Vascular endothelial cell proliferation and angiogenesis are all crucially impacted by Endothelial Growth Factor Receptor-2 (VEGFR-2). Its expression is significantly boosted throughout pathologic ...angiogenesis causing the development of tumors. Sothat, inhibition of VEGFR-2 has crucial role in cancer treatment. In this study, novel semisynthetic theobromine derivatives were rationally designed as VEGFR-2 inhibitors and subjected to in vitro testing for their ability to block VEGFR-2 activation. Furthermore, the antiproliferative effects of these derivatives were evaluated. Compound 7 g exhibited the most potent anti-VEGFR-2 activity, with an IC
50
value of 0.072 µM, and demonstrated excellent dose-dependent inhibitory activity against both MCF-7 and HepG2 cancer cells with IC
50
values of 19.35 and 27.89 µM, respectively. Notably, compound 7 g exhibited high selectivity indices of 2.6 and 1.8 against MCF-7 and HepG2 cells, respectively. Compound 7 g induced G2/M phase cell cycle arrest, promoted apoptosis, and boosted immunomodulation by downregulating TNF-α expression and upregulating IL-2 levels in MCF-7 cells. The molecular docking analysis revealed that compound 7 g could bind effectively to the active site of VEGFR-2, and molecular dynamic simulations confirmed the stability of the VEGFR-2/compound 7 g complex. Furthermore, ADME and toxicity profiling indicated the potential suitability of these compounds as drug candidates. In summary, compound 7 g hold promise as a VEGFR-2 inhibitor.
Communicated by Ramaswamy H. Sarma
The overexpression of the Epidermal Growth Factor Receptor (EGFR) marks it as a pivotal target in cancer treatment, with the aim of reducing its proliferation and inducing apoptosis. This study aimed ...at the CADD of a new apoptotic EGFR inhibitor. The natural alkaloid, theobromine, was used as a starting point to obtain a new semisynthetic (di-ortho-chloro acetamide) derivative (T-1-DOCA). Firstly, T-1-DOCA’s total electron density, energy gap, reactivity indices, and electrostatic surface potential were determined by DFT calculations, Then, molecular docking studies were carried out to predict the potential of T-1-DOCA against wild and mutant EGFR proteins. T-1-DOCA’s correct binding was further confirmed by molecular dynamics (MD) over 100 ns, MM-GPSA, and PLIP experiments. In vitro, T-1-DOCA showed noticeable efficacy compared to erlotinib by suppressing EGFRWT and EGFRT790M with IC50 values of 56.94 and 269.01 nM, respectively. T-1-DOCA inhibited also the proliferation of H1975 and HCT-116 malignant cell lines, exhibiting IC50 values of 14.12 and 23.39 µM, with selectivity indices of 6.8 and 4.1, respectively, indicating its anticancer potential and general safety. The apoptotic effects of T-1-DOCA were indicated by flow cytometric analysis and were further confirmed through its potential to increase the levels of BAX, Casp3, and Casp9, and decrease Bcl-2 levels. In conclusion, T-1-DOCA, a new apoptotic EGFR inhibitor, was designed and evaluated both computationally and experimentally. The results suggest that T-1-DOCA is a promising candidate for further development as an anti-cancer drug.
Purpose To discuss the effect of coronavirus disease 2019 (COVID-19) pandemic on ophthalmology practice and share our experience to ensure a continual ophthalmology service to the patients at Cairo ...University Hospital.
Patients and methods This is a retrospective study. Administrative measures taken to address challenges in different ophthalmology care settings during this pandemic are discussed. These include infection control measures, logistics, and manpower strategies. The effect of these measures on the number of ocular surgeries performed are analyzed in comparison with the same period of the last year. The records of all patients who underwent ocular surgeries between mid-March and mid-July 2020 at Kasr Al Ainy Hospital are compared with the records of patients who had ocular surgeries in the same time frame in 2019.
Results The total number of elective surgical cases in the period of COVID-19 lockdown (2020) was 392 in comparison with 2470 during the same period last year. The decrease was statistically significant (P=0.0035). Intravitreal injection for macular edema was the most common indication of elective surgeries during the lockdown. The total number of emergency cases operated in the period of COVID-19 lockdown was 733 in comparison with 959 during the same period last year. The difference was not statistically significant (P=0.40). Repair of globe rupture was the most common indication of emergency surgeries.
Conclusion Our protocol was able to provide sight-saving measures needed in many patients during this outbreak. With COVID-19 is expected to continue for a long time, we need to revise our protocols to improve the service presented to the patients especially those with nonurgent conditions, while maintaining the safety of both patients and health care workers.
