Publications by authors named "Eman G Khedr"

22 Publications

  • Page 1 of 1

Inhibition of PKC/MEK pathway suppresses β1-integrin and mitigates breast cancer cells proliferation.

Toxicol Rep 2021 21;8:1530-1537. Epub 2021 Jul 21.

Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt.

Prostaglandin E2 (PGE2) and β1-integrin have been correlated with breast cancer, where both could enhance progression and metastasis. Protein kinase C (PKC) and MEK have played a vital role in breast cancer development. Our study was conducted to elucidate the effect of inhibition of E-prostanoid receptor 1 (EP1)/ PKC/ MEK/ β1-integrin pathway in mitigating breast cancer progression and to evaluate the role of the intermediate signals FOXC2, E2F1, NF-ҡB and survivin. MCF7 cells were treated with 17 -PT-PGE2, an EP1 agonist, for 24 h, and β1-integrin was measured. To MCF7 cells treated with 17-PT-PGE2, inhibitors of either EP1, MEK, PKC or NF-ҡB were added followed by measurement of β1-integrin gene expression and cell proliferation in each case. Addition of 17- PT-PGE2 to MCF7 cells showed enhancement of both cell proliferation, and cell cycle transition from G1 to S phase. In addition, activation of EP1 receptor increased β1-integrin expression. On the contrary, inhibition of EP1 receptor showed a decrease in the cell proliferation, β1-integrin expression and cells transition to S phase, but increased cell count in apoptotic phase. Selective inhibition of each of MEK, PKC, and NF-ҡB suppressed 17 -PT-PGE2-mediated β1-integrin expression as well as cell proliferation. Furthermore, FOXC2, phosphorylated NF-ҡB, E2F1, and survivin levels were upregulated with 17- PT-PGE2 and suppressed by MEK, PKC and NF-ҡB inhibitors. Targeting the biochemical mediators of PKC/MEK pathway may be of value in developing new chemical entities for cancer treatment.
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http://dx.doi.org/10.1016/j.toxrep.2021.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361284PMC
July 2021

Amelioration of lithiatic injury to renal tissue by candesartan and sodium thiosulfate in a rat model of nephrolithiasis.

PLoS One 2021 13;16(5):e0251408. Epub 2021 May 13.

Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt.

Aim: Nephrolithiasis is a chronic metabolic condition affecting 10% of population worldwide. The present study aimed to investigate the possible protective role of candesartan (CAND) and sodium thiosulfate (STS) in ameliorating ethylene glycol (EG) induced nephrolithiasis.

Methods: One hundred male Wistar rats were divided into five groups: Normal control group, nephrolithiasis (EG) group (1% EG in drinking water), Cystone (CYS) group (EG + 750 mg/kg CYS, orally, once daily), STS group (EG + 0.4 gm/kg STS, intraperitoneally, 3 times/week) and CAND group (EG + 70 μg/mL CAND in drinking water). Treatments and EG administration commenced on the same day and continued for 28 days. CYS was used as reference drug. Urine, blood, and renal tissues were collected at the end of the experiment for assessment of kidney function tests (serum creatinine and urea), urinary (8-hydroxydeoxyguanosine (8-OHdG), calcium and oxalate), inflammatory and oxdative stress biomarkers (transforming growth factor beta (TGF-β), osteopontin (OPN) and ratio of reduced glutathione to oxidized glutathione (GSH/GSSG)) in renal tissue.

Results: Serum (creatinine and urea), urinary (8-OHdG and oxalate) and renal (OPN and TGF-β) were significantly reduced in CAND and STS groups compared to EG group. Furthermore, renal GSH/GSSG and urinary calcium were significantly increased in CAND and STS groups compared to EG group. Histopathological results support the biochemical findings; CAND and STS groups showed less retention of crystals and necrotic damage in kidney. Also, microscopic examination of urine revealed less crystal for CAND and STS groups.

Conclusion: Candesartan and sodium thiosulfate exhibited protective effect against nephrolithiasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251408PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118324PMC
May 2021

Immunosuppressive role of Benzo[a]pyrene in induction of lung cancer in mice.

Chem Biol Interact 2021 Jan 24;333:109330. Epub 2020 Nov 24.

Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt.

Aim: Benzo[a]pyrene [BP] is one of the major carcinogenic precursors of cigarette smoke that primary affects the lung at its first proximity. The goal of the current research was to elucidate new mechanisms underlying the tumorigenic impact of oral BP in the lung of mice, with focus on immunosuppressive effects and cancer stemming properties.

Methods: Female albino mice (n = 44) were divided into 2 groups: normal control and BP group. BP was administered orally to mice (50 mg/kg body weight), twice a week for four weeks in succession. At the end of experiment (22 weeks), gene expression were measured for transforming growth factor-β (TGF-β), cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death ligand 1(PD-L1), forkhead box protein P3 (FOXP3) and interleukin 12 (IL-12) and CD83, CD8 and CD166 cell percentage were measured in lung tissue.

