Publications by authors named "Abdelaziz Elgaml"

26 Publications

  • Page 1 of 1

Metabolic Influences of Gut Microbiota Dysbiosis on Inflammatory Bowel Disease.

Front Physiol 2021 27;12:715506. Epub 2021 Sep 27.

Faculty of Health Sciences, School of Nutrition Sciences, University of Ottawa, Ottawa, ON, Canada.

Inflammatory bowel diseases (IBD) are chronic medical disorders characterized by recurrent gastrointestinal inflammation. While the etiology of IBD is still unknown, the pathogenesis of the disease results from perturbations in both gut microbiota and the host immune system. Gut microbiota dysbiosis in IBD is characterized by depleted diversity, reduced abundance of short chain fatty acids (SCFAs) producers and enriched proinflammatory microbes such as adherent/invasive and HS producers. This dysbiosis may contribute to the inflammation through affecting either the immune system or a metabolic pathway. The immune responses to gut microbiota in IBD are extensively discussed. In this review, we highlight the main metabolic pathways that regulate the host-microbiota interaction. We also discuss the reported findings indicating that the microbial dysbiosis during IBD has a potential metabolic impact on colonocytes and this may underlie the disease progression. Moreover, we present the host metabolic defectiveness that adds to the impact of symbiont dysbiosis on the disease progression. This will raise the possibility that gut microbiota dysbiosis associated with IBD results in functional perturbations of host-microbiota interactions, and consequently modulates the disease development. Finally, we shed light on the possible therapeutic approaches of IBD through targeting gut microbiome.
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http://dx.doi.org/10.3389/fphys.2021.715506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502967PMC
September 2021

Ingestion of mannose ameliorates thioacetamide-induced intrahepatic oxidative stress, inflammation and fibrosis in rats.

Life Sci 2021 Oct 9:120040. Epub 2021 Oct 9.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address:

Background And Aims: The monosaccharide mannose has gained recent interest for its beneficial effect against certain inflammatory disorders. Nevertheless, the influence of mannose on experimentally-induced liver fibrosis and the ensued inflammation is still not fully clear to date.

Main Methods: The current study investigated the outcomes of treating rats with mannose (0.2 ml of 20% w/v, oral gavage) 30 min before the twice weekly intoxication with thioacetamide (TAA) (200 mg/kg, intraperitoneal) for a total period of 8 weeks.

Key Findings: The data indicated that mannose markedly dampened TAA-induced liver fibrosis, as indicated by lowering the fibrotic bridges shown by Masson's trichrome staining. This effect was consistent with reducing TAA-induced hepatocellular injury, as evidenced biochemically (serum ALT and AST activities) and pathologically (necroinflammation score). These hepatoprotective effects mediated by mannose were attributed to i) reversing TAA-induced rise in malondialdehyde (MDA) and decrease in reduced glutathione (GSH) expressions in the liver, ii) limiting TAA-induced release of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), iii) impairing TAA-induced activation of hepatic stellate cells by downregulating α-smooth muscle actin expression (α-SMA) and, and importantly, iv) dampening TAA-induced fibrogenesis driven by transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF).

Significance: Mannose may be an auspicious candidate for preventing oxidative stress, inflammation and fibrogenesis in the liver.
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http://dx.doi.org/10.1016/j.lfs.2021.120040DOI Listing
October 2021

Natural variability in surface antigen and reverse transcriptase domain of hepatitis B virus in treatment-naïve chronic HBV-infected Egyptian patients.

Virus Res 2021 Sep 6;302:198422. Epub 2021 Apr 6.

Microbiology and Immunology Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address:

Hepatitis B virus (HBV) infection is a serious health problem not only in Egypt, but also worldwide. We collected 57 serum samples from treatment-naïve chronic HBV-infected Egyptians. The DNA segment encoding HBV surface antigen (HBsAg) and reverse transcriptase (RT) domain was partially sequenced. Our data revealed that all viral isolates belonged to genotype D with ayw2 as the predominant serotype (89 %). Regarding HBsAg, 45 substitutions were detected in the collected isolates. Eleven substitutions were found in the major hydrophilic region, including two novel ones (M103T and G130E) that were not correlated before with genotype D. Additionally, 11 occult samples (19 %) were detected, in which the predominant mutations of HBsAg were S143L (7 samples) followed by D144A and T125M (4 samples each). Concerning the RT domain, 26 isolates (45 %) harbored 19 natural mutations that were reported to be associated with antiviral resistance. Eleven different mutations were not correlated previously with genotype D. The most predominant mutation was Y124H (47 samples, 82 %). Interestingly, such mutation was detected in 91 % of the previous reported sequences of HBV isolates collected in Egypt (157 sequences). Furthermore, our study illustrated the presence of viral quasispecies in the HBsAg (10 samples, 17.5 %) and RT domain (9 samples, 15.7 %). In conclusion, we elucidated the presence of natural substitutions in HBsAg and RT domain of HBV isolates obtained from treatment-naïve chronic HBV-infected Egyptian patients. Additionally, we detected viral quasispecies and revealed Y124H as a characteristic substitution in the RT domain for HBV isolates in Egypt. Moreover, novel substitutions in HBsAg and RT domain were reported with genotype D.
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http://dx.doi.org/10.1016/j.virusres.2021.198422DOI Listing
September 2021

Serum Soluble Fibrinogen-Like Protein 2 Represents a Novel Biomarker for Differentiation Between Acute and Chronic Egyptian Hepatitis B Virus-Infected Patients.

