Exploration of antiproliferative potential of modified triazole-benzohydrazone scaffold: Multitarget approach.

A novel series of triazole-benzohydrazone hybrids was efficiently designed and synthesized as antiproliferative agents, targeting different kinases. All compounds were screened via the National Cancer Institute (NCI) against 60 cancer cell lines, where compounds 16, 17, and 18 exhibited growth inhibition percent (GI%) of various leukemia subpanels with values of 70.33%, 64.13%, and 76.03%, respectively. Compound 18 showed broad-spectrum antiproliferative efficacy toward most cancer cells, with outstanding potency regarding melanoma (MALME-3M GI% = 101.82%) and breast cancer cell lines (MCF7 GI% = 85.87%), while proving safe toward the WI-38 normal cell line, compared to doxorubicin. Multikinase investigation including vascular endothelial growth factor receptor 2 (VEGFR-2), mesenchymal epithelial transition factor (c-Met), proto-oncogene B-Raf, mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, and phosphoinositide 3-kinase was accomplished to reveal its plausible mechanism of action, giving the ultimate potency against both VEGFR-2 and c-Met with IC50 values of 0.055 and 0.042 µM, respectively, while displaying moderate to good inhibition concerning the remaining kinases. DNA binding capability was excluded using the methyl green colorimetric assay. Further, it exhibited both early and late apoptotic induction by about 16- and 9.4-fold over the control, respectively, triggering cell cycle arrest in the G2/M phase. Physicochemical properties and bioavailability radar plot inferred drug-likeness characteristics for compound 18. The molecular docking study assessed the binding pattern with the active sites of c-Met and VEGFR-2.

Effect of Low-Level Environmental Lead Exposure on the Onset of Male Puberty.

The objective of this study was to evaluate male pubertal changes associated with environmental low-level lead (Pb) exposure. The study was conducted on 180 boys aged 15 years divided into 3 equal size groups: group 1 from El-Newayrat village, group 2 from Al-Shorafaa (0.5 and 10 km, respectively, from an industrialized area), and group 3 from Talla (25 km). Blood Pb levels (BLLs) were measured and pubertal changes evaluated by measurement of testicular volume (TV), and estimation of the follicle-stimulating hormone, luteinizing hormone, testosterone, estradiol, and prolactin. Blood Pb levels of children of El-Newayrat and Al-Shorafaa were significantly higher (6.38 [1.32] and 3.84 [0.79] µg/dL, respectively) than that of Talla children (1.85 [0.72]; P < 0.001), while height, weight, and TV were lower in boys in groups 1 and 2, compared to group 3. Genitalia and pubarche staging showed greatest retardation and marked bone growth delay in boys of group 1. Hormonal assays reported significant differences in boys of the industrialized areas when compared to that of Talla. Low-level Pb exposure in boys located near an industrial area was accompanied with altered male puberty indicators.

Effect of binder and activator composition on the characteristics of alkali-activated slag-based concrete.

Alkali Activated Slag Concrete (AASC) has been a sustained research activity over the past two decades. Its promising characteristics and being environmentally friendly compared to Ordinary Portland Cement made AASC of exceptional interest. However, there is still no firm mix design, for the AASC, that can provide desirable fresh and hardened properties based on the composition of the binder and activator. This research specifically aims to investigate the affecting parameters on the slump and compressive strength of alkali-activated slag/lime-based concrete and provide a better understanding of the potential reasons for these characteristics. The experimental program consisted of two stages; the first stage studied the effect of different binder and activator compositions, and the second stage studied the water-to-binder ratio and binder content effects on the slump and compressive strength of alkali-activated slag/lime-based concrete. The binder and activator compositions were defined through two main parameters, the hybrid factor (HF = CaO/Si2O + Al2O3) and the solution modulus (Ms = SiO2/Na2O). The compressive strength, initial slump, and slump loss were measured to evaluate the different mixes and specify the optimum range of compositions. Based on the studied parameters, the effective range to achieve desirable slump and concrete compressive strength is from HF 0.6 up to 0.8 at Ms 1.5, this would achieve a compressive strength of more than 30 MPa and a slump of 100 mm after 90 min.

Insights into Clematis cirrhosa L. Ethanol Extract: Cytotoxic Effects, LC-ESI-QTOF-MS/MS Chemical Profiling, Molecular Docking, and Acute Toxicity Study.

