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Abdel Moneim, L. M., M. W. Helmy, and H. S. El-Abhar, "Co-targeting of endothelin- and vitamin D receptors: a novel strategy to ameliorate cisplatin-induced nephrotoxicity.", Pharmacological reports : PR, vol. 71, issue 5, pp. 917-925, 2019 Sep. Abstract

BACKGROUND: Although modulation of the vitamin D receptor (VDR) and endothelin- receptor (ETR) has previously been reported to offer renoprotection against cisplatin-induced nephrotoxicity, the possible interaction between the ET-1 and vitamin D pathways remains obscure. Therefore, the present study addressed the possible interaction between these signalling pathways using BQ-123 (a selective ETR blocker) and alfacalcidol (a vitamin D3 analogue) separately or in combination.

METHODS: Male Sprague-Dawley rats were divided into the following groups: control (DMSO orally), cisplatin (single dose of 6mg/kg ip; nephrotoxicity model), cisplatin + BQ-123 (1 mg/kg BQ-123 ip 1 h before and 1 day after cisplatin), cisplatin + alfacalcidol (50 ng/kg alfacalcidol orally 5 days before and 14 days after cisplatin), and cisplatin + BQ-123+alfacalcidol. Nephrotoxicity was evaluated 96 h and 14 days following cisplatin administration.

RESULTS: Both BQ-123 and alfacalcidol counteracted cisplatin-induced nephrotoxic changes. Specifically, they reduced serum creatinine and urea levels; renal tumour necrosis factor-alpha (TNF-ct), transforming growth factor-betal (TGF-pl), and phosphorylated nuclear factor-kappa B (pNF-KB) content; and caspase-3 activity. They downregulated ET-1 and ETR expression and ameliorated cisplatin-induced acute tubular necrosis. In addition, the treatments have increased VDR and endothelin- receptor (ETR) expression; however, BQ-123 did not affect ETR. The effect of the combination regimen surpassed that of each drug alone.

CONCLUSION: These findings highlight the potential cross-talk between vitamin D and ET-1 pathways and pave the way for future preclinical/clinical studies to explore further mechanisms involved in this crosstalk.

Gowayed, M. A., K. Rothe, M. Rossol, A. S. Attia, U. Wagner, C. Baerwald, H. S. El-Abhar, and R. Refaat, "The role of α7nAChR in controlling the anti-inflammatory/anti-arthritic action of galantamine.", Biochemical pharmacology, vol. 170, pp. 113665, 2019 Dec. Abstract

OBJECTIVE: The evolution of the "cholinergic anti-inflammatory pathway" and the fact that the α 7 subunit of the nicotinic acetylcholine receptor (α7nAChR) is present in the spleen, joint and on the surface of lymphocytes, opened up the prospective in this study of targeting the α7nAChR by the anticholinesterase and cholinergic drug, galantamine, to control inflammation in rheumatoid arthritis (RA).

METHODS: Twelve-adjuvant arthritic rats were exposed to the selective α7nAChR blocker methylcaconitine citrate 15 min before galantamine treatment. As control, six adjuvant arthritic rats were treated with galantamine and six others were untreated. After five days TNF-α levels were assessed in spleen and joints, while reduced glutathione was measured in blood and joint tissue. In the second part, magnetically sorted CD4 + T cells from peripheral blood mononuclear cells of RA patients and healthy donors were used to sort CD4 + CD25 - primary T cells (Tresp) and CD4 + CD25 + CD127low Tregs. The suppressive function of Tregs was investigated after incubation with galantamine using flow cytometry. Cell culture supernatants were analyzed for TNF-α and IL-10 levels after three days incubation period of Tregs with Tresp. The effect of galantamine on Tregs was then blocked by α-Bungarotoxin and the same assay has been repeated.

RESULTS & CONCLUSION: Selective α7nAChR blockade interrupted the anti-inflammatory effect of galantamine in the spleen and joints of arthritic rats. In healthy donors, galantamine could strengthen the suppressive activity of Tregs; while in RA patients it did not modulate the function of Tregs significantly. Further studies are necessary to investigate whether modulation of the cholinergic nervous system, especially α7nAChR, could have impact on the disturbed immune system in RA, which may open up a new treatment option of autoimmune diseases.

El-Gazar, A. A., A. A. Soubh, E. A. Mohamed, A. S. Awad, and H. S. El-Abhar, "Morin post-treatment confers neuroprotection in a novel rat model of mild repetitive traumatic brain injury by targeting dementia markers, APOE, autophagy and Wnt/β-catenin signaling pathway.", Brain research, vol. 1717, pp. 104-116, 2019 Aug 15. Abstract