Results: The results indicated the tumorigenic role of BP in the lung which was evidenced by histopathological examination. BP group also showed immunosuppressive role which evidenced by increased expression of lung TGF-β, CTLA-4, PD-L1, FOXP3 genes and decreased expression of lung IL-12 gene compared with normal control group. BP group also showed decreased CD83 cells, CD8 cells and increased number of CD166 cells.

Conclusion: Our findings indicated that BP has immunosuppressive role in lung cancer besides increasing the percentage of cancer stem like cells.
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http://dx.doi.org/10.1016/j.cbi.2020.109330DOI Listing
January 2021

Inhibition of lovastatin- and docosahexaenoic acid-initiated autophagy in triple negative breast cancer reverted resistance and enhanced cytotoxicity.

Life Sci 2020 Oct 5;259:118212. Epub 2020 Aug 5.

Department of Biochemistry, Faculty of Pharmacy, Tanta University, Egypt, Postal code: 31527. Electronic address:

Aims: Autophagy plays a complex role in breast cancer by suppressing or improving the efficiency of treatment. Triple-negative breast cancer (TNBC) cell line (MDA-MB-231) is associated with aggressive response and developing therapy resistance. MDA-MB-231 cells depend on autophagy for survival. Also, the potential benefits of autophagy inhibition in ameliorating developed chemotherapy resistance towards MDA-MB-231 remains to be elucidated. Despite showing anti-tumorigenic activities, the use of lovastatin and docosahexaenoic acid (DHA) for treating different types of cancers is still limited. We aimed to investigate the protective effect of autophagy inhibition by chloroquine (CQ) in MDA-MB-231 cells resistance treated with lovastatin or DHA.

Main Methods: MDA-MB-231 cells were treated with 30 μM lovastatin and/or 100 μM DHA for 48 h plus 20 μM CQ. Autophagic flux was assessed in association with the expression of multidrug resistance gene 1 (MDR1), transforming growth factor beta 1 gene (TGF-β1), and autophagy-related 7 gene (ATG7).

Key Findings: Both drugs exhibited dose-dependent cytotoxicity, enhanced the autophagic flux represented by increased LC3BII protein concentration and decreased p62 protein concentration, and up-regulated the expression of MDR1, TGF-β1, and ATG7 genes. CQ addition enhanced the cytotoxicity of drugs and inhibited the autophagic flux which is detected by higher levels of LC3BII and p62 correlated with the reverted MDR1, TGF-β1 and ATG7 genes expression.

Significance: Autophagy inhibition by CQ showed an ameliorative effect on lovastatin- and DHA-induced resistance and enhanced their cytotoxicity, providing a promising strategy in breast cancer therapy.
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http://dx.doi.org/10.1016/j.lfs.2020.118212DOI Listing
October 2020

Stress-Based Production, and Characterization of Glutathione Peroxidase and Glutathione S-Transferase Enzymes From .

Front Bioeng Biotechnol 2020 27;8:78. Epub 2020 Feb 27.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt.

More attention has been recently directed toward glutathione peroxidase and s-transferase enzymes because of the great importance they hold with respect to their applications in the pharmaceutical field. This work was conducted to optimize the production and characterize glutathione peroxidase and glutathione s-transferase produced by KU720558 using Plackett-Burman and Box-Behnken statistical designs. To assess the impact of the culture conditions on the microbial production of the enzymes, colorimetric methods were used. Following data analysis, the optimum conditions that enhanced the s-transferase yield were the De Man-Rogosa-Sharp (MRS) broth as a basal medium supplemented with 0.1% urea, 0.075% HO, 0.5% 1-butanol, 0.0125% amino acids, and 0.05% SDS at pH 6.0 and anaerobically incubated for 24 h at 40°C. The optimum s-transferase specific activity was 1789.5 U/mg of protein, which was ~12 times the activity of the basal medium. For peroxidase, the best medium composition was 0.17% urea, 0.025% bile salt, 7.5% Na Cl, 0.05% HO, 0.05% SDS, and 2% ethanol added to the MRS broth at pH 6.0 and anaerobically incubated for 24 h at 40°C. Furthermore, the optimum peroxidase specific activity was 612.5 U/mg of protein, indicating that its activity was 22 times higher than the activity recorded in the basal medium. After SDS-PAGE analysis, GST and GPx showed a single protein band of 25 and 18 kDa, respectively. They were able to retain their activities at an optimal temperature of 40°C for an hour and pH range 4-7. The 3D model of both enzymes was constructed showing helical structures, sheet and loops. Protein cavities were also detected to define druggable sites. GST model had two large pockets; 185Å3 and 71 Å3 with druggability score 0.5-0.8. For GPx, the pockets were relatively smaller, 71 Å3 and 32 Å3 with druggability score (0.65-0.66). Therefore, the present study showed that the consortium components as well as the stress-based conditions used could express both enzymes with enhanced productivity, recommending their application based on the obtained results.
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http://dx.doi.org/10.3389/fbioe.2020.00078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057912PMC
February 2020

Modulatory Effect of Silymarin on Apoptosis in Testosterone -Induced Benign Prostatic Hyperplasia in Rats.

Pathol Oncol Res 2020 Jul 4;26(3):1947-1956. Epub 2020 Jan 4.

Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, El-Gharbia, 31527, Egypt.