BACKGROUND: In Jordanian traditional medicine, Clematis cirrhosa is commonly employed for the management of different diseases. Numerous investigations have documented the cytotoxic properties of different Clematis species against numerous types of cancer. Previously, we demonstrated the potential cytotoxicity of Clematis cirrhosa against HT-29 colorectal cancer cells. Extending our work, the current research aimed to explore the possible mechanisms underlying its antiproliferative activity with a plant safety evaluation. METHODS: This study evaluates the extract's impact on the cell cycle, apoptosis, and cell migration through in vitro assays, LC-ESI-QTOF-MS/MS analysis, docking studies, and an acute toxicity evaluation. RESULTS: The Clematis cirrhosa ethanol extract (CEE) induced G2/M phase cell cycle arrest (19.63%), triggered significant apoptosis (41.99%), and inhibited cell migration/wound healing by 28.15%. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis revealed increased expression of the proapoptotic markers BAX (6.03-fold) and caspase-3 (6.59-fold), along with the reduced expression of the antiapoptotic BCL-2, in CEE-treated cells. Moreover, CEE significantly restrained angiogenesis by reducing VEGF mRNA expression by 63.9%. High-resolution LC-ESI-QTOF-MS/MS studies identified 26 metabolites, including phenolic compounds, fatty acids, and triterpenoids. Docking studies suggested that manghaslin had the highest binding affinity for VEGFR-2, followed by calceolarioside B, quercetin 7-O-rhamnopyranoside, luteolin, and quercetin-3,7-O-diglucoside. On the other hand, salvadoraside exhibited the highest binding affinity for the inhibition of caspase-3, followed by quercetin-3,7-O-diglucoside, kaempferol-3,7-O-α-L-dirhamnoside, manghaslin, and tectoridin, supporting the observed apoptotic effects. Interestingly, the outcomes further indicate that a single oral administration of up to 5000 mg/kg CEE is safe for consumption. CONCLUSIONS: These outcomes point to the potential of Clematis cirrhosa as a promising candidate for further exploration in cancer therapy.

First Exclusive Stereo- and Regioselective Preparation of 5-Arylimino-1,3,4-Selenadiazole Derivatives: Synthesis, NMR analysis, and Computational Studies.

Isoselenocyanates are valuable coupling partners required for preparing key chemical intermediates and biologically active molecules in an accelerated and effective way. Likewise, (Z)-2-oxo-N-phenylpropanehydrazonoyl chlorides have been employed in numerous one-step heteroannulation reactions to assemble the structural core of several various kinds of heterocyclic compounds. Here, we describe the inverse electron demand 1,3-dipolar cycloaddition reaction of isoselenocyanates with a variety of substituted (Z)-2-oxo-N-phenylpropanehydrazonoyl chlorides to generate, regioselectively and stereoselectively, a series of 5-arylimino-1,3,4-selenadiazole derivatives comprising a multitude of functional groups on both aryl rings. The synthetic method features gentle room-temperature conditions, wide substrate scope, and good to high reaction yields. The selenadiazoles were separated by gravity filtration in all instances and chemical structures were validated by multinuclear NMR spectroscopy and high accuracy mass spectral measurements. First conclusive molecular structure elucidation of the observed 5-arylimino-selenadiazole regioisomer was verified by single-crystal X-ray diffraction analysis. Crystal-structure measurement was successfully carried out on (Z)-1-(4-(4-iodophenyl)-5-(p-tolylimino)-4,5-dihydro-1,3,4-selenadiazol-2-yl)ethan-1-one and (Z)-1-(5-((4-methoxyphenyl)imino)-4-(4-(methylthio)phenyl)-4,5-dihydro-1,3,4-selenadiazol-2-yl)ethan-1-one. Likewise, the (Z)-geometry of the hydrazonoyl chloride reactant was proven by X-ray diffraction studies. As representative examples, crystal-structure determination was carried out on (Z)-2-oxo-N-phenylpropanehydrazonoyl chloride and (Z)-N-(3,5-bis(trifluoromethyl)phenyl)-2-oxopropanehydrazonoyl chloride. Density functional theory calculations at the B3LYP-D4/def2-TZVP level were conducted to support the noted experimental findings and suggested mechanism.

The Essential Oil of Petroselinum crispum (Mill) Fuss Seeds from Peru: Phytotoxic Activity and In Silico Evaluation on the Target Enzyme of the Glyphosate Herbicide.

Petroselinum crispum (Mill) Fuss is an aromatic plant belonging to the Apiaceae family and used in gastronomy as a spice. Several studies have been developed in leaves but studies are limited in seeds, especially the essential oils obtained from seeds. The aim of this study was to determine the phytochemical profile of the volatile compounds of this essential oil by gas-chromatography-mass spectrometry (GC-MS) in order to evaluate its phytotoxic activity on Lactuca sativa seeds and to carry out an in silico analysis on the target enzyme of the herbicide glyphosate 5-enolpyruvylshikimate 3-phosphate synthase (EPSP). The essential oil was obtained by steam distillation for two hours and then was injected into a GC-MS, the phytotoxic assay was carried out on Lactuca seeds and the in silico evaluation on the EPSP synthase focused on the volatile compounds similar to glyphosate, docking analysis, and molecular dynamics to establish the protein-ligand stability of the most active molecule. The chromatographic analysis revealed 47 compounds, predominated by three compounds with the most abundant percentage in the total content (1,3,8-ρ-menthatriene (22.59%); apiole (22.41%); and ß-phellandrene (15.02%)). The phytotoxic activity demonstrated that the essential oil had a high activity at 5% against L. sativa seed germination, inhibition of root length, and hypocotyl length, which is comparable to 2% glyphosate. The molecular docking on EPSP synthase revealed that trans-p-menth-6-en-2,8-diol had a high affinity with the enzyme EPSP synthase and a better stability during the molecular dynamic. According to the results, the essential oil of P. crispum seeds presented a phytotoxic activity and might be useful as a bioherbicide agent against weeds.

