Evaluation of cytotoxicity and adaptability of a novel bioceramic root canal sealer: An in vitro and scanning electron microscope study.

Context: Cytotoxicity and adaptability are among the highly imperative tests that should be performed on a novel endodontic material to ensure its successful implementation in endodontic treatment. Aims: Assess a recently introduced bioceramic root canal sealer CeramoSeal with TotalFill BC and AH plus sealers regarding the cytotoxicity and adaptability. Materials and Methods: Five sealer discs were prepared for each sealer and their extracts were cultured in 96-well plates containing human fibroblasts for 24 h. After their incubation, MTT solution was added to each well plate using an enzyme-linked immunosorbent assay plate reader was implemented to calculate the percentage of viable cells. Thirty mandibular single-rooted premolars were prepared using the Edge Endo rotary system, teeth were divided into three groups (n = 10) based on the sealer type: Group 1 CeramoSeal, Group 2 Totalfill, and Group 3 AH plus sealer. Teeth were sectioned longitudinally and viewed under a scanning electron microscope where the region with the gaps was identified and quantified as a percentage of the root canal's overall area. Statistical Analysis: One-way ANOVA test was used for cytotoxicity, while Kruskal-Wallis and Friedman's tests were used for adaptability. Results: Ceramoseal statistically significantly showed the lowest viability, at high concentrations AH plus showed the highest cell viability, while at lower concentration Totalfill BC sealer showed the highest cell viability percentage. The gap percentages were statistically significantly higher in Ceramoseal group, there was no statistically significant difference between AH Plus and Totalfill groups. Conclusions: Ceramoseal sealer exhibited the lowest viability and highest gap percentage compared to the other sealers.

Design, synthesis, anticancer, and antibacterial evaluation of some quinazolinone-based derivatives as DHFR inhibitors.

Two series of quinazolinone derivatives were designed and synthesized as dihydrofolate reductase (DHFR) inhibitors. All compounds were evaluated for their antibacterial and antitumor activities. Antibacterial activity was evaluated against three strains of Gram-positive and Gram-negative bacteria. Compound 3d exhibited the highest inhibitory activity against Staphylococcus aureus DHFR (SaDHFR) with IC50 of 0.769 ± 0.04 µM compared to 0.255 ± 0.014 µM for trimethoprim. Compound 3e was also more potent than trimethoprim against Escherichia coli DHFR (EcDHFR) with IC50 of 0.158 ± 0.01 µM and 0.226 ± 0.014 µM, respectively. Compound 3e exhibited a promising antiproliferative effect against most of the tested cancer cells. It also showed potent activity against leukemia (CCRF-CEM, and RPMI-8226); lung NCI-H522, and CNS U251 with GI% of 65.2, 63.22, 73.28, and 97.22, respectively. The cytotoxic activity of compound 3e was almost half the activity of doxorubicin against CCRF-CEM cell line with IC50 of 1.569 ± 0.06 µM and 0.822 ± 0.03 µM, respectively. In addition, compound 3e inhibited human DHFR with IC50 value of 0.527 ± 0.028 µM in comparison to methotrexate (IC50 = 0.118 ± 0.006 µM). Compound 3e caused an arrest of the cell cycle mainly at the S phase and caused a rise in the overall apoptotic percentage from 2.03% to 48.51%. (23.89-fold). Treatment of CCRF-CEM cells with compound 3e produced a significant increase in the active caspase-3 level by 6.25-fold compared to untreated cells. Molecular modeling studies were performed to evaluate the binding pattern of the most active compounds in the bacterial and human DHFR.

Coumarin derivatives with potential anticancer and antibacterial activity: Design, synthesis, VEGFR-2 and DNA gyrase inhibition, and in silico studies.

