Publications by authors named "Mohamed El-Mesery"

36 Publications

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2021.120040DOI Listing
October 2021

Pevonedistat attenuates cisplatin-induced nephrotoxicity in mice by downregulating the release of inflammatory mediators.

J Biochem Mol Toxicol 2021 Sep 3:e22908. Epub 2021 Sep 3.

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

Pevonedistat (MLN4924) is a specific NEDD8-activating enzyme inhibitor that inactivates cullin-RING ligases involved in ubiquitylation and turnover of different signaling molecules. In the current study, we evaluated the effect of pevonedistat on cisplatin (CIS)-induced nephrotoxicity in mice. Serum creatinine and urea levels were analyzed in different groups. Histopathological examination of renal tissue was done using hematoxylin and eosin staining. In addition, renal IL-6 and TNF-α expressions were analyzed using the enzyme-linked immunosorbent assay technique, and IL-1β and NF-κB expressions were analyzed by immunohistochemical staining of renal tissue. Caspase-3, A20, β-catenin, and Nrf2 gene expressions in renal tissue were analyzed using the reverse-transcription polymerase chain reaction technique. Western blot analysis was adopted to assess cleaved caspase-3 and β-catenin expressions in renal tissue. Pevonedistat coadministration with CIS improved kidney functions and attenuated CIS-induced nephrotoxicity as indicated by the significant decrease in serum creatinine and urea levels. In addition, pevonedistat coadministration with CIS showed a significant decrease in caspase-3 and a significant increase in A20, β-catenin, and Nrf2 gene expressions. Also, pevonedistat decreased caspase-3 cleavage to p19 in mice treated with CIS. Moreover, pevonedistat decreased CIS-induced upregulation of IL-6, TNF-α, IL-1β, and NF-κB protein expressions in renal tissue. Thus, pevonedistat alleviated CIS-induced nephrotoxicity that might be attributed to suppression of the inflammation induced in renal tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbt.22908DOI Listing
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virusres.2021.198422DOI Listing
September 2021

Metabolic Fingerprinting of Murine L929 Fibroblasts as a Cell-Based Tumour Suppressor Model System for Methionine Restriction.

Int J Mol Sci 2021 Mar 16;22(6). Epub 2021 Mar 16.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital Wuezburg, D-97070 Wuerzburg, Germany.

Since Otto Warburg reported in 1924 that cancer cells address their increased energy requirement through a massive intake of glucose, the cellular energy level has offered a therapeutic anticancer strategy. Methionine restriction (MetR) is one of the most effective approaches for inducing low-energy metabolism (LEM) due to the central position in metabolism of this amino acid. However, no simple in vitro system for the rapid analysis of MetR is currently available, and this study establishes the murine cell line L929 as such a model system. L929 cells react rapidly and efficiently to MetR, and the analysis of more than 150 different metabolites belonging to different classes (amino acids, urea and tricarboxylic acid cycle (TCA) cycles, carbohydrates, etc.) by liquid chromatography/mass spectrometry (LC/MS) defines a metabolic fingerprint and enables the identification of specific metabolites representing normal or MetR conditions. The system facilitates the rapid and efficient testing of potential cancer therapeutic metabolic targets. To date, MS studies of MetR have been performed using organisms and yeast, and the current LC/MS analysis of the intra- and extracellular metabolites in the murine cell line L929 over a period of 5 days thus provides new insights into the effects of MetR at the cellular metabolic level.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22063039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002350PMC
March 2021

Amelioration effect of black seed oil against high-fat diet-induced obesity in rats through Nrf2/HO-1 pathway.

J Food Biochem 2021 04 14;45(4):e13693. Epub 2021 Mar 14.

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

Obesity is a chronic inflammatory disease that represents a risk factor for number of diseases including diabetes, steatohepatitis, and cancer. Using safe natural compounds to ameliorate obesity and its related metabolic syndrome is an interesting spot for research. We investigated the regulatory role and the underlying mechanism of black seed oil (BSO) on high-fat diet (HFD)-induced obesity in rats. The study included two models: the first one aimed to study the prophylactic effect of BSO (BSO administration for 10 weeks along with HFD) while the second one aimed to study the treatment role of BSO (BSO administration starting from the 10th week for 4 weeks along with HFD). BSO significantly decreased insulin resistance and body weight characteristics in both models. It also normalized lipid profile. Moreover, histopathological examination confirmed these results as BSO significantly decreased adipocyte size and hepatic lipid deposition. Besides, BSO alleviated HFD-induced oxidative stress as indicated by significant increase in the total antioxidant capacity and significant decrease in liver malondialdehyde. Moreover, BSO decreased significantly liver gluconeogenic enzymes mRNA expressions (phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) and increased significantly heme oxygenase-1 (HO-1), nuclear factor erythroid-2-related factor-2 (Nrf2) and insulin receptor mRNA expressions. In conclusion, BSO represents a natural therapy that has the ability to prevent and treat HFD-induced obesity in rats that may be mediated through Nrf2/HO-1 pathway's activation and insulin receptor expression's increase. To our best knowledge, this study represents a novel study that investigates the regulatory role of BSO on Nrf2 pathway in preventing and treating HFD-induced obesity. PRACTICAL APPLICATIONS: Black seed oil is a natural available safe supplement, thus it can be used for prevention from obesity and even treatment of obesity and obesity related complications. Introducing of black seed oil in the treatment regimen of obese patients may be promising.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jfbc.13693DOI Listing
April 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/jir.2020.0118DOI Listing
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biology10010055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828638PMC
January 2021

