Publications by authors named "Nahla E El-Ashmawy"

36 Publications

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

The plausible mechanisms of tramadol for treatment of COVID-19.

Med Hypotheses 2021 Jan 22;146:110468. Epub 2020 Dec 22.

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

Currently, no single medication has been approved for the management of coronavirus disease-2019 (COVID-19) caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, drug repositioningby investigating the use of existing drugs for management of COVID-19 patients is considered a desperate need. Tramadol is a commonly prescribed analgesic drug for treatment of moderate to severe pain with less potential for dependence and respiratory depression. Multiple evidence support that tramadol is a promising drug for treatment of COVID-19 patients. Herein, we discuss the possible beneficial effects of using tramadol against SARS-CoV-2 infection and their underlying mechanism of action. The anti-inflammatory effect of tramadol may help to suppress the COVID-19 related cytokine storm through decreasing interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Besides, tramadol activates natural killer (NK) and T-cells and enhances IL-2 secretion, which produce immune-enhancing effect against SARS-CoV-2. Recent studies confirmed that COVID-19 patients with acute respiratory failure showed increased fibrin formation and polymerization that may lead to thrombosis. Tramadol owing to its hypocoagulable effect may protect against venous thromboembolism in these patients. Moreover, tramadol can exert a cardioprotective effect via decreasing lactate dehydrogenase (LDH) level which is elevated in most of patients with COVID-19. Furthermore, the severity and mortality of COVID-19 have been correlated with old age patients, which may be due to the lack of antioxidant mechanisms and increased oxidative damage. Tramadol could protect COVID-19 patient from disease complications by increases the antioxidant enzymes superoxide dismutase and glutathione peroxidase while diminished malondialdehyde. More interestingly, tramadol as an effective analgesic and antitussive may have a beneficial effect on COVID-19 patients suffering from cough, headache, ache, and pain. The tramadol anti-psychotic effect may also protect against psychiatric disorders associated with SARS-CoV-2 infection. Moreover, tramadol has bactericidal activity against a wide range of pathogens including Pseudomonas aeruginosa which is common in severe COVID-19 patients leading to pneumonia with worse clinical outcomes. Therefore, we hypothesize that tramadol might be a promising adjuvant therapeutic option against SARS-CoV-2 infection. Based on that, tramadol should be considered as adjuvant therapy for COVID-19 clinical trials.
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http://dx.doi.org/10.1016/j.mehy.2020.110468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831961PMC
January 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

Long non-coding RNA FAM83H-AS1 as an emerging marker for diagnosis, prognosis and therapeutic targeting of cancer.

Cell Biochem Funct 2021 Apr 6;39(3):350-356. Epub 2020 Nov 6.

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

Incidence and mortality rates of cancer continue to increase greatly despite the improved diagnostic and therapeutic methods. Based on GLOBOCAN estimates, the numbers of new cancer cases reported in 2018 were ~18.1 million, while the numbers of cancer mortalities were ~9.6 million. It remains difficult to diagnose most cancer patients at early stages. Although cancer therapy market is rapidly evolving, the effectiveness of therapy is still inadequate. Therefore, exploring new biomarkers for diagnosis, prognosis and treatment is essential for cancer management. Long non-coding RNAs (lncRNAs) are unique regulatory molecules that control several cellular processes and are implicated in diverse human diseases including cancer. LncRNAs could serve as potential biomarkers for cancer patients to aid diagnosis and determine prognosis. In addition, numerous lncRNAs have proved their ability to predict response to cancer treatment. FAM83H antisense RNA 1 (FAM83H-AS1) is among those highly dysregulated lncRNAs in cancer. FAM83H-AS1 was demonstrated to participate in the progression of different malignancies and also shown to play a vital role in diagnosis, prognosis and treatment. Here, we analyse recent studies concerning the oncogenic role and molecular mechanisms of lncRNA FAM83H-AS1 in the following cancer types: bladder, breast, lung, hepatocellular, colorectal, gastric, pancreatic, ovarian, cervical cancer as well as glioma.
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http://dx.doi.org/10.1002/cbf.3601DOI Listing
April 2021

The role of WNT/β-catenin signaling pathway and glutamine metabolism in the pathogenesis of CCl-induced liver fibrosis: Repositioning of niclosamide and concerns about lithium.

