Cotton 4-coumarate-CoA ligase 3 enhanced plant resistance to Verticillium dahliae by promoting jasmonic acid signaling-mediated vascular lignification and metabolic flux.

Lignins and their antimicrobial-related polymers cooperatively enhance plant resistance to pathogens. Several isoforms of 4-coumarate-coenzyme A ligases (4CLs) have been identified as indispensable enzymes involved in lignin and flavonoid biosynthetic pathways. However, their roles in plant-pathogen interaction are still poorly understood. This study uncovers the role of Gh4CL3 in cotton resistance to the vascular pathogen Verticillium dahliae. The cotton 4CL3-CRISPR/Cas9 mutant (CR4cl) exhibited high susceptibility to V. dahliae. This susceptibility was most probably due to the reduction in the total lignin content and the biosynthesis of several phenolic metabolites, e.g., rutin, catechin, scopoletin glucoside, and chlorogenic acid, along with jasmonic acid (JA) attenuation. These changes were coupled with a significant reduction in 4CL activity toward p-coumaric acid substrate, and it is likely that recombinant Gh4CL3 could specifically catalyze p-coumaric acid to form p-coumaroyl-coenzyme A. Thus, overexpression of Gh4CL3 (OE4CL) showed increasing 4CL activity that augmented phenolic precursors, cinnamic, p-coumaric, and sinapic acids, channeling into lignin and flavonoid biosyntheses and enhanced resistance to V. dahliae. Besides, Gh4CL3 overexpression activated JA signaling that instantly stimulated lignin deposition and metabolic flux in response to pathogen, which all established an efficient plant defense response system, and inhibited V. dahliae mycelium growth. Our results propose that Gh4CL3 acts as a positive regulator for cotton resistance against V. dahliae by promoting JA signaling-mediated enhanced cell wall rigidity and metabolic flux.

Enhancement efficiency delivery of antiviral Molnupiravir-drug via the loading with self-assembly nanoparticles of pycnogenol and cellulose which are decorated by zinc oxide nanoparticles for COVID-19 therapy.

The target of the study is to modify the efficiency of Molnupiravir-drug (MOL) for COVID-19 therapy via the rearrangement of the building engineering of MOL-drug by loading it with self-assembly biomolecules nanoparticles (NPs) of pycnogenol (Pyc) and cellulose (CNC) which are decorated by zinc oxide nanoparticles. The synthesis and characterization of the modified drug are performing successfully, the loading and release process of the MOL drug on a nano surface is measured by UV-Vis spectroscopy under room temperature and different pH. The release efficiency of the MOL drug is calculated to be 65% (pH 6.8) and 69% (pH 7.4). The modified MOL drug displays 71% (pH 6.8) and 78% (pH 7.4) for CNC@Pyc.MOL nanocomposite, while CNC@Pyc.MOL.ZnO nanocomposite gave values at 76% (pH 6.8) and 78% (pH 7.4), the efficiency recorded after 19 h. The biological activity of the MOL-drug and modified MOL-drug is measured, and the cytotoxicity is performed by SRB technique, where the self-assembly (CNC@Pyc) appears to be a safe healthy, and high viability against the examined cell line. The antioxidant activity and anti-inflammatory are evaluated, where the nanocomposite that has ZnO NPs (CNC@Pyc.MOL.ZnO) gave high efficiency compared to the composite without ZnO NPs. The CPE-inhibition assay is used to identify potential antivirals against CVID-19 (229E virus), the viral inhibition (%) was reported at 37.6 % (for 800 µg/ml) and 18.02 % (for 400 µg/ml) of CNC@Pyc.MOL.ZnO. So, the modified MOL-drug was suggested as a replacement drug for the therapy of COVID-19 compared to MOL-drug, but the results need clinical trials.

Discovery of novel octahydroquinazoline scaffolds endowed with dual inhibition of tubulin polymerization/Eg5 against HCC: Apoptotic and radio-chemotherapeutic studies.

