy for type 2 diabetes patients, and may be especially beneficial in cases of diabetic retinopathy although the precise mechanisms of MET action are not fully elucidated. The current study was designed to inspect the antioxidant and modulatory actions of MET on DRET in streptozotocin-induced diabetic rats. The effect of MET on the toll-like receptor 4/nuclear factor kappa B (TLR4/NFkB), inflammatory burden and glutamate excitotoxicity was assessed. Twenty-four male rats were assigned to four experimental groups: (1) Vehicle group, (2) Diabetic control: developed diabetes by injection of streptozotocin (60 mg/kg, i.p.). (3&4) Diabetic + MET group: diabetic rats were left for 9 weeks without treatment and then received oral MET 100 and 200 mg/kg for 6 weeks. Retinal samples were utilized in biochemical, histological, immunohistochemical and electron microscopic studies. MET administration significantly decreased retinal level of insulin growth factor and significantly suppressed the diabetic induced increase of malondialdehyde, glutamate, tumor necrosis factor-α and vascular endothelial growth factor (VEGF). Further, MET decreased the retinal mRNA expression of NFkB, tumor necrosis factor-α and TLR4 in diabetic rats. The current findings shed the light on MET's efficacy as an adjuvant therapy to hinder the development of diabetic retinopathy, at least partly, via inhibition of oxidative stress-induced NFkB/TLR4 pathway and suppression of glutamate excitotoxicity.
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http://dx.doi.org/10.1016/j.intimp.2020.107193DOI Listing
January 2021

Repurposing of quinoline alkaloids identifies their ability to enhance doxorubicin-induced sub-G0/G1 phase cell cycle arrest and apoptosis in cervical and hepatocellular carcinoma cells.

Biotechnol Appl Biochem 2021 Aug 21;68(4):832-840. Epub 2020 Aug 21.

Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Egypt.

The ability of quinoline alkaloids (cinchonine, cinchonidine, quinine, and quinidine) to sensitize different human cancer cell lines to doxorubicin (DOX)-induced cell death was evaluated. Cell viability was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the alkaloids ability to enhance DOX-induced apoptosis was explored using Western blotting analysis. Also, flow cytometry was applied to analyze cell fractions in the different cell cycle phases. All alkaloids showed a significant enhancement of DOX-induced cell death in HeLa and HepG2 cell lines. The chemosensitizing activity of the quinoline alkaloids was attributed to the induction of apoptosis as indicated by splitting of caspase-3 and its substrate poly (ADP-ribose) polymerase (PARP). In addition, there was an increase in the cell fractions in sub-G0/G1 phase in case of DOX combination with the alkaloids. This study proves the ability of the quinoline alkaloids to enhance DOX-induced apoptotic cell death in human cervical and hepatocellular carcinoma cells.
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http://dx.doi.org/10.1002/bab.1999DOI Listing
August 2021

Synthesis and Antitumor Activity of Doxycycline Polymeric Nanoparticles: Effect on Tumor Apoptosis in Solid Ehrlich Carcinoma.

Molecules 2020 Jul 15;25(14). Epub 2020 Jul 15.

Department of Pharmaceutics, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.

Objectives: The aim of this study was to prepare doxycycline polymeric nanoparticles (DOXY-PNPs) with hope to enhance its chemotherapeutic potential against solid Ehrlich carcinoma (SEC).

Methods: Three DOXY-PNPs were formulated by nanoprecipitation method using hydroxypropyl methyl cellulose (HPMC) as a polymer. The prepared DOXY-PNPs were evaluated for the encapsulation efficiency (EE%), the drug loading capacity, particle size, zeta potential (ZP) and the in-vitro release for selection of the best formulation. PNP number 3 was selected for further biological testing based on the best pharmaceutical characters. PNP3 (5 and 10 mg/kg) was evaluated for the antitumor potential against SEC grown in female mice by measuring the tumor mass as well as the expression and immunohistochemical staining for the apoptosis markers; caspase 3 and BAX.

Results: The biological study documented the greatest reduction in tumor mass in mice treated with PNP3. Importantly, treatment with 5 mg/kg of DOXY-PNPs produced a similar chemotherapeutic effect to that produced by 10 mg/kg of free DOXY. Further, a significant elevation in mRNA expression and immunostaining for caspase 3 and BAX was detected in mice group treated with DOXY-PNPs.

