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.

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.

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.

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.

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.

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.

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.

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.

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