Exposure to repetitive brain trauma has gained attention for its similarity to sport-related trauma. The traumatic brain injury (TBI) is strongly associated with neurodegenerative pathology that affects cognition, memory and behavior. The current study developed a novel mild repetitive traumatic brain injury (mRTBI) model to highlight some of the possible molecular pathological mechanisms compared to those of single trauma. Additionally, the study investigated the potential post-traumatic neuroprotective effect of Morin and/or MK-801. mRTBI was induced by weight drop model once daily for 5 days using Sprague-Dawley male rats. Animals were classified into control, mild TBI, mRTBI-5, mRTBI-7, mRTBI-5+DMSO, mRTBI-5+DMSO, mRTBI-5+Morin, mRTBI-5+MK801, and mRTBI-5+Morin+MK801. All treatments, especially the combination regimen, abated the cortical contents/protein expression of dementia markers (APO-E, Aβ, p(thr231)Tau, and p(Ser33)β-catenin), inflammatory markers (p(Ser536)NF-κBp65, and TNF-α, IL-6), and caspase-3 activity. Moreover, treatments enhanced the protein expression of Wnt-1 and autophagy-related markers (LC3BII/I and Beclin-1), besides the tissue content of the anti-apoptotic marker Bcl-2. These results entailed an improvement in the behavioral outcome, histological structure, and neuronal survival. In conclusion, the study proved that mRTBI impairs memory and alters APO-E/Aβ/p(thr231)Tau via the modulation of Wnt/β-catenin trajectory, autophagy, apoptosis, and inflammation. Additionally, post-treatment with Morin and/or MK-801 ameliorated these alterations, especially the combined regimen. It is also worth mentioning that Morin alone showed the finest behavioral improvements relative to the normal group. These results are summarized in Fig. 1.

Elsayed, I., M. W. Helmy, and H. S. El-Abhar, "Inhibition of SRC/FAK cue: A novel pathway for the synergistic effect of rosuvastatin on the anti-cancer effect of dasatinib in hepatocellular carcinoma.", Life sciences, vol. 213, pp. 248-257, 2018 Nov 15. Abstract

PURPOSE: Statins extended their hypocholestremic effect to show a promising anticancer activity. Hepatocellular carcinoma (HCC), the third common cause of cancer-related death, responded positively to statins. Some in-vitro studies reveal the rosuvastatin antitumor effect, but barely in-vivo studies. Hence, we evaluated the antitumor potential of rosuvastatin in a HCC model, the possible signaling cues involved, and whether it augments the dasatinib anticancer effect.

METHOD: For the in-vitro study, the IC and the combination (CI)/dose reduction (DRI) indices were determined for HCC cell line (HepG2) treated with dasatinib and/or rosuvastatin. For the in-vivo study, mice with diethylnitrosamine-induced HCC were treated for 21 days with dasatinib and/or rosuvastatin (10 and 20 mg/kg, respectively). The p-focal adhesion kinase/p-rous sarcoma oncogene cellular homolog (p-FAK/p-Src) cascade and its downstream molecules were assessed.

RESULTS: The in-vitro study confirmed the synergistic effect of rosuvastatin with dasatinib, which entailed the in-vivo results. The two drugs decreased the p-FAK/p-Src cue along with p-Ras/c-Raf, p-STAT-3, and p-Akt levels to enhance apoptosis by an increase in caspase-3 level and a decline in survivin level. Additionally, they inhibited HGF, VEGF, and the MMP-9. Moreover, the different treatments downregulated the expression of proliferative cell nuclear antigen (PCNA) and Ki-67. The best effect was mediated by the combination regimen that surpassed the effect of either drug alone.

CONCLUSION: Our results highlighted some of the signals involved in rosuvastatin antitumor effect and nominate it as an adds-on therapy with dasatinib to yield a better effect in HCC through inhibiting the FAK/Src cascade.

Soubh, A. A., D. M. Abdallah, and H. S. El-Abhar, "Geraniol ameliorates TNBS-induced colitis: Involvement of Wnt/β-catenin, p38MAPK, NFκB, and PPARγ signaling pathways.", Life sciences, vol. 136, pp. 142-50, 2015 Sep 1. Abstract

AIMS: Geraniol, a natural component of plant essential oils, exhibits potent chemopreventive effects in the colon; however, its possible role/mechanisms in experimental colitis have not been elucidated, which is the aim of this study.

MAIN METHODS: To fulfill this goal, rats were treated for 11days with geraniol and/or sulfasalazine using a TNBS-induced colitis model.

KEY FINDINGS: Geraniol significantly hindered the colitis-clinical signs (weight loss, colon edema,ulcerative area, colon/spleen mass indices) and opposed the altered oxidative/nitrosative stress. It restored the depleted total antioxidant capacity and lessened the elevated levels of nitric oxide and lipid peroxide. TNBS induced apoptosis and inflammatory cell infiltration, whereas geraniol curtailed these effects by diminishing the levels of caspase-3, intercellular adhesion molecule-1, and myeloperoxidase. The anti-inflammatory effect was documented by inhibiting the colon contents of prostaglandin E2 and interleukin-1β. In order to delve into the anti-colitic signaling pathways, geraniol inhibited the content/expression of glycogen synthase kinase (GSK)-3β, β-catenin, p38 mitogen activated protein kinase (p38MAPK), and nuclear factor kappa B (NFκB), but upregulated that of peroxisome proliferator activated receptor γ (PPARγ). These effects were comparable to those of sulfasalazine, the standard drug, whereas its combination with geraniol mediated effects that surpassed either treatment alone.