Conclusions: The DOXY-PNPs showed greater antitumor potential against SEC grown in mice and greater values for Spearman's correlation coefficients were detected when correlation with tumor mass or apoptosis markers was examined; this is in comparison to free DOXY. Hence, DOXY-PNPs should be tested in other tumor types to further determine the utility of the current technique in preparing chemotherapeutic agents and enhancing their properties.
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http://dx.doi.org/10.3390/molecules25143230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396998PMC
July 2020

The interplay of the inhibitory effect of nifuroxazide on NF-κB/STAT3 signaling attenuates acetic acid-induced ulcerative colitis in rats.

Environ Toxicol Pharmacol 2020 Oct 9;79:103433. Epub 2020 Jun 9.

Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address:

Ulcerative colitis (UC) is a disease of increased worldwide prevalence. UC progression is associated with serious complications that leave the patient with considerable health burdens. Nifuroxazide is an oral nitrofuran antibiotic used as antidiarrheal medication. The current study places an emphasis on investigating the potential therapeutic effectiveness of nifuroxazide (10 mg/kg) and (20 mg/kg) against acetic acid (AA)-induced UC. Intra-rectal AA induced a significant colonic injury and impairment of colonic biochemical and functional incidences. Nifuroxazide in a dose-dependent manner significantly corrected UC associated injury. Macroscopic scoring of UC, serum lactate dehydrogenase (LDH) activity, C-reactive protein (CRP) titer, colon malondialdehyde (MDA) and total nitric oxide (NOx) contents significantly declined. Meanwhile, serum total antioxidant capacity (TAC) and colon catalase, superoxide dismutase (SOD) and glutathione transferase (GST) activities and reduced glutathione (GSH) concentration significantly increased in a dose-dependent way. Ultimately, histopathological, immunohistochemical and ultramicroscopic analysis of colon specimen revealed significant improvement. To pinpoint the mechanistic pathway underlying the curative effect of nifuroxazide, colon expression of NF-κB, caspase-3 was evaluated along with STAT-3 activation. Nifuroxazide induced a dose-dependent significant suppression of NF-κB and caspase-3 signaling together with STAT3 signaling. In conclusion; nifuroxazide can be proposed as a therapeutic candidate to attenuate UC and its associated symptoms. The potential underlying mechanism involves suppression of NF-κB/STAT-3/caspase- signaling.
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http://dx.doi.org/10.1016/j.etap.2020.103433DOI Listing
October 2020

The selective c-Met inhibitor capmatinib offsets cisplatin-nephrotoxicity and doxorubicin-cardiotoxicity and improves their anticancer efficacies.

Toxicol Appl Pharmacol 2020 07 22;398:115018. Epub 2020 Apr 22.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

The incorporation of mesenchymal-epithelial transition factor (c-Met) inhibitors with conventional chemotherapeutics may increase the anticancer efficacy of chemotherapeutic agents, but bears the risk of enhancing the adverse effects. To test the hypothesis, co-administration of the novel c-Met inhibitor capmatinib with cisplatin (CIS) or doxorubicin (DOX) was investigated on nephrotoxicity and cardiotoxicity induced by these agents in mice, as well as their in vitro cytotoxicities. The results demonstrated that capmatinib in vivo offered protection against nephrotoxicity and cardiotoxicity by both CIS and DOX, respectively. The underlying mechanisms behind capmatinib protective effect were found to be i) limiting excessive generation of reactive oxygen species by decreasing the level of lipid peroxidation and nitrosative stress products; and ii) suppressing overproduction of pro-inflammatory mediators like TNF-α and IL-6 that coincided with less inflammatory cell infiltration as denoted by lower levels of serum MCP-1 and Ly6G immunostaining. Besides, capmatinib effectively improved the in vivo anticancer efficacy of both CIS and DOX against solid tumors. In vitro, capmatinib increased the apoptotic activity of DOX against cancerous cells, but did not affect that of CIS. This effect might be linked to capmatinib and DOX abilities to lower IL-12(p40) that has an inhibitory effect on IL-12(p70)/IFN-γ-mediated apoptotic activity. In conclusion, the favorable effects of capmatinib can be applied clinically to decrease the toxicity of DOX and CIS chemotherapeutic agents.
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http://dx.doi.org/10.1016/j.taap.2020.115018DOI Listing
July 2020

Carbamazepine Alleviates Retinal and Optic Nerve Neural Degeneration in Diabetic Mice via Nerve Growth Factor-Induced PI3K/Akt/mTOR Activation.