Benign prostatic hyperplasia (BPH) is considered a normal part of the aging process in men, and is characterized by an imbalance between cell proliferation and apoptosis. Our study aimed to investigate the potential protective role of silymarin (SIL) against testosterone-induced BPH in rats and to elucidate the molecular mechanisms underlying SIL pro-apoptotic and anti-proliferative effects. Forty adult male Wistar rats were divided equally into four groups: control group, BPH group (3 mg/kg testosterone propionate, s.c. for 14 days, SIL group (50 mg/kg SIL, orally, once daily concomitantly with 3 mg/kg testosterone propionate s.c.) and inhibitor group (50 mg/kg SIL orally concomitantly with 3 mg/kg testosterone, s.c. and 0.5 mg/rat Z-VAD-FMK, i.p.). Silymarin induced caspase-dependent apoptosis in BPH as SIL significantly reduced prostatic Bcl-2 protein and increased Bax protein concentration. Also, SIL down-regulated survivin (Inhibitor of apoptosis protein (IAPs) gene expression in rat prostate assisting mainly caspase-dependent pathway. Silymarin significantly decreased cytochrome-c cytosolic concentration and increased caspase 3 activity compared to BPH group. Silymarin significantly increased the content of p27/ (Cyclin dependent kinase inhibitor (CDKIs) promoting cell cycle arrest. The histological features of BPH such as hypertrophy, papillary projections formation, improved in SIL group. Silymarin showed a significant anti-proliferative and pro-apoptotic role in BPH and accordingly it could be effectively and safely used as a treatment tool in cases of BPH or prostatic disorders.
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http://dx.doi.org/10.1007/s12253-019-00764-4DOI Listing
July 2020

A new strategy for enhancing antitumor immune response using dendritic cells loaded with chemo-resistant cancer stem-like cells in experimental mice model.

Mol Immunol 2019 07 30;111:106-117. Epub 2019 Apr 30.

Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt. Electronic address:

Background And Aim: Cancer stem cells (CSCs) are rare cell population present in the tumor bulk that are thought to be the reason for treatment failure following chemotherapy in terms of their intrinsic chemo-resistance. Our study aimed to develop an effective therapeutic strategy to target chemo-resistant cancer stem - like cells population in solid Ehrlich carcinoma (SEC) mice model using dendritic cells (DCs) loaded with enriched tumor cells lysate bearing CSC-like phenotype as a vaccine.

Materials And Methods: Ehrlich carcinoma cell line was exposed to different concentrations of cisplatin, doxorubicin, or paclitaxel. Drug treatment that resulted in drug surviving cells with the highest expression of CSCs markers (CD44/CD24) was selected to obtain enriched cell cultures with resistant CSCs population. Dendritic cells were isolated from mice bone marrow, pulsed with enriched CSC lysate, analyzed and identified (CD11c, CD83 and CD86). SEC-bearing mice were treated with loaded or unloaded DCs either as single treatment or in combination with repeated low doses of cisplatin. IFN- γ serum level and p53gene expression in tumor tissues were determined by ELISA and real-time PCR, respectively.

Results And Conclusion: The results revealed that vaccination with CSC loaded DCs significantly reduced tumor size, prolonged survival rate, increased IFN-γ serum levels, and upregulated p53gene expression in SEC bearing mice. These findings were more evident and significant in the group co-treated with CSC-DC and cisplatin rather than other treated groups. This study opens the field for combining CSC-targeted immunotherapy with repeated low doses chemotherapy as an effective strategy to improve anticancer immune responses.
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http://dx.doi.org/10.1016/j.molimm.2019.04.001DOI Listing
July 2019

Evaluation of the antirheumatic effects of isoflavone-free soy protein isolate and etanercept in rats with adjuvant-induced arthritis.

Exp Biol Med (Maywood) 2019 05 21;244(7):545-553. Epub 2019 Mar 21.

3 Department of Biochemistry, Faculty of Pharmacy, Horus University, New Damietta 34518, Egypt.

Impact Statement: In view of the partial clinical benefit and significant toxicity of traditional rheumatoid arthritis (RA) treatments, there is a growing trend to use complementary therapy. The antiarthritic activity of soy is related to the effect of soy isoflavones. However, little is known about the antiarthritic activity of soy protein itself. This study demonstrates that soy protein isolate (SPI) and etanercept (ETN), a tumor necrosis factor-α (TNF-α) inhibitor, protect rats against the effects of adjuvant-induced arthritis (AIA) by reducing inflammation (TNF-α and matrix metalloproteinase-3), autoantibody production (anticyclic citrullinated peptide), and lipid peroxidation (malondialdehyde). Only SPI improved dyslipidemia accompanied by RA, giving it the advantage of reducing cardiovascular risk. Additionally, the severity of arthritis-induced pathology, including inflammatory infiltrates, synovial hyperplasia, pannus formation, synovial vascularity, and cartilage erosions, was reduced by both SPI and ETN. This research ascertains the possible antiarthritic effect of SPI, making it a recommended alternative therapy for RA.
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http://dx.doi.org/10.1177/1535370219839222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545695PMC
May 2019

Effect of modification of MTDH gene expression on colorectal cancer aggressiveness.

