Publications by authors named "Naglaa F Khedr"

19 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

Effect of atorvastatin versus rosuvastatin on inflammatory biomarkers and LV function in type 2 diabetic patients with dyslipidemia.

Biomed Pharmacother 2021 Mar 2;135:111179. Epub 2021 Jan 2.

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

Background: Statins are potential drugs for decreasing risk of atherosclerotic cardiovascular complications in type 2 diabetic (T2D) patients.

Purpose: To examine the efficacy of both rosuvastatin (ROSUVA) and atorvastatin (ATORVA) on LV function and markers of inflammation in T2D patients with dyslipidemia.

Methods: One hundred-sixty T2D patients were assigned to receive either atorvastatin (ATORVA group, n = 80, 40 mg) or rosuvastatin (ROSUVA group, n = 80, 10 mg), daily for 6 months. Blood was collected for biochemical analysis. The prevalence of left ventricular abnormalities was determined by echocardiography and two-dimensional Speckle-Strain to assess Global Longitudinal Strain (GLS).

Results: ROSUVA vs. ATORVA resulted in significant (p < 0.001) reduction in HbA1c % (9.13 vs 2.35%), LDL-C (22.23% vs. 14.75%), triglycerides (13.56 % vs. 8.21 %), total cholesterol (16.10 % vs. 10.81 %), atherogenic index (18.08. % vs. 10.97%), hs-CRP (23.51 % vs.18.96%), sortilin (33.33 % % vs. 15.08 %), and leptin (31.81 % vs. 23.17 %) but increased adiponectin (97.99 % vs.76.47.1 %) and HDL-C (76.47 % vs. 0.21 %) compared with baseline, respectively. Negative correlations between adiponectin and each of hs-CRP, HbA1c%, total cholesterol, LDL-C, atherogenic index and leptin were found. Also, left ventricular functions were correlated with adiponectin, lipids, HbA1c% and hs-CRP. The areas under receiver operating characteristic curve (AUC) showed that hs-CRP, leptin, sortlin, leptin, and adiponectin were good predictors for cardiovascular events.

Conclusion: ROSUVA is more efficacious in improving lipid profile, atherogenic index and modulation of inflammatory biomarkers in dyslipidemic T2D patients compared with ATROVA. However, both statins are equivalent as cardioprotective agents in dyslipidemic T2D patients.
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http://dx.doi.org/10.1016/j.biopha.2020.111179DOI Listing
March 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

New insights into weight management by orlistat in comparison with cinnamon as a natural lipase inhibitor.

Endocrine 2020 01 13;67(1):109-116. Epub 2019 Nov 13.

Biochemistry Department, Faculty of Pharmacy, Delta University for Science and Technology, Gamasaa, Egypt.

Background And Objectives: Orlistat which is taken by obese patients may present some therapeutic assistance through its inhibition of lipase activity. Otherwise, a natural lipase inhibitor as cinnamon is widely used traditional medicine to decrease cholesterol and body weight. The current study aimed to investigate the weight management of orlistat in comparison with cinnamon through different obesity related targets.

Methods: Subjects were divided into: Group 1: subjects received cinnamon capsules for 60 days. Group 2: subjects were received orlistat twice daily for 30 days, then once daily for another 30 days. Blood samples were collected at baseline and after 2 months.

Results: Both orlistat and cinnamon groups showed a significant reduction in BMI, lipid profile, and lipase activity compared with baseline. Orlistat group showed significant elevation (p < 0.001) in glucagon, insulin-degrading enzyme (IDE) and dopamine level concomitant with the decrease of serum glutamate compared with baseline level of the same group and cinnamon group. However, cinnamon reduced serum insulin level and insulin resistance (IR) compared with baseline level of the same group and orlistat group.