Sesamol Upregulates Death Receptors and Acts as a Chemosensitizer in Solid Ehrlich Carcinoma Model in Mice.

Nutr Cancer 2021 Jan 13:1-15. Epub 2021 Jan 13.

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

Aims: The aim of the present study was to investigate the anti-tumor effect of sesamol (SML), a nutritional phenolic compound of sesame, in solid Ehrlich carcinoma (SEC) model in mice and its ability to enhance doxorubicin (DOX) anti-tumor activity. Moreover, we analyzed the ability of SML to protect against DOX-induced cardiotoxicity.

Main Methods: SML (70 mg/kg), DOX (2 mg/kg) and their combination were given to mice bearing SEC for 21 day. The mRNA level of Fas, FasL, TRAILR2, TRAIL, caspase-3 and Bcl-2 were assessed by qPCR. Tumor and cardiac tissues were examined for histopathological changes by hematoxylin and eosin. Active caspase-3 was scored by immunohistochemical analysis.

Key Findings: SML treatment significantly decreased solid tumor size and weight. In addition, SML enhanced DOX anti-tumor activity. SML treatment either alone or in combination with DOX induced upregulation of Fas/FasL and TRAILR2/TRAIL gene expression. Moreover, SML increased caspase-3 protein and gene expressions and decreased Bcl-2 gene expression.

Significance: SML upregulates death receptors expression and enhances apoptosis induction in tumor cells that may explain its anti-tumor activity. Not only that, but SML also enhances DOX anti-tumor activity and attenuates its cardiotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01635581.2020.1871496DOI Listing
January 2021

Inhibition of Bruton tyrosine kinase by acalabrutinib dampens lipopolysaccharide/galactosamine-induced hepatic damage.

Biomed Pharmacother 2020 Nov 17;131:110736. Epub 2020 Sep 17.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.

Bruton tyrosine kinase (BTK) sits at the crossroads of adaptive and innate immunities. Nevertheless, the detailed role of BTK activation in hepatic inflammatory disorders is still elusive to date. Accordingly, we investigated the impact of blocking BTK activation by acalabrutinib (ACB) on lipopolysaccharide/galactosamine (LPS/D-GaIN)-induced deleterious manifestations in the liver. This was achieved by pretreating mice with ACB (6, 12 or 24 mg/kg, oral) 2 h before challenge with LPS/D-GaIN (70 μg/kg and 700 mg/kg, respectively, i.p.) for 6 h. The results showed that ACB (6 and 12 mg/kg) (i) curbed LPS/D-GaIN-induced rise in biochemical (serum ALT, AST and LDH) and histological (necrosis, degeneration and congestion scores) indices of hepatocellular injury; (ii) attenuated LPS/D-GaIN-induced elevation in parameters of hepatocellular apoptosis (cleaved caspase 3) and proliferation (PCNA); and (iii) importantly, mitigated LPS/D-GaIN-induced recruitment and infiltration of the inflammatory cells to the liver evidenced by lowering elevated serum MCP-1 concentration and hepatic F4/80 immunostaining. These effects were linked to ACB dose-dependent inhibition of NF-κB nuclear translocation that subsequently reduced LPS/D-GaIN-mediated release of TNF-α, IL-1β and IL-22 in the blood circulation. However, a dose of 12 mg/kg of ACB elevated the hepatic TNF-α, IL-1β and IL-22 concentrations that arose from a compensatory activation of ERK and JNK. Inhibition of BTK also attenuated LPS/D-GaIN-induced overexpression of CD98, which is another contributor alongside cytokines for monocyte recruitment. Therapeutically, targeting BTK by ACB is an efficient approach for hitting multiple points with one agent that can dampen hepatocellular injury, death, immune cell recruitment and inflammation cascade.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2020.110736DOI Listing
November 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238160PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446892PMC
September 2020

Repurposing of quinoline alkaloids identifies their ability to enhance doxorubicin-induced sub-G0/G1 phase cell cycle arrest and apoptosis in cervical and hepatocellular carcinoma cells.