Front Neurosci 2019 1;13:1089. Epub 2019 Nov 1.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.

Diabetic retinopathy causes loss of vision in adults at working-age. Few therapeutic options are available for treatment of diabetic retinopathy. Carbamazepine (CARB), a widely used antiepileptic drug, was recently accounted for its neuroprotective effect. Nerve growth factor (NGF) activates various cascades among which, PI3K/Akt/mTOR pathway has a vital action in NGF-mediated neuronal differentiation and survival. This study evaluated the effect of CARB in the treatment of diabetic retina and unveiled some of the underlying molecular mechanisms. Alloxan diabetes model was induced in 36 albino well-acclimatized mice. After establishment of the diabetic model in 9 weeks, mice were assigned to treatment groups: (1) saline, (2) alloxan-diabetic, (3 and 4) alloxan+CARB (25 or 50 mg per kg p.o) for 4 weeks. After completion of the therapeutic period, mice were sacrificed and eyeballs were enucleated. Retinal levels of NGF and PI3K/Akt were assessed using real-time polymerase chain reaction. Further, total and phosphorylated TrKA, PI3K, Akt, mTOR as well as Caspase-3 were measured by Western blot analysis. Histopathological examination demonstrated that CARB attenuated vacuolization and restored normal thickness and organization of retinal cell layers. In addition, CARB increased pTrKA/TrKA ratio and ameliorated diabetes-induced reduction of NGF mRNA and immunostaining in retina. Additionally, it augmented the mRNA expression of PI3K and Akt, as well as the protein level of the phosphorylated PI3/Akt/mTOR. Results highlighted, for the first time, the neuronal protective effect for CARB in diabetic retina, which is mediated, at least in part, by activation of the NGF/PI3K/Akt/mTOR pathway.
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http://dx.doi.org/10.3389/fnins.2019.01089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838003PMC
November 2019

A dual role of 12/15-lipoxygenase in LPS-induced acute renal inflammation and injury.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 11 23;1864(11):1669-1680. Epub 2019 Jul 23.

Department of Oral Biology and Diagnostic Sciences, Augusta University, Augusta, GA, USA; Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA. Electronic address:

Recent studies suggest a potential role of bioactive lipids in acute kidney injury induced by lipopolysaccharide (LPS). The current study was designed to determine the profiling activities of various polyunsaturated fatty acid (PUFA) metabolizing enzymes, including lipoxygenases (LO), cyclooxygenase, and cytochrome P450 in the plasma of LPS-injected mice using LC-MS. Heat map analysis revealed that out of 126 bioactive lipids screened, only the 12/15-LO metabolite, 12-HETE, had a significant (2.24 ± 0.4) fold increase relative to control (P = 0.0001) after Bonferroni Correction (BCF α = 0.003). We then determined the role of the 12/15-LO in LPS-induced acute kidney injury using genetic and pharmacological approaches. Treatment of LPS injected mice with the 12/15-LO inhibitor, baicalein, significantly reduced levels of renal injury and inflammation markers including urinary thiobarbituric acid reactive substance (TBARs), urinary monocyte chemoattractant protein-1 (MCP-1), renal interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Similarly, knocking-out of 12/15-LO reduced levels of renal inflammation and injury markers elicited by LPS injection. Next, we tested whether exogenous supplementation with docosahexaenoic acid (DHA) as a substrate would divert the role of 12/15-LO from being pro-inflammatory to anti-inflammatory via increased production of the anti-inflammatory metabolite. DHA treatment restored the decreased in plasma level of resolvin D2 (RvD2) and reduced renal injury in LPS-injected mice whereas DHA treatment failed to provide any synergistic effects in reducing renal injury in LPS injected 12/15-LO knock-out mice. The ability of RvD2 to protect kidney against LPS-induced renal injury was further confirmed by exogenous RvD2 which significantly reduced the elevation in renal injury in LPS injected mice. These data suggest a double-edged sword role of 12/15-LO in LPS-induced acute renal inflammation and injury, depending on the type of substrate available for its activity.
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http://dx.doi.org/10.1016/j.bbalip.2019.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750989PMC
November 2019

Effects of GLP-1 Receptor Activation on a Pentylenetetrazole-Kindling Rat Model.

Brain Sci 2019 May 14;9(5). Epub 2019 May 14.

Chemistry and Drug Metabolism, IRP, National Institute on Drug Abuse, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224, USA.

