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Lotfy, D. M., M. M. Safar, S. H. M. Hassan, and S. A. Kenawy, "Modulation of PTZ-induced convulsions in rats using topiramate alone or combined with low dose gamma irradiation: involving AKT/m-TOR pathway.", Toxicology mechanisms and methods, vol. 32, issue 1, pp. 18-26, 2022. Abstract

The current study evaluates the anticonvulsant effect low dose whole body gamma irradiation (LDR) alone or combined with topiramate against pentylenetetrazole (PTZ)-induced convulsions. Male Wister rats received either saline or PTZ (75 mg/kg i.p.). The other three groups were pretreated with single low dose radiation (0.5 Gy), topiramate (50 mg/kg, p.o., seven days) and TPM with LDR respectively before PTZ injection. Racine' score, latency, and duration of the convulsions were assessed. Glutamate and GABA were measured. AKT/m-TOR signaling pathway including AKT (protein kinase B), mammalian target of rapamycin (m-TOR), protein S6, and caspase 3 were also assessed. Measurements of markers of oxidative stress including malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) were carried out. Histological examinations of hippocampi were done. PTZ produced behavioral changes (high Racine score, short latency, and long duration). It elevated MDA and NO contents, while reduced GSH content. TPM treatment alone or combined with LDR ameliorated the PTZ-induced convulsions and caused significant improvement in behavioral changes, brain mediators, m-TOR pathway, oxidative stress, and histological pictures in hippocampal regions. Histopathological examinations of the normal group showed normal structure with intact cells, while PTZ-treated rats exhibited necrosis, pyknosis, and atrophy of pyramidal cells. The histological findings corroborated with the amendment of biochemical parameters. The positive effects of LDR could offer a possible contributor in management of convulsions due to modulation of AkT/m-TOR signaling pathway, reduction of oxidative stress and modulation of brain amino acids. LDR improved the oxidative stress side effects of topiramate.

Ashoub, A. H., D. H. Abdel-Naby, M. M. Safar, M. A. El-Ghazaly, and S. A. Kenawy, "Ameliorative effect of fractionated low-dose gamma radiation in combination with ellagic acid on nicotine-induced hormonal changes and testicular toxicity in rats.", Environmental science and pollution research international, vol. 28, issue 18, pp. 23287-23300, 2021. Abstract

Nicotine is an active pharmacological ingredient in cigarette smoke, which may negatively influence the male reproductive system and fertility. This study aims to investigate the effect of fractionated low-dose radiation (fractionated-LDR) and/or ellagic acid (EA) on nicotine-induced hormonal changes and testicular toxicity in rats. Nicotine was administrated orally (1 mg/kg) for 30 days, afterward, rats were treated with LDR (2 × 0.25 Gy/1-week interval), EA (10 mg/kg, 14 consecutive days p.o.), or a combination of both fractionated-LDR and EA. Rats were sacrificed 24 h after the last dose of treatment, then testes were dissected for histopathology examination, along with some biochemical parameters in serum and testicular tissue were evaluated. Nicotine-induced oxidative stress was evidenced by an increase in testicular thiobarbituric acid reactive substances (TBARS) and a decrease in reduced glutathione (GSH) content. Additionally, the activities of testicular androgenic enzymes were decreased, and the activity of serum lactate dehydrogenase (LDH) was significantly increased. The hormonal changes were verified by a noticeable reduction in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone serum levels. Histological evaluation revealed that the testicular seminiferous tubules structure was distorted. On the contrary, fractionated-LDR plus EA attenuated the negative changes caused by nicotine observed through biochemical and histological findings. Accordingly, the exposure to fractionated-LDR combined with EA may be a promising candidate for treating hormonal changes and testicular toxicity caused by nicotine.

Shouman, M. M., R. M. Abdelsalam, M. M. Tawfick, S. A. Kenawy, and M. M. El-Naa, "Antisense Tissue Factor Oligodeoxynucleotides Protected Diethyl Nitrosamine/Carbon Tetrachloride-Induced Liver Fibrosis Through Toll Like Receptor4-Tissue Factor-Protease Activated Receptor1 Pathway.", Frontiers in pharmacology, vol. 12, pp. 676608, 2021. Abstract

Tissue factor (TF) is a blood coagulation factor that has several roles in many non-coagulant pathways involved in different pathological conditions such as angiogenesis, inflammation and fibrogenesis. Coagulation and inflammation are crosslinked with liver fibrosis where protease-activated receptor1 (PAR1) and toll-like receptor4 (TLR4) play a key role. Antisense oligodeoxynucleotides are strong modulators of gene expression. In the present study, antisense TF oligodeoxynucleotides (TFAS) was evaluated in treating liver fibrosis via suppression of TF gene expression. Liver fibrosis was induced in rats by a single administration of N-diethyl nitrosamine (DEN, 200 mg/kg; i. p.) followed by carbon tetrachloride (CCl4, 3 ml/kg; s. c.) once weekly for 6 weeks. Following fibrosis induction, liver TF expression was significantly upregulated along with liver enzymes activities and liver histopathological deterioration. Alpha smooth muscle actin (α-SMA) and transforming growth factor-1beta (TGF-1β) expression, tumor necrosis factor-alpha (TNF-α) and hydroxyproline content and collagen deposition were significantly elevated in the liver. Blocking of TF expression by TFAS injection (2.8 mg/kg; s. c.) once weekly for 6 weeks significantly restored liver enzymes activities and improved histopathological features along with decreasing the elevated α-SMA, TGF-1β, TNF-α, hydroxyproline and collagen. Moreover, TFAS decreased the expression of both PAR1 and TLR4 that were induced by liver fibrosis. In conclusion, we reported that blockage of TF expression by TFAS improved inflammatory and fibrotic changes associated with CCl4+DEN intoxication. In addition, we explored the potential crosslink between the TF, PAR1 and TLR4 in liver fibrogenesis. These findings offer a platform on which recovery from liver fibrosis could be mediated through targeting TF expression.