Conclusions: Orlistat can be used in weight management not only for its pancreatic lipase inhibition but also, due to its indirect appetite reduction effect through elevated glucagon, IDE and dopamine levels and its inhibitory effect on glutamate neurotransmitter, whereas, cinnamon improves BMI and glycaemic targets.
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http://dx.doi.org/10.1007/s12020-019-02127-0DOI Listing
January 2020

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

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

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

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

Fish oil and wheat germ oil supplementation modulates brain injury in streptozotocin-induced diabetic rats.

Authors:
Naglaa F Khedr

J Diabetes 2017 Nov 2;9(11):1012-1022. Epub 2017 Mar 2.

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

Background: Uncontrolled diabetes mellitus causes neuronal damage because of increased intracellular glucose. Natural products as complementary therapy may reduce neuronal complications. This study investigated whether fish oil (FO) and wheat germ oil (WGO) supplementation protects the brain in streptozotocin (STZ)-induced diabetic rats by estimating lipid peroxidation and the inflammatory and anti-oxidant status of the brain.

Methods: Diabetes was induced in male Wistar rats by a single i.p. injection of STZ (60 mg/kg). Four weeks after diabetes induction, rats were divided into an untreated group and a group supplemented with 0.4 g/kg per day FO +WGO mix, p.o., for 4 weeks. Brain oxidant status was assessed by measuring nitric oxide (NO), malondialdehyde (MDA), reduced glutathione (GSH), the GSH/oxidized glutathione (GSSG) ratio, and superoxide dismutase (SOD) and catalase (CAT) activity. Inflammatory biomarkers (tumor necrosis factor [TNF]-α levels and nuclear factor (NF)-κβ immunoreaction) were measured in brains, combined with histological studies. Cholinergic function was assessed on the basis of acetylcholine (ACh) levels and acetylcholinesterase (AChE) activity.

Results: Supplementation with FO + WGO reduced MDA and NO ( P  < 0.001) in diabetic rat brains and enhanced brain antioxidant capacity, as evidenced by increased GSH, GSH/GSSG ratio ( P  < 0.01), and SOD and CAT activity ( P  < 0.01). In addition, FO + WGO supplementation suppressed NF-κB immunoreaction and TNF-α levels ( P  < 0.001). Cholinergic function was improved by FO + WGO as a result of increased ACh levels and reduced AChE activity ( P  < 0.001).

Conclusions: Supplementation of the diet with the FO + WGO mix modulated diabetic brain injury and this mix could potentially be used for preventing diabetic neurodegenerative sequelae.
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http://dx.doi.org/10.1111/1753-0407.12518DOI Listing
November 2017

Fish oil and wheat-germ oil supplementation restores ovarian function in streptozotocin-diabetic rats.

Authors:
Naglaa F Khedr

Reprod Fertil Dev 2017 Sep;29(9):1689-1698

Department of Biochemistry, Faculty of Pharmacy, Tanta University, El-Bahar Street, Medical Compound, Tanta 31527, Egypt. Email.

Diabetes is a chronic metabolic disorder and has a profound impact on women's reproductive health. This study aimed to investigate the protective effect of a mixture of fish oil (FO) and wheat-germ oil (WGO) on ovarian dysfunction in diabetic rats. Female Albino rats were divided into control, diabetic and FO-WGO-diabetic groups. Diabetes was induced by intraperitoneal injection of 65mgkg streptozotocin (STZ). Three weeks later, rats were given oral supplement of 0.4gkg oil mix (1000mg FO+100mg WGO) daily for 3 weeks. Antioxidant activity was assessed by measuring malondialdehyde (MDA) and reduced glutathione (GSH) levels, the GSH:oxidised glutathione (GSSG) ratio and superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities. Ovary function was indicated by serum concentrations of FSH, oestradiol (E), LH, anti-Müllerian hormone (AMH), ovary histopathology and follicle counts. Anti-inflammatory properties were detected by measuring nuclear factor (NF)-κB in follicular cells by immunohistochemistry. FO-WGO supplementation enhanced CAT, SOD and GPx activities and raised GSH levels and the GSH:GSSG ratio. Supplementation also increased FSH, E, LH and AMH levels and follicle counts. Moreover, NF-kB expression and MDA were reduced. These findings indicate that FO-WGO supplementation preserved ovarian function in STZ-induced diabetic rats.
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http://dx.doi.org/10.1071/RD16135DOI Listing
September 2017

Curcumin Protects against Monosodium Glutamate Neurotoxicity and Decreasing NMDA2B and mGluR5 Expression in Rat Hippocampus.