J Interferon Cytokine Res 2021 02;41(2):52-59

Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.

Hepatitis B virus (HBV) infection is considered as one of the most serious public health problems worldwide including Egypt. Soluble fibrinogen-like protein 2 (sFGL2) is a well-known immunomodulator that is produced by the T cells and has a strong inhibitory effect on the proliferation of T cells and maturation of dendritic cells (DC). In the current study, serum levels of sFGL2 were assessed utilizing enzyme-linked immunosorbent assay (ELISA) technique among 20 acute HBV-infected patients, 55 chronic HBV-infected patients and 15 healthy individuals. In addition, serum levels of soluble FAS ligand (sFASL), soluble FAS receptor (sFAS) as well as interferon-γ (IFN-γ) were assessed and correlated to the levels of sFGL2. According to our results, serum levels of sFGL2 were significantly higher in the acute HBV-infected patients than in the chronic HBV-infected patients and healthy individuals. On the other hand, the serum levels of sFASL, sFAS and IFN-γ were significantly higher in the chronic than in acute HBV-infected patients. Also, serum sFGL2 levels were negatively correlated with the serum levels of sFASL, sFAS, IFN-γ and albumin as well as hemoglobin concentration. Furthermore, serum sFGL2 levels were positively correlated with the activities of ALT and AST and total bilirubin levels in serum. Thus, the current work highlights the possibility of utilizing serum sFGL2 level as a novel biomarker for the differentiation between acute and chronic Egyptian HBV-infected patients.
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http://dx.doi.org/10.1089/jir.2020.0118DOI Listing
February 2021

Inhibition of the Classical Pathway of Complement Activation Impairs Bacterial Clearance during Enterococcus faecalis Infection.

Infect Immun 2021 04 16;89(5). Epub 2021 Apr 16.

Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.

infections are considered a major public health concern worldwide. The complement system has a crucial role in the protection against different microbial pathogens, including Complement can be activated through three different pathways, including the classical, lectin, and alternative pathways. There is limited information on the role of the classical pathway (CP) in protection against infections caused by In the present study, we generated Fab fragments that successfully block the CP in mouse via inhibition of a key enzyme, C1s-A. Our results showed that anti-C1s-A Fab fragments block CP-mediated C3b and C4b deposition We further showed that administration of anti-C1s-A Fab fragments significantly impairs the CP functional activity Moreover, treatment of mice infected with using anti-C1s-A Fab fragments significantly impairs bacterial clearance as determined from the viable bacterial counts recovered from blood, kidneys, spleens, livers, and lungs of infected mice. Overall, this study highlights the essential role of the CP in host defense against .
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http://dx.doi.org/10.1128/IAI.00660-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091092PMC
April 2021

Gastroenterology manifestations and COVID-19 outcomes: A meta-analysis of 25,252 cohorts among the first and second waves.

J Med Virol 2021 05 23;93(5):2740-2768. Epub 2021 Feb 23.

Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, Louisiana, USA.

A meta-analysis was performed to identify patients with coronavirus disease 2019 (COVID-19) presenting with gastrointestinal (GI) symptoms during the first and second pandemic waves and investigate their association with the disease outcomes. A systematic search in PubMed, Scopus, Web of Science, ScienceDirect, and EMBASE was performed up to July 25, 2020. The pooled prevalence of the GI presentations was estimated using the random-effects model. Pairwise comparison for the outcomes was performed according to the GI manifestations' presentation and the pandemic wave of infection. Data were reported as relative risk (RR), or odds ratio and 95% confidence interval. Of 125 articles with 25,252 patients, 20.3% presented with GI manifestations. Anorexia (19.9%), dysgeusia/ageusia (15.4%), diarrhea (13.2%), nausea (10.3%), and hematemesis (9.1%) were the most common. About 26.7% had confirmed positive fecal RNA, with persistent viral shedding for an average time of 19.2 days before being negative. Patients presenting with GI symptoms on admission showed a higher risk of complications, including acute respiratory distress syndrome (RR = 8.16), acute cardiac injury (RR = 5.36), and acute kidney injury (RR = 5.52), intensive care unit (ICU) admission (RR = 2.56), and mortality (RR = 2.01). Although not reach significant levels, subgroup-analysis revealed that affected cohorts in the first wave had a higher risk of being hospitalized, ventilated, ICU admitted, and expired. This meta-analysis suggests an association between GI symptoms in COVID-19 patients and unfavorable outcomes. The analysis also showed improved overall outcomes for COVID-19 patients during the second wave compared to the first wave of the outbreak.
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http://dx.doi.org/10.1002/jmv.26836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014082PMC
May 2021

Changes of Gut-Microbiota-Liver Axis in Hepatitis C Virus Infection.

Biology (Basel) 2021 Jan 13;10(1). Epub 2021 Jan 13.

Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

The gut-liver-axis is a bidirectional coordination between the gut, including microbial residents, the gut microbiota, from one side and the liver on the other side. Any disturbance in this crosstalk may lead to a disease status that impacts the functionality of both the gut and the liver. A major cause of liver disorders is hepatitis C virus (HCV) infection that has been illustrated to be associated with gut microbiota dysbiosis at different stages of the disease progression. This dysbiosis may start a cycle of inflammation and metabolic disturbance that impacts the gut and liver health and contributes to the disease progression. This review discusses the latest literature addressing this interplay between the gut microbiota and the liver in HCV infection from both directions. Additionally, we highlight the contribution of gut microbiota to the metabolism of antivirals used in HCV treatment regimens and the impact of these medications on the microbiota composition. This review shed light on the potential of the gut microbiota manipulation as an alternative therapeutic approach to control the liver complications post HCV infection.
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http://dx.doi.org/10.3390/biology10010055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828638PMC
January 2021

Exercise-induced downregulation of serum interleukin-6 and tumor necrosis factor-alpha in Egyptian handball players.

Saudi J Biol Sci 2021 Jan 5;28(1):724-730. Epub 2020 Nov 5.

Microbiology & Immunology Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

Muscles of candidates work at various grades of intensity during handball exercises according to the pace of exercise. The movement pattern involves large number of contractions, feints, dodges and numerous changes in movements, all of which are highly responsible for changes in trainer's organs, including the immune system. In this study, inflammatory mediators involving interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in serum of 18 Egyptian male handball players, selected from Tanta club handball under 21 year's old team, were analyzed. The analysis was established on samples collected just before and immediately after intermediate reasonable exercise via enzyme linked immunosorbent assay (ELISA). Moreover, white blood cells (WBCs) count and other hematological markers including hemoglobin %, hematocrit value, and platelet count were assessed. Our results demonstrated a significant decrease in the levels of IL-6 and TNF-α after exercise compared to those before exercise. This was coupled with an increase in WBCs and platelets count. It is also noteworthy that there was a significant positive correlation between serum levels of IL-6 and TNF-α in the study subjects coupled with a significant negative correlation between IL-6 and WBCs after the exercise. Therefore, it is concluded that intermediate reasonable exercises result in decreased levels of IL-6 and TNF-α, which result in decreasing of the inflammation and help in healing and rapid recovery of muscles of the candidates.
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http://dx.doi.org/10.1016/j.sjbs.2020.10.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783837PMC
January 2021

Alterations of the Treatment-Naive Gut Microbiome in Newly Diagnosed Hepatitis C Virus Infection.

ACS Infect Dis 2021 05 29;7(5):1059-1068. Epub 2020 Oct 29.

Faculty of Health Sciences, School of Nutrition Sciences, University of Ottawa, Ottawa, Ontario K1H8M5, Canada.

Gut microbiota dysbiosis has been linked to many heath disorders including hepatitis C virus (HCV) infection. However, profiles of the gut microbiota alterations in HCV are inconsistent in the literature and are affected by the treatment regimens. Using samples collected prior to treatment from newly diagnosed patients, we characterized the gut microbiota structure in HCV patients as compared to healthy controls. Treatment-naive HCV microbiota showed increased diversity, an increased abundance of , , , , and Ruminococcaceae, and a lower abundance of , , , , , Enterobacteriaceae, Erysipelotrichaceae, Rikenellaceae, and . Predicted community metagenomic functions showed a depletion of carbohydrate and lipid metabolism in HCV microbiota along with perturbations of amino acid metabolism. Receiver-operating characteristic analysis identified five disease-specific operational taxonomic units (OTUs) as potential biomarkers of HCV infections. Collectively, our findings reveal the alteration of gut microbiota in treatment naive HCV patients and suggest that gut microbiota may hold diagnostic promise in HCV infection.
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http://dx.doi.org/10.1021/acsinfecdis.0c00432DOI Listing
May 2021

Diagnostic and prognostic value of hematological and immunological markers in COVID-19 infection: A meta-analysis of 6320 patients.

PLoS One 2020 21;15(8):e0238160. Epub 2020 Aug 21.

Division of Endocrine and Oncologic Surgery, Department of Surgery, Tulane University, School of Medicine, New Orleans, Los Angeles, United States of America.

Objective: Evidence-based characterization of the diagnostic and prognostic value of the hematological and immunological markers related to the epidemic of Coronavirus Disease 2019 (COVID-19) is critical to understand the clinical course of the infection and to assess in development and validation of biomarkers.

Methods: Based on systematic search in Web of Science, PubMed, Scopus, and Science Direct up to April 22, 2020, a total of 52 eligible articles with 6,320 laboratory-confirmed COVID-19 cohorts were included. Pairwise comparison between severe versus mild disease, Intensive Care Unit (ICU) versus general ward admission and expired versus survivors were performed for 36 laboratory parameters. The pooled standardized mean difference (SMD) and 95% confidence intervals (CI) were calculated using the DerSimonian Laird method/random effects model and converted to the Odds ratio (OR). The decision tree algorithm was employed to identify the key risk factor(s) attributed to severe COVID-19 disease.