Biotechnol Appl Biochem 2021 Aug 21;68(4):832-840. Epub 2020 Aug 21.

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

The ability of quinoline alkaloids (cinchonine, cinchonidine, quinine, and quinidine) to sensitize different human cancer cell lines to doxorubicin (DOX)-induced cell death was evaluated. Cell viability was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the alkaloids ability to enhance DOX-induced apoptosis was explored using Western blotting analysis. Also, flow cytometry was applied to analyze cell fractions in the different cell cycle phases. All alkaloids showed a significant enhancement of DOX-induced cell death in HeLa and HepG2 cell lines. The chemosensitizing activity of the quinoline alkaloids was attributed to the induction of apoptosis as indicated by splitting of caspase-3 and its substrate poly (ADP-ribose) polymerase (PARP). In addition, there was an increase in the cell fractions in sub-G0/G1 phase in case of DOX combination with the alkaloids. This study proves the ability of the quinoline alkaloids to enhance DOX-induced apoptotic cell death in human cervical and hepatocellular carcinoma cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bab.1999DOI Listing
August 2021

The NEDD8-activating enzyme inhibition with MLN4924 sensitizes human cancer cells of different origins to apoptosis and necroptosis.

Arch Biochem Biophys 2020 09 25;691:108513. Epub 2020 Jul 25.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, 72341, Saudi Arabia.

Objectives: MLN4924 is an inhibitor of NEDD8-activating enzyme (NAE) that interferes with the cullin-RING ubiquitin ligase complexes formation and the nuclear factor kappa B (NF-κB) activation. Here, we investigated the cytotoxic effect of MLN4924 and its ability to sensitize a broad range of cancer cells of different origins to tumour necrosis factor-α (TNF)-induced cell death alongside unravelling its mechanism of action.

Materials And Methods: Cell viability and caspases processing were determined after MLN4924 treatment either alone or with zVAD-fmk (pan caspase inhibitor), necrostatin-1 (nec-1, RIPK1 inhibitor) and necrosulfonamide (NSA, MLKL inhibitor). Moreover, MLN4924 ability to potentiate TNF-induced cell death was evaluated in 24 cell lines of different cancer origins. The impact of NAE inhibition with MLN4924 on TNF-induced apoptosis and necroptosis was evaluated using zVAD-fmk and nec-1, respectively.

Results: MLN4924 alone was able to induce cell death in different cell lines that was attributed to apoptosis induction. Also, MLN4924 sensitized different cancer cell lines to TNF-induced cell death. MLN4924/TNF-induced cell death was apoptosis and necroptosis dependent that may be attributed to MLN4924 inhibition of NF-κB pathway activation.

Conclusions: Targeting NAE and NF-κB pathway with MLN4924 represents a substantial approach to enhance the sensitivity of diverse types of cancer cells. Moreover, the broad in vitro screening of MLN4924 anticancer activity provides a valuable guidance for elucidating the susceptible cancer types for the prospective clinical application of MLN4924.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.abb.2020.108513DOI Listing
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmv.26166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307124PMC
November 2020

Thymoquinone potentiates miR-16 and miR-375 expressions in hepatocellular carcinoma.

Life Sci 2020 Aug 15;254:117794. Epub 2020 May 15.

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

Aims: MicroRNAs (miRNAs) are non-coding RNAs that control post-transcriptional gene expression. Recently, miRNAs were confirmed to be promising biomarkers for different pathological conditions. This study assessed the role of serum miR-16 and miR-375 in HCC development in chronic liver disease patients such as cirrhosis. Moreover, miR-16 and miR-375 levels were estimated in HCC cell lines (HepG2 and Huh7) after treatment with doxorubicin (DOX), thymoquinone (TQ) and their combination.

Main Methods: Serum miR-16 and miR-375 were analyzed in 30 HCC patients, 20 cirrhosis patients and 10 healthy volunteers using RT-PCR. Moreover, HepG2 and Huh7 cells were incubated with DOX, TQ or TQ/DOX combination for 24 h and the levels of miR-16, miR-375 and gene expression of anti-apoptotic protein BCL-2 were determined in cell lysates using RT- PCR. Moreover, the ability of DOX, TQ and TQ/DOX combination to induce apoptosis were analyzed by measuring caspase-3 expression using ELISA method.

Key Findings: Serum miR-16 and miR-375 levels were significantly decreased in HCC patients as compared to cirrhosis and healthy control group. Also, combined use of serum miR-16 and miR-375 showed a better predictive ability than each alone. Moreover, the expression level of miR-16 and miR-375 in HepG2 and Huh7 cells increased significantly after treatment with DOX and TQ. Also, TQ/DOX combination improved apoptosis by increasing caspase-3 expression and decreasing of BCL-2 expression.