El-Ghazaly, M. A., N. A. Fadel, D. H. Abdel-Naby, H. A. Abd El-Rehim, H. F. Zaki, and S. A. Kenawy, "Amelioration of adjuvant-induced arthritis by exposure to low dose gamma radiation and resveratrol administration in rats.", International journal of radiation biology, vol. 96, issue 7, pp. 857-867, 2020. Abstract

Low dose radiation has been reported as an effective treatment for rheumatoid arthritis via multiple dose exposures. The present study was designed to increase the therapeutic efficacy of low dose radiation with the minimum exposure level in arthritic rats by concurrent administration of resveratrol (RSV) as an adjunctive therapy with anti-inflammatory properties. Rats were rendered arthritic by sub-plantar injection of Freund's complete adjuvant (FCA) and exposed to low dose radiation at a total exposure level of 0.5 Gy (2 × 0.25). During the exposure course, RSV (50 mg/kg) was orally administered once daily for two weeks. Diclofenac (3 mg/kg) was administered as a standard anti-inflammatory drug. Paw volume was measured every 4 days. After 28 days of induction, rats were sacrificed and serum was collected for estimation of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), thiobarbituric acid reactive substances (TBARS), and total nitrate/nitrite (NO). Furthermore, paws were dissected for histopathological examinations and immuno-histochemical estimation of nuclear factor-kappa B p65 (NF-κB p65) expression. Administration of RSV during the low dose radiation exposure course produced a significant decrease in the paw swelling and a potentiated inhibition in the serum levels of TNF-α, IL-1β, TBARs, and NO. The dual treatment strategy alleviated the histopathological damage to a greater extent than that produced by each treatment. Moreover, a pronounced suppression of NF-κB p65 expression in the synovial tissue was observed in the combination group. The combination treatment showed a nearly similar potency to that observed in the diclofenac treated group. Administration of RSV augmented the modulatory activity of low dose radiation with minimum exposure level on the disease progression.

Gowifel, A. M. H., M. G. Khalil, S. A. Nada, S. A. Kenawy, K. A. Ahmed, M. M. Salama, and M. M. Safar, "Combination of pomegranate extract and curcumin ameliorates thioacetamide-induced liver fibrosis in rats: impact on TGF-β/Smad3 and NF-κB signaling pathways.", Toxicology mechanisms and methods, vol. 30, issue 8, pp. 620-633, 2020. Abstract

Protection against liver injury and its consequences is considered an essential issue to minimize the number of annual deaths caused by liver diseases. The present study was designed to evaluate the potential role of pomegranate extract (PE) and/or curcumin in the regression of thioacetamide (TAA)-induced liver fibrosis, focusing on their modulatory effects on Nrf2/HO-1, NF-κB, and TGF-β/Smad3 signaling pathways. Liver fibrosis was induced in male Wistar rats by intraperitoneal injection of TAA (100 mg/kg) three times a week, for 8 weeks. To assess the protective effects of PE and/or curcumin against TAA-induced liver fibrosis, rats were treated on a daily basis with oral doses of PE (200 mg/kg) and/or curcumin (200 mg/kg) for 8 weeks. The results indicated that PE and/or curcumin attenuated TAA-induced liver fibrogenesis, as evidenced by a significant improvement in the liver function tests (AST, ALT, ALP, and albumin), oxidative stress biomarkers (MDA, SOD, and GSH), and inflammatory biomarkers (NF-ĸB, TNF-α, IL-1β, iNOS, TGF-β, and MPO), compared to TAA group. Moreover, treatment with PE and/or curcumin exerted a significant upregulation of / gene expressions along with significant downregulation of NF-ĸB, TGF-β, and phospho-Smad3 protein expressions, as well as and gene expressions. The histopathological examination has corroborated these findings. In conclusion, hepatoprotective activities of PE and/or curcumin could be linked to their abilities to modulate Nrf2/HO-1, NF-κB, and TGF-β/Smad3 signaling pathways. It is worth noting that the combination of PE and curcumin exerted superior hepatoprotective effects against TAA-induced liver fibrosis, as compared to monotherapy.

Gheita, T. A., and S. A. Kenawy, "Egypt's groundwork blessing during the COVID-19 pandemic curse: Rheumatologic experience.", European journal of rheumatology, vol. 7, issue Suppl 2, pp. S134-S136, 2020.
Abdelkader, N. F., H. E. Eitah, Y. A. Maklad, A. A. Gamal El Din, M. A. Badawi, and S. A. Kenawy, "New combination therapy of gliclazide and quercetin for protection against STZ-induced diabetic rats.", Life sciences, vol. 247, pp. 117458, 2020. Abstract

AIMS: The use of natural agents with anti-diabetic effect in combination therapy adds further positive clinical implications in the management of diabetes mellitus. Interestingly, quercetin is one of the most potent naturally occurring antioxidant which possesses various pharmacological actions including anti-diabetic effect. Thus, this research was conducted to assess the efficiency of a new combination from gliclazide and quercetin on glycemic control as well as pancreatic islets and beta cells in STZ-experimental model of diabetes.