Cytokine 2020 12 1;136:155250. Epub 2020 Sep 1.

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

Background: Liver fibrosis is a serious health problem which may lead to advanced liver cirrhosis and hepatocellular carcinoma.

Objective: The present study aimed to investigate the role of Wnt/β-catenin signaling pathway and glutamine aminohydrolase enzyme (l-glutaminase) in the pathogenesis of liver fibrosis and the potential benefits of niclosamide in treating liver fibrosis.

Methods: Ninety male Albino rats were divided into 6 equal groups (n = 15) as follows: a normal control group (NC), CCl-only treated group (Fib.) which received 1 mg/kg CCl two times weekly, niclosamide-treated group (Niclo.) which received 5 mg/kg of niclosamide one time daily, lithium chloride-treated group (LiCl) which received 100 mg/kg of LiCl one time daily, niclosamide-and-CCl-treated group (Niclo. + Fib.) which received same doses of niclosamide and CCl given to other groups, and finally lithium chloride-and-CCl-treated rat group (LiCl + Fib.) which received same doses of LiCl and CCl given to other groups. All treatments were administered orally for 8 weeks. Liver tissue was assessed for l-hydroxyproline, beta-catenin (β-catenin), l-glutaminase activity, as well as the gene expression of transforming growth factor beta-1 (TGF-β1) and Dishevelled-2 (Dvl2). Histopathological and immunohistochemical analyses of alpha smooth muscle actin α-SMA were performed. Serum alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin were measured.

Results: The group of niclosamide-and-CCl-treated rats showed a significant decrease in total bilirubin, ALT and AST, β-catenin, l-hydroxyproline, l-glutaminase activity, and gene expression of TGF-β1 and Dvl2. Moreover, the liver tissue in this group of rats showed mild α-SMA reactivity compared with the rats treated with CCl only (fibrosis group). On the other hand, lithium chloride-and-CCl-treated rats showed a significant increase in liver indices, TGF-β1 expression, β-catenin, l-hydroxyproline, and l-glutaminase activity with severe α-SMA reactivity and apoptosis in the liver tissue.

Conclusions: Niclosamide protected rats against liver fibrosis by inhibiting the Wnt/β-catenin pathway and glutaminolysis.
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http://dx.doi.org/10.1016/j.cyto.2020.155250DOI Listing
December 2020

TNM staging for GIT cancers is correlated with the level of MMPs and TGF-β1.

Clin Exp Med 2020 Nov 8;20(4):545-555. Epub 2020 Aug 8.

Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt.

Gastrointestinal (GIT) cancers represent the third common cancers worldwide, characterized by rapid progression and higher mortality rate. Matrix metalloproteinases (MMPs) play an important role in cancer metastases. The present study was conducted to estimate and evaluate the role of MMP-7, -9, -10 and -12 and TGF β1 along with conventional biomarkers (CEA and CA19-9) in gastric (GC), pancreatic (PC) and colorectal cancer (CRC) staging system according to tumor size (T), included lymph node (N) and metastasis (M). Seventy-five patients were divided into GC group (n = 25), PC group (n = 25), CRC group (n = 25) and twenty-five healthy subjects (control group). Serum levels of MMP-7, -10 and -12 were assayed simultaneously using luminex multiplex technique. Also, MMP-9, TGF-β1, CA19-9 and CEA were determined by ELISA. MMP-7,-9,-10, -12, TGF-β1 and CEA levels were significantly (p < 0.001) higher in GIT cancer groups compared with control. CA19-9 was significantly (p < 0.001) higher in PC and CRC groups compared with control. MMP-9 was positively correlated with TNM staging in PC patients. MMP-12 was negatively correlated with T in PC and positively correlated with M in CRC group. CA 19-9 was positively correlated with M grade in CRC. Depending on the estimated cutoff values of area under receiver curve; CA19-9 and MMP-7 were excellent diagnostic markers in PC, CEA and MMP-7 were excellent in CRC, and MMP-7 and MMP-9 were excellent in GC. Our findings indicated the clinical utility of MMPs in diagnosis and TNM staging of GIT cancers along with CEA and CA19-9.
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http://dx.doi.org/10.1007/s10238-020-00651-2DOI Listing
November 2020