: To study the possible anti-seizure and neuroprotective effect of glucagon like peptide 1 (GLP1) analogue (liraglutide) in a pentylenetetrazole (PTZ) induced kindled rat model and its underlying mechanisms. : Thirty Sprague Dawley rats were allocated into 3 equal groups; i) Normal group: normal rats received normal saline, ii) PTZ (kindling) group: received PTZ (50 mg/Kg intraperitoneally (i.p.)) every other day for 2 weeks and iii) PTZ + GLP1 group: same as the PTZ group but rats received liraglutide (75 µg/kg i.p. daily) for 2 weeks before PTZ injection. Seizure severity score, seizure latency and duration were assessed. Also, the expression of caspase-3 (apoptotic marker) and β-catenin (Wnt pathway) by western blotting, markers of oxidative stress (GSH, CAT and MDA) by biochemical assay and the expression of LC3 (marker of autophagy) and heat shock protein 70 (Hsp70) by immunostaining were assessed in hippocampal regions of brain tissues. : PTZ caused a significant increase in Racine score and seizure duration with a significant decrease in seizure latency. These effects were associated with a significant increase in MDA, β-catenin, caspase-3, Hsp70 and LC3 in brain tissues ( < 0.05). Meanwhile, liraglutide treatment caused significant attenuation in PTZ-induced seizures, which were associated with significant improvement in markers of oxidative stress, reduction in LC3, caspase-3 and β-catenin and marked increase in Hsp70 in hippocampal regions ( < 0.05). : Activation of GLP1R might have anticonvulsant and neuroprotective effects against PTZ-induced epilepsy. These effects could be due to suppression of oxidative stress, apoptosis and autophagy and upregulation of Hsp70.
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http://dx.doi.org/10.3390/brainsci9050108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562858PMC
May 2019

Effects of metformin on apoptosis and α-synuclein in a rat model of pentylenetetrazole-induced epilepsy.

Can J Physiol Pharmacol 2019 Jan 11;97(1):37-46. Epub 2018 Oct 11.

e Chemistry and Drug Metabolism, IRP, National Institute on Drug Abuse, National Institutes of Health, Biomedical Research Center, Baltimore, MD, USA.

The present study was designed to examine the possible neuroprotective and antiepileptic effects of metformin (Metf) in a rat model of pentylenetetrazole (PTZ)-induced epilepsy and its possible underlying mechanisms. Forty male albino rats were assigned to 4 groups of equal size: (1) normal control (NC) group, (2) Metf group: daily treatment with Metf (200 mg/kg, i.p.) for 2 weeks, (3) PTZ group: treatment with PTZ (50 mg/kg, i.p.) every other day for 2 weeks, and (4) Metf + PTZ group: daily treatment with PTZ and metformin (200 mg/kg, i.p.) for 2 weeks. Administration of PTZ caused a significant increase in seizure score and duration, induced a state of oxidative stress (high malondialdehyde, low reduced glutathione and catalase activity), and led to the upregulation of β-catenin, caspase-3, and its cleavage products, Hsp70 and α-synuclein, in hippocampal regions as well as a significant reduction in seizure latency. While Metf treatment significantly ameliorated PTZ-induced seizures, attenuated oxidative stress, and upregulated α-synuclein and β-catenin expression, it also inhibited caspase-3 activation and the release of the cleavage product and caused more upregulation in Hsp70 expression in hippocampal regions (p < 0.05). In conclusion, the antiepileptic and neuroprotective effects of Metf in PTZ-induced epilepsy might be due to the inhibition of apoptosis, attenuation of oxidative stress and α-synuclein expression, and upregulation of Hsp70.
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http://dx.doi.org/10.1139/cjpp-2018-0266DOI Listing
January 2019

Vitamin D nanoemulsion enhances hepatoprotective effect of conventional vitamin D in rats fed with a high-fat diet.

Chem Biol Interact 2018 May 11;288:65-75. Epub 2018 Apr 11.

Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Egypt. Electronic address:

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with hyperlipidemia, obesity and type II diabetes. Due to increasing prevalence of these diseases globally, NAFLD is considered as a common form of chronic liver diseases. Vitamin D is a fat soluble vitamin with reported anti-inflammatory, anti-oxidant and immune modulating activity. Hypovitaminosis D often coexists with NAFLD and various studies reported beneficial role of vitamin D in modulating NAFLD. However, variable oral bioavailability, poor water solubility, and chemical degradation hinder the clinical application of vitamin D.