Significance: This study proved that the combined use of serum miR-16 and miR-375 was better than each alone for HCC detection. Moreover, TQ induced apoptosis and upregulatedmiR-16 and miR-375 expression in HCC cells that may explain its anticancer activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2020.117794DOI Listing
August 2020

The selective c-Met inhibitor capmatinib offsets cisplatin-nephrotoxicity and doxorubicin-cardiotoxicity and improves their anticancer efficacies.

Toxicol Appl Pharmacol 2020 07 22;398:115018. Epub 2020 Apr 22.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

The incorporation of mesenchymal-epithelial transition factor (c-Met) inhibitors with conventional chemotherapeutics may increase the anticancer efficacy of chemotherapeutic agents, but bears the risk of enhancing the adverse effects. To test the hypothesis, co-administration of the novel c-Met inhibitor capmatinib with cisplatin (CIS) or doxorubicin (DOX) was investigated on nephrotoxicity and cardiotoxicity induced by these agents in mice, as well as their in vitro cytotoxicities. The results demonstrated that capmatinib in vivo offered protection against nephrotoxicity and cardiotoxicity by both CIS and DOX, respectively. The underlying mechanisms behind capmatinib protective effect were found to be i) limiting excessive generation of reactive oxygen species by decreasing the level of lipid peroxidation and nitrosative stress products; and ii) suppressing overproduction of pro-inflammatory mediators like TNF-α and IL-6 that coincided with less inflammatory cell infiltration as denoted by lower levels of serum MCP-1 and Ly6G immunostaining. Besides, capmatinib effectively improved the in vivo anticancer efficacy of both CIS and DOX against solid tumors. In vitro, capmatinib increased the apoptotic activity of DOX against cancerous cells, but did not affect that of CIS. This effect might be linked to capmatinib and DOX abilities to lower IL-12(p40) that has an inhibitory effect on IL-12(p70)/IFN-γ-mediated apoptotic activity. In conclusion, the favorable effects of capmatinib can be applied clinically to decrease the toxicity of DOX and CIS chemotherapeutic agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.taap.2020.115018DOI Listing
July 2020

Polo-like kinase 1 as a promising diagnostic biomarker and potential therapeutic target for hepatocellular carcinoma.

Tumour Biol 2020 Apr;42(4):1010428320914475

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

Hepatocellular carcinoma is a major cause of cancer mortality worldwide. The outcome of hepatocellular carcinoma depends mainly on its early diagnosis. To date, the performance of traditional biomarkers is unsatisfactory. Polo-like kinase 1 is a serine/threonine kinase that plays essential roles in cell cycle progression and deoxyribonucleic acid damage. Moreover, polo-like kinase 1 knockdown decreases the survival of hepatocellular carcinoma cells; therefore, polo-like kinase 1 is an attractive target for anticancer treatments. Nobiletin, a natural polymethoxy flavonoid, exhibits a potential antiproliferative effect against a wide variety of cancers. This study targets to identify a reliable diagnostic biomarker for hepatocellular carcinoma and provide a potential therapeutic target for its treatment. Polo-like kinase 1 levels were analyzed in 44 hepatocellular carcinoma patients, 33 non-hepatocellular carcinoma liver cirrhosis patients and 15 healthy controls using the enzyme-linked immunosorbent assay method. Receiver operating characteristics curve analysis was used to establish a predictive model for polo-like kinase 1 relative to α-fetoprotein in hepatocellular carcinoma diagnosis. Furthermore, in the in vitro study, gene expressions were assessed by quantitative polymerase chain reaction in two human hepatocellular carcinoma cell lines after treatment with doxorubicin and polo-like kinase 1 inhibitor volasertib (Vola) either alone or in combination with nobiletin. Cell viability was also determined using the crystal violet assay.: Serum polo-like kinase 1 levels in hepatocellular carcinoma patients were significantly higher than liver cirrhosis and control groups (p < 0.0001). Polo-like kinase 1 showed a reasonable sensitivity, specificity, positive predictive value, and negative predictive value in hepatocellular carcinoma diagnosis. Moreover, nobiletin improved inhibition of cell growth induced by Vola and doxorubicin. Regarding reverse transcription polymerase chain reaction results, nobiletin suppressed expressions of polo-like kinase 1 and proliferating cell nuclear antigen and elevated expressions of P53, poly (ADPribose) polymerase 1, and caspase-3. Nobiletin/doxorubicin and nobiletin/Vola showed a significant increase in caspase-3 activity indicating cell apoptosis. Polo-like kinase 1 may be a potential biomarker for hepatocellular carcinoma diagnosis and follow-up during treatment with chemotherapies. In addition, nobiletin synergistically potentiates the doxorubicin and Vola-mediated anticancer effect that may be attributed partly to suppression of polo-like kinase 1 and proliferating cell nuclear antigen expression and enhancement of chemotherapy-induced apoptosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1010428320914475DOI Listing
April 2020

The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1 subgroup of multiple myeloma cells for TNF-induced cell death.