Neurosignals 2016 17;24(1):81-87. Epub 2016 Aug 17.

Biochemistry Department, Faculty of Pharmacy, AL-Delta University, Gamasa,Egypt.

Background: Monosodium glutamate (MSG) is a flavor enhancer used in food industries. MSG is well documented to induce neurotoxicity. Curcumin (CUR) reportedly possesses beneficial effects against various neurotoxic insults. Hence, this present study has been designed to evaluate the neuroprotective effect of curcumin on MSG-induced neurotoxicity in rats.

Methods: Thirty-two male Wister rats were divided into four groups (n=8): Control group, MSG group, CUR group and MSG + CUR group. CUR (Curcumin 150 mg/kg, orally) was given day after day for four weeks along with MSG (4 mg/kg, orally). After 4 weeks, rats were sacrificed and brain hippocampus was isolated immediately on ice. Inflammatory marker TNFα and acetylcholinesterase (AChE) activity (marker for cholinergic function) were estimated. Gene expressions of metabotropic glutamate receptor 5 (mGluR5) and N-methyl-D-aspartate receptor 2B (NMDA2B) along with glutamate concentration were assessed.

Results: Treatment with CUR significantly attenuated AChE activity and TNFα in MSG-treated animals. The anti-inflammatory properties of CUR may be responsible for this observed neuroprotective action. A possible role of CUR to attenuate both glutamate level and gene expression of NMDA2B and mGLUR5 in brain hippocampus was established when compared to MSG group.

Conclusion: We concluded that CUR as flavor enhancer protects against MSG-induced neurotoxicity in rats.
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http://dx.doi.org/10.1159/000442614DOI Listing
August 2016

Effect of hesperidin on mice bearing Ehrlich solid carcinoma maintained on doxorubicin.

Tumour Biol 2015 Dec 23;36(12):9267-75. Epub 2015 Jun 23.

Biochemistry Department, Faculty of Pharmacy, AL-Delta University, Gamasa, Egypt.

Doxorubicin (DOX) is widely used in cancer therapy of many carcinomas types. Unfortunately, DOX is not sufficiently effective in many cases, and increasing the dosage of it is limited due to its systemic toxicity. A citrus flavonoid hesperidin (HES) is proved to be potent antioxidant and protective agent against many diseases including cancer. In this context, the objective of this study was to examine effect of HES along with DOX on solid Ehrlich carcinoma (SEC) in mice. Forty male mice were divided into four equal groups (n = 10): control SEC, DOX, HES, and DOX + HES. HES (50 mg/kg body weight orally) was given day after day for 16 days along with DOX (4 mg/kg body weight i.p. injection) for 5 cycles every 4 days in ESC-inoculated mice. After 20 days, tumor volume, tumor weight, survival rate, tumor glutathione, nitric oxide content, and serum glutathione were determined. Tumor tissue was examined for histopathological and immunohistochemical study for p53 and VEGF. Tumor resistance for mdr1a gene was assessed in tumor tissue by RT-PCR. HES induced significant increase in tissue and serum glutathione with significant decrease in tumor volume and tumor weight. A possible role of HES to modulate gene expression of mdr1a in tumor tissue was established. In addition, HES alleviated the histopathological changes with significant decrease in p53 and VEGF expression. The use of HES as adjuvant therapy with DOX would enhance the therapeutic efficacy and alleviate the resistance to DOX in treatment of solid tumors.
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http://dx.doi.org/10.1007/s13277-015-3655-0DOI Listing
December 2015

Renoprotective effects of montelukast, a cysteinyl leukotriene receptor antagonist, against methotrexate-induced kidney damage in rats.