SIGNIFICANCE: Geraniol in the current study improved experimental colitis partly via its antioxidant, anti-inflammatory, and immunosuppressive potentials, possibly by modulating the Wnt/GSK-3β/β-catenin, p38MAPK, NFκB, and PPARγ signaling pathways. The study also revealed that geraniol represents a valuable asset against colitis alone or in combination with the conventional anti-colitic therapies.

Gowayed, M. A., R. Refaat, W. M. Ahmed, and H. S. El-Abhar, "Effect of galantamine on adjuvant-induced arthritis in rats.", European journal of pharmacology, vol. 764, pp. 547-53, 2015 Oct 5. Abstract

Stimulation of the vagus nerve suppresses cytokine production and macrophage activation, via the interaction of its neurotransmitter acetylcholine (ACh) with the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR), present on neurons and inflammatory cells. The present study aimed to verify the potential anti-inflammatory effect of galantamine against experimental arthritis induced in rats. Fourteen days post adjuvant injection, Sprague-Dawley rats were treated orally with three doses of galantamine (1.25, 2.5 and 5 mg/kg) or leflunomide (10 mg/kg) for 2 weeks and arthritis progression was assessed by hind paw swelling. Additionally, serum biomarkers, viz., anti-cyclic citrullinated peptide antibodies (Anti-CCP), tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1) were measured. Radiological examination of the hind paws was also carried out to evaluate the degree of joint damage. Adjuvant arthritis led to a significant weight loss, marked swelling of the hind paw and alteration in the serum levels of anti-CCP, TNF-α, IL-10 and MCP-1. These alterations were associated with significant radiological changes of the joints. Galantamine, in a dose-dependent manner, reduced significantly all biomarkers of inflammation, with the highest dose showing the best beneficial anti-inflammatory effect that was superior in magnitude to the reference drug leflunomide in most of the studied parameters. In conclusion, these results suggest that galantamine may represent a novel, inexpensive and effective therapeutic strategy in the treatment of rheumatoid arthritis.

Mohamed, W. A., M. F. Schaalan, and H. S. El-Abhar, "Camel Milk: Potential Utility as an Adjunctive Therapy to Peg-IFN/RBV in HCV-4 Infected Patients in Egypt.", Nutrition and cancer, vol. 67, issue 8, pp. 1305-13, 2015 Nov-Dec. Abstract

The present prospective study aims to investigate the potential therapeutic effect and the underlying mechanisms of drinking camel milk for 60 days as an adjunctive therapy to the standard treatment PEG/RBV. Twenty-five hepatitis C virus (HCV)-infected Egyptian patients, with mild to moderate parenchymal affection to mild cirrhosis were enrolled in this study after proper history taking and clinical examination. Their biomarkers were evaluated before and after the addition of camel milk. The improving effect of camel milk was reflected on the marked inhibition of the serum levels of the proinflammatory markers, viz., tumor necrosis factor-α, monocyte chemotactic protein-1, hyaluronic acid, and TGF-β1, besides PCR, AST, ALT, GGT, bilirubin, prothrombin time, INR, and alpha-fetoprotein. In addition, camel milk elevated significantly (P < 0.001) the serum levels of albumin, the antiapoptotic protein BCL-2, the total antioxidant capacity, interleukin-10, and vitamin D. In conclusion, our study revealed a regulatory function of camel milk on multiple parameters of inflammatory mediators, immunomodulators, antiapoptosis, and antioxidants, giving insight into the potential therapeutic benefit underlying the anti-HCV actions of camel milk. The limitations of the current study include the small sample size recruited and the failure to test it on cohorts with severe stages of hepatitis; like Child-Pugh stage C, and hepatocellular carcinoma.

Ali, M. A., H. S. El-Abhar, M. A. Kamel, and A. S. Attia, "Antidiabetic Effect of Galantamine: Novel Effect for a Known Centrally Acting Drug.", PloS one, vol. 10, issue 8, pp. e0134648, 2015. Abstract