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

Serum LncRNA-ATB and FAM83H-AS1 as diagnostic/prognostic non-invasive biomarkers for breast cancer.

Life Sci 2020 Oct 5;259:118193. Epub 2020 Aug 5.

Department of Biochemistry, Faculty of Pharmacy, Tanta University, 31511, Egypt. Electronic address:

Aims: Circulating long non-coding RNAs (lncRNAs) have proven to be useful non-invasive tools for diagnosis of various cancers. FAM83H antisense RNA 1 (FAM83H-AS1) and lncRNA activated by TGF β (lncRNA-ATB) are two lncRNAs that have been shown to play an important role in different cancer types including breast cancer. The primary aim of our study was to investigate the potential role of serum FAM83H-AS1 and lncRNA-ATB as diagnostic/prognostic markers for breast cancer patients.

Main Methods: Serum expression levels of FAM83H-AS1 and lncRNA-ATB were analyzed in 90 breast cancer patients and 30 age- and sex-matched healthy controls using RT-qPCR.

Key Findings: We found that FAM83H-AS1 and lncRNA-ATB were significantly overexpressed in sera of breast cancer patients compared to controls (p = 0.000 for both). Analysis of receiver operating characteristic curve demonstrated that lncRNA-ATB had a higher area under curve (AUC) value than the conventional tumor marker cancer antigen 15-3 (CA15-3) (AUC: 0.844, p = 0.000 versus 0.738, p = 0.002) for early diagnosis of breast cancer in patients with stage I-II. On the other hand, FAM83H-AS1 showed a significant correlation with tumor-node metastasis (TNM) stages, large tumor size and lymph node metastasis, suggesting a prognostic rather than diagnostic value.

Significance: This is the first study to demonstrate that serum lncRNA-ATB could be used as a non-invasive diagnostic marker for early stages of breast cancer. Furthermore, serum FAM83H-AS1 has a potential ability for monitoring of progression and staging of breast cancer.
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http://dx.doi.org/10.1016/j.lfs.2020.118193DOI Listing
October 2020

Is hesperidin essential for prophylaxis and treatment of COVID-19 Infection?

Med Hypotheses 2020 Nov 6;144:109957. Epub 2020 Jun 6.

Internal Medicine and Nephrology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.

SARS-CoV-2 or COVID-19 is representing the major global burden that implicated more than 4.7 million infected cases and 310 thousand deaths worldwide in less than 6 months. The prevalence of this pandemic disease is expected to rise every day. The challenge is to control its rapid spread meanwhile looking for a specific treatment to improve patient outcomes. Hesperidin is a classical herbal medicine used worldwide for a long time with an excellent safety profile. Hesperidin is a well-known herbal medication used as an antioxidant and anti-inflammatory agent. Available shreds of evidence support the promising use of hesperidin in prophylaxis and treatment of COVID 19. Herein, we discuss the possible prophylactic and treatment mechanisms of hesperidin based on previous and recent findings. Hesperidin can block coronavirus from entering host cells through ACE2 receptors which can prevent the infection. Anti-viral activity of hesperidin might constitute a treatment option for COVID-19 through improving host cellular immunity against infection and its good anti-inflammatory activity may help in controlling cytokine storm. Hesperidin mixture with diosmin co-administrated with heparin protect against venous thromboembolism which may prevent disease progression. Based on that, hesperidin might be used as a meaningful prophylactic agent and a promising adjuvant treatment option against SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.mehy.2020.109957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274964PMC
November 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

Docosahexaenoic acid-flurbiprofen combination ameliorates metaflammation in rats fed on high-carbohydrate high-fat diet.