Purpose: We evaluated the potential protective effect of Vitamin D nanoemulsion (developed by sonication and pH-Shifting of pea protein isolate and canola oil) compared to conventional vitamin D against liver injury in rats fed with high fat diet (HFD).

Methods: We analyzed liver function enzymes, lipid profile, lipid metabolism, levels and histopathology of inflammation and fibrosis in rat liver tissues.

Results: HFD fed rats exhibited deterioration of liver function, poor lipid profile, decreased fatty acid oxidation and up-regulation of inflammatory cytokines and extracellular matrix deposition. Vitamin D administration reduced elevated liver enzymes, improved lipid profile, enhanced fatty acid oxidation and attenuated liver inflammation and fibrosis. Interestingly, vitamin D nanoemulsion was superior to conventional vitamin D with remarkable hepatoprotective effect against HFD-induced liver injury.

Conclusion: This study demonstrated vitamin D nanoemulsion as a more efficient formulation with more prominent hepatoprotective effect against HFD-induced liver injury compared to conventional oral vitamin D.
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http://dx.doi.org/10.1016/j.cbi.2018.04.010DOI Listing
May 2018

Genetic Polymorphisms of Fas/FasL Promoter Associated with Hepatitis C cirrhosis and HCC

Asian Pac J Cancer Prev 2017 10 26;18(10):2683-2688. Epub 2017 Oct 26.

Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Egypt. Email:

Aim: The present study was performed to determine any associations of genetic polymorphisms of Fas/FasL promoter regions, at Fas670 and Fas1377 and FasL844, with hepatitis C cirrhosis and HCC, with a focus on severity of disease. Methods: Totals of 120 patients with cirrhosis and 101 with hepatocellular carcinoma (HCC) were enrolled. All had chronic HCV infection as indicated by positive anti-HCV antibodies and positive HCV RNA on real time PCR. One hundred healthy control subjects were also included in the study. Patients were subjected to full clinical, radiological and histopathological examinations. In addition to routine laboratory tests for liver function tests, Fas670 and Fas1377 and FasL844 genetic polymorphisms of Fas/FasL promoter regions were assessed by RFLP-PCR (restriction fragment length polymorphism with polymerase chain reaction). Results: Significant higher levels of the AG genotype in Fas670 and Fas1773 were observed in patients with cirrhosis and HCC (P=0.0001) as compared to control subjects. In addition, the CC genotype in FASL844 was also more common in patients (P=0.01). Furtehrmore, there was a significant association of substitution of A by G alleles in Fas670 and Fas1773 with advanced BCA staging (P=0.02, P=0.0001 respectively) and larger tumor size >5cm (P=0.01, P=0.0001 respectively) and in Fas670 with advanced pathological grading (P=0.0001). Moreover the CC genotype of FASL844 was significantly linked with advanced BCA, large tumor size >5cm and advanced pathological grading (P=0.0001). Conclusion: The findings of the present study highlight associations of genetic polymorphisms of promoter regions in Fas and Fas L with cirrhosis and HCC associated with chronic HCV. Support was also obtained for the conclusion that single nucleotide polymorphisms of the Fas/ FasL system impact on clinical and histopathological grading of HCCs. Further large scale studies are recommended for confirmation.
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http://dx.doi.org/10.22034/APJCP.2017.18.10.2683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747390PMC
October 2017

Sitagliptin enhances the neuroprotective effect of pregabalin against pentylenetetrazole-induced acute epileptogenesis in mice: Implication of oxidative, inflammatory, apoptotic and autophagy pathways.

Neurochem Int 2018 05 12;115:11-23. Epub 2017 Oct 12.

Pharmacology and Toxicology, College of Pharmacy, Taibahu University, El-Madina El- Munawarah, Saudi Arabia; Clinical Pharmacology Department, Faculty of Medicine, Suez Canal University, Egypt.