Cell Death Dis 2019 08 13;10(8):611. Epub 2019 Aug 13.

Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Auvera Haus Grombühlstraße 12, 97080, Würzburg, Germany.

The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1 myeloma cells and a TNF tumor microenvironment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-019-1860-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690881PMC
August 2019

Bioactive Brominated Oxindole Alkaloids from the Red Sea Sponge .

Mar Drugs 2019 Aug 9;17(8). Epub 2019 Aug 9.

Department of Pharmacognosy, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt.

In the present study, LC-HRESIMS-assisted dereplication along with bioactivity-guided isolation led to targeting two brominated oxindole alkaloids (compounds and ) which probably play a key role in the previously reported antibacterial, antibiofilm, and cytotoxicity of crude extracts. Both metabolites showed potent antibacterial activity against Gram-positive bacteria, (minimum inhibitory concentration (MIC) = 8 and 4 µg/mL) and (MIC = 16 and 4 µg/mL), respectively. Furthermore, they displayed moderate biofilm inhibitory activity in (49.32% and 41.76% inhibition, respectively), and moderate in vitro antitrypanosomal activity (13.47 and 10.27 µM, respectively). In addition, they revealed a strong cytotoxic effect toward different human cancer cell lines, supposedly through induction of necrosis. This study sheds light on the possible role of these metabolites (compounds and ) in keeping fouling organisms away from the sponge outer surface, and the possible applications of these defensive molecules in the development of new anti-infective agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/md17080465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723499PMC
August 2019

Thymoquinone upregulates TRAIL/TRAILR2 expression and attenuates hepatocellular carcinoma in vivo model.

Life Sci 2019 Sep 20;233:116673. Epub 2019 Jul 20.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

Aims: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. Indeed, chemotherapeutic drugs-induced systemic toxicity results in suboptimal cancer treatment. Consequently, there is a need for exploring of a safe and effective therapy for cancer patients. This study aimed to evaluate the hepatoprotective effect of thymoquinone (TQ) against thioacetamide (TAA)-induced HCC. Also, we investigated TQ's ability to sensitize cancer cells toward TRAIL/TRAILR2 apoptotic pathway.

Main Methods: Forty male Sprague Dawley rats were divided into 4 groups (n = 10) as follows: control group, CMC group, HCC group and HCC + TQ group. Serum levels of liver function biomarkers and Alpha-Fetoprotein (AFP), as well as hepatic levels of glutathione (GSH) and Alpha-Fetoprotein (MDA) were measured. Transforming growth factor-beta 1 (TGF-β1), TRAILR2, TRAIL, caspase-3, caspase-9, caspase-8 and B cell lymphoma-2 (Bcl-2) mRNA levels were assessed by Quantitative, Real-Time PCR. Fibrosis percentage and necroinflammation were quantified by histopathological examination.

Key Findings: Our results indicated improvement in liver functions, decrease in AFP level and attenuation of HCC progression in TQ treated rats. TQ upregulated TRAIL/TRAILR2 and subsequently enhanced apoptosis as hinted by caspase-3 upregulation and Bcl-2 downregulation. Also, TQ decreased TGF-β1 gene expression level. Moreover, HCC + TQ group showed significant increase in hepatic GSH level and marked decrease in hepatic MDA level.

Significance: This study proved that TQ is able to suppress HCC development via decreasing oxidative stress, suppression of TGF-β1 and induction of TRAIL-mediated apoptosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2019.116673DOI Listing
September 2019

Effects of GLP-1 Receptor Activation on a Pentylenetetrazole-Kindling Rat Model.

Brain Sci 2019 May 14;9(5). Epub 2019 May 14.

Chemistry and Drug Metabolism, IRP, National Institute on Drug Abuse, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224, USA.