Biomed Pharmacother 2019 Jan 2;109:233-241. Epub 2018 Nov 2.

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

Objective: Potential benefits of combining docosahexaenoic acid (DHA), an omega-3 fatty acid with flurbiprofen (Flu), a non-steroidal anti-inflammatory drug in ameliorating obesity remain to be elucidated. This study aimed to investigate the possible protective effects of DHA and Flu, either alone or in combination, against obesity-induced metaflammation and to clarify the underlying molecular mechanisms.

Methods: Seventy-five male Wistar rats were divided into five groups: normal diet (ND) group, high-carbohydrate high-fat diet (HCHFD) control group, DHA group (HCHFD + 200 mg/kg DHA), Flu group (HCHFD + 10 mg/kg Flu), and DHA + Flu group (HCHFD + DHA + Flu). Treatments were administered orally daily for 8 consecutive weeks, parallel with the start of diets.

Results: Plasma levels of glucose, insulin, and TGs were significantly reduced in DHA, Flu, and DHA + Flu treated groups, while HDL-C concentrations were significantly elevated in the same groups, compared to HCHFD control group. Only Flu and DHA + Flu groups showed a significant decrease in plasma levels of leptin, TC, and LDL-C, relative to HCHFD control group. Concentrations of phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) and resolvin D1 (RvD1) in epididymal adipose tissue (EAT) were significantly increased in the three treated groups, compared with HCHFD control group. Expression of AMPK-α subunit in EAT was significantly increased, whereas expression of nuclear factor kappa B (NF-κB) was significantly decreased in EAT of the three treated groups, relative to HCHFD control group.

Conclusions: Docosahexaenoic acid-flurbiprofen combination showed an ameliorative effect on obesity-associated metaflammation and its consequences in rats.
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http://dx.doi.org/10.1016/j.biopha.2018.10.049DOI Listing
January 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

Upregulation of PPAR-γ mediates the renoprotective effect of omega-3 PUFA and ferulic acid in gentamicin-intoxicated rats.

Biomed Pharmacother 2018 Mar 20;99:504-510. Epub 2018 Feb 20.

Faculty of Pharmacy, Tanta University Tanta, El-Gharbia, 31527, Egypt. Electronic address:

Ferulic acid (FrA) is a natural product containing phenolic compounds. ω-3 PUFA is the major constituent of fish oil. The aim of this study was to investigate the renoprotective role of FrA and FO in gentamicin (GM)-induced nephrotoxicity in rats. Forty four male rats were divided equally into 4 groups: Control group, GM group, FrA + GM group and FO + GM group. Each of the treated groups was injected with GM (40 mg/kg) i.p. for 9 consecutive days. FrA (100 mg/kg) and FO (5 mL/kg) were given to rats orally daily for 10 days prior to GM and then concomitantly with GM for additional 9 days. Kidney function was assessed by serum BUN and creatinine, urinary albumin excretion and N-acetyl-beta-D-glucosaminidase (NAG) activity and histopathological examination. The anti-inflammatory property was evaluated by measuring renal resolvin E1 and gene expression of PPAR-γ. The antioxidant activity was indicated by renal catalase (CAT) activity. GM-induced nephrotoxicity was evidenced by the renal histopathological changes along with increased renal indices. Prior and concomitant treatment with FrA or FO ameliorated nephrotoxic effect of GM as indicated by the significant decrease of serum BUN and creatinine, urinary albumin excretion and urinary NAG activity. Both treatments significantly enhanced CAT activity and gene expression of PPAR-γ. Resolvin E1 was significantly elevated in FO but not in FrA group. FrA and FO proved anti-inflammatory and renoprotective effects, which could be through their PPAR-γ agonist activity. Because FrA and FO are natural products, they could provide a safe intervention strategy in cases of exposure to nephrotoxins.
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http://dx.doi.org/10.1016/j.biopha.2018.01.036DOI Listing
March 2018

Anti-inflammatory and Antioxidant Effects of Captopril Compared to Methylprednisolone in L-Arginine-Induced Acute Pancreatitis.