A series of coumarin derivatives were designed, synthesized, and evaluated for their antiproliferative activity. Compound 3e exhibited significant antiproliferative activity and was further evaluated at five doses at the National Cancer Institute. It effectively inhibited vascular endothelial growth factor receptor-2 (VEGFR-2) with an IC50 value of 0.082 ± 0.004 µM compared with sorafenib. While compound 3e significantly downregulated total VEGFR-2 and its phosphorylation, it markedly reduced the HUVEC's migratory potential, resulting in a significant disruption in wound healing. Furthermore, compound 3e caused a 22.51-fold increment in total apoptotic level in leukemia cell line HL-60(TB) and a 6.91-fold increase in the caspase-3 level. Compound 3e also caused cell cycle arrest, mostly at the G1/S phase. Antibacterial activity was evaluated against Gram-positive and Gram-negative bacterial strains. Compound 3b was the most active derivative, with the same minimum inhibitory concentration and minimum bactericidal concentration value of 128 µg/mL against K. pneumonia and high stability in mammalian plasma. Moreover, compounds 3b and 3f inhibited Gram-negative DNA gyrase with IC50 = 0.73 ± 0.05 and 1.13 ± 0.07 µM, respectively, compared to novobiocin with an IC50 value of 0.17 ± 0.02 µM. The binding affinity and pattern of derivative 3e toward the VEGFR-2 active site and compounds 3a-c and 3f in the DNA gyrase active site were evaluated using molecular modeling. Overall, ADME studies of the synthesized coumarin derivatives displayed promising pharmacokinetic properties.

New trends in synthetic drugs and natural products targeting 20S proteasomes in cancers.

Cancer is a global health challenge that remains to be a field of extensive research aiming to find new anticancer therapeutics. The 20S proteasome complex is one of the targets of anticancerdrugs, as it is correlated with several cancer types. Herein, we aim to discuss the 20S proteasome subunits and investigatethe currently studied proteasome inhibitors targeting the catalytically active proteasome subunits. In this review, we summarize the proteindegradation mechanism of the 20S proteasome complex and compareit with the 26S proteasome complex. Afterwards, the localization of the 20S proteasome is summarized as well as its use as a diagnosticandprognostic marker. The FDA-approved proteasome inhibitors (PIs) under clinical trials are summarized and their current limited use in solid tumors is also reviewed in addition to the expression of theß5 subunit in differentcell lines. The review discusses in-silico analysis of the active subunit of the 20S proteasome complex. For development of new proteasome inhibitor drugs, the natural products inhibiting the 20S proteasome are summarized, as well as novel methodologies and challenges for the natural product discovery and current information about the biosynthetic gene clusters encoding them. We herein briefly summarize some resistancemechanismsto the proteasomeinhibitors. Additionally, we focus on the three main classes of proteasome inhibitors: 1] boronic acid, 2] beta-lactone and 3] epoxide inhibitor classes, as well as other PI classes, and their IC50 values and their structure-activity relationship (SAR). Lastly,we summarize several future prospects of developing new proteasome inhibitors towards the treatment of tumors, especially solid tumors.

Design and synthesis of novel quinazolinone-based derivatives as EGFR inhibitors with antitumor activity.

Nineteen new quinazolin-4(3H)-one derivatives 3a-g and 6a-l were designed and synthesised to inhibit EGFR. The antiproliferative activity of the synthesised compounds was tested in vitro against 60 different human cell lines. The most potent compound 6d displayed superior sub-micromolar antiproliferative activity towards NSC lung cancer cell line NCI-H460 with GI50 = 0.789 µM. It also showed potent cytostatic activity against 40 different cancer cell lines (TGI range: 2.59-9.55 µM). Compound 6d potently inhibited EGFR with IC50 = 0.069 ± 0.004 µM in comparison to erlotinib with IC50 value of 0.045 ± 0.003 µM. Compound 6d showed 16.74-fold increase in total apoptosis and caused cell cycle arrest at G1/S phase in breast cancer HS 578T cell line. Moreover, the most potent derivatives were docked into the EGFR active site to determine their binding mode and confirm their ability to satisfy the pharmacophoric features required for EGFR inhibition.

Design, synthesis and evaluation of anticancer activity of new pyrazoline derivatives by down-regulation of VEGF: Molecular docking and apoptosis inducing activity.

Two series of pyrazoline compounds were designed and synthesized as antiproliferative agents by VEGFR pathway inhibition. All synthesized compounds were screened by the National Cancer Institute (NCI), Bethesda, USA for anticancer activity against 60 human cancer cell lines. Compound 3f exhibited the highest anticancer activity on the ovarian cell line (OVCAR-4) with IC50 = 0.29 µM and on the breast cell line (MDA-MB-468) with IC50 = 0.35 µM. It also exhibited the highest selectivity index (SI = 74). Compound 3f caused cell cycle arrest in OVCAR-4 cell line at the S phase which consequently inhibited cell proliferation and induced apoptosis. Moreover, 3f showed potent down-regulation of VEGF and p-VEGFR-2. Docking studies showed that compound 3f interacts in a similar pattern to axitinib on the VEGFR-2 receptor. The same compound was also able to fit into the gorge of STAT3 binding site, the transcription factor for VEGF, which explains the VEGF down-regulation.