Results: Cohorts with elevated levels of white blood cells (WBCs) (OR = 1.75), neutrophil count (OR = 2.62), D-dimer (OR = 3.97), prolonged prothrombin time (PT) (OR = 1.82), fibrinogen (OR = 3.14), erythrocyte sedimentation rate (OR = 1.60), procalcitonin (OR = 4.76), IL-6 (OR = 2.10), and IL-10 (OR = 4.93) had higher odds of progression to severe phenotype. Decision tree model (sensitivity = 100%, specificity = 81%) showed the high performance of neutrophil count at a cut-off value of more than 3.74x109/L for identifying patients at high risk of severe COVID-19. Likewise, ICU admission was associated with higher levels of WBCs (OR = 5.21), neutrophils (OR = 6.25), D-dimer (OR = 4.19), and prolonged PT (OR = 2.18). Patients with high IL-6 (OR = 13.87), CRP (OR = 7.09), D-dimer (OR = 6.36), and neutrophils (OR = 6.25) had the highest likelihood of mortality.

Conclusions: Several hematological and immunological markers, in particular neutrophilic count, could be helpful to be included within the routine panel for COVID-19 infection evaluation to ensure risk stratification and effective management.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238160PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446892PMC
September 2020

Association of cardiac biomarkers and comorbidities with increased mortality, severity, and cardiac injury in COVID-19 patients: A meta-regression and decision tree analysis.

J Med Virol 2020 11 6;92(11):2473-2488. Epub 2020 Jul 6.

Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.

Background: Coronavirus disease-2019 (COVID-19) has a deleterious effect on several systems, including the cardiovascular system. We aim to systematically explore the association of COVID-19 severity and mortality rate with the history of cardiovascular diseases and/or other comorbidities and cardiac injury laboratory markers.

Methods: The standardized mean difference (SMD) or odds ratio (OR) and 95% confidence intervals (CIs) were applied to estimate pooled results from the 56 studies. The prognostic performance of cardiac markers for predicting adverse outcomes and to select the best cutoff threshold was estimated by receiver operating characteristic curve analysis. Decision tree analysis by combining cardiac markers with demographic and clinical features was applied to predict mortality and severity in patients with COVID-19.

Results: A meta-analysis of 17 794 patients showed patients with high cardiac troponin I (OR = 5.22, 95% CI = 3.73-7.31, P < .001) and aspartate aminotransferase (AST) levels (OR = 3.64, 95% CI = 2.84-4.66, P < .001) were more likely to develop adverse outcomes. High troponin I more than 13.75 ng/L combined with either advanced age more than 60 years or elevated AST level more than 27.72 U/L was the best model to predict poor outcomes.

Conclusions: COVID-19 severity and mortality are complicated by myocardial injury. Assessment of cardiac injury biomarkers may improve the identification of those patients at the highest risk and potentially lead to improved therapeutic approaches.
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http://dx.doi.org/10.1002/jmv.26166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307124PMC
November 2020

Genetic polymorphisms of TP53 (rs1042522) and MDM2 (rs2279744) and colorectal cancer risk: An updated meta-analysis based on 59 case-control studies.

Gene 2020 Apr 27;734:144391. Epub 2020 Jan 27.

Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia.

Objective: Several earlier reports implicated TP53 (rs1042522) and MDM2 (rs2279744) variants in outcome of colorectal cancer (CRC), but with inconclusive findings. This current meta-analysis designed to uncover the role of these variants in CRC risk.

Methodology: Two independent investigators extracted 59 eligible case-control studies from different electronic databases involving Scopus, Web of Science and PubMed prior to June 2019. Pooled odds ratios (ORs) and "95% confidence intervals (CIs)" were computed for different hereditary models. Stratification and heterogeneity analyses, and "Begg's funnel plots" were conducted. In silico data analyses of the functional and structural properties of the study variants were applied.

Results: In general, 47 and 16 case-control reports for TP53 (11,589 patients and 13,622 controls) and MDM2 (6841 CRC patients and 8792 healthy controls), respectively were enrolled in this meta-analysis. A significant association of TP53 (rs1042522) variant with increased CRC risk in overall pooled subjects under recessive model [(CC vs. GC + GG, OR = 1.134, 95% CI = 1.006-1.278, P = 0.039)] was observed. Moreover, an evidence of MDM2 (rs2279744) association with increased CRC risk in overall pooled subjects under dominant and heterozygote models [(TG + GG vs. TT, OR = 1.120, 95% CI = 1.003-1.250, P = 0.044) and (TG vs. TT, OR = 1.189, 95% CI = 1.076-1.313, P = 0.001), respectively] was reported. Additionally, TP53 (rs1042522) and MDM2 (rs2279744) showed an association with CRC risk among Asians and Africans under a recessive model, and among Asians under different genetic models, respectively, by stratification analysis.

Conclusion: TP53 (rs1042522) and MDM2 (rs2279744) variants might represent candidate risk factors for CRC susceptibility.
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http://dx.doi.org/10.1016/j.gene.2020.144391DOI Listing
April 2020

Biotechnological applications of quorum sensing inhibition as novel therapeutic strategies for multidrug resistant pathogens.

Microb Pathog 2019 Feb 29;127:138-143. Epub 2018 Nov 29.

Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taibah University, Al Madinah Al Munawwarah, 30078, Saudi Arabia; Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, 35516, Egypt. Electronic address:

High incidence of antibiotic resistance among bacterial clinical isolates necessitates the discovery of new targets for inhibition of microbial pathogenicity, without stimulation of microbial resistance. This could be achieved by targeting virulence determinants, which cause host damage and disease. Many pathogenic bacteria elaborate signaling molecules for cellular communication. This signaling system is named quorum sensing system (QS), and it is contingent on the bacterial population density and mediated by signal molecules called pheromones or autoinducers (AIs). Bacteria utilize QS to regulate activities and behaviors including competence, conjugation, symbiosis, virulence, motility, sporulation, antibiotic production, and biofilm formation. Hence, targeting bacterial communicating signals and suppression of QS exhibit a fundamental approach for competing microbial communication. In this review, we illustrate the common up to date approaches to utilize QS circuits in pathogenic bacteria, including Vibrio fischeri, Pseudomonas aeruginosa, Escherichia coli and Acinetobacter baumannii, as novel therapeutic targets.
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http://dx.doi.org/10.1016/j.micpath.2018.11.043DOI Listing
February 2019

Bacteriophage Therapy Increases Complement-Mediated Lysis of Bacteria and Enhances Bacterial Clearance After Acute Lung Infection With Multidrug-Resistant Pseudomonas aeruginosa.

J Infect Dis 2019 04;219(9):1439-1447

Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Egypt.

Emergence of multidrug-resistant (MDR) bacterial infections is a major problem in clinical medicine. Development of new strategies such as phage therapy may be a novel approach for treatment of life-threatening infections caused by MDR bacteria. A newly isolated phage, MMI-Ps1, with strong lytic activity was used for treatment of acute lung infection with Pseudomonas aeruginosa in a mouse model. Intranasal administration of a single dose of MMI-Ps1 immediately after infection provided a significant level of protection and increased the survival duration. Moreover, treatment of infected mice with phage as late as 12 hours after infection was still protective. Our in vitro results are the first to show the synergistic elimination of serum-resistant Pseudomonas strains by phage and complement. Phage therapy increases the efficacy of complement-mediated lysis of serum-resistant P. aeruginosa strains, indicating the importance of an intact complement system in clearing Pseudomonas infection during phage therapy.
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http://dx.doi.org/10.1093/infdis/jiy678DOI Listing
April 2019

Phytochemical, antimicrobial and antiquorum-sensing studies of L.: a revision on the structure of 1β,2α,3β,19α,23-pentahydroxy-urs-12-en-28-oic acid.

Nat Prod Res 2020 Mar 13;34(6):804-809. Epub 2018 Nov 13.

Department of Microbiology Botany Department, Faculty of Science, Mansoura University, Mansoura, Egypt.

Phytochemical study of the aerial part of L. led to the isolation of nine compounds. The structure of 1β,2α,3β,19α,23-pentahydroxy-urs-12-en-28-oic acid () was revised and confirmation of the stereochemical configuration of the hydroxyl groups was established using NOESY and selective decoupling experiments. The other compounds were identified as 1,2-dehydro-1,10α-dihydropseudoivalin (), axillarin (), grandifloric acid-15-β-glucoside (), myrianthic acid (), caffeic acid (), quercetin (), paniculoside IV () and caffeic anhydride (). The structures were characterized by 1 D, 2 D NMR spectroscopy and confirmed with HRMS. Antimicrobial and antiquorum-sensing activities of the different extracts and isolated compounds of the plant were investigated. Generally, the phenolic rather than the terpenoidal compounds exhibited remarkable antimicrobial and antiquorum-sensing activity.[Formula: see text].
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http://dx.doi.org/10.1080/14786419.2018.1503658DOI Listing
March 2020

Molecular Design and Synthesis of New 3,4-Dihydropyrimidin-2(1H)-Ones as Potential Anticancer Agents with VEGFR-2 Inhibiting Activity.

Anticancer Agents Med Chem 2019 ;19(3):310-322

Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

Background: Two series of 3,4-dihydropyrimidin-2(1H)-one derivatives were designed based on the main structural features characterizing reported anticancer compounds with potent VEGFR-2 inhibiting activity.

Methods: All the target compounds were synthesized and investigated for their in vitro anticancer activity using MTT assay and NCI protocol. The most active compounds were further investigated for the VEGFR-2 inhibiting activity using enzyme inhibition assay.

Result: Of these derivatives, compound 8b possessed significant activity against Caco-2 (IC50 of 24.9 µM) and MCF7 (IC50 of 29.4 µM), compound 10 showed excellent potency against HCT-116 (IC50 of 32.6 µM), HEPG2 (IC50 of 16.4 µM) and MCF7 (IC50 of 32.8 µM), while compound 11b exhibited moderate anticancer activity towards MCF7 (IC50 of 41.7µM). Both 8b and 10 exhibited good potency regarding the inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2), with an IC50 of 14.00 and 21.62 nM, respectively.

Conclusion: The activity was rationalized based on molecular docking study that supported their VEGFR-2 inhibitory activity; as indicated by their favorable binding with the active site.
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http://dx.doi.org/10.2174/1871520618666180717125906DOI Listing
December 2019

Antimicrobial and antiquorum-sensing activity of extracts and ricinine derivatives.