Dig Dis Sci 2018 Jun 29;63(6):1497-1505. Epub 2018 Mar 29.

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

Background: Acute pancreatitis (AP) is an inflammatory disease mediated by damage in acinar cells and pancreatic inflammation with infiltration of leukocytes. The pancreatic renin-angiotensin system may play an important role in the pathogenesis of AP.

Aim: The present study aimed to investigate the possible protective role of captopril (CAP), an angiotensin-converting enzyme inhibitor, in attenuating L-arginine-induced AP rat model and to elucidate the underlying molecular mechanisms.

Methods: Forty-eight adult male Wister rats were divided into four equal groups: control group (vehicle, orally for 10 days), AP group (3 g/kg L-arginine, single i.p.) on 10th day of the experiment, CAP group (50 mg/kg captopril, orally, once daily), and MP group (30 mg/kg methylprednisolone, orally, once daily). CAP and MP were administered for 10 days prior to L-arginine injection. Rats were sacrificed 24 h after arginine injection. Inflammatory biomarkers; tumor necrosis factor alpha (TNF-α) concentration, myeloperoxidase (MPO) activity, and inducible nitric oxide synthase (iNOS) gene expression were determined in pancreas. Oxidative stress biomarkers; pancreatic nitric oxide (NO) and reduced glutathione (GSH) concentrations were measured. Moreover, serum α-amylase and lipase activities were measured and histopathological studies of the pancreas were done.

Results: CAP group showed a significant reduction in pancreatic TNF-α concentration, MPO activity, NO concentration, and downregulation of iNOS gene expression compared to AP group. CAP group also showed a significant increase in GSH concentration with amelioration of histological changes of AP as well as MP group.

Conclusion: Captopril treatment showed a protective and comparable effect with MP treatment in AP rat model.
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http://dx.doi.org/10.1007/s10620-018-5036-1DOI Listing
June 2018

Suppression of inducible nitric oxide synthase and tumor necrosis factor-alpha level by lycopene is comparable to methylprednisolone in acute pancreatitis.

Dig Liver Dis 2018 Jun 2;50(6):601-607. Epub 2018 Feb 2.

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

Background: Oxidative stress and inflammation may play a key role in the pathogenesis of acute pancreatitis (AP). Lycopene, a natural carotenoid, has antioxidant scavenger capacity and inhibits inflammation in many experimental models.

Aim: The study was designed to investigate whether lycopene can ameliorate l-arginine-induced pancreatitis in rats and to elucidate the underlying molecular mechanisms of these effects.

Methods: Forty-eight adult male Wistar rats were divided into: control group (vehicle, orally, 10 days), AP group (3 g/kg l-arginine, single i.p. injection, on day 10th of the experiment), lycopene group (50 mg/kg) and methylprednisolone group (30 mg/kg). Lycopene and methylprednisolone were given orally, once daily for 10 days prior to l-arginine injection. Rats were sacrificed 24 h after l-arginine injection. Inflammation/oxidative stress and pancreatic markers were assessed. Pancreatic histopathological studies were done.

Results: Lycopene group showed a significant reduction in tumor necrosis factor alpha (TNF-α), myeloperoxidase activity, and down-regulation of inducible nitric oxide synthase (iNOS) gene expression. Pancreatic nitric oxide concentration was reduced and pancreatic GSH was increased in lycopene group. Serum α-amylase and lipase activities were reduced by lycopene treatment. The histology of pancreas was improved in lycopene group as well as methylprednisolone group.