MAIN METHODS: Diabetes has been induced by a single intraperitoneal injection of streptozotocin (STZ; 45 mg/kg) in adult male Wistar rats. For 3 consecutive weeks, diabetic rats were given orally either gliclazide (10 mg/kg), quercetin (50 mg/kg), or their combination. At the end of the experiment, histological, immunohistochemical and morphometrical examination of pancreatic tissues was performed. Furthermore, the changes in glucose metabolism, lipid profile, oxidative and inflammatory status were evaluated.

KEY FINDINGS: Treatment with gliclazide alone decreased serum glucose, total cholesterol, triglycerides, malondialdehyde, tumor necrosis factor-alpha and nuclear factor kappa-Beta while increased serum C-peptide, superoxide dismutase, reduced glutathione and adiponectin levels. Combined administration of quercetin with gliclazide markedly augmented serum superoxide dismutase and reduced glutathione more than gliclazide alone and normalized all the above-mentioned parameters. Besides, this combination therapy restored immunostaining intensity, number of pancreatic islets and beta cells along with its area and perimeter.

SIGNIFICANCE: Based on the aforementioned results, this combination could be considered a promising one in diabetes mellitus management.

Gheita, A. A., T. A. Gheita, and S. A. Kenawy, "The potential role of B5: A stitch in time and switch in cytokine.", Phytotherapy research : PTR, vol. 34, issue 2, pp. 306-314, 2020. Abstract

The wound healing process is a multifaceted sequence of activities associated with tissue restoration. Novel approaches for the perfection of wound healing have been determined as a stitch in time saves nine. Dysregulation of the immune response is a key element in the pathogenesis of rheumatic diseases and serves as a potential target for novel therapeutic strategies. Vitamin B5 (VB5), also known as pantothenate or "anti-stress vitamin," is the precursor of coenzyme A, which is essential in every micro-organism. Many pantothenic acid amides acquire persuasive antimicrobial activity. Pantothenic acid improves surgical wounds healing with moisturizing and skin barrier enhancing potential. Its deficiency leads to reduced cortisol production, increased arthritic pain, myalgia, fatigue, headache, depression, insomnia, and widespread "proinflammatory" effects on the immune-system. VB5 triggers immune cells to produce cytokines and is multifunctional. The paradoxical effect of VB5 on the switch of anti-inflammatory and proinflammatory cytokines has been revealed. This review aims to present the long research journey of B5 as it is becoming a forerunner in the healing of wounds and in enhancing the immune function, thus providing potentially important therapeutic implications. As its role in healing a wound stitch is promising, amending the immune system damage too is a hopeful target.

Bishr, A., N. Sallam, M. Nour El-Din, A. S. Awad, and S. A. Kenawy, "Ambroxol attenuates cisplatin-induced hepatotoxicity and nephrotoxicity via inhibition of p-JNK/p-ERK.", Canadian journal of physiology and pharmacology, vol. 97, issue 1, pp. 55-64, 2019. Abstract

Hepatotoxicity and nephrotoxicity are important drawbacks of cisplatin. The objective of this study is to evaluate the ability of ambroxol in 2 different doses (35 and 70 mg/kg, i.p.) to protect liver and kidney from damage induced by a single dose of cisplatin (10 mg/kg, i.p.) in comparison with N-acetylcysteine (250 mg/kg, i.p.). Inflammatory, oxidative stress, and apoptotic biomarkers were investigated to show the influence of ambroxol on hepatotoxicity and nephrotoxicity. Ambroxol decreased the elevated activity of liver enzymes (aspartate aminotransferase and alanine aminotransferase) and kidney function tests (blood urea nitrogen and creatinine). Ambroxol mitigated cisplatin inflammatory damage by inhibition of tumor necrosis factor-α, interleukin-1β, and nuclear factor kappa-B and elevation of nuclear factor erythroid 2-related factor 2. Moreover, ambroxol inhibited oxidative damage indicated by reduction of malondialdehyde and replenished the store of reduced glutathione likely by upregulating glutathione reductase and superoxide dismutase. Elevation of phosphorylated c-Jun N-terminal kinases (p-JNK) and phosphorylated extracellular signal-regulated kinase (p-ERK) were attenuated by ambroxol associated with a decrease in the expression of caspase-3; these results were consistent with histopathological results. These results recommend ambroxol to be co-administered with cisplatin in cancer patients to ameliorate liver and kidney damage, and this was confirmed by MTT assay.

Eitah, H. E., Y. A. Maklad, N. F. Abdelkader, A. A. Gamal El Din, M. A. Badawi, and S. A. Kenawy, "Modulating impacts of quercetin/sitagliptin combination on streptozotocin-induced diabetes mellitus in rats.", Toxicology and applied pharmacology, vol. 365, pp. 30-40, 2019. Abstract

BACKGROUND: Since many diabetic patients require combination therapy, the use of herbal remedies with anti-diabetic activity represents a vital option in diabetes mellitus (DM) management. It has been reported that quercetin has hypoglycemic alongside anti-inflammatory and antioxidant activities.

AIM: The present study aimed to investigate the effectiveness of combining quercetin with sitagliptin; a selective dipeptidyl peptidase-IV (DPP-IV) inhibitor, in the management of streptozotocin (STZ)-induced diabetic rats.

