Part I: Synthesis, cancer chemopreventive activity and molecular docking study of novel quinoxaline derivatives

The reaction of o-phenylene diamine and ethyl oxamate is reinvestigated and led to 3-aminoquinoxalin-2(1H)-one rather than benzimidazole-2-carboxamide as was previously reported. The structure of the obtained quinoxaline has been confirmed by X-ray. The anti-tumor activity of synthesized quinoxalines 1-21 has been evaluated by studying their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the studied compounds 1-21, compounds 12, 8, 13, 18, 17 and 19, respectively, demonstrated strong inhibitory effects on the EBV-EA activation without showing any cytotoxicity and their effects being stronger than that of a representative control, oleanolic acid. Furthermore, compound 12 exhibited a remarkable inhibitory effect on skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter. The result of the present investigation indicated that compound 12 might be valuable as a potent cancer chemopreventive agent. Moreover, the molecular docking into PTK (PDB: 1t46) has been done for lead optimization of the aforementioned compounds as potential PTK inhibitors.     

Original Article--Predictors of Persistent Functional Tricuspid Regurgitation After Transcatheter Closure of Atrial Septal Defect and its Relationship to Tricuspid Valve Remodeling

ObjectivesThe aim of this study is assessment of persistent functional tricuspid regurgitation in patients with atrial septal defect before and after successful device closure and its relationship to tricuspid valve remodeling.MethodsThe current study was conducted on 60 patients referred to Tanta University Hospital Cardiology Department with the provisional diagnosis of atrial septal defect secundum type for transcatheter closure from December 2017 to December 2019. All patients were subjected to history taking, clinical examination, 12 lead electrocardiography, plain chest X-ray, full two dimension transthoracic echocardiography (for assessment of tricuspid regurgitation severity) before and at 3, 6 months after transcatheter closure.ResultsTricuspid regurgitation was decreased significantly after atrial septal defect closure due to remodeling in the right side. Age, estimated systolic pulmonary artery pressure, right atrium end systolic area, right ventricular end diastolic area, tricuspid valve tenting area and height, tricuspid septal leaflet angle and tricuspid annular diameter were predictors of persistent tricuspid regurgitation after 3 and 6 months of closure. Only estimated systolic pulmonary artery pressure, tricuspid septal leaflet angle and tricuspid annular diameter were independent predictors of persistent tricuspid regurgitation after 3, and 6 months of closure.ConclusionTricuspid regurgitation significantly improved after transcatheter atrial septal defect closure despite its significance at baseline due to remodeling in right side and tricuspid valve.     

Essential oil from halophyte Lobularia maritima: protective effects against CCl4-induced hepatic oxidative damage in rats and inhibition of the production of proinflammatory gene expression by lipopolysaccharide-stimulated RAW 264.7 macrophages

The present study evaluates the chemical profiling of the essential oil of a halophyte, L. maritima (LmEO), and its protective potential against CCl₄-induced oxidative stress in rats. Forty compounds have been identified in LmEO. The major components are α-pinene (3.51%), benzyl alcohol (8.65%), linalool (22.43%), pulegone (3.33%), 1-phenyl butanone (7.33%), globulol (4.32%), γ-terpinene (6.15%), terpinen-4-ol (4.31%), α-terpineol (3.9%), ledol (3.59%), epi-α-cadinol (3.05%) and α-cadinol (4.91%). In comparison with the CCl₄-intoxicated group, LmEO treatment resulted in decreased liver serum marker enzymes, decreased lipid peroxidation and increased antioxidant enzyme levels, with overall further amelioration of oxidative stress. The administration of LmEO to CCl₄-treated rats at a dose of 250 mg kg⁻¹ body weight significantly reduced the toxic effects and the oxidative stress on the liver, thus validating the traditional medicinal claim of this plant. Moreover, the anti-inflammatory activity of LmEO was evaluated in lipopolysaccharide-stimulated murine RAW 264.7 cells. Our oil could modulate the inflammatory mode of the macrophages by causing reduction in iNOS and COX₂ enzymes as well as in IL-1β, IL-6, and TNF-α cytokine levels. These findings suggest that LmEO exerts anti-inflammatory effects by regulating the expression of inflammatory cytokines.

The present study evaluates the chemical profiling of the essential oil of a halophyte, L. maritima (LmEO), and its protective potential against CCl₄-induced oxidative stress in rats.     

NT-proBNP correlated with strain and strain rate imaging of the right ventricle before and after transcatheter closure of atrial septal defects