: To study the possible anti-seizure and neuroprotective effect of glucagon like peptide 1 (GLP1) analogue (liraglutide) in a pentylenetetrazole (PTZ) induced kindled rat model and its underlying mechanisms. : Thirty Sprague Dawley rats were allocated into 3 equal groups; i) Normal group: normal rats received normal saline, ii) PTZ (kindling) group: received PTZ (50 mg/Kg intraperitoneally (i.p.)) every other day for 2 weeks and iii) PTZ + GLP1 group: same as the PTZ group but rats received liraglutide (75 µg/kg i.p. daily) for 2 weeks before PTZ injection. Seizure severity score, seizure latency and duration were assessed. Also, the expression of caspase-3 (apoptotic marker) and β-catenin (Wnt pathway) by western blotting, markers of oxidative stress (GSH, CAT and MDA) by biochemical assay and the expression of LC3 (marker of autophagy) and heat shock protein 70 (Hsp70) by immunostaining were assessed in hippocampal regions of brain tissues. : PTZ caused a significant increase in Racine score and seizure duration with a significant decrease in seizure latency. These effects were associated with a significant increase in MDA, β-catenin, caspase-3, Hsp70 and LC3 in brain tissues ( < 0.05). Meanwhile, liraglutide treatment caused significant attenuation in PTZ-induced seizures, which were associated with significant improvement in markers of oxidative stress, reduction in LC3, caspase-3 and β-catenin and marked increase in Hsp70 in hippocampal regions ( < 0.05). : Activation of GLP1R might have anticonvulsant and neuroprotective effects against PTZ-induced epilepsy. These effects could be due to suppression of oxidative stress, apoptosis and autophagy and upregulation of Hsp70.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/brainsci9050108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562858PMC
May 2019

The Selection of NFκB Inhibitors to Block Inflammation and Induce Sensitisation to FasL-Induced Apoptosis in HNSCC Cell Lines Is Critical for Their Use as a Prospective Cancer Therapy.

Int J Mol Sci 2019 Mar 15;20(6). Epub 2019 Mar 15.

Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D-97070 Würzburg, Germany.

Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors-Cortisol, MLN4924, QNZ and TPCA1-on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20061306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471923PMC
March 2019

Design, synthesis and docking study of novel picolinamide derivatives as anticancer agents and VEGFR-2 inhibitors.

Eur J Med Chem 2019 Apr 22;168:315-329. Epub 2019 Feb 22.

Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. Electronic address:

Two series of picolinamide derivatives bearing (thio)urea and dithiocarbamate moieties were designed and synthesized as VEGFR-2 kinase inhibitors. All the new compounds were screened for their cytotoxic activity against A549 cancer cell line and VEGFR-2 inhibitory activity. Compounds 7h, 9a and 9l showed potent inhibitory activity against VEGFR-2 kinase with IC values of 87, 27 and 94 nM, respectively in comparison to sorafenib (IC = 180 nM) as a reference. Compounds 7h, 9a and 9l were further screened for their antitumor activity against specific resistant human cancer cell lines from different origins (Panc-1, OVCAR-3, HT29 and 786-O cell lines) where compound 7h showed significant cell death in most of them. Multi-kinase inhibition assays were performed for the most potent VEGFR-2 inhibitors where compound 7h showed enhanced potency towards EGFR, HER-2, c-MET and MER kinases. Cell cycle analysis of A549 cells treated with 9a showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2019.02.050DOI Listing
April 2019

Effects of metformin on apoptosis and α-synuclein in a rat model of pentylenetetrazole-induced epilepsy.

Can J Physiol Pharmacol 2019 Jan 11;97(1):37-46. Epub 2018 Oct 11.

e Chemistry and Drug Metabolism, IRP, National Institute on Drug Abuse, National Institutes of Health, Biomedical Research Center, Baltimore, MD, USA.

The present study was designed to examine the possible neuroprotective and antiepileptic effects of metformin (Metf) in a rat model of pentylenetetrazole (PTZ)-induced epilepsy and its possible underlying mechanisms. Forty male albino rats were assigned to 4 groups of equal size: (1) normal control (NC) group, (2) Metf group: daily treatment with Metf (200 mg/kg, i.p.) for 2 weeks, (3) PTZ group: treatment with PTZ (50 mg/kg, i.p.) every other day for 2 weeks, and (4) Metf + PTZ group: daily treatment with PTZ and metformin (200 mg/kg, i.p.) for 2 weeks. Administration of PTZ caused a significant increase in seizure score and duration, induced a state of oxidative stress (high malondialdehyde, low reduced glutathione and catalase activity), and led to the upregulation of β-catenin, caspase-3, and its cleavage products, Hsp70 and α-synuclein, in hippocampal regions as well as a significant reduction in seizure latency. While Metf treatment significantly ameliorated PTZ-induced seizures, attenuated oxidative stress, and upregulated α-synuclein and β-catenin expression, it also inhibited caspase-3 activation and the release of the cleavage product and caused more upregulation in Hsp70 expression in hippocampal regions (p < 0.05). In conclusion, the antiepileptic and neuroprotective effects of Metf in PTZ-induced epilepsy might be due to the inhibition of apoptosis, attenuation of oxidative stress and α-synuclein expression, and upregulation of Hsp70.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1139/cjpp-2018-0266DOI Listing
January 2019

Vitamin D potentiates anti-tumor activity of 5-fluorouracil via modulating caspase-3 and TGF-β1 expression in hepatocellular carcinoma-induced in rats.

Can J Physiol Pharmacol 2018 Dec 11;96(12):1218-1225. Epub 2018 Sep 11.

a Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.