METHODS: DM was induced by a single injection of STZ (45 mg/kg, i.p.) in male adult albino Wistar rats. Diabetic rats were orally treated with sitagliptin (70 mg/kg), quercetin (50 mg/kg) or their combination daily for three consecutive weeks. Serum levels of glucose, C-peptide, total cholesterol, triglycerides, malondialdehyde (MDA), superoxide dismutase, (SOD), reduced glutathione (GSH), tumor necrosis factor alpha, (TNF-α), nuclear factor kappa-B, (NF-κB) and adiponectin were estimated. In addition, histopathological, morphometrical and immunohistochemical examinations of pancreatic tissues were conducted.

RESULTS: The combined administration of quercetin and sitagliptin normalized serum C-peptide, MDA, and significantly increased SOD, GSH and decreased NF-κB more than sitagliptin alone. Moreover, this combination normalized Islet number, β-cells' number, area and perimeter alongside restoring the immunostaining intensity of β-cells.

CONCLUSION: Our results suggest the use of quercetin/sitagliptin combination for treating DM based on the observed improvements in glycemic control, metabolic profile, oxidative and inflammatory status, islet structure as well as β-cells function compared with either treatment alone.

Gad, S. A., H. E. A. Ali, R. Gaballa, R. M. Abdelsalam, M. Zerfaoui, H. I. Ali, S. H. Salama, S. A. Kenawy, E. Kandil, and Z. Y. Abd Elmageed, "Targeting CDC7 sensitizes resistance melanoma cells to BRAF-specific inhibitor by blocking the CDC7/MCM2-7 pathway.", Scientific reports, vol. 9, issue 1, pp. 14197, 2019. Abstract

Although the utilization of selective BRAF inhibitors is associated with improved overall survival in patients with metastatic melanoma, a growing challenge of drug resistance has  emerged. CDC7 has been shown to be overexpressed and associated with poor prognosis in various cancers including melanoma. Thus, we aimed to elucidate the biological role of CDC7 in promoting Vemurafenib resistance and the anticipated benefits of dual targeting of BRAF and CDC7 in melanoma cells. We performed exosomes-associated microRNA profiling and functional assays to determine the role of CDC7 in drug resistance using Vemurafenib-sensitive and resistant melanoma cells. Our results demonstrated that Vemurafenib-resistant cells exhibited a persistent expression of CDC7 in addition to prolonged activity of MCM2 compared to drug-sensitive cells. Reconstitution of miR-3613-3p in resistant cells downregulated CDC7 expression and reduced the number of colonies. Treatment of cells with low concentrations of CDC7 inhibitor TAK-931 sensitized resistant cells to Vemurafenib and reduced the number of cell colonies. Taken together, CDC7 overexpression and downregulation of miR-3613-3p were associated with Vemurafenib resistance in BRAF- bearing melanoma cells. Dual targeting of CDC7 and BRAF reduced the development of resistance against Vemurafenib. Further studies are warranted to investigate the clinical effect of targeting CDC7 in metastatic melanoma.

Lotfy, D. M., M. M. Safar, S. H. Mohamed, and S. A. Kenawy, "Effect of valproic acid alone or combined with low dose gamma irradiation in modulating PTZ-induced convulsions in rats involving AKT/m-TOR pathway.", Life sciences, vol. 212, pp. 261-266, 2018. Abstract

AIM: The current study evaluates the anticonvulsant effect of valproic acid (VPA) alone or combined with low dose γ-irradiation (LDR) against pentylenetetrazol-induced convulsions in rats.

MATERIAL AND METHODS: Five groups of rats were used, group I served as normal control, group II served as PTZ- control and the other three groups were pretreated with single LDR(o.5 Gy), VPA(150 mg/kg i.p.5 days) and VPA with LDR respectively before PTZ injection. Racine score, latency and duration of convulsions were assessed. Evaluation of brain neurotransmitters (glutamate and GABA) as well as AKT/m-TOR pathway (protein kinase B [AKT], mammalian target of rapamycin [m-TOR], protein S6 and caspase 3). Measurement of oxidative stress (Malondialdehyde, glutathione and nitric oxide) was carried out. Histopathological examinations of hippocampi were done.

KEY FINDINGS: PTZ resulted in behavioural changes (high Racine score, long seizure duration and short latency).PTZ enhanced oxidative stress state (high MDA and NO, as well as low GSH) compared to normal control. VPA alone or combined with LDR ameliorated, the convulsions and caused significant improvement in behavioural changes and other tested parameters compared to normal control. Histopathological examination of hippocampi was carried out to adjoin the biochemical changes. Certain changes were observed after PTZ injection. However, normal pictures of the other tested groups.

SIGNIFICANCE: The previously mentioned findings support that LDR purveyed novel anticonvulsant activity which could offer a possible contributor in the basic treatment of convulsions. This effect might be due to modulation of AkT/m-TOR pathway, reduction of oxidative stress and modulation of neurotransmitters.