BackgroundAtrial septal defects (ASD) account for 10% of all congenital heart lesions and represent the third most congenital cardiac defect seen in adults.ObjectivesUsing strain and strain rate imaging (SRI) to assess right ventricular (RV) function in patients with ASD and correlate the results with the level of N-terminal pro-brain natriuretic peptide (NT-proBNP) before and after transcatheter closure.MethodsAt the Hungarian Institute of Cardiology, 27 females and 18 males (mean age 21.53 years) were diagnosed with ASD and admitted for percutaneous closure. Echocardiography was done to assess theleft ventricular (LV), RV and left atrial (LA) diameters. For assessment of systolic RV function, we measured Tricuspid annular plane systolic excursion (TAPSE), strain, and SRI. Amplatzer ASD closure was done under general anesthesia. NT-proBNP levels were measured before and three months after closure.ResultsASD closure was achieved in all patients. The mean ASD diameter was 15.15 mm. The size of the occluder ranged from 10 to 24 mm. The mean LA diameter in the pre-closure group was significantly higher than the control; mean left ventricular end diastolic diameter (LVEDD) showed a non-significant difference from either the control group or the post-closure group, while the mean right ventricular end diastolic diameter (RVEDD) markedly reduced post-closure, and it was significantly higher than the control group. Global RV strain and peak systolic strain rate (PSSR) were significantly higher in ASD group than in the control. The NT-proBNP levels were found to be correlated with pulmonary arterial pressure (PAP), TAPSE, global RV strain and PSSR.ConclusionVolume overload induced by ASD is associated with increased strain values, which return to normal after closure. NT-proBNP is a parameter which correlates to RV pressure, PAP and the amount of shunt volume caused by an ASD.     

Genotoxicity of all-trans retinoic acid (ATRA) and its steroidal analogue EA-4 in human lymphocytes and mouse cells in vitro

The aim of our study is to: (a) investigate whether ATRA and its steroidal analogue EA-4 enhance micronucleation in human lymphocytes and mouse cells in vitro and clarify the micronucleation mechanism by FISH and CREST analysis respectively, and (b) analyze their effect on spindle organization by immunofluorescence of β- and γ-tubulin in mouse cells. We found that they: (a) induce micronucleation mainly via chromosome breakage and chromosome delay in a lesser extent, (b) disturb microtubule network, chromosome orientation and centrosome duplication/separation, (c) accumulate cell cycle at ana-telophases, which exert micronucleation, multiple γ-tubulin signals, nucleoplasmic bridges and multinucleation, and (d) generate multinucleated and multimicronucleated interphase cells.     

Resolved hepatitis B infection in patients receiving immunosuppressive therapy: Monitor versus prophylaxis against viral reactivation

Risk of hepatitis B virus reactivation (HBVr) in patients with resolved HBV infection receiving immunosuppressive therapy has been a growing concern, particularly in the era of biological and targeted therapies. HBV monitoring versus antiviral prophylaxis against HBVr in those patients remains controversial. The aim of the study was to determine the incidence of HBVr and HBV-related hepatitis in resolved HBV patients who received immunosuppressive therapy with or without antiviral prophylaxis. This retrospective study included 64 patients with resolved HBV infection who received different regimens of immunosuppressive medications, with moderate risk of HBVr, for variable underlying diseases. Patients who had chronic HBV infection or other viral infections were excluded. Patients who received B-cell depleting therapies were ruled out. They were divided into 2 groups: group 1 included 31 patients who received immunosuppressive therapy without antiviral prophylaxis, and group 2 included 33 patients who received antiviral prophylaxis (entecavir) within 2 weeks of commencing the immunosuppressive therapy. HBVr, HBV-related hepatitis, and HBV-unrelated hepatitis were assessed along a 1-year duration. The overall HBVr incidence was 1.56% (1/64). This patient who had HBVr was seen in group 1. There were no significant differences between the 2 groups regarding the incidence of HBVr, HBV-related hepatitis, HBV-unrelated hepatitis, and immunosuppressive therapy interruption along a 1-year duration. Based on this retrospective study, close monitoring was equal to antiviral prophylaxis regarding the outcome of resolved HBV patients who received moderate risk immunosuppressive therapy. HBV treatment should commence once HBVr is confirmed.     

Elevated Cytomegalovirus and Epstein-Barr virus burden in rheumatoid arthritis: A true pathogenic role or just a coincidence

BackgroundCytomegalovirus (CMV) and Epstein-Barr virus (EBV) have created great interest as their immunomodulatory action and latent forms could play a role in the advance of autoimmune diseases.Aim of the workTo investigate the viral load of CMV and EBV in the serum of rheumatoid arthritis (RA) patients’ and study their association with the clinical and laboratory profiles.Patients and methodsThe study included 50 RA patients and 32 healthy controls. Disease activity score (DAS28) was assessed and the medications received reported. Quantitation of CMV and EBV DNA in serum of all subjects was achieved by real-time polymerase chain reaction.ResultsPatients were 38 females and 12 males with mean age of 43.1 ± 12 years, disease duration of 6.5 ± 5.7 years; age of onset 36.6 ± 12.8 years. CMV DNA was detected in serum of 68% (34\50) patients, while EBV DNA was detected in 40% (20\50). Fourteen (28%) patients had both EBV and CMV DNA detected in serum. No viruses were detected in serum of 10/50 (20%) patients or in healthy controls. The mean viral load of CMV and EBV detected were 42005 ± 24805 copies/ml and 18756 ± 24937 copies/ml respectively. A significant increased frequency of anemia (p < 0.0001), Raynaud's (p < 0.0001), oral ulcers (p = 0.014) and arthritis (p < 0.0001) was detected in those infected with CMV versus those infected with EBV.ConclusionsA high incidence of CMV and EBV was detected in RA patients with increased viral load than described previously. Frequencies of RA disease manifestations are significantly higher in CMV infected patients compared to those infected with EBV.