Mitotic kinesin Eg5 isozyme as a motor protein plays a critical role in cell division of tumor cells. Kinesin Eg5 selective inhibitors and Colchicine binding site suppressors are essential targets for many anticancer drugs and radio chemotherapies. On this work, a new series of octahydroquinazoline as anti-mitotic candidates 2-13 has been synthesized with dual inhibition of tubulin polymerization/Eg5 against HCC cell line. All octahydroquinazolines have been in vitro assayed against HepG-2 cytotoxicity, Eg5 inhibitory and anti-tubulin polymerization activities. The most active analogues 7, 8, 9, 10, and 12 against HepG-2 were further subjected to in vitro cytotoxic assay against HCT-116 and MCF-7 cell lines. Chalcones 9, 10, and 12 displayed the most cytotoxic potency and anti-tubulin aggregation in comparable with reference standard colchicine and potential anti-mitotic Eg5 inhibitory activity in comparison with Monastrol as well. Besides, they exhibited cell cycle arrest at the G2/M phase. Moreover, good convinced apoptotic activities have been concluded as overexpression of caspase-3 levels and tumor suppressive gene p53 in parallel with higher induction of Bax and inhibition of Bcl-2 biomarkers. Octahydroquinazoline 10 displayed an increase in caspase-3 by 1.12 folds compared to standard colchicine and induce apoptosis and demonstrated cell cycle arrest in G2/M phase arrest by targeting p53 pathway. Analogue 10 has considerably promoted cytotoxic radiation activity and boosted apoptotic induction in HepG-2 cells by 1.5 fold higher than standard colchicine.

Exploring predictors and prevalence of postpartum depression among mothers: Multinational study.

BACKGROUND: Postpartum depression (PPD) affects around 10% of women, or 1 in 7 women, after giving birth. Undiagnosed PPD was observed among 50% of mothers. PPD has an unfavorable relationship with women's functioning, marital and personal relationships, the quality of the mother-infant connection, and the social, behavioral, and cognitive development of children. We aim to determine the frequency of PPD and explore associated determinants or predictors (demographic, obstetric, infant-related, and psychosocial factors) and coping strategies from June to August 2023 in six countries. METHODS: An analytical cross-sectional study included a total of 674 mothers who visited primary health care centers (PHCs) in Egypt, Yemen, Iraq, India, Ghana, and Syria. They were asked to complete self-administered assessments using the Edinburgh Postnatal Depression Scale (EPDS). The data underwent logistic regression analysis using SPSS-IBM 27 to list potential factors that could predict PPD. RESULTS: The overall frequency of PPD in the total sample was 92(13.6%). It ranged from 2.3% in Syria to 26% in Ghana. Only 42 (6.2%) were diagnosed. Multiple logistic regression analysis revealed there were significant predictors of PPD. These factors included having unhealthy baby adjusted odds ratio (aOR) of 11.685, 95% CI: 1.405-97.139, p = 0.023), having a precious baby (aOR 7.717, 95% CI: 1.822-32.689, p = 0.006), who don't receive support (aOR 9.784, 95% CI: 5.373-17.816, p = 0.001), and those who are suffering from PPD. However, being married and comfortable discussing mental health with family relatives are significant protective factors (aOR = 0.141 (95% CI: 0.04-0.494; p = 0.002) and (aOR = 0.369, 95% CI: 0.146-0.933, p = 0.035), respectively. CONCLUSION: The frequency of PPD among the mothers varied significantly across different countries. PPD has many protective and potential factors. We recommend further research and screenings of PPD for all mothers to promote the well-being of the mothers and create a favorable environment for the newborn and all family members.

Comprehensive study of allergenic tree species: Palynological insights enhanced by HPLC and GC-MS profiling.