Gene 2019 May 2;698:92-99. Epub 2019 Mar 2.

Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt. Electronic address:

Background: Metadherin (MTDH) is an oncogene that has been overexpressed in numerous types of malignancies including colorectal cancer (CRC). However, few investigations associated with the biological behavior of MTDH in CRC have been performed. The aim of the present study was to investigate the effect of modification of MTDH gene expression (knockdown and overexpression) on the biological behavior of CRC in vitro.

Methods: MTDH gene expression was analyzed in two CRC cell lines (Caco-2 and HCT116) by qPCR. MTDH was down-regulated via siRNA-mediated knockdown of human MTDH in HCT116 cells, which express high endogenous levels of MTDH gene. Also, MTDH gene was up-regulated via transfection of Caco-2 cells, which express low endogenous levels of MTDH gene, with a plasmid carrying human MTDH gene.

Results: Knockdown of MTDH gene expression significantly decreased the gene expression of multidrug resistance gene (MDR1), Snail and NF-κB p65, but increased the gene expression of E-cadherin. Furthermore, MTDH-knockdown significantly decreased anaerobic glycolysis (glucose consumption and lactate production), cell proliferation ability and transformation into cancer stem cell. Moreover, up-regulation of MTDH gene significantly increased the gene expression of MDR1, Snail and NF-κB p65, deceased the gene expression of E-cadherin, enhanced cell proliferation, and anaerobic glycolysis and activated transformation into cancer stem cells.

Conclusions: MTDH has an important role in promoting CRC aggravation. Also, inhibition of MTDH expression may attenuate the carcinogenic behavior of CRC cells. Furthermore, MTDH-associated NF-κB p65 signaling pathways may be involved in mediating the biological behavior of CRC.
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http://dx.doi.org/10.1016/j.gene.2019.02.069DOI Listing
May 2019

Activation of EMT in colorectal cancer by MTDH/NF-κB p65 pathway.

Mol Cell Biochem 2019 Jul 1;457(1-2):83-91. Epub 2019 Mar 1.

Biochemistry Department, Faculty of Pharmacy, Tanta University, Tanta, 31111, Egypt.

Epithelial-mesenchymal transition (EMT) leads to tumor dissemination and metastasis. Metadherin (MTDH) is an oncogene that plays an important role in metastasis regulation. This study tries to investigate the effect of MTDH gene up-regulation on the activation of EMT in colorectal cancer (CRC) cells and identify the role of NF-κB p65. The CaCO2 cells were divided into three groups: one control group of cultured CaCO2 cells (C1), and two groups of CaCO2 cells co-transfected using human MTDH expression plasmid with either siRNA targeting human NF-κB p65 or its negative control (C2 and C3 respectively). The gene modification was confirmed by qPCR and the effect of gene modification on CRC aggravation was studied. MTDH up-regulation significantly promoted CRC cell proliferation, activated anaerobic respiration (glucose consumption and lactate production), and increased gene expression of multidrug resistance gene (MDR1), Snail transcription factor and NF-κB p65, but decreased the gene expression of E-cadherin. Moreover, MTDH up-regulation led to a significant increase in the acquisition of surface markers of CRC stem cells. Interference with NF-κB p65 gene expression reversed the action of MTDH gene up-regulation on MDR1 and E-cadherin gene expression and anaerobic respiration. Moreover, NF-κB p65 interference significantly decreased MTDH-induced cell proliferation and acquisition of surface markers of CRC stem cells but didn't affect the Snail transcription factor. MTDH-dependent EMT in CRC is activated via NF-κB p65 and is mediated by up-regulation of Snail. These results identify a pathway by which MTDH regulates NF-κB p65 induced EMT during CRC cell metastasis.
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http://dx.doi.org/10.1007/s11010-019-03514-xDOI Listing
July 2019

Immunotherapeutic strategies for treatment of hepatocellular carcinoma with antigen-loaded dendritic cells: in vivo study.

Clin Exp Med 2018 Nov 30;18(4):535-546. Epub 2018 Jul 30.

Department of Biochemistry, Faculty of Pharmacy, Tanta University, El-Bahr Street, Tanta, El-Gharbiya, 31111, Egypt.

Hepatocellular carcinoma (HCC) is one of the major health problems in the world. DCs-based vaccines are a promising immunotherapeutic strategy that aims at the optimal for induction of a specific antitumor immune response and destruction of tumor cells. The present study was conducted to investigate the immunogenic characters of whole tumor lysate-pulsed DCs vaccine and its ability to induce a specific antitumor immune response in HCC mice model. We also evaluate the effectiveness of prophylactic and therapeutic immunization strategies against HCC in mice models. Mice-derived DCs were in vitro loaded with whole tumor lysate prepared from liver tissue of HCC mice and evaluated for expression of surface maturation markers CD83 and CD86. In vivo immunization of mice with whole tumor lysate-pulsed DCs was performed in two strategies; prophylactic (pre-exposure to HCC) and therapeutic (post-exposure to HCC). Effectiveness of both protocols was investigated in terms of histopathological examination of liver sections and measurement of serum levels of immune cytokines interferon-γ (IFN-γ) and interleukin-2 (IL-2). Loading of DCs with whole tumor cell lysate exhibited a significant increase in expression of CD83 and CD86. In vivo administration of prophylactic doses of whole tumor lysate-pulsed DCs in mice before induction of HCC evokes a strong antitumor immune response presented by absence of malignant cells in liver sections and the significant increase in IFN-γ and IL-2. Data herein indicated that prophylactic vaccination with whole tumor lysate-pulsed DCs exhibited an effective antitumor immune response against HCC more than therapeutic protocol.
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http://dx.doi.org/10.1007/s10238-018-0521-6DOI Listing
November 2018