Comparative study of 2 anesthesia techniques for pediatric refractive surgery.

PURPOSE: To compare the effectiveness of 2 anesthesia techniques for pediatric refractive surgery, propofol/fentanyl and ketamine/midazolam. SETTING: Department of Ophthalmology, Magraby Eye & Ear Center, Muscat, Oman. METHODS: This prospective clinical study was of children ranging in age range from 3 to 12 years who were followed for myopic anisometropia with amblyopia after failure of conventional correction or patients with superficial stromal corneal opacities. The children were scheduled to have refractive surgery under general anesthesia using propofol/fentanyl (P/F group) or ketamine/midazolam (K/M group). All drugs were administered intravenously. RESULTS: Thirty patients were included in the study and were divided randomly into 2 equal groups. Both groups were comparable in age, weight, sex, duration of anesthesia, and duration of surgery. Time to complete recovery was significantly shorter in the P/F group. The hemodynamic changes observed in this study were not of clinical significance. Three patients in the P/F group showed arterial oxygen (O2) saturation of less than 90% and supplemental O2 was given by nasal cannula. The incidence of postoperative agitation and vomiting was significantly higher in the K/M group, while the need for jaw thrust was significantly higher in the P/F group. The difference between both groups in the ophthalmologist satisfaction score was not significant. CONCLUSIONS: Propofol offered some advantages for brief procedures outside the traditional operating rooms. It is short acting, and has a rapid offset resulting in shorter postoperative monitoring and a smoother recovery profile. It has greater potential for respiratory depression than ketamine. Hence, greater vigilance and experience with the pediatric airway is recommended with its use.

Flexible Ahmed valve for selected cases of refractory glaucoma.

PURPOSE: Glaucoma drainage implants are a useful alternative in treating glaucomas that are resistant to medical therapy and conventional glaucoma filtration surgery. The aim of this study is to evaluate flexible Ahmed glaucoma valve implant for selected cases of refractory glaucoma regarding its efficiency in controlling intraocular pressure (IOP) and possible postoperative complications of its implantation and their management. METHOD: Patients included in this study were selected from patients with uncontrolled IOP by conventional filtration surgery as well as maximum tolerable topical medical treatment when surgery or laser is unlikely to control IOP. For every patient, complete history of age, sex, and history of previous ocular disease was done. Ocular examination for IOP measurement, best-corrected visual acuity measurement, and condition of conjunctiva was done. Ahmed glaucoma valve flexible plate implant (FP7 and FP8) was used. RESULTS: The present study included 40 eyes of 40 patients and preoperative IOP ranged from 32 mmHg to 58 mmHg with a mean of 40.36 ± 7.78 mmHg. The postoperative IOP ranged between 14.0 mmHg and 28.0 mmHg with a mean of 18.73 ± 4.8 mmHg. The criteria of success were applied in 37 eyes of 40 eyes (92.5%); they included 30 eyes (81.8%) with absolute success and 7 eyes (18.9%) with partial success. CONCLUSIONS: Flexible Ahmed glaucoma valve plate implant is a satisfactory method for controlling elevated IOP in cases of refractory glaucoma with success rate of 92.5% and lower incidence of immediate postoperative and implant-related complications.

Values of using QTc and N-terminal fragment of B-type natriuretic peptide as markers for early detection of acute antipsychotic drugs-induced cardiotoxicity.

We aimed at studying the acute cardiotoxicity of the most commonly used antipsychotics in Egypt using QTc interval and NT-proBNP as markers for the early detection of such cases. Eighty-two admitted patients, at El-Minia PCC (period from 1-7-2005 to 30-6-2010), were classified into 3 groups: I: acute thioridazine overdose (n = 28), II: acute pimozide overdose (n = 23), and III: acute clozapine overdose (n = 31). Patients were investigated for NT-proBNP level and QTc on admission (day 0) and after 24 h (day 1). All the studied drugs had the ability to induce cardiotoxicity in the form of hypotension and dysrhythmias. Thioridazine and pimozide had potentially serious cardiotoxic effects than clozapine. NT-proBNP levels were elevated significantly in all groups on days 0 and 1 when compared with the reference value and a significant decrease in the same parameter on day 1 when compared with that of day 0 within the same group. QTc showed a significant prolongation in all studied groups on days 0 and 1, and there was a significant shortening of QTc on day 1 when compared with that of day 0 within the same group. A significant positive correlation of NT-proBNP level elevation with QTc prolongation was reported in all groups on days 0 and 1. Serious dysrhythmias were associated with QTc prolongation greater than 500 ms. And it was concluded that NT-proBNP, in adjunction with QTc measurement, may be a valuable and sensitive laboratory biomarker to predict cardiotoxicity of antipsychotic overdose. Larger multicenter studies are still needed to verify this possible relationship.