El-ezz, D. A., A. Maher, N. Sallam, A. El-brairy, and S. Kenawy, "Trans-cinnamaldehyde Modulates Hippocampal Nrf2 Factor and Inhibits Amyloid Beta Aggregation in LPS-Induced Neuroinflammation Mouse Model.", Neurochemical research, vol. 43, issue 12, pp. 2333-2342, 2018. Abstract

Trans-cinnamaldehyde (CNM) has recently drawn attention due to its potent anti-inflammatory and antioxidant properties. The current study explored the memory enhancing effects of CNM against lipopolysaccharide (LPS)-induced neuroinflammation in mice. CNM and curcumin (a reference antioxidant) were administered at a dose of 50 mg/kg i.p. 3 h after a single LPS injection (0.8 mg/kg, i.p.) and continued daily for 7 days. Our results displayed that CNM and curcumin significantly ameliorated the LPS-induced impairment of learning and memory, neuroinflammation, oxidative stress and neuronal apoptosis. Memory functions and locomotor activity were assessed by Morris water maze, object recognition test and open field test. Both CNM and curcumin activated the nuclear factor erythroid 2 related factor 2 (Nrf2) and restored levels of downstream antioxidant enzymes superoxide dismutase and glutathione-S-transferase (GST) in the hippocampus. They also attenuated LPS-induced increase in hippocampal contents of interleukin-1β (IL-1β), malondialdehyde and caspase-3. Immunohistochemistry results showed that both CNM and curcumin reduced Aβ protein accumulation in brain of mice. Remarkably CNM's effect on IL-1β was less pronounced than curcumin; however it showed higher GST activity and more potent anti-apoptotic and anti-amylodogenic effect. We conclude that, CNM produces its memory enhancing effects through modulation of Nrf2 antioxidant defense in hippocampus, inhibition of neuroinflammation, apoptosis and amyloid protein burden.

El-Ghazaly, M. A., N. Fadel, E. Rashed, A. El-Batal, and S. A. Kenawy, "Anti-inflammatory effect of selenium nanoparticles on the inflammation induced in irradiated rats.", Canadian journal of physiology and pharmacology, vol. 95, issue 2, pp. 101-110, 2017. Abstract

Selenium (Se) has been reported to possess anti-inflammatory properties, but its bioavailability and toxicity are considerable limiting factors. The present study aimed to investigate the possible anti-inflammatory and analgesic effects of selenium nanoparticles (Nano-Se) on inflammation induced in irradiated rats. Paw volume and nociceptive threshold were measured in carrageenan-induced paw edema and hyperalgesia model. Leukocytic count, tumor necrosis factor-α (TNF-α), prostaglandin E (PGE), thiobarbituric acid reactive substances (TBAR), and total nitrate/nitrite (NOx) were estimated in the exudate collected from 6 day old air pouch model. Irradiated rats were exposed to 6 Gy gamma (γ)-irradiation. Nano-Se were administered orally in a dose of 2.55 mg/kg once before carrageenan injection in the first model and twice in the second model. The paw volume but not the nociceptive response produced by carrageenan in irradiated rats was higher than that induced in non-irradiated rats. Nano-Se were effective in reducing the paw volume in non-irradiated and irradiated rats but it did not alter the nociceptive threshold. The inflammation induced in irradiated rats increased all the estimated parameters in the exudate whereas; Nano-Se decreased their elevation in non-irradiated and irradiated rats. Nano-Se possess a potential anti-inflammatory activity on inflammation induced in irradiated rats.

Shibrya, E. E., R. R. Radwan, M. A. Abd El Fattah, E. A. Shabaan, and S. A. Kenawy, "Evidences for amelioration of reserpine-induced fibromyalgia in rat by low dose of gamma irradiation and duloxetine.", International journal of radiation biology, vol. 93, issue 5, pp. 553-560, 2017. Abstract

OBJECTIVE: Fibromyalgia is a prevalent disorder characterized by chronic widespread pain and complex symptoms. This study was conducted to investigate the potential therapeutic effect of low-dose irradiation (LDI) alone or in combination with duloxetine on the reserpine-induced fibromyalgia in rats.

METHODS: Fibromyalgia was induced by administration of reserpine (1 mg/kg/s.c) for 3 consecutive days. Duloxetine (30 mg/kg, p.o) was administered 60 min before a forced swimming test (FST), and rats were exposed to a single dose of γ-radiation (0.5 Gy) 1 day before the FST.

RESULTS: Reserpine significantly increased immobility time in the FST, decreased the amount of 5-hydroxytryptamine, dopamine, and norepinephrine in cerebral cortex. It also increased malondialdehyde and nitric oxide and reduced glutathione contents in brain tissue. LDI alone or combined with duloxetine completely antagonized reserpine-induced fibromyalgia as assessed by the measured parameters. One of the most significant findings in this study was that the therapeutic effect of duloxetine was more pronounced by its combination with LDI. A possible mechanism of action of LDI and duloxetine responsible for their therapeutic effect was discussed.

CONCLUSION: On the basis of the presented evidences, it could be concluded that LDI alone or combined with duloxetine could be of value in the management of fibromyalgia.

Mahfouz, M. M., R. M. Abdelsalam, M. A. Masoud, H. A. Mansour, O. A. Ahmed-Farid, and S. A. Kenawy, "The neuroprotective effect of mesenchymal stem cells on an experimentally induced model for multiple sclerosis in mice.", Journal of biochemical and molecular toxicology, vol. 31, issue 9, 2017. Abstract

Multiple sclerosis (MS) is a chronic autoimmune demyelinating neurodegenerative central nervous system disorder. The aim of the present study was to investigate the prophylactic effect exerted by the one-time intraperitoneal injection of mesenchymal stem cells (MSCs) 1 × 10 and 14-day intraperitoneal injection of methylprednisolone (MP) 40 mg/kg in an experimental autoimmune encephalomyelitis (EAE). EAE was induced by intradermal injection of rat spinal cord homogenate with complete Freund's adjuvant in Swiss mice. Results of MSCs and MP-treated mice showed a significantly milder disease and fewer clinical scores compared to control mice. They suppressed tumor necrosis factor-alpha and myeloperoxidase and increased interleukin 10, whereas thiobarbituric acid reactive substances and nitric oxide brain contents were reduced to comparable levels between treatment groups. Brain content of GSH was significantly higher in MSCs-treated mice than control mice. It is evident that MSCs have relevant prophylactic effect in an animal model of MS and might represent a valuable tool for stem cell based therapy in MS.