Loading of doxorubicin and thymoquinone with F2 gel nanofibers improves the antitumor activity and ameliorates doxorubicin-associated nephrotoxicity.

Life Sci 2018 Aug 6;207:461-470. Epub 2018 Jun 6.

Biochemistry Department, Faculty of Pharmacy, Menoufia University, Egypt.

Aims: This study aimed to elucidate the benefits of nanoformulation of doxorubicin (DOX) and thymoquinone (TQ) loaded with nanofibers of poly-N-acetyl glucosamine (pGlcNAc), which is known as F2 gel, over their conventional free forms. Moreover, evaluate the role of TQ in improving chemotherapeutic effect and ameliorating nephrotoxicity of DOX.

Main Methods: The drugs were loaded into F2 gel followed by measurement of physicochemical characterization. Next, MCF-7 and HEPG2 cells were treated with the prepared formulations and assessed for apoptosis alongside with cellular proliferation. Furthermore, we experimentally induced Heps liver carcinoma in mice and at the end of the treatment, mice were sacrificed and serum samples were used to assess nephrotoxicity markers; blood urea nitrogen (BUN) and creatinine. Additionally, renal tissue was used for determination of oxidative markers and antioxidant enzymes; whereas, tumor tissue was utilized to measure nuclear factor kappa B (NF-κB) and caspase 3.

Key Findings: Nanoformulation showed dramatic increase in apoptosis, caspase 3, and antioxidant enzymes; in contrast to, dramatic fall in cell viability, tumor volume, oxidative and nephrotoxicity markers, and NF-κB compared to corresponding free therapies. Combined therapy was superior in conserving the measured parameters compared to other treated groups.

Significance: F2 gel loaded with DOX and TQ revealed enhanced antitumor activity with minimal toxicity. Moreover, using TQ as an adjuvant with DOX could augment its cytotoxicity and ameliorate nephrotoxicity.
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http://dx.doi.org/10.1016/j.lfs.2018.06.008DOI Listing
August 2018

Muscle proteolytic system modulation through the effect of taurine on mice bearing muscular atrophy.

Mol Cell Biochem 2018 Jul 2;444(1-2):161-168. Epub 2017 Dec 2.

Biochemistry Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt.

Skeletal muscle atrophy occurs in different catabolic conditions and mostly accompanied with upregulation of Muscle ring finger 1 (MuRF1) gene which is one of the master regulatory genes in muscle atrophy. Taurine amino acid is widely distributed in different tissues and has anti-inflammatory and antioxidant effects. This study aimed to investigate the potential influence of taurine on muscle atrophy induced by reduced mechanical loading. Twenty-eight Albino mice were used, and divided equally into four groups: group I (control); group II (immobilization); group III (immobilization + taurine); and group IV (taurine). Quadriceps muscle sections were taken for histopathology, immunohistochemical analysis of caspase 3 expression, and qRT-PCR of MuRF1 gene. Our data revealed Zenker necrosis associated with axonal injury of the nerve trunk of the immobilized muscle together with increase of caspase 3 expression and upregulation of MuRF1 gene. While, taurine supplementation alleviated the muscular and neural tissues damage associated with disuse skeletal muscle atrophy through downregulation of MuRF1 gene and decrease of tissue caspase 3 expression. In conclusion, taurine may be helpful to counteract apoptosis and up-regulated MuRF1 gene expression related to muscle atrophy, which might be hopeful for a large number of patients.
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http://dx.doi.org/10.1007/s11010-017-3240-5DOI Listing
July 2018

Effect of human umbilical cord blood-derived mononuclear cells on diabetic nephropathy in rats.

Biomed Pharmacother 2018 Jan 9;97:1040-1045. Epub 2017 Nov 9.

Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt. Electronic address:

Diabetic nephropathy (DN) is damage to the kidney which can lead to chronic renal failure, eventually requiring dialysis. Diabetes mellitus is the most common cause of adult kidney failure worldwide in the developed world. The current work was designed to elucidate the effect of mononuclear cells (MNCs) injection on reverse DN in rats exposed to streptozotocin (STZ) injection compared to metformin as a known hypoglycemic drug, 40 Male rats were divided equally into 4 groups; normal control group, diabetic control group, MNCs group were diabetic rats treated with MNCs (30×10 MNCs/rat once iv dose) in the tail vein of the rat, and metformin group were diabetic rats treated with metformin (100mg/kg orally daily dose) for four weeks. The results indicated an improvement effect of MNCs and metformin on STZ-induced DN in rats, which was evidenced by significant decrease in urinary albumin/creatinine ratio, N-acetyl-β-d-glucosaminidase (NAG), urinary kidney injury molecule-1 (KIM-1), serum urea, serum creatinine and fasting blood glucose and significant increase in C- peptide level, compared to diabetic control group. Additionally MNCs treated group exhibited pronounced effects in all previous parameters compared to metformin treated group. It is proved that MNCs treatment was superior to metformin in controlling hyperglycemia, and improving renal function in diabetic rats.
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http://dx.doi.org/10.1016/j.biopha.2017.10.151DOI Listing
January 2018

Enhanced anticancer effect and reduced toxicity of doxorubicin in combination with thymoquinone released from poly-N-acetyl glucosamine nanomatrix in mice bearing solid Ehrlish carcinoma.

Eur J Pharm Sci 2017 Nov 7;109:525-532. Epub 2017 Sep 7.

Biochemistry Department, Faculty of Pharmacy, Menoufia University, Egypt. Electronic address:

The incidence of breast cancer remarkably increases all over the world. Therefore, there is a great demand to introduce new approaches into cancer treatment field. The current study was designated to evaluate the role of doxorubicin (DOX) and/or thymoquinone (TQ) nanomatrix in potentiating the cytotoxicity of either drug, and to investigate the ability of TQ to reduce cardiotoxicity of DOX in solid Ehrlich carcinoma (SEC)-bearing mice. DOX and TQ were loaded into F2 gel, which is a fully-acetylated poly-N-acetyl glucosamine nanofiber. SEC was induced in female albino mice as a model for experimentally induced breast cancer. Mice were randomly divided into eight groups (n=10): normal control, tumor control, F2 gel, free DOX, DOX+F2 gel, free TQ, TQ+F2 gel, and DOX+TQ+F2 gel. On day 28th from tumor inoculation, mice were sacrificed and blood samples were collected for measurement of the cardiac markers; lactate dehydrogenase (LDH) and creatine kinase (CK-MB). In addition, cardiac tissue was utilized for determination of lipid peroxide, and tumor tissue was used for measurement of anti-apoptotic protein Bcl-2 as well as gene expression of the tumor suppressor gene P53. DOX and/or TQ showed a significant reduction in tumor volume, cardiac markers, tumor Bcl-2, and P53 upregulation compared to free conventional therapies. Co-treatment with DOX+TQ+F2 gel was superior to all other groups in exerting beneficial effects. Use of TQ as an adjuvant therapy with DOX could improve its cytotoxic effects and limit its cardiac toxicity. Furthermore, loading of DOX and/or TQ into F2 gel showed a remarkable anti-cancer activity.
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http://dx.doi.org/10.1016/j.ejps.2017.09.012DOI Listing
November 2017

Branched chain amino acids supplementation modulates TGF-β1/Smad signaling pathway and interleukins in CCl -induced liver fibrosis.

Fundam Clin Pharmacol 2017 Oct 19;31(5):534-545. Epub 2017 Jul 19.

Faculty of Pharmacy, Tanta University, Postal number: 31527, Tanta, Egypt.

The alterations and low levels of circulating branched chain amino acids (BCAAs), leucine, isoleucine, and valine, are associated with liver diseases. The study was designed to evaluate hepatoprotective effect of BCAAs on CCl -induced liver fibrosis and to investigate the molecular mechanisms underlying these effects in rats. In all, 30 male rats were divided into three groups. Control group (n = 10) and CCl group (n = 10), where rats were injected with CCl (1 mL/kg of 0.5 : 1 v/v injected i.p. twice weekly for 12 weeks). In CCl + BCAAs group (n = 10), rats were injected with similar doses of CCl and supplemented with a mixture of 600 mg/kg BCAAs (2 : 1 : 1.2 leucine : isoleucine : valine) by oral gavage, three times/week for 12 weeks. Liver fibrosis was assessed by measuring total bilirubin, total protein, alanine aminotransferase, and aspartate aminotransferase, hydroxyproline content, and serum IL-6 and IL-10. Histopathologic studies and α-smooth muscle actin (α-SMA) were detected immunohistochemically in liver. Serum insulin level, blood glucose, liver malodialdehyde concentration (MDA), glutathione peroxidase, and superoxide dismutase (SOD) activities were quantified. TGF-β1, Smad3, and Smad7 gene expressions were estimated by qRT-PCR. BCAAs suppressed liver fibrosis induced by CCl treatment. BCAAs modulated liver indices and downregulated TGF-β1, Smad3, and Smad7 expressions in hepatocytes. BCAAs enhanced liver antioxidant enzyme activities (P < 0.001), reduced serum levels of TGF-β1, IL-6, and IL-10 compared to CCL group and ameliorated histopathologic changes in rat liver. BCAAs may have a protective role against liver fibrosis via antioxidant and anti-inflammatory mechanisms.
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http://dx.doi.org/10.1111/fcp.12297DOI Listing
October 2017

Optimization of Reduced Glutathione Production by a Isolate Using Plackett-Burman and Box-Behnken Designs.