Design and synthesis of methoxyphenyl- and coumarin-based chalcone derivatives as anti-inflammatory agents by inhibition of NO production and down-regulation of NF-κB in LPS-induced RAW264.7 macrophage cells.

Exaggerated inflammatory responses may cause serious and debilitating diseases such as acute lung injury and rheumatoid arthritis. Two series of chalcone derivatives were prepared as anti-inflammatory agents. Methoxylated phenyl-based chalcones 2a-l and coumarin-based chalcones 3a-f were synthesized and compared for their inhibition of COX-2 enzyme and nitric oxide production suppression. Methoxylated phenyl-based chalcones showed better inhibition to COX-2 enzyme and nitric oxide suppression than the coumarin-based chalcones. Among the 18 synthesized chalcone derivatives, compound 2f exhibited the highest anti-inflammatory activity by inhibition of nitric oxide concentration in LPS-induced RAW264.7 macrophages (IC50 = 11.2 µM). The tested compound 2f showed suppression of iNOS and COX-2 enzymes. Moreover, compound 2f decreases in the expression of NF-κB and phosphorylated IκB in LPS-stimulated macrophages. Finally, docking studies suggested the inhibition of IKKß as a mechanism of action and highlighted the importance of 2f hydrophobic interactions.

Lipid Biomarkers as Predictors of Diastolic Dysfunction in Diabetes with Poor Glycemic Control.

Uncontrolled type-1 diabetes (T1DM) can lead to dyslipidaemia and albuminuria, which may promote cardiovascular injuries. However, some lipidemic factors could be useful in predicting cardiac dysfunction. Seventy-eight adolescents under insulin treatment due to a 6-year history of T1DM and were retrospectively examined. Glycemia, lipidemia, and albuminuria were measured in addition to development of cardiovascular abnormalities Both girls and boys showed higher HbA1c and fasting blood glucose and 27.1% females and 33.3% males exhibited microalbuminuria though their plasma levels of total cholesterol (TC), triglycerides (TG), and low-density lipoproteins (LDL) and high-density lipoproteins (HDL lipoproteins were in the normal range. They exhibited a preserved systolic function, but 50% of females and 66.6% of males had developed diastolic failures. Interestingly, girls with diastolic dysfunction showed significantly lower concentrations of HDL and higher TC/HDL and TG/HDL ratios. In fact, low HDL levels (OR 0.93; 95% CI 0.88-0.99; p = 0.029) and high TC/HDL (OR 2.55; 95% CI 1.9-5.45; p = 0.016) and TG/HDL (OR 2.74; 95% CI 1.12-6.71; p = 0.028) ratios associated with the development of diastolic complications. The cut-off values for HDL, TC/HDL, and TG/HDL were 49 mg/dL, 3.0 and 1.85, respectively. HDL and TC/HDL and TG/HDL ratios may be useful for predicting diastolic dysfunction in girls with uncontrolled T1DM.

New guidelines for diagnosis of rheumatic fever; do they apply to all populations?

BACKGROUND AND OBJECTIVES: To evaluate the efficacy of recently updated Jones criteria for diagnosis of rheumatic fever in high incidence populations like Egypt. METHODS: Clinical data of 891 Egyptian patients with rheumatic fever, aged 5-15 years in a highly specialized rheumatic fever clinic were reviewed retrospectively from March 2014 to March 2016. Discriminant analysis was used to detect the most effective predictors for diagnosis of rheumatic fever in our patients incorporating echocardiographic criteria. We compared our results to the most recent update by the American Heart Association. RESULTS: The most effective predictors of rheumatic fever included arthritis, carditis, chorea, aortic regurgitation, grades of mitral regurgitation ≥10mm length and velocity ≥2.5 m/s, thick anterior mitral valve leaflets, elevated acute phase reactants, positive family history and prolonged PR interval. Our predictors showed a high sensitivity of 93%, a specificity of 62% and an overall prediction accuracy of 81.4%. CONCLUSION: We concluded that strict application of updated Jones criteria may lead to under diagnosis of rheumatic fever in highly endemic countries. We recommend further studies to examine the sensitivity of the most recent update of Jones criteria on other highly endemic populations.

Association of ficolin-2 (FCN2) functional polymorphisms and protein levels with rheumatic fever and rheumatic heart disease: relationship with cardiac function.