El-Meligy, R. M., A. S. Awaad, G. A. Soliman, S. A. Kenawy, and S. I. Alqasoumi, "Prophylactic and curative anti-ulcerogenic activity and the possible mechanisms of action of some desert plants.", Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society, vol. 25, issue 3, pp. 387-396, 2017. Abstract

The present study aimed to evaluate the anti-ulcerogenic activities and the possible mechanisms of action of seven desert plants from different families. (L.) Desf. (Asteraceae), L. (Euphorpiaceae), L., lanigera L. (Lamiaceae), L., Linn. (Solanaceae) and (Del.) Hayne. (Asclepiadaceae), were tested using prophylactic and curative models of absolute ethanol-induced ulcer, at three doses (125, 250 & 500 mg/kg) of each extract. The investigated extracts possessed dose dependent anti-ulcerogenic activities in both models, with LD higher than 5 g/kg. The most effective extracts were and with percent protection of control ulcer; 91.1% and 85.4% respectively. The antisecretory activity of both and appears to be mainly related to the suppression of gastrin release. The potential radical (DPPH) scavenging activities of the investigated extracts were well supported with the reduction in gastric MDA (50.6% and 43.3%) and enhancing the level of reduced GSH (2.84, 2.59 mg/g tissue) for and respectively. In addition, suppression of the inflammatory mediator TNF-α may be one of the possible mechanisms of action. The alcohol extracts of and showed no alteration on liver and kidney functions. Phytochemical screening of the investigated extracts revealed the presence of flavonoids, tannins and sterols which could be related to the activities.

Atwa, A., R. Hegazy, R. Mohsen, N. Yassin, and S. Kenawy, "Protective Effects of the Third Generation Vasodilatory Βeta - Blocker Nebivolol against D-Galactosamine - Induced Hepatorenal Syndrome in Rats.", Open access Macedonian journal of medical sciences, vol. 5, issue 7, pp. 880-892, 2017. Abstract

BACKGROUND: Renal dysfunction is very common in patients with advanced liver cirrhosis and portal hypertension. The development of renal failure in the absence of clinical, anatomical or pathological causes renal of failure is termed hepatorenal syndrome (HRS).

AIM: The present study was constructed to investigate the possible protective effects of nebivolol (Nebi) against D-galactosamine (Gal)-induced HRS in rats.

MATERIAL AND METHODS: Rats were treated with Nebi for ten successive days. On the 8th day of the experiment, they received a single dose of Gal. Serum levels of Cr, BUN, Na+ and K+ as well as AST, ALT, total bilirubin (TB), NH3 and endothelin-1 (ET-1) were determined following Gal administration. Moreover, renal and liver contents of MDA, GSH, F2-isoprostanes (F2-IPs), tumor necrosis factor-alpha (TNF-α), nuclear factor kappa-B (NF-κB), total nitric oxide (NO), in addition to activities of caspase-3 (Cas-3), heme oxygenase-1 (HO-1), inducible and endothelial NO synthase (iNOS and eNOS) enzymes were also assessed. Finally, histopathological examination was performed.

RESULTS: Nebi attenuated Gal-induced renal and hepatic dysfunction. It also decreased the Gal-induced oxidative stress and inflammatory recruitment.

CONCLUSION: Results demonstrated both nephroprotective and hepatoprotective effects of Nebi against HRS and suggested a role of its antioxidant, anti-inflammatory, anti-apoptotic and NO-releasing properties.

Hessin, A. F., R. R. Hegazy, A. A. Hassan, N. Z. Yassin, and S. A. - B. Kenawy, "Resveratrol prevents liver fibrosis via two possible pathways: Modulation of alpha fetoprotein transcriptional levels and normalization of protein kinase C responses.", Indian journal of pharmacology, vol. 49, issue 4, pp. 282-289, 2017. Abstract

OBJECTIVE: Liver fibrosis is a global health problem that causes approximately 1.4 million deaths per year. It is associated with inflammation, oxidative stress, necrosis and ends with cirrhosis, liver cancer, or liver failure. Therefore, the present study was constructed to investigate the protective effect of resveratrol (RVT) on liver fibrosis, focusing on the possible involvement of alpha 1-fetoprotein and protein kinase C signaling.

MATERIALS AND METHODS: Rats received thioacetamide (TAA) (200 mg/kg, intraperitoneal) twice weekly, for 4 successive weeks to induce liver fibrosis. RVT (30 mg/kg, per os) and vehicle were administered orally for 1 month before and another month during TAA intoxication. Body weights and mortality rate were assessed during the experiment. Liver functions and protein concentration were determined in serum, while liver tissues were analyzed for oxidative and fibrotic biomarkers. Moreover, histological examinations were performed to liver biopsies.

RESULTS: RVT prevented the debility of TAA; liver functions including alanine aminotransferase, aspartate aminotransferase, bilirubin, and albumin were also protected. RVT prevented TAA oxidative stress, and normal liver contents of malondialdehyde and reduced glutathione were markedly preserved. In addition, RVT abolished the stimulant effect of TAA to fibrosis markers and conserved normal liver contents of nuclear factor kappa B, hydroxyproline, and alpha fetoprotein. Histological examinations indicated normal liver architecture in RVT-administered rats as compared to their TAA-administered peers.