Front Microbiol 2017 9;8:772. Epub 2017 May 9.

Department of Nucleic Acid Research, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology ApplicationsAlexandria, Egypt.

In this work, we aim to optimize the production of reduced glutathione (GSH) synthesized intracellularly by a food-grade microorganism through a statistical approach. Using a colorimetric method, 25 isolates were screened in an attempt to find a GSH-producing strain. It was found that 36% of the tested isolates showed positive result. Isolate (L) was found to produce 152.61 μM glutathione per gram which was the highest amount produced intracellularly. Accordingly, the later isolate was selected for the optimization process using Plackett-Burman and Box-Behnken designs. Temperature, amino acids, and urea were found to be the most significant independent variables. Following data analysis, the composition of the optimized medium was De Man-Sharp-Rogosa broth as a basal medium supplemented with NaCl (5%), HO (0.05%), sodium dodecyl sulfate (0.05%), amino acids (0.0281%), and urea (0.192%). The pH of the medium was adjusted to 8 and incubated for 24 h at 40°C. The GSH amount was increased by 10-fold (851%) using the optimized medium. Hence, our optimization design estimated the biotechnological potential of (L) for the production of GSH in the industry.
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http://dx.doi.org/10.3389/fmicb.2017.00772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422468PMC
May 2017

Chemopreventive effect of omega-3 polyunsaturated fatty acids and atorvastatin in rats with bladder cancer.

Tumour Biol 2017 Feb;39(2):1010428317692254

Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt.

Bladder cancer remains a huge concern for the medical community because of its incidence and prevalence rates, as well as high percentage of recurrence and progression. Omega-3 polyunsaturated fatty acids and atorvastatin proved anti-inflammatory effects through peroxisome proliferator-activated receptor gamma mechanism. However, their chemopreventive effect still remained to be examined and clarified. In this study, bladder cancer was induced in rats by the chemical carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine. Omega-3 polyunsaturated fatty acids (docosahexaenoic acid and eicosapentaenoic acid: 2:3 w/w; 1200 mg/kg) and/or atorvastatin (6 mg/kg) were given orally daily to rats for eight consecutive weeks concomitantly with N-butyl-N-(4-hydroxybutyl)nitrosamine and continued for further 4 weeks after cessation of N-butyl-N-(4-hydroxybutyl)nitrosamine administration. The histopathological examination of rat bladder revealed the presence of tumors and the absence of apoptotic bodies in sections from N-butyl-N-(4-hydroxybutyl)nitrosamine group, while tumors were absent and apoptotic bodies were clearly observed in sections from rat groups treated with omega-3 polyunsaturated fatty acids, atorvastatin, or both drugs. The study of the molecular mechanisms illustrated downregulation of COX-2 and P53 (mutant) genes and suppression of transforming growth factor beta-1 and the lipid peroxidation product malondialdehyde in serum of rats of the three treated groups. This chemopreventive effect was confirmed by and associated with lower level of bladder tumor antigen in urine. However, the combined treatment with both drugs exhibited the major protective effect and nearly corrected the dyslipidemia that has been induced by N-butyl-N-(4-hydroxybutyl)nitrosamine. Collectively, omega-3 polyunsaturated fatty acids and atorvastatin, besides having anti-inflammatory properties, proved a chemopreventive effect against bladder cancer, which nominates them to be used as adjuvant therapy with other chemotherapeutics.
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http://dx.doi.org/10.1177/1010428317692254DOI Listing
February 2017

Effect of Pomegranate Hull Extract on Liver Neoplastic Changes in Rats: More than an Antioxidant.

Nutr Cancer 2016 Aug-Sep;68(6):1044-51. Epub 2016 Jul 6.

a Department of Biochemistry, Faculty of Pharmacy , Tanta University.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. The current work was designed to elucidate the molecular mechanisms underlying the antitumorigenic effect of pomegranate hull extract (PHE) in livers of rats exposed to the hepatocarcinogen diethyl nitrosamine (DENA) with emphasis on oxidative stress, proliferation, and apoptosis. Male albino rats were divided into three groups: normal control, DENA group, and PHE group. PHE was given to rats orally 3 times weekly for 10 wk, 4 wk before and 6 wk after DENA (200 mg/kg, single i.p. dose). The results indicated a prophylactic effect of PHE against neoplastic changes in the liver, which was evidenced by the decrease of tumor size, liver index, and the anti-apoptotic protein Bcl-2; and the increase of glutathione. PHE group also showed decreased expression of liver cyclin D1 and β-catenin genes compared with DENA group. It is proved that PHE has antitumorigenic effect and could be a candidate for anticancer drugs.
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http://dx.doi.org/10.1080/01635581.2016.1192205DOI Listing
December 2017

Nebivolol prevents indomethacin-induced gastric ulcer in rats.

J Immunotoxicol 2016 07 25;13(4):580-9. Epub 2016 May 25.

a Department of Biochemistry, Faculty of Pharmacy , Tanta University , Tanta , El-Gharbia , Egypt.

