Design, synthesis, molecular modeling, in vitro and in vivo biological evaluation of potent anthranilamide derivatives as dual P-glycoprotein and CYP3A4 inhibitors.

Paclitaxel (PTX) is considered the blockbuster chemotherapy treatment for cancer. Paclitaxel's (PTX) oral administration has proven to be extremely difficult, mostly because of its susceptibility to intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP3A4). The concurrent local inhibition of intestinal P-gp and CYP3A4 is a promising approach to improve the oral bioavailability of paclitaxel while avoiding potential unfavorable side effects of their systemic inhibition.

Patterns and outcomes of acute toxicological cases before, during, and after COVID-19 lockdown in Sohag University hospitals, Egypt.

Background: Toxicologists manage poisoning by preventing, detecting, and treating it, which requires continuous data collection and analysis of toxicological hazards.

Aim Of The Work: The study aims to report and compare the pattern and outcome of acute toxicological cases admitted to Sohag University Hospitals during the COVID-19 lockdown (2020-2021) with the year before (2019) and the year after (2022).

Methods: This comparative study reviewed the sociodemographic and clinical data in the medical records.

Design, synthesis, molecular modelling and biological evaluation of novel 6-amino-5-cyano-2-thiopyrimidine derivatives as potent anticancer agents against leukemia and apoptotic inducers.

Herein, a novel series of 6-amino-5-cyano-2-thiopyrimidines and condensed pyrimidines analogues were prepared. All the synthesized compounds and were evaluated for anticancer activity by the National Cancer Institute (NCI; MD, USA) against 60 cell lines. Compound showed promising anticancer activity and was selected for the five-dose testing.

Integration of immunoinformatics and cheminformatics to design and evaluate a multitope vaccine against and coinfection.

() and () are the most common Gram-negative bacteria associated with pneumonia and coinfecting the same patient. Despite their high virulence, there is no effective vaccine against them. In the current study, the screening of several proteins from both pathogens highlighted FepA and OmpK35 for in addition to HasR and OprF from as promising candidates for epitope mapping.

Pulmonary function and complication prevention: A randomized controlled trial on lung expansion modalities of older adults undergoing upper abdominal surgery.

Postoperative pulmonary complications (PPCs) are a major catastrophic consequence of upper abdominal surgery, resulting in morbidity and mortality. Therefore, the study aims to assess the effect of lung expansion modalities (LEMs) on older adults' pulmonary function and the incidence of pulmonary complications. The study randomly allocated 80 older adults (40 cases and 40 controls).

Down-regulation of hepatic expression of GHR/STAT5/IGF-1 signaling pathway fosters development and aggressiveness of HCV-related hepatocellular carcinoma: Crosstalk with Snail-1 and type 2 transforming growth factor-beta receptor.

Background And Aims: So far, few clinical trials are available concerning the role of growth hormone receptor (GHR)/signal transducer and activator of transcription 5 (STAT5)/insulin like growth factor-1 (IGF-1) axis in hepatocarcinogenesis. The aim of this study was to evaluate the hepatic expression of GHR/STAT5/IGF-1 signaling pathway in hepatocellular carcinoma (HCC) patients and to correlate the results with the clinico-pathological features and disease outcome. The interaction between this signaling pathway and some inducers of epithelial-mesenchymal transition (EMT), namely Snail-1 and type 2 transforming growth factor-beta receptor (TGFBR2) was studied too.

Neuropilin-2 axis in regulating secretory phenotype of neuroendocrine-like prostate cancer cells and its implication in therapy resistance.

Neuroendocrine (NE)-like tumors secrete various signaling molecules to establish paracrine communication within the tumor milieu and to create a therapy-resistant environment. It is important to identify molecular mediators that regulate this secretory phenotype in NE-like cancer. The current study highlights the importance of a cell surface molecule, Neuropilin-2 (NRP2), for the secretory function of NE-like prostate cancer (PCa).