Nat Prod Res 2019 Jun 15;33(11):1556-1562. Epub 2018 Jan 15.

b Department of Pharmacognosy, Faculty of Pharmacy , Mansoura University , Mansoura , Egypt.

Ricinine (), a known major alkaloid in plant, was used as a starting compound for the synthesis of six ricinine derivatives; two new and four known compounds. The new derivatives; 3-amino-5-methyl-1-pyrazolo[4,3-c]pyridin-4(5)-one (), and 3-amino-5-methyl-1-(phenylsulfonyl)-1-pyrazolo[4,3-c]pyridin-4(5)-one (), as well as the previously prepared derivatives (-) were subjected for antimicrobial and antiquorum-sensing evaluation in comparison to different extracts. Acetyl ricininic acid derivative ( showed the highest antimicrobial activity among all tested derivatives against , , , and . However, compound (4-methoxy-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide) showed the highest antiquorum-sensing activity among all tested compounds and extracts. These findings proved the usefulness of ricinine as a good scaffold for the synthesis of new antimicrobial and antiquorum-sensing derivatives in spite of its poor contribution to the antimicrobial activity of the plant extracts.
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http://dx.doi.org/10.1080/14786419.2017.1423306DOI Listing
June 2019

Correlation of Serum Soluble Fibrinogen-Like Protein 2 with Soluble FAS Ligand and Interferon Gamma in Egyptian Hepatitis C Virus-Infected Patients and Hepatocellular Carcinoma Patients.

J Interferon Cytokine Res 2017 08 13;37(8):342-347. Epub 2017 Jun 13.

3 Department of Tropical Medicine, Faculty of Medicine, Mansoura University , Mansoura, Egypt .

Infection with hepatitis C virus (HCV) remains one of the serious human diseases worldwide, especially in Egypt, which can lead to cirrhosis or hepatocellular carcinoma (HCC). However, the exact molecular mechanism of HCC progress in HCV-infected patients remains unclear. Soluble fibrinogen-like protein 2 (sFGL2) is a modulator of the immune response that is secreted by T cells and inhibits maturation of dendritic cells and T cell proliferation. In the current study, serum sFGL2 levels were analyzed by enzyme-linked immunosorbent assay (ELISA) technique in 30 chronic HCV-infected patients (HCV group), 30 chronic HCV-infected patients with HCC (HCC group), and 12 healthy individuals (control group). Moreover, serum levels of soluble FAS ligand (sFASL) and interferon gamma (IFN-γ) were analyzed and correlated with sFGL2 levels. According to our results, serum sFGL2 levels were significantly elevated in all patients with chronic HCV infection. However, HCC patients showed lower sFGL2 levels than HCV-infected patients without HCC incidence. In addition, serum sFASL levels were significantly elevated in both HCV and HCC groups, whereas serum IFN-γ levels were only elevated in the HCC group. Interestingly, sFGL2 correlated positively with serum total bilirubin level and negatively with serum levels of sFASL, IFN-γ, and albumin in HCV and HCC groups. Thus, conclusively, sFGL2 level increases in Egyptian HCV-infected and HCC patients. Taken together, the current work may open future possibility of designing new treatment strategies for HCV infection targeting sFGL2 and its immunosuppressive effect.
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http://dx.doi.org/10.1089/jir.2016.0128DOI Listing
August 2017

Molecular analysis of Hepatitis B virus sub-genotypes and incidence of preS1/preS2 region mutations in HBV-infected Egyptian patients from Mansoura.

J Med Virol 2017 09 23;89(9):1559-1566. Epub 2017 May 23.

Faculty of Medicine, Department of Tropical Medicine, Mansoura University, Mansoura, Egypt.

Hepatitis B virus (HBV) is one of the major causes of viral hepatitis worldwide. Despite the prevalence of HBV infection in Egypt, few studies have focused on sub-genotyping of the virus. Moreover, no studies are available regarding the mutational analysis of the preS1/preS2 region of the viral genome, or its impact on hepatocellular carcinoma (HCC) development in Egypt. In this study, we have analyzed the sub-genotypes and incidence of mutations in the preS1/preS2 region of HBV present in HBV-infected patients, from Mansoura city (located in the center of Nile Delta region of Egypt), via partial sequencing of this specific region. Moreover, we have investigated the impact of these mutations on HCC development by measuring serum alpha fetoprotein (AFP) level and abdominal ultrasound examination of the HBV-infected patients. According to our results, all samples were genotype D in which sub-genotype D1 was predominant. In addition, the results revealed mutations in the preS1/preS2 region, which could result in either immature preS1 protein or completely inhibit the translation of the preS2 protein. However, there was no incidence of HCC development in patients infected with mutated HBV in the preS1/preS2 region. In summary, for the first time our work has proved the predominance of sub-genotype D1 among HBV-infected Egyptian patients in Mansoura city, Nile Delta region, Egypt, and incidence of mutations in the preS1/preS2 region of HBV genome. This current study opens up research opportunities to discuss the impact of HBV mutations on the development of HCC in Egypt.
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http://dx.doi.org/10.1002/jmv.24828DOI Listing
September 2017

Regulation systems of protease and hemolysin production in Vibrio vulnificus.

