Papers by Dr. Tamer Abdelghany
The FASEB Journal, Apr 1, 2013
Dysfunction of endothelial nitric oxide synthase (eNOS) occurs in a wide range of cardiovascular ... more Dysfunction of endothelial nitric oxide synthase (eNOS) occurs in a wide range of cardiovascular disease and has been linked to cigarette smoking (CS)‐induced endothelial dysfunction (ED). Glutathionylation has recently been reported as a novel mechanism for eNOS uncoupling in ED. However, the role of eNOS glutathionylation in CS‐induced ED remains to be investigated. Bovine aortic endothelial cells (BAECs) were exposed to cigarette smoke extract (CSE) at different concentrations for two hours. Nitric oxide (NO) production, superoxide (O2• −) generation and glutathione level were assessed. Formation of glutathionylated proteins was determined in the lysate or after pull down of eNOS following exposure to CSE with or without N‐acetyl cysteine (NAC). We show that exposure of BAECs to CSE decreased NO production with a concomitant increase in O2•− generation and depletion of cellular reduced glutathione. More importantly, formation of protein glutathionylation was significantly higher in CSE‐exposed cells. Pre‐incubation with NAC enhanced eNOS function, decreased eNOS glutathionylation and increased reduced glutathione in CSE‐exposed cells. Our data indicate that CS‐induced ED could be explained, at least in part, through eNOS glutathionylation. The role of CS‐induced eNOS glutathionylation, in the process of ED, and reversal of such modifications in animal models or human subjects warrants further investigation.(NIH# HL38324 to JLZ; and Egyptian government)
A new source for 2S*,11S*,12R*-isosarcophytoxide (1), along with six known metabolites; 7R,8S-dih... more A new source for 2S*,11S*,12R*-isosarcophytoxide (1), along with six known metabolites; 7R,8S-dihydroxydeepoxy-ent-sarcophine (2), sarcophytolol (3), sarcotrocheliol acetate (4), ent-sarcophine (5), guaiacophine (6) and gorgosten-5(E)-3β-ol (7), was identified as Sarcophyton glaucum. The chemical structures were determined based on spectroscopic measurements (NMR, UV, IR and MS). The total extract and isolated compounds were evaluated against four cancer cell lines; HCT116 (human colorectal cancer), HT29 (human colon cancer), CACO-2 (colonic adenocarcinoma) and HepG-2 (human hepatocarcinoma). All tested compounds exhibited cytotoxicity against two cancer cell lines with IC50 in range 8.9–500 µmol/L. Compounds (3) and (4) had significant cytotoxic effects towards HCT116, IC50 = 8.9 ± 0.092 µmol/L and 17.5 ± 0.0.067 µmol/L, respectively and against HepG-2, IC50 20.0 ± 0.032 µmol/L and 19.9 ± 0.062 µmol/L, respectively. The antiproliferative activities of compounds (3) and (4) can be attributed, at least partly, to their ability to induce cell cycle arrest, particularly in G0/G1 and S phases.
Pathology Research and Practice, Jul 1, 2023
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Chemical & Pharmaceutical Bulletin, Oct 1, 2018
The 2-styryl-3,5-dihydro-4H-imidazol-4-one might be considered as a system with isosteric propert... more The 2-styryl-3,5-dihydro-4H-imidazol-4-one might be considered as a system with isosteric properties similar to trans-cinnamaldehyde (styrylaldehyde), a safe natural compound that exhibited interesting activities against various cancers. We synthesized a series of compounds that differ structurally in having different alkyl, aryl and heterocyclic substituents at the N3 position of the 2-styryl-4-imidaolone pharmacophore. The compounds were assayed for their cytotoxicity against both cancer and normal cell lines. In addition, their cellular mechanism of action as reactive oxygen species (ROS) inducers were investigated. Many of the synthesized compounds showed higher activities on colon, breast and hepatic cancer cell lines than the parent trans-cinnamaldehyde. Compounds 3a and 3e showed selective antiproliferative activity against cancer cell lines at low micromolar to sub-micromolar IC 50 value. Compounds were extremely less toxic on normal cell lines baby hamster kidney fibroblasts (BHK) and human lung tissue fibroblast (WI-38). Similar to transcinnamaldehyde, the colon cancer cell cycle analysis indicated cell cycle changes consistent with increased oxidative stress leading to apoptosis. Compound 3e caused elevation of all cell oxidative indicators of ROS such as a decrease in reduced glutathione, increased malondialdehyde and suppression of catalase and superoxide dismutase activities. Dihydroethidium staining, nuclear fragmentation and increased caspase-3 further confirmed extensive apoptotic induction due to ROS accumulation upon treatment of human colon adenocarcinoma (HCT116) cells with compounds 3a and 3e. Changes in human breast adenocarcinoma (MCF7) cells were less revealing for ROS induction and increased oxidative stress. Conclusion: The compounds represent an example of efficient rescaffolding of a natural compound to a highly potent drug-like analogues.