Novel pyrrolopyrimidine derivatives: design, synthesis, molecular docking, molecular simulations and biological evaluations as antioxidant and anti-inflammatory agents.

Current medical approaches to control the Covid-19 pandemic are either to directly target the SARS-CoV-2 innovate a defined drug and a safe vaccine or indirectly target the medical complications of the virus. One of the indirect strategies for fighting this virus has been mainly dependent on using anti-inflammatory drugs to control cytokines storm responsible for severe health complications. We revealed the discovery of novel fused pyrrolopyrimidine derivatives as promising antioxidant and anti-inflammatory agents.

Discovery and Characterization of Potent Dual P-Glycoprotein and CYP3A4 Inhibitors: Design, Synthesis, Cryo-EM Analysis, and Biological Evaluations.

Targeted concurrent inhibition of intestinal drug efflux transporter P-glycoprotein (P-gp) and drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is a promising approach to improve oral bioavailability of their common substrates such as docetaxel, while avoiding side effects arising from their pan inhibitions. Herein, we report the discovery and characterization of potent small molecule inhibitors of P-gp and CYP3A4 with encequidar (minimally absorbed P-gp inhibitor) as a starting point for optimization. To aid in the design of these dual inhibitors, we solved the high-resolution cryo-EM structure of encequidar bound to human P-gp.

Polyphenolic Profile of Aerial Parts: Antioxidant, Anticancer and In Silico 5-LOX Inhibitory Evaluations.

Five new compounds kaempferol 3--(4″-galloyl)--d-glucopyranosyl-(1‴→6″)--β-d-glucopyranoside (), kaempferol 3---d-mannuronopyranoside (), kaempferol 3---d-mannopyranoside (), quercetin 3---d-mannuronopyranoside (), 2, 3 (S)- hexahydroxydiphenoyl]-d-glucose () along with fifteen known compounds were isolated from 80% aqueous methanol extract (AME) of . AME and compounds exerted similar or better antioxidant activity to ascorbic acid using DPPH, O, and NO inhibition methods. In addition, compounds , , and showed cytotoxic activity against MCF-7 cell lines while , and exhibited strong activity against HepG2.

Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity.

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay.

Design, synthesis, and evaluation of a novel benzamidine-based inhibitor of VEGF-C binding to Neuropilin-2.

The Neuropilin (Nrp) family of cell surface receptors have key physiological and pathological functions. Nrp2 is of particular interest due to its involvement in tumor metastasis. Currently, peptide and small molecule inhibitors that target Nrp utilize arginine-based molecules which have limitations due to high inherent flexibility and issues related to stability.

Design, synthesis, molecular modelling and biological evaluation of novel 3-(2-naphthyl)-1-phenyl-1H-pyrazole derivatives as potent antioxidants and 15-Lipoxygenase inhibitors.

Oxidative stress is one of the main causes of significant severe diseases. The discovery of new potent antioxidants with high efficiency and low toxicity is a great demand in the field of medicinal chemistry. Herein, we report the design, synthesis molecular modelling and biological evaluation of novel hybrids containing pyrazole, naphthalene and pyrazoline/isoxazoline moiety.

Soft white cheese ripening using bacterial protease enzyme.

Background: Microbial proteases are the most important enzymes in the industry, accounting for 60% of total enzyme sales in the world. The proteases of lactic acid bacteria (LAB) have received special attention because of their importance in the food and dairy industry.

Methods: The crude extract and purified protease enzyme produced from an isolated bacte- rial strain identified as Lactobacillus plantarum were used in the ripening and flavor improvement of soft white cheese (Domiati-type).

Predictive role of IL-17A/IL-10 ratio in persistent asthmatic patients on vitamin D supplement.

Asthma is an airway inflammatory disorder. Vitamin (Vit) D is a potent immuno-modulator. It suppresses Interleukin (IL)-17 and induces IL-10.