CONCLUSION: RVT was able to enhance liver functions, prevent oxidative stress, and eliminate liver fibrosis. Hence, the present data highlight the therapeutic potential of RVT as a protective agent against liver fibrosis.

El Gazzar, I. I., H. M. Fathy, T. A. Gheita, A. M. NourEl-Din, E. A. Rasheed, R. H. Bassyouni, and S. A. Kenawy, "Tumor necrosis factor-α -308 A/G gene polymorphism in children with juvenile idiopathic arthritis: relation to disease activity, damage, and functional status.", Clinical rheumatology, vol. 36, issue 8, pp. 1757-1763, 2017. Abstract

The study aims to evaluate the clinical significance of serum levels of tumor necrosis factor alpha (TNF-α) and -308 A/G promoter polymorphism in juvenile idiopathic arthritis (JIA) patients and find any association to the subsets, clinical and laboratory features, disease activity, and damage as well as functional disability. Forty-eight JIA children and 30 controls were included in the present study. Juvenile arthritis disease activity score in 27 joints (JADAS-27) was calculated, juvenile arthritis damage index (JADI) was assessed, and Childhood Health Assessment Questionnaire (CHAQ) measured the functional status. Serum TNF-α was assayed by ELISA and gene (-308) promoter polymorphism was determined by polymerase chain reaction. The 48 JIA children (mean age 11.5 ± 2.8 years) were 13 systemic, 17 oligoarticular, and 18 polyarticular onset. The serum TNF-α was significantly higher in patients (90.4 ± 6.3 ng/ml) compared to control (3.5 ± 2.6 ng/ml) (p < 0.0001) with a tendency to be higher in the polyarticular subtype. All controls had TNF-α -308 GG alleles. The frequency of GG genotype tended to be higher in systemic onset compared to oligoarticular and polyarticular subtypes. The serum TNF-α significantly correlated with JADAS-27 (r = 0.32, p = 0.03) and CHAQ (r = 0.37, p = 0.01) and negatively with the presence of GG alleles (r = -0.48, p = 0.001). The GG alleles were significantly negatively associated with C-reactive protein (r = -0.32, p = 0.03) with a tendency to negatively correlate with JADAS-27, CHAQ, and JADI-extrarticular (r = -0.28, p = 0.06; r = -0.25, p = 0.09 and r = -0.25, p = 0.09, respectively). There is evidence of a possible influence of the -308 SNP promoter position on the production of TNF-α, the severity of JIA which may consequently influence the response to anti-TNF-α treatment.

Gheita, T. A., H. A. Gheita, and S. A. Kenawy, "The potential of genetically guided treatment in Behçet's disease.", Pharmacogenomics, vol. 17, issue 10, pp. 1165-1174, 2016. Abstract

Continuous identification of specific targets and candidate genes together with novel approaches offers new promises for the future of gene therapy design in Behçet's disease (BD). Personalized medicine based on pharmacogenomics is being developed at the clinical stage to improve treatment response. Screening the whole gene and regulatory regions is important when searching for novel variants associated with such complex diseases. Different host genetic factors play significant roles in susceptibility to BD. Thus, identifying these genes responsible for susceptibility and resistance to BD may offer a notable contribution toward understanding its pathogenesis, and may lead to the development of novel prophylactic and treatment strategies. Evidenced-based treatment strategy is recommended for the management in BD patients. This review sheds light on the immunopathogenesis and pharmacogenetics of BD with special attention to the treatment targeting gene polymorphisms. In conclusion, the potential of genetically guided treatment in BD takes us back to the future for an accurate management strategy of this serious rheumatic disease. The ongoing discovery of pivotal genes related to the susceptibility, manifestations, disease activity and treatment options provide substantial hope to the reduced frequency of BD, effective control and improvement in the prognosis. Targeted gene therapy could be a leading option in the treatment armamentarium of BD.

Atwa, A., R. Hegazy, N. Shaffie, N. Yassin, and S. Kenawy, "Protective Effects of Vasodilatory Βeta-Blockers Carvedilol and Nebivolol against Glycerol Model of Rhabdomyolysis-Induced Acute Renal Failure in Rats.", Open access Macedonian journal of medical sciences, vol. 4, issue 3, pp. 329-336, 2016. Abstract

BACKGROUND: Rhabdomyolysis (RM)-induced acute renal failure (ARF) accounts for about 10-40% of all cases of ARF.

AIM: The present study investigated the possible protective effect of two nitric oxides (NO)-releasing third generation β-blockers, carvedilol (Carv) and nebivolol (Nebi), against RM-mimicking glycerol (Gly)-induced ARF in rats.

MATERIAL AND METHODS: After 24 h dehydration, rats received a single dose of 50% Gly (8 ml/kg, im). They were treated with vehicle, Carv (2.5 mg/kg/day, po) or Nebi (10 mg/kg, po) for 3 successive days starting from an hour prior to Gly injection. Evaluation of blood pressure and locomotor activity was performed during the experiment. 72 h following Gly administration, total protein in the urine, serum levels of creatinine, blood urea nitrogen, sodium and potassium as well as the renal contents of malondialdehyde, reduced glutathione and NO were assessed, together with a histopathological examination of renal tissues.

RESULTS: Carv and Nebi attenuated Gly-induced renal dysfunction and histopathological alterations. They decreased the Gly-induced oxidative stress and increased renal NO concentration. Restoration of normal blood pressure and improvement of locomotor activity were also observed.