We investigated the role of vitamin D (Vit D) alone and in combination with 5-fluorouracil (5-FU) in thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) in rats. Fifty male Sprague-Dawley rats were randomized into a control group and 4 groups that received TAA (200 mg/kg, i.p.) twice per week for 16 weeks. These 4 groups were further divided as follows: HCC group; 5-FU group (75 mg/kg, i.p., once weekly for 3 weeks starting from the 12th week); Vit D group (200 IU/kg daily by oral tube for 16 weeks); and 5-FU + Vit D group (received the previously mentioned dosage regimens of 5-FU and Vit D). HCC was detected by histopathological changes in liver sections and the elevation of serum α-fetoprotein (AFP). Treatment with 5-FU + Vit D significantly decreased gene expression of nuclear factor erythroid 2-related factor 2 (NrF2) and transforming growth factor β1 (TGF-β1) at both the gene and protein level and serum AFP concentrations in comparison with their corresponding monotherapy. Moreover, 5-FU + Vit D treatment enhanced apoptosis by increasing caspase-3 gene and protein expression. Conclusively, Vit D enhances antitumor activity of 5-FU in an HCC-induced model and improves liver function of treated animals. Combination therapy in a TAA-induced HCC rat model was more effective than 5-FU or Vit D through the modulation of TGF-β1, caspase-3, and NrF2 expressions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1139/cjpp-2018-0445DOI Listing
December 2018

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1871520618666180717125906DOI Listing
December 2019

l-Carnitine Modulates Epileptic Seizures in Pentylenetetrazole-Kindled Rats via Suppression of Apoptosis and Autophagy and Upregulation of Hsp70.

Brain Sci 2018 Mar 14;8(3). Epub 2018 Mar 14.

Neuroimaging Research Branch, IRP, National Institute on Drug Abuse, National Institutes of Health, Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD 21224, USA.

l-Carnitine is a unique nutritional supplement for athletes that has been recently studied as a potential treatment for certain neuropsychiatric disorders. However, its efficacy in seizure control has not been investigated. Sprague Dawley rats were randomly assigned to receive either saline (Sal) (negative control) or pentylenetetrazole (PTZ) 40 mg/kg i.p. × 3 times/week × 3 weeks. The PTZ group was further subdivided into two groups, the first received oral l-carnitine (l-Car) (100 mg/kg/day × 4 weeks) (PTZ + l-Car), while the second group received saline (PTZ + Sal). Daily identification and quantification of seizure scores, time to the first seizure and the duration of seizures were performed in each animal. Molecular oxidative markers were examined in the animal brains. l-Car treatment was associated with marked reduction in seizure score ( = 0.0002) that was indicated as early as Day 2 of treatment and continued throughout treatment duration. Furthermore, l-Car significantly prolonged the time to the first seizure ( < 0.0001) and shortened seizure duration ( = 0.028). In addition, l-Car administration for four weeks attenuated PTZ-induced increase in the level of oxidative stress marker malondialdehyde (MDA) ( < 0.0001) and reduced the activity of catalase enzyme ( = 0.0006) and increased antioxidant GSH activity ( < 0.0001). Moreover, l-Car significantly reduced PTZ-induced elevation in protein expression of caspase-3 ( < 0.0001) and β-catenin ( < 0.0001). Overall, our results suggest a potential therapeutic role of l-Car in seizure control and call for testing these preclinical results in a proof of concept pilot clinical study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/brainsci8030045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870363PMC
March 2018

Silymarin and caffeine combination ameliorates experimentally-induced hepatic fibrosis through down-regulation of LPAR1 expression.

Biomed Pharmacother 2018 May 22;101:49-57. Epub 2018 Feb 22.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

Aims: Lysophosphatidic acid is a lipid mediator that is supposed to be implicated in hepatic fibrosis. Silymarin and caffeine are natural compounds known for their anti-inflammatory and antioxidant effects. Our study aimed to explore the effect of silymarin, caffeine, and their combination on lysophosphatidic acid receptor 1 (LPAR1) pathway in thioacetamide (TAA)-induced hepatic fibrosis.

Main Methods: Hepatic fibrosis was induced in male Sprague-Dawley rats by intraperitoneal injection of 200 mg/kg of TAA twice a week for 8 weeks. Silymarin (50 mg/kg), caffeine (50 mg/kg), and their combination (50 mg/kg silymarin + 50 mg/kg caffeine) were orally given to rats every day for 8 weeks along with TAA injection. Liver functions were measured. Histopathological examination of liver tissues was performed using hematoxylin and eosin and Masson's trichrome staining. mRNA expressions of LPAR1, transforming growth factor beta 1 (TGF-β1), connective tissue growth factor (CTGF), and alpha smooth muscle actin (α-SMA) were measured using RT-PCR. LPAR1 tissue expression was scored using immunohistochemistry.

