Al-Ghobashy, M. A., ElMeshad A. N., Abdelsalam R. M., Nooh M. M., Al-Shorbagy M. Y., & Laible G. (2017).  Development and Pre-Clinical Evaluation of Recombinant Human Myelin Basic Protein Nano Therapeutic Vaccine in Experimental Autoimmune Encephalomyelitis Mice Animal Model.. Scientific reports. 7, 46468. Abstract

Recombinant human myelin basic protein (rhMBP) was previously produced in the milk of transgenic cows. Differences in molecular recognition of either hMBP or rhMBP by surface-immobilized anti-hMBP antibodies were demonstrated. This indicated differences in immunological response between rhMBP and hMBP. Here, the activity of free and controlled release rhMBP poly(ε-caprolactone) nanoparticles (NPs), as a therapeutic vaccine against multiple sclerosis (MS) was demonstrated in experimental autoimmune encephalomyelitis (EAE) animal model. Following optimization of nanoformulation, discrete spherical, rough-surfaced rhMBP NPs with high entrapment efficiency and controlled release pattern were obtained. Results indicated that rhMBP was loaded into and electrostatically adsorbed onto the surface of NPs. Subcutaneous administration of free or rhMBP NPs before EAE-induction reduced the average behavioral score in EAE mice and showed only mild histological alterations and preservation of myelin sheath, with rhMBP NPs showing increased protection. Moreover, analysis of inflammatory cytokines (IFN-γ and IL-10) in mice brains revealed that pretreatment with free or rhMBP NPs significantly protected against induced inflammation.

IN CONCLUSION: i) rhMBP ameliorated EAE symptoms in EAE animal model, ii) nanoformulation significantly enhanced efficacy of rhMBP as a therapeutic vaccine and iii) clinical investigations are required to demonstrate the activity of rhMBP NPs as a therapeutic vaccine for MS.

Aldakinah, A. - A. A., Al-Shorbagy M. Y., Abdallah D. M., & El-Abhar H. S. (2017).  Trigonelline and vildagliptin antidiabetic effect: improvement of insulin signalling pathway.. The Journal of pharmacy and pharmacology. Abstract

OBJECTIVES: Trigonelline (TRG) is known to have an antidiabetic efficacy; however, its mechanism is not entirely elucidated.

METHODS: Hence, its effect on insulin signaling, besides its effectiveness in combination with vildagliptin (VLD) in a Type 2 diabetes model has been tested.

KEY FINDINGS: TRG (50 mg/kg; p.o) lowered serum glucose, fructosamine, insulin, and HOMA-IR index and increased insulin sensitivity in soleus muscle via augmenting insulin receptor autophosphorylation (IR-PH), pT308-Akt, and glucose transporter 4 (GLUT4). Additionally, it reduced muscle advanced glycation end products and lipid peroxides with increased glutathione. TRG showed an anti-lipidemic effect lowering serum and/or muscle total cholesterol, triglycerides, and FFAs to decrease body weight, and visceral/epididymal indices. Furthermore, VLD (3 and 10 mg/kg, p.o) increased IR-PH, pT308-Akt, and GLUT4 to improve insulin signaling. The combined effect of TRG with the low dose of VLD was mostly confined to the reduction of the aberrant lipid profile.

CONCLUSIONS: The beneficial effect of TRG on insulin sensitivity and glucose/ lipid homeostasis is mediated by the enhancement of the insulin signaling and antioxidant property. Moreover, the positive impact of VLD on pT308-Akt is an integral part in insulin signaling, and hence its antidiabetic effect.

Al-Shorbagy, M. Y., & Nassar N. N. (2017).  Octreotide ameliorates inflammation and apoptosis in acute and kindled murine PTZ paradigms.. Naunyn-Schmiedeberg's archives of pharmacology. 390(1), 61-68. Abstract

In the present study, the role of octreotide (OCT) in pentylenetetrazole (PTZ) kindling as well as in acute convulsion models was evaluated. Mice were allocated in groups as (1) control saline; (2) acute PTZ (PTZ-a; 60 mg/kg, i.p.), as a single convulsive dose; and (3) kindled (PTZ-k) receiving nine subconvulsive doses of PTZ (40 mg/kg, i.p.) for 17 days. Groups 4-7 received either valproic acid (VPA) 50 mg/kg or OCT (50 μg/kg, Sandostatin®) 30 min by oral gavage before PTZ-a or PTZ-k. The median seizure stage, latency onset of first stage 4/5 seizures, and incidence of convulsing animals were recorded. Cortical dopamine (DA), tumor necrosis factor (TNF)-α, interleukin (IL)-10, caspase (Casp)-3, myeloperoxidase (MPO), and nitric oxide (NO) were assessed in addition to inducible nitric oxide synthase (iNOS) that was evaluated immunohistochemically in a different set of groups. OCT halted PTZ-induced epilepsy delaying convulsion latency via modulating MPO and TNF-α and normalizing IL-10 with both treatment regimens. In PTZ-k, it decreased Casp-3 activity, NO level, and iNOS immunoreactivity. OCT in both paradigms decreased DA concentration. The current investigation implicates a crucial role for OCT in modulating PTZ-induced kindling by regulating inflammatory and apoptotic effects.

