Ibrahim, A. B., H. F. Zaki, W. W. Ibrahim, M. M. Omran, and S. A. Shouman, "Evaluation of tamoxifen and simvastatin as the combination therapy for the treatment of hormonal dependent breast cancer cells.", Toxicology reports, vol. 6, pp. 1114-1126, 2019. Abstract

Tamoxifen (TAM) is a nonsteroidal antiestrogen drug, used in the prevention and treatment of all stages of hormone-responsive breast cancer. Simvastatin (SIM), a lipid-lowering agent, has been shown to inhibit cancer cell growth. The study aimed at investigating the impact of using SIM with TAM in estrogen receptor-positive (ER+) breast cancer cell line, T47D, as well as in mice-bearing Ehrlich solid tumor. The cell line was treated with different concentrations of TAM or/and SIM for 72 h. The effects of treatment on cytotoxicity, oxidative stress markers, apoptosis, angiogenesis, and metastasis were investigated. Our results showed that the combination treatment decreased the oxidative stress markers, glucose uptake, VEGF, and MMP 2 &9 in the cell line compared to TAM- treated cells. Drug interaction of TAM and SIM was synergistic in T47D by increasing the apoptotic makers Bax/BCL-2 ratio and caspase 3 activity. Additionally, , the combination regimen resulted in a non-significant decrease in the tumor volume compared to TAM treated group. Moreover, the combined treatment decreased the protein expression of TNF-α, NF-kB compared to control. In conclusion, our results suggest that SIM may serve as a promising treatment with TAM for improving the efficacy against estrogen receptor-positive (ER+) breast cancer.

Fahim, V. F., W. Wadie, A. N. Shafik, and M. I. Attallah, "Role of simvastatin and insulin in memory protection in a rat model of diabetes mellitus and dementia.", Brain research bulletin, vol. 144, pp. 21-27, 2019. Abstract

OBJECTIVES: The memory protective role of simvastatin and/or insulin, in a rat model of diabetes mellitus (DM) and dementia was examined.

METHODS: DM was induced by an intraperitoneal injection of streptozotocin. Diabetic rats were divided into untreated; insulin treated; simvastatin treated with 10 and 20 mg/kg/day; and combined insulin plus simvastatin treatment in the previous doses. Treatment started after blood glucose elevation and persisted for 6 weeks. Morris water maze and Y maze tests were held to detect behavioral changes. Serum glucose, cholesterol and insulin levels, the hippocampi insulin, amyloid beta (Aß) 1-42 and oxidative stress markers were measured.

RESULTS: Insulin increased the time spent in the target quadrant in the Morris water maze test and the percentage of alternations in the Y maze test, despite the mild improvements in brain parameters demonstrated by amyloid beta 1-42, malondialdehyde and reduced glutathione levels; while simvastatin in both doses improved brain parameters with no positive impact on behavioral tests. Insulin combined with simvastatin 20 mg/kg/day was effective in enhancing the behavioral tests and the measured brain parameters.

CONCLUSIONS: Treatment with insulin and simvastatin could provide a promising memory protective effect in diabetics.

Khayyal, M. T., W. Wadie, E. A. Abd El-Haleim, K. A. Ahmed, O. Kelber, R. M. Ammar, and H. Abdel-Aziz, "STW 5 is effective against nonsteroidal anti-inflammatory drugs induced gastro-duodenal lesions in rats.", World journal of gastroenterology, vol. 25, issue 39, pp. 5926-5935, 2019. Abstract

BACKGROUND: Proton pump inhibitors are often used to prevent gastro-intestinal lesions induced by nonsteroidal anti-inflammatory drugs. However, they are not always effective against both gastric and duodenal lesions and their use is not devoid of side effects.

AIM: To explore the mechanisms mediating the clinical efficacy of STW 5 in gastro-duodenal lesions induced by nonsteroidal anti-inflammatory drugs (NSAIDs), exemplified here by diclofenac, in a comparison to omeprazole.

METHODS: Gastro-duodenal lesions were induced in rats by oral administration of diclofenac (5 mg/kg) for 6 successive days. One group was given concurrently STW 5 (5 mL/kg) while another was given omeprazole (20 mg/kg). A day later, animals were sacrificed, stomach and duodenum excised and divided into 2 segments: One for histological examination and one for measuring inflammatory mediators (tumor necrosis factor α, interleukins-1β and 10), oxidative stress enzyme (heme oxygenase-1) and apoptosis regulator (B-cell lymphoma 2).

RESULTS: Diclofenac caused overt histological damage in both tissues, associated with parallel changes in all parameters measured. STW 5 and omeprazole effectively prevented these changes, but STW 5 superseded omeprazole in protecting against histological damage, particularly in the duodenum.

CONCLUSION: The findings support the therapeutic usefulness of STW 5 and its superiority over omeprazole as adjuvant therapy to NSAIDs to protect against their possible gastro-duodenal side effects.

Ibrahim, A. B., H. F. Zaki, W. Wadie, M. M. Omran, and S. A. Shouman, "Simvastatin Evokes An Unpredicted Antagonism For Tamoxifen In MCF-7 Breast Cancer Cells.", Cancer management and research, vol. 11, pp. 10011-10028, 2019. Abstract

Purpose: Tamoxifen (TAM) is a non-steroidal antiestrogen drug, used in the prevention and treatment of all stages of hormone-responsive breast cancer. Simvastatin (SIM) is a lipid-lowering agent and has been shown to inhibit cancer cell growth. The study aimed to investigate the effect of the combination of TAM and SIM in the treatment of estrogen receptor positive (ER+) breast cancer cell line, MCF-7, and in mice-bearing Ehrlich solid tumors.