The cholinergic anti-inflammatory pathway is one of the putative biochemical pathways that link diabetes with Alzheimer disease. Hence, we aimed to verify the potential antidiabetic effect of galantamine, unveil the possible mechanisms and evaluate its interaction with vildagliptin. The n5-STZ rat model was adopted and the diabetic animals were treated with galantamine and/or vildagliptin for 4 weeks. Galantamine lowered the n5-STZ-induced elevation in body weight, food/water intake, serum levels of glucose, fructosamine, and ALT/AST, as well as AChE in the tested organs. Moreover, it modulated successfully the lipid profile assessed in serum, liver, and muscle, and increased serum insulin level, as well as % β-cell function, in a pattern similar to that of vildagliptin. Additionally, galantamine confirmed its antioxidant (Nrf2, TAC, MDA), anti-inflammatory (NF-κB, TNF-α, visfatin, adiponectin) and anti-apoptotic (caspase-3, cytochrome c) capabilities by altering the n5-STZ effect on all the aforementioned parameters. On the molecular level, galantamine/vildagliptin have improved the insulin (p-insulin receptor, p-Akt, GLUT4/GLUT2) and Wnt/β-catenin (p-GSK-3β, β-catenin) signaling pathways. On almost all parameters, the galantamine effects surpassed that of vildagliptin, while the combination regimen showed the best effects. The present results clearly proved that galantamine modulated glucose/lipid profile possibly through its anti-oxidant, -apoptotic, -inflammatory and -cholinesterase properties. These effects could be attributed partly to the enhancement of insulin and Wnt/β-catenin signaling pathways. Galantamine can be strongly considered as a potential antidiabetic agent and as an add-on therapy with other oral antidiabetics.

Mahmoud-Awny, M., A. S. Attia, M. F. Abd-Ellah, and H. S. El-Abhar, "Mangiferin Mitigates Gastric Ulcer in Ischemia/ Reperfused Rats: Involvement of PPAR-γ, NF-κB and Nrf2/HO-1 Signaling Pathways.", PloS one, vol. 10, issue 7, pp. e0132497, 2015. Abstract

Mangiferin (MF), a xanthonoid from Mangifera indica, has been proved to have antisecretory and antioxidant gastroprotective effects against different gastric ulcer models; however, its molecular mechanism has not been previously elucidated. Therefore, the aim of this study was to test its modulatory effect on several signaling pathways using the ischemia/reperfusion model for the first time. Animals were treated with MF, omeprazole (OMP), and the vehicle. The mechanistic studies revealed that MF mediated its gastroprotective effect partly via inducing the expression of Nrf2, HO-1 and PPAR-γ along with downregulating that of NF-κB. Surprisingly, the effect of MF, especially the high dose, exceeded that mediated by OMP except for Nrf2. The molecular results were reflected on the biomarkers measured, where the antioxidant effect of MF was manifested by increasing total antioxidant capacity and glutathione, besides normalizing malondialdehyde level. Additionally, MF decreased the I/R-induced nitric oxide elevation, an effect that was better than that of OMP. In the serum, MF, dose dependently, enhanced endothelial nitric oxide synthase, while reduced the inducible isoform. Regarding the anti-inflammatory effect of MF, it reduced serum level of IL-1β and sE-selectin, effects that were mirrored on the tissue level of myeloperoxidase, the neutrophil infiltration marker. In addition, MF possessed an antiapoptotic character evidenced by elevating Bcl-2 level and reducing that of caspase-3 in a dose related order. As a conclusion, the intimated gastroprotective mechanisms of MF are mediated, partially, by modulation of oxidative stress, inflammation and apoptosis possibly via the Nrf2/HO-1, PPAR-γ/NF-κB signaling pathways.

Attia, Y. M., H. S. El-Abhar, M. M. Al Marzabani, and S. A. Shouman, "Targeting glycolysis by 3-bromopyruvate improves tamoxifen cytotoxicity of breast cancer cell lines.", BMC cancer, vol. 15, pp. 838, 2015. Abstract

BACKGROUND: Tamoxifen is the standard endocrine therapy for ER+ breast cancer; however, many women still relapse after long-term therapy. 3-Bromopyruvate, a glycolytic inhibitor, has shown high selective anti-tumor activity in vitro, and in vivo. The aim of this study was to evaluate the possible augmentation of the effect of tamoxifen via reprograming cancer cell metabolism using 3-bromopyruvate.

METHODS: An in vitro screening of antitumor activity as well as the apoptotic, anti-metastatic, and anti-angiogenic potentials of the combination therapy were carried out using different techniques on breast cancer cell lines MCF7and T47D. In addition the antitumor effect of the combined therapy was done on mice bearing tumor.

RESULTS: Our results showed modulation in apoptosis, angiogenesis and metastatic potential by either drug alone; however, their combination has surpassed that of the individual one. Combination regimen enhanced activated caspases-3, 7 and 9, as well as oxidative stress, signified by increased malondialdehyde and decreased glutathione level. Additionally, the angiogenesis and metastasis markers, including hypoxia inducing factor-1α, vascular endothelia growth factor, and metaloproteinases-2 and 9 were decreased after using the combination regimen. These results were further confirmed by the in vivo study, which depicted a decrease in the tumor volume and angiogenesis and an increase in oxidative stress as well.

CONCLUSION: 3-bromopyruvate could be a valuable compound when added with tamoxifen in breast cancer treatment.