INTRODUCTION: A role for ficolin (FCN) 2 gene polymorphisms in the pathogenesis of recurrent severe streptococcal infections and rheumatic carditis has been suggested. The aim of the study was to evaluate a possible relationship between single nucleotide polymorphisms located at positions -602 and -4 of the FCN2 gene and FCN2 serum levels and risk of development of rheumatic fever (RF) and rheumatic heart disease (RHD). MATERIAL AND METHODS: Seventy-seven Caucasian Egyptian patients with RF were recruited with a control group of 43 healthy subjects. DNA was extracted for analysis of the FCN2 gene at positions -602 and -4 and serum protein level was measured by ELISA. RESULTS: FCN2 AA genotype at the -4 position was more frequently observed in RF and RHD patients, as compared to healthy subjects (p = 0.005 and p = 0.013, respectively); furthermore, the A allele was identified as a possible risk factor for the development of RF (p = 0.023, OR = 1.852, 95% CI: 1.085-3.159). The haplotype -602/-4 G/A, which was associated with low median levels of L-ficolin, was observed more frequently in the RF group when compared to the healthy subjects (74/162, 48.1% vs. 29/420, 33.7%, OR = 1.834, 95% CI: 1.034-3.252, p = 0.038). Low serum ficolin-2 level was associated with ESV and EDV increases. FCN 2 level was significantly lower with AA genotypes than GG+AG genotypes of the -4 position (56.68 ±17.90 vs. 66.05 ±18.79, p = 0.008). CONCLUSIONS: Polymorphisms linked to low levels of L-ficolin may render an individual at risk of recurrent and/or severe streptococcal infection. The -4 AA genotype and -602/-4 G/A haplotype are possible risk factors for the development of carditis.

New 3-Substituted-2-(4-hydroxyanilino)pyridine Derivatives: Synthesis, Antitumor Activity, and Tubulin Polymerization Inhibition.

A series of new pyridine derivatives 4a-c, 5a-d, 6a-d, 7a-f, and 8a-f structurally related to ABT-751 were synthesized and characterized by spectroscopic means and elemental analysis. All the synthesized compounds were tested for their cytotoxic activity in vitro against the HCT-116 and HepG-2 cancer cell lines using the MTT assay. The results showed that compound 8d has higher cytotoxic activity than the reference antimitotic agent colchicine, against both tested cell lines, with IC50 = 0.52 and 1.40 µM, respectively. The three most active compounds, 5d, 8b, and 8d, were further screened in vitro for inhibition of tubulin and showed remarkable results in comparison to colchicine.

Synthesis of New N1-Substituted-5-aryl-3-(3,4,5-trimethoxyphenyl)-2-pyrazoline Derivatives as Antitumor Agents Targeting the Colchicine Site on Tubulin.

A series of pyrazoline derivatives 2a-e, 3a-e and 4a-e structurally related to combretastatin A4 (CA-4) were synthesized and characterized by spectroscopic means and elemental analyses. In these compounds, the cis double bond of CA-4 was replaced with the pyrazoline ring aiming to enhance the cytotoxic effects displayed by CA-4 and to prevent the cis/trans isomerization that is associated with inactivation of CA-4. The cytotoxic activity of all new compounds was investigated in vitro against MCF-7 and HCT-116 cell lines. The inhibition of tubulin polymerization by the most active compounds 3d, 4a and e was evaluated. The cytotoxicity of 4e was correlated with induction of apoptosis and caspase-3 activation in vitro thus indicating the apoptotic pathway of anticancer effect of these compounds. Furthermore, in vivo evaluation of the synthesized compounds was carried out against Ehrlich's ascites carcinoma (EAC) solid tumor grown in mice. Compounds 2c, 3a and e showed significant reduction in tumor weight, and about 2-4 fold increase in caspase-3 expression.

Design, Synthesis, and Antitumor Activity of Novel 5-Pyridyl-1,3,4-oxadiazole Derivatives against the Breast Cancer Cell Line MCF-7.

Various 1,3,4-oxadiazole-2-thiol derivatives have considerable potential in the field of antitumor activity. On the basis of the structure of the highly active reported oxadiazole analogues, 36 novel compounds were designed. Their molecular transport properties were predicted using a computer-aided program, and they were then synthesized and tested for anticancer activity against the breast cancer cell line MCF-7. Most of the tested compounds showed excellent to potent cytotoxic activity. Docking studies were carried out to examine the possibilities of the target compounds to become lead compounds in the future after more biological investigations. Compounds 18 and 22 were more active than the reference drug with IC50 values of 0.010 µM and 0.012 µM, respectively, and binding energy scores of -10.32 and -10.25, respectively.