Methods: MCF-7 cells were treated with different concentrations of TAM or/and SIM for 72 hours and the effects of the combination treatment on cytotoxicity, oxidative stress markers, apoptosis, angiogenesis, and metastasis were investigated using different techniques. In addition, tumor volume, oxidative markers, and inflammatory markers of the combined therapy were explored in mice bearing solid EAC tumors.

Results: The results showed that treatment of MCF-7 cells with the combination of 10 µM TAM, and 2 µM SIM significantly inhibited the increase in oxidative stress markers, LDH, and NF-kB induced by TAM. In addition, there was a significant decrease in the total apoptotic ratio, caspase-3 activity, and glucose uptake, while there was a non-significant change in Bax/bcl-2 ratio compared to the TAM-treated group. Using the isobologram equation, the drug interaction was antagonistic with combination index, CI=1.18. On the other hand, the combination regimen decreased VEGF, and matrix metalloproteinases, MMP 2&9 compared to TAM-treated cells. Additionally, in vivo, the combination regimen resulted in a non-significant decrease in the tumor volume, decreased oxidative markers, and the protein expression of TNF-α, and NF-B compared to the TAM treated group.

Conclusion: Although the combination regimen of TAM and SIM showed an antagonistic drug interaction in MCF-7 breast cancer, it displayed favorable antiangiogenic, anti-metastatic, and anti-inflammatory effects.

Abdo, S. A., W. Wadie, R. M. Abdelsalam, and M. M. Khattab, "Potential Anti-Inflammatory Effect of Escitalopram in Iodoacetamide-Induced Colitis in Depressed Ovariectomized Rats: Role of α7-nAChR.", Inflammation, vol. 42, issue 6, pp. 2056-2064, 2019. Abstract

Escitalopram, a drug of choice in the treatment of depression, was recently shown to possess an anti-inflammatory activity. The aim of the present study was to elucidate the effect of escitalopram on peripheral inflammatory cascades in iodoacetamide-induced colitis associated with depressive behavior in ovariectomized rats. Moreover, the role of α-7 nicotinic acetylcholine receptor in mediating the anti-colitic effect of escitalopram was examined using a nicotinic receptor antagonist methyllycaconitine citrate. Colitis was induced by intracolonic injection of 4% iodoacetamide in ovariectomized rats. Escitalopram (10 mg/kg/day, i.p.) was then injected for 1 week and several parameters including macroscopic (colon mass index and ulcerative area), microscopic (histopathology and scoring), and biochemical (myeloperoxidase and tumor necrosis factor-α) were determined. Colitis induction in ovariectomized rats resulted in a marked increase in colon mass index, ulcerative area, histopathological scoring, myeloperoxidase activity and tumor necrosis factor-α levels. These effects were ameliorated by escitalopram, even in the presence of methyllycaconitine indicating that α-7 nicotinic acetylcholine receptor does not mediate the anti-inflammatory effect of escitalopram. The present study revealed the beneficial effect of escitalopram in iodoacetamide induced colitis in ovariectomized rats and suggests that it may represent a new therapeutic agent for the treatment of inflammatory bowel disease, especially in patients with or at high risk of depressive behavior.

El-Abhar, H., M. A. E. A. Fattah, W. Wadie, and D. M. El-Tanbouly, "Cilostazol disrupts TLR-4, Akt/GSK-3β/CREB, and IL-6/JAK-2/STAT-3/SOCS-3 crosstalk in a rat model of Huntington's disease.", PLoS One, vol. 13, issue 9, pp. 1-16, 2018.
Soliman, S. M., W. Wadie, S. A. Shouman, and A. A. Ainshoka, "Sodium selenite ameliorates both intestinal and extra-intestinal changes in acetic acid-induced colitis in rats", Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 391, issue 6, pp. 639-647, 2018.
Wazea, S. A., W. Wadie, A. K. Bahgat, and H. S. El-Abhar, "Galantamine anti-colitic effect: Role of alpha-7 nicotinic acetylcholine receptor in modulating Jak/STAT3, NF-κB/HMGB1/RAGE and p-AKT/ Bcl-2 pathways", Scientific Reports , vol. 8, issue 5110, pp. 1-10, 2018.
Wadie, W., H. Abdel-Aziz, H. F. Zaki, O. Kelber, D. Weiser, and M. T. Khayyal, "STW 5 is effective in dextran sulfate sodium-induced colitis in rats.", International journal of colorectal disease, vol. 27, issue 11, pp. 1445-53, 2012 Nov. Abstract

PURPOSE: An herbal preparation, STW 5, used clinically in functional dyspepsia and irritable bowel syndrome, has been shown to possess properties that may render it useful in inflammatory bowel disease (IBD). The present work was conducted to study its effectiveness in a rat model of IBD.

METHODS: An experimental model reflecting ulcerative colitis in man was adopted, whereby colitis was induced in Wistar rats by feeding them 5 % dextran sulfate sodium (DSS) in drinking water for one week. STW 5 and sulfasalazine (as a reference standard) were administered orally daily for 1 week before colitis induction and continued during DSS feeding. The animals were then sacrificed, and the severity of colitis was evaluated macroscopically and microscopically. Colon samples were homogenized for determination of reduced glutathione, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-3 as well as myeloperoxidase, glutathione peroxidase, and superoxide dismutase. In addition, colon segments were suspended in an organ bath to test their reactivity towards carbachol, KCl, and trypsin.

RESULTS: STW 5 and sulfasalazine were both effective in preventing the shortening of colon length and the increase in both colon mass index and total histology score as well as the changes in biochemical parameters measured except changes in dismutase activity. DSS-induced colitis led to marked depression in colonic responsiveness to the agents tested ex vivo, an effect which was normalized by both drugs.

CONCLUSIONS: The findings point to a potential usefulness of STW 5 in the clinical setting of ulcerative colitis.