El-Abhar, H. S., and M. F. Schaalan, "Phytotherapy in diabetes: Review on potential mechanistic perspectives.", World journal of diabetes, vol. 5, issue 2, pp. 176-97, 2014 Apr 15. Abstract

Diabetes mellitus (DM) is a widely spread epidemic disease that results from the absence of insulin, decreased secretion and/or impaired function. Since DM is a multi-factorial disease, the available pharmaceuticals, despite their sensible treatment, target mostly one pathway to control hyperglycemia and encounter several side effects. Therefore, new therapeutic paradigms aim to hit several pathways using only one agent. Traditionally, antidiabetic plants and/or their active constituents may fulfill this need. More than 200 species of plants possess antidiabetic properties which were evaluated mostly by screening tests without digging far for the exact mode of action. Searching among the different literature resources and various database and in view of the above aspects, the present article provides a comprehensive review on the available antidiabetic plants that have been approved by pharmacological and clinical evaluations, and which their mechanism(s) of action is assured. These plants are categorized according to their proved mode of action and are classified into those that act by inhibiting glucose absorption from intestine, increasing insulin secretion from the pancreas, inhibiting glucose production from hepatocytes, or enhancing glucose uptake by adipose and muscle tissues. The current review also highlights those that mimic in their action the new peptide analogs, such as exenatide, liraglutide and dipeptidylpeptidase-4 inhibitors that increase glucagon-like peptide-1 serum concentration and slow down the gastric emptying.

Amin, M. M., G. F. Asaad, R. M. Abdelsalam, H. S. El-Abhar, and M. S. Arbid, "Novel CoQ10 antidiabetic mechanisms underlie its positive effect: modulation of insulin and adiponectine receptors, Tyrosine kinase, PI3K, glucose transporters, sRAGE and visfatin in insulin resistant/diabetic rats.", PloS one, vol. 9, issue 2, pp. e89169, 2014. Abstract

UNLABELLED: As a nutritional supplement, coenzyme Q10 (CoQ10) was tested previously in several models of diabetes and/or insulin resistance (IR); however, its exact mechanisms have not been profoundly explicated. Hence, the objective of this work is to verify some of the possible mechanisms that underlie its therapeutic efficacy. Moreover, the study aimed to assess the potential modulatory effect of CoQ10 on the antidiabetic action of glimebiride. An insulin resistance/type 2 diabetic model was adopted, in which rats were fed high fat/high fructose diet (HFFD) for 6 weeks followed by a single sub-diabetogenic dose of streptozotocin (35 mg/kg, i.p.). At the end of the 7(th) week animals were treated with CoQ10 (20 mg/kg, p.o) and/or glimebiride (0.5 mg/kg, p.o) for 2 weeks. CoQ10 alone opposed the HFFD effect and increased the hepatic/muscular content/activity of tyrosine kinase (TK), phosphatidylinositol kinase (PI3K), and adiponectin receptors. Conversely, it decreased the content/activity of insulin receptor isoforms, myeloperoxidase and glucose transporters (GLUT4; 2). Besides, it lowered significantly the serum levels of glucose, insulin, fructosamine and HOMA index, improved the serum lipid panel and elevated the levels of glutathione, sRAGE and adiponectin. On the other hand, CoQ10 lowered the serum levels of malondialdehyde, visfatin, ALT and AST. Surprisingly, CoQ10 effect surpassed that of glimepiride in almost all the assessed parameters, except for glucose, fructosamine, TK, PI3K, and GLUT4. Combining CoQ10 with glimepiride enhanced the effect of the latter on the aforementioned parameters.

CONCLUSION: These results provided a new insight into the possible mechanisms by which CoQ10 improves insulin sensitivity and adjusts type 2 diabetic disorder. These mechanisms involve modulation of insulin and adiponectin receptors, as well as TK, PI3K, glucose transporters, besides improving lipid profile, redox system, sRAGE, and adipocytokines. The study also points to the potential positive effect of CoQ10 as an adds- on to conventional antidiabetic therapies.

El-Abhar, H. S., and M. F. Schaalan, "Topiramate-induced modulation of hepatic molecular mechanisms: an aspect for its anti-insulin resistant effect.", PloS one, vol. 7, issue 5, pp. e37757, 2012. Abstract

Topiramate is an antiepileptic drug known to ameliorate insulin resistance besides reducing body weight. Albeit liver plays a fundamental role in regulation of overall insulin resistance, yet the effect of topiramate on this organ is controversial and is not fully investigated. The current work aimed to study the potential hepatic molecular mechanistic cassette of the anti-insulin resistance effect of topiramate. To this end, male Wistar rats were fed high fat/high fructose diet (HFFD) for 10 weeks to induce obese, insulin resistant, hyperglycemic animals, but with no overt diabetes. Two HFFD-groups received oral topiramate, 40 or 100 mg/kg, for two weeks. Topiramate, on the hepatic molecular level, has opposed the high fat/high fructose diet effect, where it significantly increased adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreased insulin receptor isoforms. Besides, it improved the altered glucose homeostasis and lipid profile, lowered the ALT level, caused subtle, yet significant decrease in TNF-α, and boosted adiponectin in a dose dependent manner. Moreover, topiramate decreased liver weight/, visceral fat weight/, and epididymal fat weight/body weight ratios. The study proved that insulin-resistance has an effect on hepatic molecular level and that the topiramate-mediated insulin sensitivity is ensued partly by modulation of hepatic insulin receptor isoforms, activation of tyrosine kinase, induction of GLUT2 and elevation of adiponectin receptors, as well as their ligand, adiponectin, besides its known improving effect on glucose tolerance and lipid homeostasis.