International Journal of Molecular Sciences
Sixteen new thalidomide analogs were synthesized. The new candidates showed potent in vitro antip... more Sixteen new thalidomide analogs were synthesized. The new candidates showed potent in vitro antiproliferative activities against three human cancer cell lines, namely hepatocellular carcinoma (HepG-2), prostate cancer (PC3), and breast cancer (MCF-7). It was found that compounds XII, XIIIa, XIIIb, XIIIc, XIIId, XIVa, XIVb, and XIVc showed IC50 values ranging from 2.03 to 13.39 µg/mL, exhibiting higher activities than thalidomide against all tested cancer cell lines. Compound XIIIa was the most potent candidate, with an IC50 of 2.03 ± 0.11, 2.51 ± 0.2, and 0.82 ± 0.02 µg/mL compared to 11.26 ± 0.54, 14.58 ± 0.57, and 16.87 ± 0.7 µg/mL for thalidomide against HepG-2, PC3, and MCF-7 cells, respectively. Furthermore, compound XIVc reduced the expression of NFκB P65 levels in HepG-2 cells from 278.1 pg/mL to 63.1 pg/mL compared to 110.5 pg/mL for thalidomide. Moreover, compound XIVc induced an eightfold increase in caspase-8 levels with a simultaneous decrease in TNF-α and VEGF levels in...
Pathology - Research and Practice
Al-Azhar Journal of Pharmaceutical Sciences, Sep 1, 2022
Aim: the aim of this study was to compare the impact of silymarin on the liver fibrosis induced b... more Aim: the aim of this study was to compare the impact of silymarin on the liver fibrosis induced by diethylnitrosamine (DEN) between both sexes of Wistar rats and proposing possible mechanisms. Main Methods: twenty-four Wistar male and twenty-four Wistar female rats were randomly assigned into 8 groups according to their sex (n=6) for administration of vehicle, DEN, silymarin or both DEN and silymarin for 8 weeks. At the end of the experiment, the traditional rat body and liver weight parameters, liver injury biomarkers (serum ALT, AST, ALP, and total bilirubin) were measured. Furthermore, hematological parameters, lipid profiles (TC, LDL-C, HDL-C, and TG) and oxidative stress biomarkers (TBARS, SOD, CAT, and GSH) were determined. Also, the inflammatory biomarkers in liver tissue homogenate (TNF-α, TGF-β) were evaluated. Histopathological subjective scoring system graded the damage markers of liver tissue. Expression of NF-kB was measured immunohistochemically. Results: Markedly diminished DEN induced liver fibrosis markers in female groups while worsened in male groups. Silymarin regimen improved liver functions and fibrosis markers. Additionally, it counteracted DEN-induced oxidative stress, lipid peroxidation and inflammations, silymarin provided these ameliorative effects either in males or females rats. Conclusion: Silymarin plays an ameliorative role of DEN-induced liver fibrosis in male and female rats via reducing oxidative stress and inflammations.