CONCLUSION: The results clearly demonstrate protective effects of Carv and Nebi against renal damage involved in RM-induced ARF and suggest a role of their antioxidant and NO-releasing properties.

Zaafan, M. A., H. F. Zaki, A. I. El-Brairy, and S. A. Kenawy, "Pyrrolidinedithiocarbamate attenuates bleomycin-induced pulmonary fibrosis in rats: Modulation of oxidative stress, fibrosis, and inflammatory parameters.", Experimental lung research, vol. 42, issue 8-10, pp. 408-416, 2016. Abstract

OBJECTIVE: The current study aimed to investigate the modulatory effects of pyrrolidinedithiocarbamate (PDTC; 100 mg/kg) on bleomycin-induced pulmonary fibrosis (5 mg/kg; intratracheal) in rats.

MATERIALS AND METHODS: Rats were randomly assigned to three groups: normal control, bleomycin control, and PDTC-treated groups. Lung injury was evaluated through histological examination, immunohistochemical detection of inducible nitric oxide synthase (iNOS) in lung tissue and evaluating the total and differential leucocytes count in bronchoalveolar lavage fluid. Lung tissue was used for biochemical assessment of lung content of hydroxyproline, transforming growth factor beta-1 (TGF-β1), tumor necrosis factor-alpha (TNF-α) as well as analysis of lipid peroxides, reduced glutathione (GSH), and total nitrite contents.

RESULTS: PDTC attenuated bleomycin-induced pulmonary fibrosis as evidenced by histological observations, decreased iNOS expression and prevention of bleomycin-induced altered total and differential leukocytes count. Additionally, PDTC caused a significant decrease in lung contents of hydroxyproline, TGF-β1, TNF-α, lipid peroxides, and total nitrite coupled with increase in lung GSH content as compared to bleomycin control group.

CONCLUSION: PDTC attenuated bleomycin-induced pulmonary fibrosis in rats via its anti-inflammatory, antioxidant, and antifibrotic activities.

Gheita, T. A., S. Sayed, H. A. Gheita, and S. A. Kenawy, "Vitamin D status in rheumatoid arthritis patients: relation to clinical manifestations, disease activity, quality of life and fibromyalgia syndrome.", International journal of rheumatic diseases, vol. 19, issue 3, pp. 294-9, 2016. Abstract

AIM: To assess vitamin D levels in rheumatoid arthritis (RA) patients and to find their relation to clinical parameters, fibromyalgia syndrome (FMS), quality of life (QoL) and disease activity.

METHODS: The study included 63 RA patients and 62 controls. Clinical examination and laboratory investigations were performed. For patients, the Disease Activity Score (DAS-28), QoL index, Health Assessment Questionnaire II (HAQ II) and Modified Larsen score were calculated. 25-OH-vitamin D was measured in patients and controls.

RESULTS: The patients' mean age was 41.59 ± 9.69 years and disease duration 5.89 ± 3.67 years. The level of vitamin D in RA patients was significantly lower (23.11 ± 12.71 ng/mL) than that in the controls (32.59 ± 13.06 ng/mL) (P = 0.005) being deficient in 50.8%, insufficient in 23.8% and normal in 25.4%. The RA patients with FMS (n = 33) had significantly lower levels of vitamin D (19.08 ± 10.59 ng/mL) than those without (27.55 ± 13.51 ng/mL) (P = 0.008). The difference was significant on comparing those receiving hydroxychloroquine (17.39 ± 7.84 ng/mL) to those not (31.85 ± 13.85 ng/mL) (P < 0.001). Vitamin D significantly correlated with QoL index (r = 0.58, P < 0.001) and negatively with HAQ II (r = -0.36, P = 0.004) and BMI (r = -0.39, P = 0.001).

CONCLUSION: Special attention is required regarding vitamin D levels in RA patients with FMS and decreased QoL. Vitamin D should be corrected and supplementation considered among the RA management armamentarium.

Hammam, O. A., N. Elkhafif, Y. M. Attia, M. T. Mansour, M. M. Elmazar, R. M. Abdelsalam, S. A. Kenawy, and A. S. El-Khatib, "Wharton's jelly-derived mesenchymal stem cells combined with praziquantel as a potential therapy for Schistosoma mansoni-induced liver fibrosis.", Scientific reports, vol. 6, pp. 21005, 2016. Abstract

Liver fibrosis is one of the most serious consequences of S. mansoni infection. The aim of the present study was to investigate the potential anti-fibrotic effect of human Wharton's jelly-derived mesenchymal stem cells (WJMSCs) combined with praziquantel (PZQ) in S. mansoni-infected mice. S. mansoni-infected mice received early (8(th) week post infection) and late (16(th) week post infection) treatment with WJMSCs, alone and combined with oral PZQ. At the 10(th) month post infection, livers were collected for subsequent flow cytometric, histopathological, morphometric, immunohistochemical, gene expression, and gelatin zymographic studies. After transplantation, WJMSCs differentiated into functioning liver-like cells as evidenced by their ability to express human hepatocyte-specific markers. Regression of S. mansoni-induced liver fibrosis was also observed in transplanted groups, as evidenced by histopathological, morphometric, and gelatin zymographic results besides decreased expression of three essential contributors to liver fibrosis in this particular model; alpha smooth muscle actin, collagen-I, and interleukin-13. PZQ additionally enhanced the beneficial effects observed in WJMSCs-treated groups. Our results suggest that combining WJMSCs to PZQ caused better enhancement in S. mansoni-induced liver fibrosis, compared to using each alone.