El-Abhar, H. S., "Coenzyme Q10: a novel gastroprotective effect via modulation of vascular permeability, prostaglandin E₂, nitric oxide and redox status in indomethacin-induced gastric ulcer model.", European journal of pharmacology, vol. 649, issue 1-3, pp. 314-9, 2010 Dec 15. Abstract

Coenzyme Q10 is an essential cofactor in the mitochondrial electron transport pathway, and is endowed for its potent antioxidant capacity; characters that endorse its implication in several clinical practices and as a food supplement. Nevertheless, its potential gastro-protective effect, in acute models, has never been assessed, which is the objective of this study. Since indomethacin mediated gastropathy is multifaceted, including mitochondrial dysfunction and generation of reactive oxygen species, thus, the indomethacin-induced gastric injury serves as a convenient animal model for this work. Rats treated with indomethacin revealed mucosal hemorrhagic lesions, increased microvascular permeability and inhibited prostaglandin E₂ and mucus content. Redox imbalance was reflected by decreased mucosal glutathione (GSH), nitric oxide and glutathione peroxidase contents/activity, along with elevated lipid peroxides. Pretreatment with CoQ10 caused discernible decrease in indomethacin-induced gastric lesions, vascular permeability and lipid peroxide content. In addition, prostaglandin E₂ and GSH levels were restored, while those of nitric oxide and glutathione peroxidase were elevated significantly above normal; however, mucus formation was not altered significantly. The positive effects were comparable to those of sucralfate, the standard drug used herein, except for the mucus and prostaglandin E₂ levels that were increased above normal by sucralfate. CoQ10-mediated gastroprotective effect involves preservation of microvascular permeability, elevation of prostaglandin E₂, improvement of redox status, as well as boosting of nitric oxide. Nevertheless, maintaining gastric mucus content is ruled out.

Schaalan, M., H. S. El-Abhar, M. Barakat, and E. S. El-Denshary, "Westernized-like-diet-fed rats: effect on glucose homeostasis, lipid profile, and adipocyte hormones and their modulation by rosiglitazone and glimepiride.", Journal of diabetes and its complications, vol. 23, issue 3, pp. 199-208, 2009 May-Jun. Abstract

Wersternized diet, containing high fat diet intake combined with high consumption of softdrinks, is accused with the emerge of modern epidemic obesity and diabesity. Therefore, we aimed to study the effect of this diet combination on the homeostasis of glucose, lipids, and some adipohormones in rats and to simulate the metabolic perturbations induced by the unhealthy Westernized diet intake, leading to the development of type 2 diabetes. To achieve this, we divided male Wistar rats (80-120 g) into two main groups: the first was fed commercial normal fat diet and the second received an in-house-prepared high-fat diet (HFD), combined with fructose in drinking water for a period of 6 weeks, followed by a subdiabetogenic dose of streptozotocin (STZ) (35 mg/kg) to produce frank hyperglycemia. The effect of this diet alone or after 2 weeks of treatment with rosiglitazone or glimepiride on glucose homeostasis, lipid profile, and levels of resistin and leptin was studied. The HFD/fructose/STZ diet elevated fasting plasma glucose, fructosamine, insulin, and homeostasis model assessment (HOMA) index, as well as serum triglycerides (TGs), total cholesterol (TC), and low-density lipoprotein cholesterol, with a decrease in high-density lipoprotein cholesterol. Hepatic TG and TC levels, as well as serum activities of aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH), were increased, suggesting a diet-induced hepatic steatosis, beside the increased levels of serum resistin and leptin. Rosiglitazone corrected the altered parameters measured, except for liver TGs; similarly, glimepiride reinstated the inverted parameters but raised insulin level and, consequently, the HOMA index. These results show that this diet could be used to induce an effect that mimics human type 2 diabetes with its metabolic disturbances and is suitable for screening the antidiabetic agents used for management of this disease.

Abdallah, D. M., H. S. El-Abhar, and D. H. Abdel-Aziz, "TEMPOL, a membrane-permeable radical scavenger, attenuates gastric mucosal damage induced by ischemia/reperfusion: a key role for superoxide anion.", European journal of pharmacology, vol. 603, issue 1-3, pp. 93-7, 2009 Jan 28. Abstract