Pathology - Research and Practice
Gene Reports, 2017
5-Fluorouracil (5-FU), Irinotecan and Oxaliplatin are the main chemotherapeutic drugs for treatme... more 5-Fluorouracil (5-FU), Irinotecan and Oxaliplatin are the main chemotherapeutic drugs for treatment of colorectal cancer (CRC). MicroRNAs (miRNAs) dysregulation was reported in many solid tumors, some miRNAs act as oncogenic and thus overexpressed, while others act as tumor suppressor and downregulated in the cancer cells. Alteration of miRNAs expression was observed after chemotherapy suggesting that this alteration may play an important role in yet unexplored molecular mechanisms of chemotherapeutic drugs. To evaluate the possible role of miRNAs as indicator for treatment outcome of CRC, we examined the expression of four miRNAs (miR-16, miR-143, miR-135b, and miR-155) in Caco-2 CRC cell line after treatment with 5-FU, Irinotecan, and Oxaliplatin. The expression of miRNAs was determined in treated cells and compared with their expression in control cells using real time PCR. Treatment of the CRC cells with 5-FU, Irinotecan, or Oxaliplatin resulted in overexpression of miR-135 and down-expression of miR-155. While the expression of miR-16 and miR-143 was variable. In conclusion; alteration in miR-155 expression after treatment of CRC cells may be a good indicator for the success of chemotherapeutic treatment.
Chemical and pharmaceutical bulletin, 2018
The 2-styryl-3,5-dihydro-4H-imidazol-4-one might be considered as a system with isosteric propert... more The 2-styryl-3,5-dihydro-4H-imidazol-4-one might be considered as a system with isosteric properties similar to trans-cinnamaldehyde (styrylaldehyde), a safe natural compound that exhibited interesting activities against various cancers. We synthesized a series of compounds that differ structurally in having different alkyl, aryl and heterocyclic substituents at the N3 position of the 2-styryl-4-imidaolone pharmacophore. The compounds were assayed for their cytotoxicity against both cancer and normal cell lines. In addition, their cellular mechanism of action as reactive oxygen species (ROS) inducers were investigated. Many of the synthesized compounds showed higher activities on colon, breast and hepatic cancer cell lines than the parent trans-cinnamaldehyde. Compounds 3a and 3e showed selective antiproliferative activity against cancer cell lines at low micromolar to sub-micromolar IC 50 value. Compounds were extremely less toxic on normal cell lines baby hamster kidney fibroblasts (BHK) and human lung tissue fibroblast (WI-38). Similar to transcinnamaldehyde, the colon cancer cell cycle analysis indicated cell cycle changes consistent with increased oxidative stress leading to apoptosis. Compound 3e caused elevation of all cell oxidative indicators of ROS such as a decrease in reduced glutathione, increased malondialdehyde and suppression of catalase and superoxide dismutase activities. Dihydroethidium staining, nuclear fragmentation and increased caspase-3 further confirmed extensive apoptotic induction due to ROS accumulation upon treatment of human colon adenocarcinoma (HCT116) cells with compounds 3a and 3e. Changes in human breast adenocarcinoma (MCF7) cells were less revealing for ROS induction and increased oxidative stress. Conclusion: The compounds represent an example of efficient rescaffolding of a natural compound to a highly potent drug-like analogues.
This research purposed to formulate an optimized imatinib mesylate (IM)eloaded niosomes to improv... more This research purposed to formulate an optimized imatinib mesylate (IM)eloaded niosomes to improve its chemotherapeutic efficacy. The influence of 3 formulation factors on niosomal vesicular size (Y1), zeta potential (Y2), entrapment capacity percentage (Y3), the percentage of initial drug release after 2 h (Y4), and the percentage of cumulative drug release after 24 h (Y5) were studied and optimized using Box-Behnken design. Optimum desirability was specified and the optimized formula was prepared, stability tested, morphologically examined, checked for vesicular bilayer formation and evaluated for its in vitro cytotoxicity on 3 different cancer cell lines namely MCF-7, HCT-116, and HepG-2 in addition to 1 normal cell line to ensure its selectivity against cancer cells. The actual responses of the optimized IM formulation were 425.36 nm, � 62.4 mV, 82.96%,18.93%, and 89.45% for Y1 ,Y 2 ,Y 3 ,Y 4, and Y5, respectively. The optimized IM-loaded niosomes confirmed the spherical vesicul...