Microbiol Immunol 2017 Jan;61(1):1-11

Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-Ku, Okayama 700-8530, Japan.

Vibrio vulnificus, a gram-negative halophilic estuarine bacterium, is an opportunistic human pathogen that causes rapidly progressive fatal septicemia and necrotizing wound infection. This species also causes hemorrhagic septicemia called vibriosis in cultured eels. It has been proposed that a range of virulence factors play roles in pathogenesis during human and/or eel infection. Among these factors, a metalloprotease (V. vulnificus protease [VVP]) and a cytolytic toxin (V. vulnificus hemolysin [VVH]) are of significant importance. VVP elicits the characteristic edematous and hemorrhagic skin damage, whereas VVH exhibits powerful hemolytic and cytolytic activities and contributes to bacterial invasion from the intestine to the blood stream. In addition, a few V. vulnificus strains isolated from diseased eels have recently been found to produce a serine protease designated as V. vulnificus serine protease (VvsA) instead of VVP. Similarly to VVP, VvsA may possess various toxic activities such as collagenolytic, cytotoxic and edema-forming activity. In this review, regulation of V. vulnificus VVP, VVH and VvsA is clarified in terms of expression at the mRNA and protein levels. The explanation is given on the basis of the quorum sensing system, which is dependent on bacterial cell density. In addition, the roles of environmental factors and global regulators, such as histone-like nucleoid structuring protein, cyclic adeno monophosphate receptor protein, RpoS, HlyU, Fur, ToxRS, AphB and LeuO, in this regulation are outlined. The cumulative impact of these regulatory systems on the pathogenicity of V. vulnificus is here delineated.
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http://dx.doi.org/10.1111/1348-0421.12465DOI Listing
January 2017

Emergence of Multidrug-Resistant New Delhi Metallo-β-Lactamase-1-Producing Klebsiella pneumoniae in Egypt.

Microb Drug Resist 2017 Jun 30;23(4):480-487. Epub 2016 Aug 30.

2 Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University , Mansoura, Egypt .

Despite expansion of the New Delhi metallo-β-lactamase-1 (NDM-1) worldwide, the incident of outbreaks regarding Egypt is still uncommon. In this survey, we denounce the emanation of multidrug-resistant NDM-1-producing Klebsiella pneumoniae in Egypt. We have reclaimed 46 unrepeatable carbapenem-resistant K. pneumoniae isolates at El-demerdash hospital, Ain Shams University, Cairo, Egypt. All the isolates showed a decreased sensitivity to imipenem and meropenem via the disc diffusion method. Among the isolates, 10 were proven as NDM-1 producers by utilizing the phenotypic methods (modified Hodge test and EDTA synergistic test) and specific PCR detection of NDM-1 encoding gene, bla. The isolates hosting the bla showed an elevated resistance to several classes of β-lactam and non β-lactam antibiotics. All bla-harboring isolates have showed positivity for one or more other plasmid-mediated bla genes; in addition, the isolates carried class 1 integron. Enterobacterial repetitive intergenic consensus (ERIC)-PCR results revealed that majority of the isolates, including the NDM-1 producers, are unrelated to each other. This highlights the danger of horizontal transfer of plasmids encoding for such carbapenemases, including NDM-1, between the isolates of K. pneumoniae. In summary, this study has confirmed the incidence of bla together with other bla genes among the K. pneumoniae isolates in Egypt. Control and prevention of infection can be achieved through early detection of resistance genes among bacterial isolates; through limiting the dispersal of these organisms.
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http://dx.doi.org/10.1089/mdr.2016.0003DOI Listing
June 2017

The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis.

Exp Biol Med (Maywood) 2016 12 28;241(18):2015-2022. Epub 2016 Jul 28.

3 Faculty of Pharmacy, Department of Microbiology and Immunology, Mansoura University, Mansoura 35516, Egypt.

The inhibitors of apoptosis proteins are implicated in promoting cancer cells survival and resistance toward immune surveillance and chemotherapy. Second mitochondria-derived activator of caspases (SMAC) mimetics are novel compounds developed to mimic the inhibitory effect of the endogenous SMAC/DIABLO on these IAPs. Here, we examined the potential effects of the novel SMAC mimetic BV6 on different human cancer cell lines. Our results indicated that BV6 was able to induce cell death in different human cancer cell lines. Mechanistically, BV6 dose dependently induced degradation of IAPs, including cIAP1 and cIAP2. This was coincided with activating the non-canonical NF -kappa B (NF-κB) pathway, as indicated by stabilizing NF-κB-inducing kinase (NIK) for p100 processing to p52. More interestingly, BV6 was able to sensitize some of the resistant cancer cell lines to apoptosis induced by the death ligands tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) that are produced by different cells of the immune system. Such cell death enhancement was mediated by inducing an additional cleavage of caspase-9 to augment that of caspase-8 induced by death ligands. This eventually led to more processing of the executioner caspase-3 and poly (ADP-ribose) polymerase (PARP). In conclusion, therapeutic targeting of IAPs by BV6 might be an effective approach to enhance cancer regression induced by immune system. Our data also open up the future possibility of using BV6 in combination with other antitumor therapies to overcome cancer drug resistance.
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http://dx.doi.org/10.1177/1535370216661779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102137PMC
December 2016

Regulation of Vibrio mimicus metalloprotease (VMP) production by the quorum-sensing master regulatory protein, LuxR.