The pathogenesis of gastric mucosal injury is a multifaceted process involving reactive oxygen and nitrogen species, both of which play a crucial role in the ischemia/reperfusion model of gastric damage. Hence, several studies have evaluated the anti-ulcerogenic effect of metal chelators, antioxidative enzymes, and low-molecular-weight antioxidants. Low molecular weight superoxide dismutase (SOD) mimetics have been shown to play a protective role against oxidative damage. Therefore, the aim of the current study was to investigate the modulatory effect of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl [TEMPOL (50 mg/kg)], a SOD mimetic, and the SOD inhibitor, diethyldithiocarbamate [DETCA (100 mg/kg)] on gastric lesions induced by ischemia/reperfusion. This insult produced typical gastric lesions, a significant fall in the gastric mucosal glutathione (GSH) and nitric oxide (NO) levels, accompanied by an increase in malondialdehyde (MDA) content and myeloperoxidase (MPO) activity. TEMPOL markedly minimized gastric ulceration and restored MDA, NO, and MPO levels, but did not alter GSH level, which dropped drastically in DETCA treated group, an effect that was not reflected on gross lesions induced by ischemia/reperfusion. In conclusion, TEMPOL can confer protection from gastric ischemia/reperfusion injury possibly by reducing the level of superoxide anion (O(2)(*-)), replenishing NO, and minimizing neutrophil infiltration. Therefore, specific SOD mimetics could be beneficial as complementary agents in the management of gastric ulceration.

El-Abhar, H. S., L. N. A. Hammad, and H. A. S. Gawad, "Modulating effect of ginger extract on rats with ulcerative colitis.", Journal of ethnopharmacology, vol. 118, issue 3, pp. 367-72, 2008 Aug 13. Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Ginger rhizomes are used traditionally for management of different gastrointestinal disturbances. Several studies proved that the rhizome possesses diverse biological activities such as cytotoxic, antioxidant, and anti-inflammatory effects. Recently, interest in ginger for treatment of chronic inflammatory conditions has been renewed.

AIM OF THE STUDY: The purpose of the present study is to evaluate the potential role of ginger extract [GE] in modulating the extent and severity of ulcerative colitis (UC), a chronically recurrent inflammatory bowel disease of unknown origin.

MATERIALS AND METHODS: Male Wistar rats received 3 different doses of GE, sulfasalazine, or vehicle for 3 consecutive days before induction of UC by intra-rectal acetic acid administration, and continued further for 7 days after the induction. The colonic mucosal injury was assessed by macroscopic scoring, and histological examination. Furthermore, the mucosal content of malondialdehyde (MDA), protein carbonyl (PCO), and reduced glutathione (GSH) with the catalase (CAT) and superoxide dismutase (SOD) activity, were appraised as parameters of the redox state. Acute inflammatory response was determined by measuring myeloperoxidase (MPO), tumor necrosis factor (TNF-alpha), and prostaglandin E2 (PGE2).

RESULTS: All parameters were altered in ulcerated rats, and improved in animals receiving GE, an effect that was comparable to that of the standard sulfasalazine, especially at the highest dose level. Colonic mucosal injury parallels with the histological and biochemical evaluations.

CONCLUSIONS: Results showed a valuable effect of ginger extract against acetic acid-induced ulcerative colitis possibly by its antioxidant and anti-inflammatory properties.

El-Abhar, H. S., and H. A. M. El Gawad, "Modulation of cortical nitric oxide synthase, glutamate, and redox state by nifedipine and taurine in PTZ-kindled mice.", Epilepsia, vol. 44, issue 3, pp. 276-81, 2003 Mar. Abstract

PURPOSE: Correlation between pentylenetetrazol (PTZ)-induced kindling and the cortical nitric oxide synthase (NOS), intracellular calcium [Ca2+]i, glutamate, and free radicals was studied in mice, as well as the modulatory action of nifedipine and taurine on these parameters.

METHODS: Male Swiss albino mice were used. Mice in one group received a single convulsive dose of PTZ (50 mg/kg, i.p), and were killed 24 h later. To induce kindling, PTZ was injected in a subconvulsive dose (40 mg/kg, i.p.) every other day for 3 weeks. One kindled group was used as control, whereas two other groups were injected 30 min before PTZ with either nifedipine (30 mg/kg, i.p) or taurine (100 mg/kg, i.p). All three kindled groups were killed 24 h after the last injection.

RESULTS: Compared with normal control group, PTZ-kindled mice had significantly higher levels of [Ca2+]i, malonaldehyde (MDA), NOS, and lactate dehydrogenase (LDH) but had lower levels of superoxide dismutase (SOD) and reduced glutathione (GSH). Acute seizures of the same intensity did not induce these alterations, indicating their link to the kindling phenomenon and not to seizure activity. The effect of taurine, known as an antioxidant, was more pronounced than that of the Ca2+-channel blocker, nifedipine. The first drug reversed the PTZ-kindled action on [Ca2+]i, NOS, LDH, GSH, and SOD, whereas nifedipine restored only LDH and GSH levels. However, both drugs did not restore the elevated MDA level.

CONCLUSIONS: This study suggests that free radicals, as well as NOS, are implicated in PTZ-induced kindling, and that antioxidants could play a role in controlling the accompanying changes.