Considering the limited data available on tree species in Uzbekistan, this research aimed to provide new insights. We gathered plant samples from different locations within Samarkand city and thoughtfully selected 15 tree species that represent the country's flora. Using scanning electron microscopy, we conducted comprehensive analyses of pollen morphology, revealing a diverse range of variations in the shapes, dimensions, and surface characteristics displayed by pollen grains. Distinct ornamentations such as micro-echinate, reticulate, rugulate, gemmate-verrucate, and verrucate-scabrate patterns facilitated the differentiation of species. These scanning electron microscopy findings enhance our comprehension of tree species diversity, adaptation, and ecological roles. In addition, leaf extracts were analyzed using HPLC and GC-MS, revealing a plethora of bioactive compounds, including catechins, chlorogenic acid, vanillic acid, and others. Furthermore, GC-MS analysis revealed the presence of seven key compounds, including 1-hexadecyne, 2-chloroethanol, 1,6-heptadiene, 2-methyl-, 5-bromoadamantan-2-one, ethyl 3-(3-pyridyl) propenoate, bis (2-ethylhexyl) phthalate, and quercetin. This study demonstrates the effectiveness of this method in assessing the quality of leaf extracts from tree species by examining both microscopic characteristics and chemical composition. This multifaceted approach has deepened our understanding of the characteristics and chemical compositions of these trees, thus contributing to a more profound appreciation of their ecological significance and potential applications.

Systematic Implications of Palynomorph Diversity Using Microscopic Trends Among Asteraceous Flora From the Drylands of Baluchistan, Pakistan.

Pollen micromorphological traits with taxonomic implications are first reported from the study area for 50 Asteraceous taxa belonging to nine tribes. Cichorieae (21 taxa), Cardueae (11 taxa), Inuleae (six taxa), and Anthemideae (four taxa) are the leading tribes. The research included Cousinia haeckeliae, Himalaiella afghana, Pterachaenia stewartii (endemic to Afghanistan and Pakistan), and Xylanthemum macropodum (endemic to Baluchistan). Light and scanning electron microscopy were employed for the visualization of pollen photomicrographs. The data was analyzed statistically via SPSS, PAST, and Origin. Significant diagnostic qualitative and quantitative palynological traits were explored for discrimination down to the species level within the tribes. All the investigated taxa possessed radial symmetry, isopolarity, and monad form (characters for distinction at the subdivision level). The aperture types were trizonocolporate, tetrazonocolporate, and tricolporate with number position and character (NPC) formulas N3P4C5, N4P4C5, and N3P4C3. Goniotreme, peritreme, and ptychotreme types of amb were recognized. Echinate, echinate lophate, scabrate, and gemmate sculpturing were present with and without perforated surface patterns. Variations in the shapes in polar and equatorial views and lacuna shapes further assisted the separation of taxa. The observed shape classes were perprolate, prolate spheroidal, prolate, subprolate, oblate spheroidal, suboblate, and oblate. Principal component analysis, correlation, standard probability plots, and ridge line paired features plot for quantitative variables determined the positive correlation between the length and width of colpi in equatorial and polar view with polar axis and equatorial diameter and number of spines between colpi with the number of spines per pollen. The number of spines per pollen was negatively correlated with the width and length of colpi in the polar view. Multiple sample analysis of variance (ANOVA) concluded that a high statistically significant difference exists among the means of analyzed traits. The examined qualitative and quantitative palynological traits revealed noticeable variations, thus providing the source for species discrimination in Asteraceous tribes.

Hazardous waste management (Buxus papillosa) investment for the prosperity of environment and circular economy: Response surface methodology-based simulation.

Dealing with the current defaults of environmental toxicity, heating, waste management, and economic crises, exploration of novel non-edible, toxic, and waste feedstock for renewable biodiesel synthesis is the need of the hour. The present study is concerned with Buxus papillosa with seeds oil concentration (45% w/w), a promising biodiesel feedstock encountering environmental defaults and waste management; in addition, this research performed simulation based-response surface methodology (RSM) for Buxus papillosa bio-diesel. Synthesis and application of novel Phyto-nanocatalyst bimetallic oxide with Buxus papillosa fruit capsule aqueous extract was advantageous during transesterification. Characterization of sodium/potassium oxide Phyto-nanocatalyst confirmed 23.5 nm nano-size and enhanced catalytic activity. Other characterizing tools are FTIR, DRS, XRD, Zeta potential, SEM, and EDX. Methyl ester formation was authenticated by FTIR, GC-MS, and NMR. A maximum 97% yield was obtained at optimized conditions i.e., methanol ratio to oil (8:1), catalyst amount (0.37 wt%), reaction duration (180 min), and temperature of 80 °C. The reusability of novel sodium/potassium oxide was checked for six reactions. Buxus papillosa fuel properties were within the international restrictions of fuel. The sulphur content of 0.00090% signified the environmental remedial nature of Buxus papillosa methyl esters and it is a highly recommendable species for biodiesel production at large scale due to a t huge number of seeds production and vast distribution.