Key Findings: Silymarin, caffeine, and their combination significantly improved liver function. They caused significant decrease in fibrosis and necro-inflammatory scores. Combination of silymain and caffeine caused a significant decrease in the necro-inflammatory score than the single treatment with silymarin or caffeine. In addition, silymarin, caffeine, and their combination significantly decreased hepatic LPAR1, TGF-β1, CTGF, and α-SMA gene expressions and LPAR1 tissue expression.

Significance: Silymarin, caffeine, and their combination protect against liver fibrosis through down-regulation of LPAR1, TGF-β1, and CTGF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2018.02.064DOI Listing
May 2018

Chloroquine upregulates TRAIL/TRAILR2 expression and potentiates doxorubicin anti-tumor activity in thioacetamide-induced hepatocellular carcinoma model.

Chem Biol Interact 2018 Jan 10;279:84-94. Epub 2017 Nov 10.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.

Impaired apoptosis and systemic toxicity of chemotherapeutic drugs make cancer treatment suboptimal. Thus, there is urgency for drug repurposing which facilitates discovery of safe and effective combination therapy. This study aimed to evaluate chloroquine's (CQ) ability to trigger TRAIL/TRAILR2 apoptotic pathway in thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) either alone or in combination with doxorubicin (DOX). Moreover, its ability to attenuate DOX-induced cardiotoxicity was investigated. TAA was injected in male Sprague Dawely rats (200 mg/kg; ip; 2 times/week) for 16 weeks. After the 16th week, rats were further divided into different groups (n = 10) and treated for 7 weeks. CQ group (received CQ 25 mg/kg/day; orally), DOX group (received DOX 1 mg/kg; ip; 2 times/week) and CQ/DOX group. Liver function biomarkers, AFP, hepatic levels of MDA and GSH, serum CK-MB and LDH enzymes activity were measured. Quantitative, Real-Time PCR was used to measure TRAIL, TRAILR2, caspase-8, caspase-9, caspase-3, BCL-2 and TGF-β1 genes expression levels. Necroinflammation and fibrosis were scored by histopathological examination. CQ improved liver functions, reduced AFP level and attenuated HCC progression. CQ induced apoptosis via upregulation of TRAIL/TRAILR2, caspase-8, caspase-3 and caspase-8 genes and downregulation of BCL-2 gene. Moreover, CQ/DOX showed marked decrease in hepatic MDA level, serum CK-MB, LDH enzymes activity, as well as marked increase in hepatic GSH level. In conclusion, this work assess the in vivo efficacy of CQ/DOX combination therapy in this HCC model that not only has enhanced anti-tumor activity but it also protects against DOX-induced cardiotoxicity. Nevertheless, more studies should be performed to illustrate the molecular mechanism of CQ's cardioprotective effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cbi.2017.11.009DOI Listing
January 2018

Glycyrrhizin ameliorates high fat diet-induced obesity in rats by activating NrF2 pathway.

Life Sci 2018 Jan 10;193:159-170. Epub 2017 Nov 10.

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

Aim: Obesity based on insulin resistance is a state of chronic oxidative stress and inflammation that are highly regulated through nuclear factor Erythroid 2-related factor 2 (NrF2) pathway.

Materials And Methods: 70 male Wistar rats were randomized into two models. The prophylactic model was 10weeks and rats were grouped into: normal group, GL group (received glycyrrhizin 50mg/kg/day orally along with normal pellet diet), HFD group and HFD+ GL group (received glycyrrhizin along with HFD). The treatment model was 14weeks and rats were grouped into: normal group, HFD group and HFD+GL group (received glycyrrhizin from the week 10).

Key Findings: Glycyrrhizin decreased significantly rat weights and insulin resistance, normalized lipid profile and reduced significantly the adipocytes size in adipose tissue and lipid deposition in the liver tissue through histopathologic examination. Furthermore, glycyrrhizin ameliorated obesity-induced oxidative stress which indicated by significant decrease in liver malondialdehyde level (P<0.001) and increase in the total antioxidant capacity (P<0.001). Interestingly, molecular mechanism of glycyrrhizin was explored, that included significant reduction of liver gluconeogenic enzymes mRNA expression (P<0.001), a significant increase of liver insulin receptor, NrF2 and homooxygenase-1 mRNA expressions (P<0.001) and significant increase and nuclear translocation of NrF2 in liver tissue.

Significance: Glycyrrhizin ameliorates HFD-induced obesity in rats that may be attributed to its ability to increase insulin receptor expression and to activate NrF2 and subsequent homooxygenase-1 pathway. Thus, this work represents a safe natural compound (glycyrrhizin) that has a great role either as prophylaxis or treatment for insulin resistance related to obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2017.11.005DOI Listing
January 2018
-->