Abouzid, K. A. M., and H. S. El-Abhar, "Synthesis and antiinflammatory activity of novel indazolones.", Archives of pharmacal research, vol. 26, issue 1, pp. 1-8, 2003 Jan. Abstract

In this study, a series of new N2 substituted 1,2-dihydro-3H-indazol-3-ones (3a-d) as well as their condensed pyrazolo, pyridazino derivatives such as pyridazino[1,2-a]indazole-6,9,11-triones (4a-h) and 3,9-dioxo-3H,9H-pyrazolo[1,2-a]indazole (7) were synthesized. The antiinflammatory activity of some synthesized compounds was determined by carrageenan-induced rat paw edema technique using diclofenac as reference drug. The pharmacological data showed that most of the tested compounds exhibited a significant long lasting antiinflammatory activity, which in the case of compound 3b was superior to that of diclofenac.

El-Abhar, H. S., D. M. Abdallah, and S. Saleh, "Gastroprotective activity of Nigella sativa oil and its constituent, thymoquinone, against gastric mucosal injury induced by ischaemia/reperfusion in rats.", Journal of ethnopharmacology, vol. 84, issue 2-3, pp. 251-8, 2003 Feb. Abstract

Ischaemia/reperfusion (I/R) induced gastric lesion, is known to be linked with free radical (FR) formation. Therefore, this model was used to assess the antioxidant effects of Nigella sativa oil (N.O) and thymoquinone (TQ) on gastric mucosal redox state and gastric lesions, 1 and 24 h after reperfusion. Male Wistar rats were subjected to I/R and were injected with either N.O (2.5 and 5 ml/kg, p.o) or TQ (5, 20, 50 and 100 mg/kg, p.o). The results showed that I/R elevated the levels of lipid peroxide (LPX) and lactate dehydrogenase (LDH), while decreased those of reduced glutathione (GSH) and superoxide dismutase (SOD). These biochemical changes were accompanied by an increase in the formation of gastric lesions, which was reduced by either treatment. N.O tended to normalize the level of LDH, GSH and SOD. However, its effect to restore LPX was only seen 24 h after reperfusion. Moreover, the aforementioned parameters were nearly reinstated by TQ. On the other hand, high doses of TQ (50 and 100 mg/kg) severely reduced the GSH content, 1 h after reperfusion. These results indicate that both N.O and TQ possess gastroprotective effect against gastric lesions which may be related to the conservation of the gastric mucosal redox state.

El-Abhar, H. S., M. Shaalan, M. Barakat, and E. S. El-Denshary, "Effect of melatonin and nifedipine on some antioxidant enzymes and different energy fuels in the blood and brain of global ischemic rats.", Journal of pineal research, vol. 33, issue 2, pp. 87-94, 2002 Sep. Abstract

The brain normally derives most of its energy from the aerobic oxidation of glucose and therefore it must be nourished with a rich supply of both glucose and oxygen. Interference with the blood supply, such as in ischemia, could shift the brain to search for another source of energy and to spare its own glucose. Ischemia results not only in energy fuel disturbance, but also in free radical formation and Ca(2+) homeostasis disruption. Therefore, our investigations studied the influence of ischemia on energy fuels, on some natural free radical scavengers, and the relationship between the changes of these parameters in brain and blood. Each of these was also studied under the influence of melatonin, a well-known free radical scavenger, and nifedipine, a Ca(2+)-channel blocker and antioxidant, during ischemia followed by reperfusion (I/R). Adult male Wistar rats were subjected to global ischemia by occlusion of the two carotid arteries for 1 hr (group I), followed by reperfusion for another hour in group II. Drugs were injected after ischemia (group I), and before or after reperfusion onset in the second group. Two series of animals were used. In the first series the effect of the two drugs on the activity of superoxide dismutase (SOD), glutathione reductase (GR), and lactate dehydrogenase (LDH) was investigated in the cytosolic fraction of four brain areas, viz., cortex (CC), thalamus/hypothalamus (T/TH), midbrain (MB) and medulla, pons and cerebellum (MPC). Moreover, the level of both SOD and GR in the erythocytes of these rats was also estimated. In the second series, we studied the effect of each drug on the content of glucose and beta-hydroxybutyrate (beta-HB) in whole brain, in addition to the plasma levels of glucose, beta-HB and lactate. The results showed that (i), ischemia elevated the brain levels of LDH and beta-HB, as well as the plasma level of glucose, beta-HB, lactate and erythocytic GR. Conversely, it lowered glucose, SOD and GR levels in the brain; (ii), reperfusion reversed the ischemic effect on all the previously altered parameters except for plasma levels of lactate and glucose; (iii), melatonin (10 mg/kg, i.p) and nifedipine (1.5 mg/kg, i.p), restored the energy fuel levels in the brain of ischemic and I/R rats, as well as the ischemic effect on the erythocyte activities of SOD and GR. Furthermore, both drugs reversed I/R effect on the cytosolic activities of the antioxidant enzymes. We conclude that melatonin and nifedipine are both neuroprotective with improvement in the antioxidant system and energy fuels.