Phytochemicals, Health-Promoting Effects, and Enzyme Inhibition Traits of Phlomis stewartii Extracts.

Phlomis stewartii is a wild, perennial woody plant used for diverse therapeutic targets. The present work evaluated the influence of independent variables such as extraction time, solvent concentration, and speed in the range of (100 mL, 150 mL, and 200 mL), (2 h, 5 h, and 8 h), and (100 rpm, 150 rpm, and 200 rpm), respectively, on extraction yields, phytochemical components, total phenolic contents (TPC), and total flavonoid contents (TFC) of P. stewartii extract. In the present work, response surface methodology (RSM) was applied to optimize the extraction yield. High-performance liquid chromatography (HPLC) was performed to detect the bioactive constituents of the extracts. The potent extracts were analyzed to study α-amylase and α-glucosidase inhibitory activities. Under the optimized conditions of solvent concentration (200 mL), extraction time (8 h), and speed (150 rpm), the whole plant methanol extract (WPME) showed a maximum extraction yield of 13.5%, while the leaves methanol extract (LME) showed a maximum TPC of 19.5 ± 44 mg of gallic acid equivalent (GAE) per gram of extract and a maximum TFC of 4.78 ± 0.34 mg of quercetin equivalent (QE) per gram of extract. HPLC analysis showed the presence of p-coumaric, gallic acid, quercetin, salicylic acid, sinapic acid, and vanillic acid. LME showed the highest α-amylase inhibitory activity (IC50 = 46.86 ± 0.21 µg/mL) and α-glucosidase inhibitory activity (IC50 value of 45.81 ± 0.17 µg/mL). Therefore, in conclusion, LME could be considered to fix the α-amylase and α-glucosidase-mediated disorders in the human body to develop herbal phytomedicine.

Clinicopathological significance of protein disulphide isomerase A3 and phosphorylated signal transducer and activator of transcription 3 in cervical carcinoma.

Introduction: Death in cervical cancer patients is usually due to invasion and metastasis due to the aggressive nature of the tumour. Therefore, it is critical to identify potent therapeutic targets and prognostic markers to detect high-risk patients. Material and methods: We assessed the immunohistochemical expression of protein disulphide isomerase A3 (PDIA3) and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in 50 cases of cervical carcinoma, and we investigated their association with clinicopathological characteristics. Results: High PDIA3 was detected in 50% of cases, and statistical analysis revealed a positive correlation between high PDAI3 expression and tumour grade (p < 0.001) and large tumour size (p = 0.010), depth of stromal invasion (p = 0.017), lymph-vascular invasion (p = 0.005), parametrial invasion (p < 0.001), nodal metastasis (p < 0.001), and higher International Federation of Gynaecology and Obstetrics stages (p < 0.001). Positive nuclear expression of p-STAT3 was detected in 44% of cases and showed significant association with histological grade (p = 0.036), tumour stage (p = 0.021), nodal metastasis (p = 0.020), and parametrial invasion (p = 0.045); statistical analysis of the patient's survival data revealed that shorter overall survival and disease-free survival, S, were associated with high PDIA3 expression and positive p-STAT3 immunoexpression. Conclusions: The high expression of PDIA3 and p-STAT3 was related to highly aggressive cervical carcinoma with poor prognosis, and high risk of recurrence after the standardised protocol of treatment. Hence, both PDIA3 and p-STAT3 could be considered as novel biomarkers for tumour progression and promising targets in the management of cervical carcinoma patients.

Outcomes of Left Main Revascularization in Patients with Anemia: Gulf Left Main Registry.