High prevalence of complex congenital cardiac anomalies detected by fetal echocardiography in a cohort of Saudi women referred for prenatal assessment.

With the new advances in computer technology, fetal echocardiography (FE) is becoming an accurate reliable tool for prenatal diagnosis of congenital heart diseases (CHD) which affect the postnatal care and management plans. We retrospectively described FE studies of 50 Saudi women referred for prenatal assessment. The mean maternal age was 30.6 -/+ 4.4 years; mean gestational age during the study was 26.16 -/+ 4.2 weeks. 58% had consanguineous marriage, and 72% had positive family history of CHD. CHD was found in 28% of cases. Postnatal echocardiographic study confirmed the prenatal diagnosis. The most common referral reason was history of CHD (56%) followed by abnormal sonographic findings during routine assessment (32%). However, the prevalence of CHD was higher in the second group (37.5%) than the first one (28.6%).There was no significant difference between cases with normal FE and those with CHD as regard the referral reasons. The most frequent lesion detected was those with univentricular morphology (42.85%), followed by atrioventricular septal defect (21.4%) and ventricular septal defect (VSD) (14.3%). When we categorized the structural CHD according to severity, complex CHD constituted 78.57%, while significant lesions were 14.3%. Eight cases had dysrhythmia, none of them had CHD.

Influence of pulmonary hypertension on outcome of Egyptian patients with congenital diaphragmatic hernia: an experience in low-resource settings.

Congenital Diaphragmatic Hernia (CDH) is a rare congenital anomaly that includes pulmonary hypoplasia and pulmonary hypertension and associated with high mortality and morbidity. Pulmonary hypertension is considered the main cause of mortality in patients with CDH. Recently, many new management modalities mainly directed to control pulmonary hypertension have been introduced which led to improved survival. These modalities are not available in countries with low resource settings as in Africa and Asia. This work detected the effect of pulmonary hypertension on the outcome of patients with CDH in absence of such new management modalities. The study included retrospective analysis of 50 patients with CDH referred to the echocardiography unit, Cairo University Children's Hos-pital from the Neonatal Surgical Unit (September 2010 to September 2011). 60% of patients were male with a median age 6.5 days. (41) 82% had CDH repair at a median of 4 days from admission, 26 (63.4%) needed postoperative inotropic support. The median hospital stay was 8 days. There was 50% mortality rate, 18% of them without surgical intervention. The mean pre-operative PAP was significantly higher than postoperatively (p value .000). Non survival patients had significantly higher mean PAP both pre and post operatively, more inotropic support, more delayed surgery, and lower age at admission compared to survival. Patients were classificed regarding severity of PH, those with severe PH had significantly younger age, more delayed surgery, needed more inotropic support postoperatively and with highest mortality compared to the mild/moderate PH ones. There was a significant negative correlation between preoperative PAP and age at admission and positive correlation with both, day of surgery and postoperative PAP. Post-operative PAP had positive correlation with day of surgery and hospital stay. There was an association between both pre and postoperative PAP and use of inotropes. Logistic re-gression analysis showed that postoperative PAP is a significant predictor for morta-lity (P value .001, OR 1.164, 95.0% C.I. for OR 1.068:1.270).

Treatment of streptococcal pharyngitis with once-daily amoxicillin versus intramuscular benzathine penicillin G in low-resource settings: a randomized controlled trial.

BACKGROUND: Primary prevention of acute rheumatic fever is achieved by proper antibiotic treatment of group A ß -hemolytic streptococcal (GAS) pharyngitis. METHODS: To assess noninferiority of oral amoxicillin to intramuscular benzathine penicillin G (IM BPG). Children (2 to 12 years) meeting enrollment criteria were randomized 1:1 to receive antibiotic treatment in 2 urban outpatient clinics in Egypt and Croatia. RESULTS: A total of 558 children (Croatia = 166, Egypt = 392) were randomized, with 368 evaluable in an intention-to-treat (ITT) analysis, and 272 evaluable in the per protocol (PP) analysis. In Croatia, ITT and PP treatment success rates were comparable for IM BPG and amoxicillin (2.5% difference vs 1.1% difference, respectively). In Egypt, amoxicillin was not comparable with IM BPG in ITT analysis (15.1% difference), but was comparable in PP analysis (-9.3% difference). CONCLUSION: If compliance is a major issue, a single dose of IM BPG may be preferable for treatment of GAS pharyngitis.