Naunyn Schmiedebergs Arch Pharmacol 2014 Apr 22;387(4):341-53. Epub 2013 Dec 22.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt,

Methotrexate (MTX) is a cytotoxic chemotherapeutic agent used for treatment of several cancers. Nephrotoxicity, an adverse side effect of high-dose MTX, is attributed to abnormal production of reactive oxygen species (ROS), inflammatory mediators, and neutrophil infiltration. Montelukast (MON) is a cysteinyl leukotriene receptor antagonist. Recently, it has gained a considerable interest as a ROS scavenger and inflammatory modulator. In this study, we investigated the effect of MON against MTX-induced nephrotoxicity. Rats were divided into four groups: control group, MON group (10 mg/kg, orally), MTX group (20 mg/kg, i.p., single injection), and MON + MTX group (MON was administered 5 days before and 5 days after MTX administration). At the end of the experiment, serum was collected for analysis of blood urea nitrogen (BUN) and creatinine. Glutathione (GSH), lipid peroxides (malondialdehyde), tumor necrosis factor alpha (TNF-α) levels, superoxide dismutase, myeloperoxidase activities, and nuclear factor kappa beta (NF-κB) protein expression were determined in renal tissues. In addition, kidney tissues were examined histopathologically and immunohistochemically for NF-κB. MTX administration produced acute renal damage as indicated from severe elevation in BUN and serum creatinine. The role of oxidative stress and inflammatory mechanisms in MTX-induced nephrotoxicity was evidenced from the unbalance in tissue oxidative parameters, increased TNF-α levels, and NF-κB expression in renal tissues. On the other hand, MON significantly reduced the toxic effects of MTX as indicted from normalization of kidney-specific parameters, oxidative stress, and inflammatory mediators. This data was further supported by histopathological studies. Thus, co-administration of MON may be promising in alleviating the systemic side effects of MTX.
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http://dx.doi.org/10.1007/s00210-013-0949-xDOI Listing
April 2014

Modulation of bone turnover in orchidectomized rats treated with raloxifene and risedronate.

Fundam Clin Pharmacol 2013 Oct 4;27(5):526-34. Epub 2012 Jul 4.

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

Osteoporosis is a reduction in bone mineral density (BMD). It develops less often in men than in women. This study aimed to evaluate the bone protective effects of raloxifene (RAL), risedronate (RIS), and their combination on osteoporotic male rats. Forty male Wister rats (12 weeks) were randomly divided into five groups: sham-operated group (n = 8), orchidectomized (ORX) group (n = 7), RAL group (n = 9), RIS group (n = 7) and RAL + RIS group (n = 7). RAL was orally administered at 3 mg/kg three times/week, and RIS was given subcutaneously at 5 μg/kg, twice weekly. After 6 weeks of treatment, serum cathepsin-K, alkaline (ALP) and acid phosphatase activities, serum osteocalcin, serum Ca²⁺, and Pi were determined. Urinary Ca²⁺ and deoxypyridinoline levels, BMD, and Ca²⁺ content of femur ash were estimated. Histochemical localization of ALP activity of tibia and histomorphometry was examined. As compared to sham, ORX rats showed a significant increase in bone turnover markers, and histochemical activity of ALP was increased markedly in proximal tibia of ORX rats, whereas BMD and Ca²⁺ content of femur ash were reduced after ORX. These changes were modulated after treatment with RAL and RIS or both to ORX rats; BMD of femur was improved by each treatment, and bone turnover markers were reduced as compared to ORX vehicle group. We concluded that orchidectomy induced osteoporosis and increased bone turnover in male rats because of withdrawal of sex hormones. Both RAL and RIS could treat osteoporosis in ORX rats; they reduced bone turnover markers and maintained BMD.
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http://dx.doi.org/10.1111/j.1472-8206.2012.01047.xDOI Listing
October 2013
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