BACKGROUNDThis study focuses on the development and evaluation of (E)-N-(3-(1-(2-(4-bromobenzoyl)hydrazono)ethyl)phenyl)nicotinamide (BHEPN) as a potential inhibitor of Vascular Endothelial Growth ...Factor Receptor-2 (VEGFR-2).METHODSComputational investigations as density function theory (DFT), docking, molecular dynamics (MD) simulations, and ADMET) in addition to in vitro (VEGFR-2 inhibition, cytotoxicity against HepG2 and MCF-7 cancer cell lines, selectivity index, cells cycle analysis, apoptosis investigation, and cells migration assay) studies were conducted.RESULTSDFT calculations determined the three-dimensional structure and indicated the reactivity of BHEPN. Molecular docking, and MD simulations analysis showed the BHEPN's binding affinity and its potential as a VEGFR-2 inhibitor. ADMET assessments predicted BHEPN's safety and drug-like characteristics. In vitro investigations confirmed the inhibition of VEGFR-2 with an IC50 value of 0.320 ± 0.012 µM. BHEPN also exhibited remarkable cytotoxic effects against HepG2 and MCF-7 cancer cell lines, with IC50 values of 0.19 ± 0.01 µM and 1.18 ± 0.01 µM, respectively, outperforming Sorafenib's IC50 values (2.24 ± 0.06 µM and 3.17 ± 0.01 µM), respectively. Notably, BHEPN displayed a higher IC50 value of 4.11 ± 0 µM against the non-carcinogenic Vero cell lines, indicating selectivity index values of 21.6 and 3.4 against the tested cancer cell lines, respectively. In a flow cytometry assay, BHEPN induced HepG2 cell cycle arrest at the G1/S phase. Moreover, BHEPN increased the incidence of early and late apoptosis in HepG2 cell lines (from 1.38% and 0.22%) in control cells to (4.11-26.02%) in the treated cells, respectively. Additionally, the percentage of necrosis raised to 13.39%, in contrast to 0.62% in control cells. Finally, BHEPN was able to reduce the migration and wound healing abilities in HepG2 cells to 38.89% compared to 87.92% in untreated cells after 48 h. These in vitro results aligned with the computational predictions, providing strong evidence of BHEPN's efficacy and safety in anticancer applications.CONCLUSIONSBHEPN is a promising candidate for the development of novel anticancer agents through further in vitro and in vivo investigations.
VEGFR-2 is one of the most effective targets in cancer treatment.
The design and semi-synthesis of new theobromine derivatives as potential VEGFR-2 inhibitors.
and
evaluation of the synthesized ...compounds.
Compound
demonstrated excellent antiproliferative and VEGFR-2 inhibitory effects with significant apoptotic activity. It modulated the immune response by increasing IL-2 and reducing TNF-α levels. Docking and molecular dynamics simulations revealed the compound’s binding affinity with VEGFR-2. Lastly, computational absorption, distribution, metabolism, excretion and toxicity studies indicated the high potential of compound
for drug development.
Compound
could be a promising anticancer agent targeting VEGFR-2.
The eukaryotic CDC45/MCM2-7/GINS (CMG) helicase unwinds the DNA double helix during DNA replication. The GINS subcomplex is required for helicase activity and is, therefore, essential for DNA ...replication and cell viability. Here, we report the identification of 7 individuals from 5 unrelated families presenting with a Meier-Gorlin syndrome-like (MGS-like) phenotype associated with hypomorphic variants of GINS3, a gene not previously associated with this syndrome. We found that MGS-associated GINS3 variants affecting aspartic acid 24 (D24) compromised cell proliferation and caused accumulation of cells in S phase. These variants shortened the protein half-life, altered key protein interactions at the replisome, and negatively influenced DNA replication fork progression. Yeast expressing MGS-associated variants of PSF3 (the yeast GINS3 ortholog) also displayed impaired growth, S phase progression defects, and decreased Psf3 protein stability. We further showed that mouse embryos homozygous for a D24 variant presented intrauterine growth retardation and did not survive to birth, and that fibroblasts derived from these embryos displayed accelerated cellular senescence. Taken together, our findings implicate GINS3 in the pathogenesis of MGS and support the notion that hypomorphic variants identified in this gene impaired cell and organismal growth by compromising DNA replication.