Salem, H. A., & Al-Shorbagy M. Y. (2017).  Evaluation of the relaxant effect of levetiracetam on isolated rat duodenum.. Fundamental & clinical pharmacology. 31(1), 75-82. Abstract

Levetiracetam (LEV) is an approved drug for the treatment of some epileptic disorders. With few and controversial reports addressing its possible pharmacodynamic interactions, the current study aimed at studying the effect of LEV on isolated rat duodenal strips to enlighten its possible intestinal adverse effects using the isolated smooth muscle strips of rat duodenum. LEV showed a dose-dependent inhibition in KCl (80 mm)-induced contractions in normal Tyrode's solution. Moreover, preincubation with LEV (3 mm) in K(+) -rich/Ca(2+) -free medium led to a significant decrease in the maximum contractions (Emax ) coupled to a right shift of the cumulative CaCl2 concentration curves implying a possible Ca(2+) channel blocking potential. In addition, LEV exhibited a typical noncompetitive inhibition in the cumulative carbachol concentration curves evidenced as a decrease in Emax without the alteration of EC50 , thus eliminating any possible role of the muscarinic receptors in the relaxant effect. To rule out other possible relaxant mechanisms, tests were conveyed in Tyrode's solution containing either 100 μm l-NAME or 10 μm glimepiride to test the possible relaxant roles exhibited by nitric oxide (NO) and KATP channel opening, respectively. None of the tested pathways was involved in LEV-mediated relaxation. Taken altogether, the results of the current study entail that LEV might exert a relaxant effect on intestinal smooth muscles through blocking L-type voltage-operated calcium channels, but not involving either NO release or KATP channel opening.

Biological Standardization (PME5)

Semester: 
Summer

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Abd-ElSalam, H. - A. H., Al-Ghobashy M. A., Al-Shorbagy M., Nassar N., Zaazaa H. E., & Ibrahim M. A. (2016).  Correlation of In Vivo and In Vitro Assay Results for Assessment of Free Radical Scavenging Activity of Green Tea Nutraceuticals.. Journal of food science. Abstract

Green tea (GT)-derived catechins; epigallocatechin gallate (EGCG) in particular are commonly used nutraceuticals for their free-radical scavenging activity (FRSA). The influence of photodegradation on the protective power of GT nutracenticals against oxidative stress was thoroughly explored. Photodegradation of GT extracts was carried out and monitored using orthogonal stability-indicating testing protocol; in vitro and in vivo assays. Total polyphenol content (TPC) and FRSA were determined spectrophotometrically while EGCG was selectively monitored using SPE-HPLC. In vivo assessment of photodegraded samples was investigated via measuring a number of biomarkers for hepatic oxidative stress and apoptosis (caspase-3, inducible nitric oxide synthase, nitric oxide, mitogen-activated protein kinase, glutathione, thiobarbituric acid reactive substances, nuclear factor kappa beta, and nuclear factor erythroid 2-related factor) as well as liver damage (alanine transaminase and aspartate transaminase) in serum of rats previously subjected to oxidative stress. Results showed complete degradation of EGCG in photodegraded green tea samples with no correlation with either TPC or FRSA. On the other hand, in vivo assay results revealed not only loss of activity but formation of harmful pro-oxidants. Photostability was found crucial for the protective effect of GT extract against lead acetate insult. Results confirmed that careful design of quality control protocols requires correlation of chemical assays to bioassays to verify efficacy, stability, and most importantly safety of nutraceuticals.

Nursing Applied Pharmacology

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Arab, H. H., Al-Shorbagy M. Y., Abdallah D. M., & Nassar N. N. (2014).  Telmisartan attenuates colon inflammation, oxidative perturbations and apoptosis in a rat model of experimental inflammatory bowel disease.. PloS one. 9(5), e97193. AbstractWebsite

Accumulating evidence has indicated the implication of angiotensin II in the pathogenesis of inflammatory bowel diseases (IBD) via its proinflammatory features. Telmisartan (TLM) is an angiotensin II receptor antagonist with marked anti-inflammatory and antioxidant actions that mediated its cardio-, reno- and hepatoprotective actions. However, its impact on IBD has not been previously explored. Thus, we aimed to investigate the potential alleviating effects of TLM in tri-nitrobenezene sulphonic acid (TNBS)-induced colitis in rats. Pretreatment with TLM (10 mg/kg p.o.) attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI), colon weight/length ratio, macroscopic damage, histopathological findings and leukocyte migration. TLM suppressed the inflammatory response via attenuation of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) and myeloperoxidase (MPO) activity as a marker of neutrophil infiltration besides restoration of interleukin-10 (IL-10). TLM also suppressed mRNA and protein expression of nuclear factor kappa B (NF-κB) p65 and mRNA of cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proinflammatory genes with concomitant upregulation of PPAR-γ. The alleviation of TLM to colon injury was also associated with inhibition of oxidative stress as evidenced by suppression of lipid peroxides and nitric oxide (NO) besides boosting glutathione (GSH), total anti-oxidant capacity (TAC) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). With respect to apoptosis, TLM downregulated the increased mRNA, protein expression and activity of caspase-3. It also suppressed the elevation of cytochrome c and Bax mRNA besides the upregulation of Bcl-2. Together, these findings highlight evidences for the beneficial effects of TLM in IBD which are mediated through modulation of colonic inflammation, oxidative stress and apoptosis.

Al-Shorbagy, M. Y., El-Sayeh B. M., & Abdallah D. M. (2013).  Additional Antiepileptic Mechanisms of Levetiracetam in Lithium-Pilocarpine Treated Rats. PLoS One. 8(10), e76735.Website
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