J Basic Microbiol 2016 Oct 10;56(10):1051-1058. Epub 2016 May 10.

Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-Ku, Okayama, Japan.

Vibrio mimicus is an estuarine bacterium, while it can cause severe diarrhea, wound infection, and otitis media in humans. This pathogen secretes a relatively important toxin named V. mimicus metalloprotease (VMP). In this study, we clarified regulation of the VMP production according to the quorum-sensing master regulatory protein named LuxR. First, the full length of luxR gene, encoding LuxR, was detected in V. mimicus strain E-37, an environmental isolate. Next, the putative consensus binding sequence of LuxR protein could be detected in the upstream (promoter) region of VMP encoding gene, vmp. Finally, the effect of disruption of luxR gene on the expression of vmp and production of VMP was evaluated. Namely, the expression of vmp was significantly diminished by luxR disruption and the production of VMP was severely altered. Taken together, here we report that VMP production is under the positive regulation of the quorum-sensing master regulatory protein, LuxR.
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http://dx.doi.org/10.1002/jobm.201600002DOI Listing
October 2016

Role of the Histone-Like Nucleoid Structuring Protein (H-NS) in the Regulation of Virulence Factor Expression and Stress Response in Vibrio vulnificus.

Biocontrol Sci 2015 ;20(4):263-74

Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University.

Temperature is one of the important parameters regulating the expression of virulence factors in bacteria. The global regulator, a histone-like nucleoid structuring protein (H-NS), is known to play a crucial role in this regulation. In the present study, we first clarified the role of H-NS in the temperature-dependent regulation of virulence factor production in Vibrio vulnificus, including that of the cytolytic toxin (V. vulnificus hemolysin: VVH) and the proteolytic enzyme (V. vulnificus protease: VVP). The expression of hns itself was subjected to temperature regulation, where hns was expressed more at 26 ℃ than at 37 ℃. VVH production and the expression of its gene vvhA were increased by disruption of the hns gene. H-NS appeared to affect the vvhA expression by the well-documented transcriptional silencing mechanism. On the other hand, hns disruption resulted in the reduction of VVP production and the expression of its gene vvpE. H-NS was suggested to positively regulate vvpE expression through the increase in the level of the rpoS mRNA. Moreover, H-NS was found to contribute to the survival of V. vulnificus in stressful environments. When compared to the wild type strain, the hns mutant exhibited reduced survival rates when subjected to acidic pH, hyperosmotic and oxidative stress.
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http://dx.doi.org/10.4265/bio.20.263DOI Listing
October 2016

Presence of Nitric Oxide-Sensing Systems in the Human Pathogen Vibrio vulnificus.

Biocontrol Sci 2015 ;20(3):199-203

Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University.

Vibrio vulnificus is a halophilic estuarine bacterium, but this species causes fatal septicemia in humans. V. vulnificus may encounter many kinds of stresses either in the natural environment or in the human body. One of the striking stresses is the exposure to the reactive oxygen species including nitric oxide (NO). The present study revealed that NO could participate in the regulation of the V. vulnificus community behavior. When the bacterium was cultivated in the presence of sub-lethal doses of an NO donor, the expression of the genes encoding NO-detoxifying enzymes was significantly increased. The NO donor was also found to cause significant increase in production of a metalloprotease, a putative virulence factor, by the bacterium.
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http://dx.doi.org/10.4265/bio.20.199DOI Listing
June 2016

Effects of temperature, growth phase and luxO-disruption on regulation systems of toxin production in Vibrio vulnificus strain L-180, a human clinical isolate.

World J Microbiol Biotechnol 2014 Feb 26;30(2):681-91. Epub 2013 Sep 26.

Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-Ku, Okayama, Okayama, 700-8530, Japan,

Vibrio vulnificus is a halophilic estuarine bacterium while it causes fatal septicemia or necrotizing wound infections in humans. This pathogen secretes the metalloprotease (V. vulnificus protease: VVP) and the cytolysin (V. vulnificus hemolysin: VVH) as protein toxins; however, their production was coordinated in response to the bacterial cell density. This regulation is termed quorum sensing (QS) and is mediated by the small diffusible molecule called autoinducer 2 (AI-2). In the present study, we investigated effects of disruption of luxO encoding a central response regulator of the QS circuit, as well as effects of temperature and growth phase, on the toxin production by V. vulnificus. Disruption of luxO was found to increase VVP production and expression of its gene vvpE. The expression of smcR, crp and rpoS, of which products positively regulate vvpE expression, and luxS encoding the AI-2 synthetase were also significantly increased. On the other hand, the luxO disruption resulted in reduction of VVH production and expression of its gene vvhA. Expression of other two genes affecting the QS circuit, luxT and rpoN, were also significantly decreased. The regulation systems of VVP production were found to exert their action during the stationary phase of the bacterial growth and to be operated strongly at 26 °C. By contrast, those of VVH production apparently started at the log phase and were operated more effectively at 37 °C.
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http://dx.doi.org/10.1007/s11274-013-1501-3DOI Listing
February 2014
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