INTRODUCTION: The aim of this study was to evaluate the effects of baseline anemia and anemia following revascularization on outcomes in patients with unprotected left main coronary artery (ULMCA) disease. METHODS: This was a retrospective, multicenter, observational study conducted between January 2015 and December 2019. The data on patients with ULMCA who underwent revascularization through percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) were stratified by the hemoglobin level at baseline into anemic and non-anemic groups to compare in-hospital events. The pre-discharge hemoglobin following revascularization was categorized into very low (<80 g/L for men and women), low (≥80 and ≤119 g/L for women and ≤129 g/L for men), and normal (≥130 g/L for men and ≥120 g/L for women) to assess impact on follow-up outcomes. RESULTS: A total of 2,138 patients were included, 796 (37.2%) of whom had anemia at baseline. A total of 319 developed anemia after revascularization and moved from being non-anemic at baseline to anemic at discharge. There was no difference in hospital major adverse cardiac and cerebrovascular event (MACCE) and mortality between CABG and PCI in anemic patients. At a median follow-up time of 20 months (interquartile range [IQR]: 27), patients with pre-discharge anemia who underwent PCI had a higher incidence of congestive heart failure (CHF) (p < 0.0001), and those who underwent CABG had significantly higher follow-up mortality (HR: 9.85 (95% CI: 2.53-38.43), p = 0.001). CONCLUSION: In this Gulf LM study, baseline anemia had no impact upon in-hospital MACCE and total mortality following revascularization (PCI or CABG). However, pre-discharge anemia is associated with worse outcomes after ULMCA disease revascularization, with significantly higher all-cause mortality in patients who had CABG, and a higher incidence of CHF in PCI patients, at a median follow-up time of 20 months (IQR: 27).

Left Main Coronary Artery Revascularization in Patients with Impaired Renal Function: Percutaneous Coronary Intervention versus Coronary Artery Bypass Grafting.

INTRODUCTION: The evidence about the optimal revascularization strategy in patients with left main coronary artery (LMCA) disease and impaired renal function is limited. Thus, we aimed to compare the outcomes of LMCA disease revascularization (percutaneous coronary intervention [PCI] vs. coronary artery bypass grafting [CABG]) in patients with and without impaired renal function. METHODS: This retrospective cohort study included 2,138 patients recruited from 14 centers between 2015 and 2,019. We compared patients with impaired renal function who had PCI (n= 316) to those who had CABG (n = 121) and compared patients with normal renal function who had PCI (n = 906) to those who had CABG (n = 795). The study outcomes were in-hospital and follow-up major adverse cardiovascular and cerebrovascular events (MACCE). RESULTS: Multivariable logistic regression analysis showed that the risk of in-hospital MACCE was significantly higher in CABG compared to PCI in patients with impaired renal function (odds ratio [OR]: 8.13 [95% CI: 4.19-15.76], p < 0.001) and normal renal function (OR: 2.59 [95% CI: 1.79-3.73]; p < 0.001). There were no differences in follow-up MACCE between CABG and PCI in patients with impaired renal function (HR: 1.14 [95% CI: 0.71-1.81], p = 0.585) and normal renal function (HR: 1.12 [0.90-1.39], p = 0.312). CONCLUSIONS: PCI could have an advantage over CABG in revascularization of LMCA disease in patients with impaired renal function regarding in-hospital MACCE. The follow-up MACCE was comparable between PCI and CABG in patients with impaired and normal renal function.

Synthesis of bis-thiohydantoin derivatives as an antiproliferative agents targeting EGFR inhibitory pathway.

(R)/(S)-the two enantiomers of 3-substituted-1-[2-(5)-3-substituted-4-benzyl-5-oxo-4-phenyl-2-thioxoimid-azolidin-1-yl]ethyl/propyl-5-benzyl-5-phenyl-2-thioxoimidazolidin-4-ones were formed during the diastereoselective reaction between N,N″-1,ω-alkanediylbis[N'-organylthiourea] derivatives and 2,3-diphenylcyclopropenone in refluxing ethanol. The structures of the isolated compounds were confirmed by NMR, IR, mass spectra and elemental analyses. Moreover, single-crystal X-ray structure analysis was also used to elucidate the structure of the isolated compounds. The mechanism describes the reaction was also discussed. The tested compounds showed EGFR inhibitory activity with IC50 values ranging from 90 to 178 nM in comparison to the erlotinib as a reference with IC50 value of 70 nM. Compound 4c (R = allyl, n = 3) was found as the most potent antiproliferative, had the highest inhibitory effect on EGFR with an IC50 value of 90 nM, compared to erlotinib's IC50 value of 70 nM. The second and third-most active compounds were 4e (R = phenyl, n = 3) and 4d (R = ethyl, n = 3) and with IC50 values of 107 nM and 128 nM. These findings imply that the compounds tested had a significant antiproliferative effect as well as the ability to act as an EGFR inhibitor. Docking studies showed that compound 4c showed high affinity to EGFR based on its docking score (S; kcal/mol) within five test compounds.