Linagliptin (Lina) is a DPP-4 inhibitor used to treat type II diabetes. However, it has a poor oral bioavailability of 29.5% due to both first-pass effect and P-glycoprotein efflux, offering a ...significant drawback to its general use. Our research goals were to increase Lina bioavailability and develop an injectable sustained release nanoparticle (NP) formulation with a lower administration frequency to improve patient compliance. All formulations were prepared by single emulsion solvent evaporation technique using poly d,l-lactic-co-glycolic acid (PLGA) as a polymer according to a design of experiment (DoE). The dependent variables were lactide concentration, polymer concentration, and organic phase ratio, while the independent variables were entrapment efficiency, particle size, and in-vitro release after 7 days. In-vivo study on rats through evaluation of pharmacodynamics and pharmacokinetics parameters. The selected formula consisted of a 65:35 lactide concentration, with 150 mg PLGA, and 10 % organic solvent, while TEM of the formula showed a sphere-shaped structure with a smooth surface. Particle size was 541.178 ± 10.4 nm, and entrapment efficiency was 67.134 %, with a long-term sustained release reach of seven days. The pharmacokinetic results showed that AUC 0-∞ increased significantly from 33.73 to 60.53 ng/ml.h, t1/2 was significantly prolonged (231.6 ± 43.9 vs. 11.8 ± 0.3 h), Mean residence time (MRT) was 344.1 ± 61 vs. 3.9 ± 1.5 h, and Vd was 4731 ± 393.7 vs 161.4 ± 87.20 ng/ml, for Lina NPs and oral Lina solutions, respectively (P > 0.05). Pharmacodynamics study of optimized formulation show obvious decrease in blood glucose level in comparison to oral Lina. These findings suggest that the PLGA Lina NPs offer a novel strategy for the development of a once-weekly injectable medicine to help manage blood glucose in individuals who have exhibited the capability to manage type 2 diabetes mellitus.
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Construction Engineering and Management (CEM) is a broad domain with publications covering interrelated subdisciplines and considered a key source of knowledge sharing. Previous studies used ...scientometric methods to assess the current impact of CEM publications; however, there is a need to predict future citations of CEM publications to identify the expected high-impact trends in the future and guide new research efforts. To tackle this gap in the literature, the authors conducted a study using Machine Learning (ML) algorithms and Social Network Analysis (SNA) to predict CEM-related citation metrics. Using a dataset of 93,868 publications, the authors trained and tested two machine learning classification algorithms: Random Forest and XGBoost. Validation of the RF and XGBoost resulted in a balanced accuracy of 79.1% and 79.5%, respectively. Accordingly, XGBoost was selected. Testing of the XGBoost model revealed a balanced accuracy of 80.71%. Using SNA, it was found that while the top CEM subdisciplines in terms of the number of predicted impactful papers are “Project planning and design”, “Organizational issues”, and “Information technologies, robotics, and automation”; the lowest was “Legal and contractual issues”. This paper contributes to the body of knowledge by studying the citation level, strength, and interconnectivity between CEM subdisciplines as well as identifying areas more likely to result in highly cited publications.
•New nicotinamide derivatives were designed and synthesized as VEGFR-2 inhibitors.•Cytotoxicity against MCF-7, HepG2, and HCT-116 cells was evaluated.•Evaluation of VEGFR-2 inhibition, apoptotic ...effect, and cell cycle analyses were carried out.•The effect on caspase-3, TNF-, and IL-6 were assessed.•In silico docking, MD simulations, ADMET, and toxicity studies were performed.
As an extension to our preceding studies on nicotinamide derivatives as anticancer agents, new nicotinamide-based candidates were designed and synthesized as VEGFR-2 inhibitors. The in vitro cytotoxic activity of the synthesized compounds was evaluated against three human cancer cell lines (MCF-7, HepG-2 and HCT-116). The IC50 values for compound 17 were 2.61± 0.01, 3.20 ± 0.02, and 2.46 ± 0.01 µM, respectively, compared to sorafenib (4.21±0.03, 3.40 ± 0.02, and 5.30 ± 0.04 µM) against MCF-7, HePG-2, and HCT-116. This indicated that compound 17 possess double strength relative to sorafenib against both MCF-7 and HCT-116. Compound 17 was the most promising VEGFR-2 inhibitor with IC50 value of 0.34 μM that was slightly better than that of sorafenib (0.38 μM). Further studies displayed the ability of compound 17 to arrest the growth of HCT-116 cells at the Pre-G1 and S phases. Additionally, compound 17 induced a significant increase in the total apoptosis rate of HCT-116 cells from 1.82 % to 26.69 %. Moreover, it showed high selectivity indices against HCT-116, HepG2, and MCF-7 cancer cells. Furthermore, compound 17 showed potent inhibitory activities on TNF-α and IL-6 and showed a notable rise in caspase-3 level. In addition, the potentiality of the designed derivatives to bind with and inhibit the VEGFR-2 enzyme was indicated by molecular docking assessments. MD simulation studies revealed the stability of compound 17 in the active site of VEGFR-2 for 100 ns. Based on the previous findings, compound 17 appears to be a promising apoptotic VEGFR-2 inhibitor and could potentially direct future efforts towards the development of novel anticancer medications.
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