The current investigation aimed at studying the anti-epileptogenic effect of sitagliptin. The possible effect of the drug in combination with pregabalin in pentylenetetrazole (PTZ)- induced seizures was studied. In addition, the postulated mechanisms that could mediate such effect were explored namely, suppression of oxidative stress and neuro-inflammatory markers, autophagy and apoptosis. Seven days prior to PTZ (60 mg/kg, sc) injection, mice were treated with sitagliptin (5, 15, and 60 mg/kg, twice daily, orally) or pregabalin (30 mg/kg, once daily, orally) or their combination. At the end of the experiment, several parameters were assessed including: oxidative/nitro-oxidative stress such as superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GP-x) catalase (CAT), and lipid peroxidation assessed as malondialdehyde (MDA), nitrate/nitrite (NOx), 3-nitrotyrosine (3-NT). Seizure latency was evaluated. Neuronal damage was also assessed by performing tissue staining by hematoxylin and eosin, estimating hippocampus level of glutamate, gamma-aminobutyric acid (GABA), glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor (BDNF). Also, markers for inflammation, autophagy and apoptosis were measured, nuclear factor erythroid-derived 2- like 2 (Nrf2), nuclear factor kappa-B (NF-κB), phosphatidylethanolamine-conjugated form of microtubule-associated protein light chain-3 (LC3-II), casapase-3, Bcl-2-like protein 4 (BAX) and glucagon like peptide-1 (GLP-1) activity. Sitagliptin significantly suppressed epileptogenesis in PTZ-induced seizures. Sitagliptin counteracted neuronal damage and all biochemical, and histo-chemical alteration induced by PTZ. Also, a more significant protective effect was observed after combination with pregabalin. This study is indicative for the antiepileptogenic potential of sitagliptin with or without pregabalin in the PTZ model of epilepsy which is likely to be through its effect on antioxidant, anti-apoptotic and autophagic pathways.
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http://dx.doi.org/10.1016/j.neuint.2017.10.006DOI Listing
May 2018

Targeting of 12/15-Lipoxygenase in retinal endothelial cells, but not in monocytes/macrophages, attenuates high glucose-induced retinal leukostasis.

Biochim Biophys Acta Mol Cell Biol Lipids 2017 Jun 27;1862(6):636-645. Epub 2017 Mar 27.

Department of Oral Biology and Anatomy, Dental College of Georgia, Augusta University, Augusta, GA, USA; Department of Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, USA; Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Cellular Biology and Anatomy, MCG, Augusta University, Augusta, GA, USA. Electronic address:

Aims: Our previous studies have established a role for 12/15-lipoxygenase (LO) in mediating the inflammatory response in diabetic retinopathy (DR). However, the extent at which the local or systemic induction of 12/15-LO activity involved is unclear. Thus, the current study aimed to characterize the relative contribution of retinal endothelial versus monocytic/macrophagic 12/15-LO to inflammatory responses in DR.

Materials & Methods: We first generated a clustered heat map for circulating bioactive lipid metabolites in the plasma of streptozotocin (STZ)-induced diabetic mice using liquid chromatography coupled with mass-spectrometry (LC-MS) to evaluate changes in circulating 12/15-LO activity. This was followed by comparing the in vitro mouse endothelium-leukocytes interaction between leukocytes isolated from 12/15-LO knockout (KO) versus those isolated from wild type (WT) mice using the myeloperoxidase (MPO) assay. Finally, we examined the effects of knocking down or inhibiting endothelial 12/15-LO on diabetes-induced endothelial cell activation and ICAM-1 expression.

Results: Analysis of plasma bioactive lipids' heat map revealed that the activity of circulating 12/15-LO was not altered by diabetes as evident by no significant changes in the plasma levels of major metabolites derived from 12/15-lipoxygenation of different PUFAs, including linoleic acid (13-HODE), arachidonic acid (12- and 15- HETEs), eicosapentaenoic acid (12- and 15- HEPEs), or docosahexaenoic acid (17-HDoHE). Moreover, leukocytes from 12/15-LO KO mice displayed a similar increase in adhesion to high glucose (HG)-activated endothelial cells as do leukocytes from WT mice. Furthermore, abundant proteins of 12-LO and 15-LO were detected in human retinal endothelial cells (HRECs), while it was undetected (15-LO) or hardly detectable (12-LO) in human monocyte-like U937 cells. Inhibition or knock down of endothelial 12/15-LO in HRECs blocked HG-induced expression of ICAM-1, a well-known identified important molecule for leukocyte adhesion in DR.

Conclusion: Our data support that endothelial, rather than monocytic/macrophagic, 12/15-LO has a critical role in hyperglycemia-induced ICAM-1 expression, leukocyte adhesion, and subsequent local retinal barrier dysfunction. This may facilitate the development of more precisely targeted treatment strategies for DR.
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http://dx.doi.org/10.1016/j.bbalip.2017.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504079PMC
June 2017
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