Conclusion: Lycopene prior treatment proved anti-inflammatory and antioxidant effects against AP rat model via different mechanisms.
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http://dx.doi.org/10.1016/j.dld.2018.01.131DOI Listing
June 2018

Roflumilast, type 4 phosphodiesterase inhibitor, attenuates inflammation in rats with ulcerative colitis via down-regulation of iNOS and elevation of cAMP.

Int Immunopharmacol 2018 Mar 10;56:36-42. Epub 2018 Jan 10.

Faculty of Pharmacy, Tanta University, Tanta, El-Gharbia 31527, Egypt. Electronic address:

Background: Roflumilast (Rof), a phosphodiesterase 4 (PDE4) inhibitor, has been shown to be an effective agent in inflammatory diseases and marketed for chronic obstructive pulmonary disease.

Objective: This study was conducted to examine the potential anti-inflammatory effects of Rof in dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) in rats and to investigate the molecular mechanisms underlying these effects.

Methods: Forty male Wistar rats were divided into four groups: normal control, colitis group (rats received 5% DSS in their drinking water continuously for 7 days), Rof group, and sulfasalazine (SLZ) group. The Rof (5 mg/kg) and SLZ (500 mg/kg) groups underwent pretreatment with DSS one week ahead of DSS challenge and parallel with DSS. Colitis was determined by assessing colon length, weight loss, histologic colon score, quantifying the concentration of tumor necrosis factor alpha (TNF-α), nitric oxide (NO), cyclic adenosine monophosphate (cAMP), myeloperoxidase (MPO) activity and inducible nitric oxide synthase (iNOS) gene expression in colon tissue.

Results: Rof attenuated the severity of colitis as evidenced by increased colon length, prevention of body weight loss, and improved colon histologic score compared to DSS group. Rof also suppressed the inflammatory response induced in DSS colitis group by decreasing colon concentration of TNF-α, NO and MPO activity and down- regulation of iNOS gene expression. The level of cAMP was increased by Rof compared to DSS group. The obtained results of Rof were comparable to those exerted by SLZ.

Conclusion: These findings revealed the beneficial effects of Rof in alleviating inflammation in DSS colitis.
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http://dx.doi.org/10.1016/j.intimp.2018.01.004DOI Listing
March 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

Downregulation of iNOS and elevation of cAMP mediate the anti-inflammatory effect of glabridin in rats with ulcerative colitis.

Inflammopharmacology 2018 Apr 13;26(2):551-559. Epub 2017 Jul 13.

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

Background: Alternative medicine is widely accepted by public and becoming an attractive approach for treatment of various diseases. Glabridin (Gla), a major flavonoid present in licorice root, was reported to have antioxidant and anti-inflammatory properties.

Objective: The study aimed to investigate the possible protective role of Gla against dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) in rats and to clarify the molecular mechanisms underlying Gla function.

Methods: Forty male Wistar rats were divided into control, colitis group (rats received 5% DSS in drinking water for 7 days), Gla group (50 mg/kg, orally, once daily), and sulfasalazine (SLZ) group (500 mg/kg, orally, once daily). Each of Gla and SLZ was administered 1 week ahead of DSS and parallel with its administration.

Results: Gla ameliorated the inflammatory alterations induced by DSS. Gla group showed a reduction in colon concentration of tumor necrosis factor-alpha (TNF-α) and a decreased colon myeloperoxidase activity (MPO). Gla treatment downregulated inducible nitric oxide synthase (iNOS) gene expression in rat colon with a decreased content of nitric oxide (NO). Gla also increased cyclic AMP (cAMP) concentration in rat colon compared to colitis group. Such findings were comparable to or even better than those obtained by SLZ treatment. The histological features of UC such as ulceration and inflammatory cell infiltrations were improved in rat group treated by Gla.

Conclusion: Gla proved a potent anti-inflammatory role in UC through different mechanisms and, being a natural product, it could be safely used as a protective measure in inflammatory bowel diseases.
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http://dx.doi.org/10.1007/s10787-017-0373-9DOI Listing
April 2018

Metformin augments doxorubicin cytotoxicity in mammary carcinoma through activation of adenosine monophosphate protein kinase pathway.