Gastric ulcer is a very common gastrointestinal disease that may lead to dangerous complications and even death. This study was conducted to evaluate the prophylactic effect of nebivolol against indomethacin [INDO]-induced gastric ulcer. Male Wistar rats were divided into four groups: normal control, ulcer control (INDO only), omeprazole before INDO and nebivolol before INDO. Each rat to receive nebivolol and omeprazole was given the agent orally (by gavage) daily for 10 days prior to induction of ulcer by oral dosing with INDO. Four hours after INDO treatment, all rats were euthanized and their stomachs obtained for measures of gastric acidity, oxidative stress and inflammatory markers, as well as cytoprotective mediators. The results showed that a single oral dose of INDO (100 mg/kg) induced gastric acidity, an ulcer index of 2900 and significantly increased levels of gastric tumor necrosis factor (TNF)-α and malondialdehyde (MDA) and significantly decreased levels of gastric prostaglandin E2 (PGE2), glutathione (GSH) and nitric oxide (NO), compared to in normal control counterpart stomachs. Giving nebivolol before INDO corrected the gastric acidity and resulted in a significant increase in GSH, PGE2 and NO and a significant decrease in TNFα and MDA gastric levels, compared to ulcer control values. Results obtained with nebivolol were comparable to those with omeprazole; the preventive index in the nebivolol group was 90.7% compared to 94.5% in rats in the omeprazole group. These studies showed that nebivolol provided a valuable role in preventing gastric ulcers induced by INDO and provided a promise for potentially protecting hypertensive patients from experiencing gastric ulcer. Thus, it is possible that, pending further studies, nebivolol could be used for pre-exposure prophylaxis from gastric ulcer in these patients.
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http://dx.doi.org/10.3109/1547691X.2016.1142488DOI Listing
July 2016

Gastroprotective effect of garlic in indomethacin induced gastric ulcer in rats.

Nutrition 2016 Jul-Aug;32(7-8):849-54. Epub 2016 Jan 21.

Biochemistry Department, Faculty of Pharmacy, Tanta University, Tanta, El-Gharbia, Egypt. Electronic address:

Objective: Garlic, in its natural plant state, has a great history in ancient medicine as a remedy for many diseases. In our study, the gastroprotective effect of aged garlic extract (AGE) and the possible underlying mechanisms were investigated in an experimental model of indomethacin-induced gastric ulcer.

Methods: Male Wistar rats were divided into four groups: (normal control, n = 20), ulcer control (indomethacin group, n = 20), (omeprazole group, n = 30) and (garlic group, n = 20). Each dose of garlic and omeprazole was given to rats orally daily for 10 consecutive days before induction of ulcer by indomethacin. Indomethacin was given as a single oral dose (100 mg/kg). Four hours later after indomethacin treatment, the rats were sacrificed and gastric tissue was obtained for histopathological examination, calculation of ulcer index and measurement of oxidative stress markers as well as gastroprotective mediators.

Results: The results showed that indomethacin induced gastric ulcer (ulcer index = 2900), was associated with a significant increase of tumor necrosis factor-alpha and malondialdehyde, and significant decrease of the gastroprotective mediators prostaglandin E2, glutathione (GSH) and nitric oxide (NO) compared with normal control. Pretreatment with AGE produced comparable results with those obtained in the omeprazole group; the preventive index in the AGE group was 83.4% compared with 94.5% in the omeprazole group. The prophylactic role of AGE in indomethacin-induced ulcer was, in part, mediated by decreasing oxidative stress and increasing gastric level of PGE2, GSH, and NO.

Conclusion: AGE corrected the histopathological abnormalities in gastric tissue and proved a promising gastroprotective role in gastric ulcer.
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http://dx.doi.org/10.1016/j.nut.2016.01.010DOI Listing
March 2017

Sorafenib effect on liver neoplastic changes in rats: more than a kinase inhibitor.

Clin Exp Med 2017 May 16;17(2):185-191. Epub 2016 Apr 16.

Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt.

Although sorafenib was approved as antiangiogenic agent in case of hepatocellular carcinoma (HCC), the pathways mediating its antitumorigenic effects were not fully examined in vivo. This study was conducted to elucidate the molecular mechanisms underlying the antineoplastic effect of sorafenib in livers of rats exposed to the hepatocarcinogen diethyl nitrosamine (DENA) regarding oxidative stress, proliferation, and apoptotic pathways. Male albino rats were divided into three groups: normal control, DENA group, and sorafenib group. Sorafenib (10 mg/kg) was given daily to rats orally for 2 weeks, started 6 weeks after DENA (200 mg/kg, single i.p. dose). The histopathological results proved that sorafenib corrected neoplastic changes in the liver as evidenced by a decrease in size of hepatocellular foci. The liver index, glutathione, as well as Bcl-2 were significantly decreased in sorafenib group compared with DENA group. Sorafenib also exhibited antiproliferative effect through suppression of gene expression of cyclin D1 and β-catenin. Thus, the apoptotic and proliferative pathways in HCC could be interrupted by sorafenib, supporting the role of sorafenib as antineoplastic agent and nominating it as a candidate drug for other neoplasms.
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http://dx.doi.org/10.1007/s10238-016-0416-3DOI Listing
May 2017
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