Design, synthesis, molecular modelling, and biological evaluation of novel substituted pyrimidine derivatives as potential anticancer agents for hepatocellular carcinoma.

New anticancer agents are highly needed to overcome cancer cell resistance. A novel series of pyrimidine pyrazoline-anthracene derivatives (PPADs) ( were designed and synthesised. The anti-liver cancer activity of all compounds was screened against two hepatocellular carcinoma (HCC) cell lines (HepG2 and Huh-7) as well as normal fibroblast cells by resazurin assay.

Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Thiouracil Derivatives as Potential Antithyroid Agents.

Hyperthyroidism is the result of uncontrolled overproduction of the thyroid hormones. One of the mostly used antithyroid agents is 6-propyl-2-thiouracil (PTU). The previously solved X-ray crystal structure of the PTU bound to mammalian lactoperoxidase (LPO) reveals that the LPO-PTU binding site is basically a hydrophobic channel.

Percutaneous Carillon Mitral Contour System Deployment Followed by CRT-D Implantation: First Case Report from Oman.

Mitral valve regurgitation (MR) is a common problem in patients with cardiac issues especially those with dilated cardiomyopathy (DCM) due to mitral annular dilatation and malcoaptation of the mitral valve leaflets. Although DCM is associated with high mortality rates, there has been no global agreement about the best method of treatment. Treatment of MR in such cases can be done by surgery, which has many limitations due to high-risk concerns.

The Predictive Value of Multidetector High Resolution Computed Tomography in Evaluation of Suspected Sputum Smear Negative Active Pulmonary Tuberculosis in Egyptian Zagazig University Hospital Patients.

The aim of this work is to study the usage of multi-detector HRCT chest in diagnosing pulmonary TB cases whose sputum smears are negative and making a correlation between their CT features and their sputum culture results. This study was carried out from December 2014 to December 2016 at Zagazig university hospitals, Radiodiagnosis department. It included 150 patients.

Modulating hydrogen-bond basicity within the context of protein-ligand binding: A case study with thrombin inhibitors that reveals a dominating role for desolvation.

Understanding subtle aspects of hydrogen bonding is a challenging but crucial task to improve our ability to design ligands with high affinity for protein hosts. To gain a deeper understanding of these aspects, we investigated a series of thrombin inhibitors in which the basicity of the ligand's group that accepts an H-bond from Gly216 was modulated via bioisosterism; e.g.

Ligand binding cooperativity: Bioisosteric replacement of CO with SO2 among thrombin inhibitors.

Ligand-protein binding is a complex process that involves the formation of number of non-covalent interactions, e.g. H-bonds and hydrophobic interactions, between the ligand and the protein host.

Resolution of overlapped spectra for the determination of ternary mixture using different and modified spectrophotometric methods.

Four new spectrophotometric methods were developed, applied to resolve the overlapped spectra of a ternary mixture of [aliskiren hemifumarate (ALS)-amlodipine besylate (AM)-hydrochlorothiazide (HCT)] and to determine the three drugs in pure form and in combined dosage form. Method A depends on simultaneous determination of ALS, AM and HCT using principal component regression and partial least squares chemometric methods. In Method B, a modified isosbestic spectrophotometric method was applied for the determination of the total concentration of ALS and HCT by measuring the absorbance at 274.

Binding cooperativity between a ligand carbonyl group and a hydrophobic side chain can be enhanced by additional H-bonds in a distance dependent manner: A case study with thrombin inhibitors.

One of the underappreciated non-covalent binding factors, which can significantly affect ligand-protein binding affinity, is the cooperativity between ligand functional groups. Using four different series of thrombin inhibitors, we reveal a strong positive cooperativity between an H-bond accepting carbonyl functionality and the adjacent P3 hydrophobic side chain. Adding an H-bond donating amine adjacent to the P3 hydrophobic side chain further increases this positive cooperativity thereby improving the Ki by as much as 546-fold.