Bioorganic chemistry, 2020
Curcumin and trans-cinnamaldehyde are acrolein-based Michael acceptor compounds that are commonly... more Curcumin and trans-cinnamaldehyde are acrolein-based Michael acceptor compounds that are commonly found in domestic condiments, and known to cause cancer cell death via redox mechanisms. Based on the structural features of these compounds we designed and synthesized several 2-cinnamamido-N-substituted-cinnamamide (bis-cinnamamide) compounds. One of the derivatives, (Z)-2-[(E)-cinnamamido]-3-phenyl-N-propylacrylamide 8 showed a moderate antiproliferative potency (HCT-116 cell line inhibition of 32.0 µM), no inhibition of normal cell lines C-166, and proven cellular activities leading to apoptosis. SAR studies led to more than 10-fold increase in activity. Our most promising compound, [(Z)-3-(1H-indol-3-yl)-N-propyl-2-[(E)-3-(thien-2-yl)propenamido)propenamide] 45 killed colon cancer cells at IC50 = 0.89 µM (Caco-2), 2.85 µM (HCT-116) and 1.65 µM (HT-29), while exhibiting much weaker potency on C-166 and BHK normal cell lines (IC50 = 71 µM and 77.6 µM, respectively). Cellular studies ...
5-Fluorouracil (5-FU), Irinotecan, and Oxaliplatin are the main chemotherapeutic drugs for treatm... more 5-Fluorouracil (5-FU), Irinotecan, and Oxaliplatin are the main chemotherapeutic drugs for treatment of col-orectal cancer (CRC). MicroRNAs (miRNAs) dysregulation was reported in many solid tumors, some miRNAs act as oncogenic and thus overexpressed, while others act as tumor suppressor and downregulated in the cancer cells. Alteration of miRNAs expression was observed after chemotherapy suggesting that this alteration may play an important role in yet unexplored molecular mechanisms of chemotherapeutic drugs. To evaluate the possible role of miRNAs as indicator for treatment outcome of CRC, we examined the expression of four miRNAs (miR-16, miR-143, miR-135b, and miR-155) in Caco-2 CRC cell line after treatment with 5-FU, Irinotecan, and Oxaliplatin. The expression of miRNAs was determined in treated cells and compared with their expression in control cells using real time PCR. Treatment of the CRC cells with 5-FU, Irinotecan, or Oxaliplatin resulted in overexpression of miR-135 an...
Pharmaceutics
Critical adverse effects and frequent administration, three times per day, limit the use of fluta... more Critical adverse effects and frequent administration, three times per day, limit the use of flutamide (FLT) as a chemotherapeutic agent in the treatment of prostate cancer. Therefore, our research aimed to develop new cholesterol-based nanovesicles for delivering FLT to malignant cells in an endeavor to maximize its therapeutic efficacy and minimize undesired adverse effects. Draper–Lin small composite design was used to optimize the critical quality attributes of FLT-loaded niosomes and ensure the desired product quality. The influence of the selected four independent variables on mean particle size (Y1), zeta potential (Y2), drug entrapment efficiency (Y3), and the cumulative drug release after 24 h (Y4) was examined. The optimized nanovesicles were assessed for their in vitro cytotoxicity, ex-vivo absorption via freshly excised rabbit intestine as well as in vivo pharmacokinetics on male rats. TEM confirmed nanovescicles’ spherical shape with bilayer structure. Values of dependen...
American Journal of Physiology-Heart and Circulatory Physiology
A chronic mouse exposure model that mimics human e-cigarette vaping and allows comparison with to... more A chronic mouse exposure model that mimics human e-cigarette vaping and allows comparison with tobacco cigarette smoking was developed and utilized to perform longitudinal studies of alterations in cardiovascular function. E-cigarette exposure led to the onset of cardiovascular disease similar to that with tobacco cigarette smoking. Impaired endothelium-dependent and endothelium-independent vasodilation with increased adrenergic vasoconstriction were observed, paralleling the onset of systemic hypertension and subsequent cardiac hypertrophy. This cardiovascular toxicity was dependent on exposure duration and nicotine dose.
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Papers by Dr. Tamer Abdelghany