Tumour Biol 2017 May;39(5):1010428317692235

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

Since the incidence of breast cancer increases dramatically all over the world, the search for effective treatment is an urgent need. Metformin has demonstrated anti-tumorigenic effect both in vivo and in vitro in different cancer types. This work was designed to examine on molecular level the mode of action of metformin in mice bearing solid Ehrlich carcinoma and to evaluate the use of metformin in conjunction with doxorubicin as a combined therapy against solid Ehrlich carcinoma. Ehrlich ascites carcinoma cells were inoculated in 60 female mice as a model of breast cancer. The mice were divided into four equal groups: Control tumor, metformin, doxorubicin, and co-treatment. Metformin (15 mg/kg) and doxorubicin (4 mg/kg) were given intraperitoneally (i.p.) for four cycles every 5 days starting on day 12 of inoculation. The anti-tumorigenic effect of metformin was mediated by enhancement of adenosine monophosphate protein kinase activity and elevation of P53 protein as well as the suppression of nuclear factor-kappa B, DNA contents, and cyclin D1 gene expression. Metformin and doxorubicin mono-treatments exhibited opposing action regarding cyclin D1 gene expression, phosphorylated adenosine monophosphate protein kinase, and nuclear factor-kappa B levels. Co-treatment markedly decreased tumor volume, increased survival rate, and improved other parameters compared to doxorubicin group. In parallel, the histopathological findings demonstrated enhanced apoptosis and absence of necrosis in tumor tissue of co-treatment group. Metformin proved chemotherapeutic effect which could be mediated by the activation of adenosine monophosphate protein kinase and related pathways. Combining metformin and doxorubicin, which exhibited different mechanisms of action, produced greater efficacy as anticancer therapeutic regimen.
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http://dx.doi.org/10.1177/1010428317692235DOI Listing
May 2017

Ginger extract adjuvant to doxorubicin in mammary carcinoma: study of some molecular mechanisms.

Eur J Nutr 2018 Apr 22;57(3):981-989. Epub 2017 Feb 22.

Department of Biochemistry, Faculty of Pharmacy, Tanta University, 31527, Tanta, Egypt.

Purpose: The present study aimed to investigate the molecular mechanisms underlying the anticancer properties of ginger extract (GE) in mice bearing solid Ehrlich carcinoma (SEC) and to evaluate the use of GE in combination with doxorubicin (DOX) as a complementary therapy against SEC.

Methods: SEC was induced in 60 female mice. Mice were divided into four equal groups: SEC, GE, DOX and GE + DOX. GE (100 mg/kg orally day after day) and DOX (4 mg/kg i.p. for 4 cycles every 5 days) were given to mice starting on day 12 of inoculation. On the 28th day, blood samples were collected, mice were scarified, tumor volume was measured, and tumor tissues were excised.

Results: The anti-cancer effect of GE was mediated by activation of adenosine monophosphate protein kinase (AMPK) and down-regulation of cyclin D1 gene expression. GE also showed pro-apoptotic properties as evidenced by elevation of the P53 and suppression of nuclear factor-kappa B (NF-κB) content in tumor tissue. Co-administration of GE alongside DOX markedly increased survival rate, decreased tumor volume, and increased the level of phosphorylated AMPK (PAMPK) and improved related pathways compared to DOX group. In addition, the histopathological results demonstrated enhanced apoptosis and absence of multinucleated cells in tumor tissue of GE + DOX group.

Conclusion: AMPK pathway and cyclin D1 gene expression could be a molecular therapeutic target for the anticancer effect of GE in mice bearing SEC. Combining GE and DOX revealed a greater efficacy as anticancer therapeutic regimen.
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http://dx.doi.org/10.1007/s00394-017-1382-6DOI Listing
April 2018

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
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