Micromorphological Sculptural Diversity in Foliar Epidermis and Trichomes Features among Invasive Species.

This study examines the role of light microscopic (LM) and scanning electron microscopic (SEM) micromorphological traits of the epidermis in identifying and classifying invasive plants. SEM was conducted to increase our understanding of microscopic qualities that are not visible in light microscopy and to elucidate unclear affinities among invasive species. The study examines invasive species' morphological and anatomical characteristics from the Pothohar Plateau of Pakistan for the first time. The results showed that various micromorphological features are very useful for species' accurate identification. Adaxial and abaxial surfaces of leaves showed variations in subsidiary cells, glands, anticlinal wall patterns, stomata, and epidermal cells. Epidermal cell shapes observed were irregular, elongated, rectangular, and polygonal. Epidermal cells having maximum length were calculated in Stellaria media (126.3 µm) on adaxial side. On the abaxial surface, the minimum length was noticed in Eucalyptus camaldulensis (28.5 µm). Both glandular and nonglandular trichomes were examined, ranging from unicellular to multicellular. Most of the investigated specimens of leaves were amphistomatic, while some were hypostomatic, like Alternanthera pungens, Calotropis procera, Cannabis sativa, Lantana camara, and Thevetia peruviana. Leaf epidermal morphology contains numerous useful systematic features for accurate identifications of plant species. The micromorphological attributes under observation provide a standard criterion to the researcher for identifications of invasive flora in future morpho-taxonomic studies.

A Neurophysiological Evaluation of Cognitive Load during Augmented Reality Interactions in Various Industrial Maintenance and Assembly Tasks.

Augmented reality (AR) has been shown to improve productivity in industry, but its adverse effects (e.g., headaches, eye strain, nausea, and mental workload) on users warrant further investigation. The objective of this study is to investigate the effects of different instruction methods (i.e., HoloLens AR-based and paper-based instructions) and task complexity (low and high-demanding tasks) on cognitive workloads and performance. Twenty-eight healthy males with a mean age of 32.12 (SD 2.45) years were recruited in this study and were randomly divided into two groups. The first group performed the experiment using AR-based instruction, and the second group used paper-based instruction. Performance was measured using total task time (TTT). The cognitive workload was measured using the power of electroencephalograph (EEG) features and the NASA task load index (NASA TLX). The results showed that using AR instructions resulted in a reduction in maintenance times and an increase in mental workload compared to paper instructions, particularly for the more demanding tasks. With AR instruction, 0.45% and 14.94% less time was spent on low- and high-demand tasks, respectively, as compared to paper instructions. According to the EEG features, employing AR to guide employees during highly demanding maintenance tasks increased information processing, which could be linked with an increased germane cognitive load. Increased germane cognitive load means participants can better facilitate long-term knowledge and skill acquisition. These results suggested that AR is superior and recommended for highly demanding maintenance tasks since it speeds up maintenance times and increases the possibility that information is stored in long-term memory and encrypted for recalls.

Pharmacophore-Based Virtual Screening and In-Silico Explorations of Biomolecules (Curcumin Derivatives) of Curcuma longa as Potential Lead Inhibitors of ERBB and VEGFR-2 for the Treatment of Colorectal Cancer.

The newly FDA-approved drug, Axitinib, is an effective therapy against RTKs, but it possesses severe adverse effects like hypertension, stomatitis, and dose-dependent toxicity. In order to ameliorate Axitinib's downsides, the current study is expedited to search for energetically stable and optimized pharmacophore features of 14 curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) derivatives. The rationale behind the selection of curcumin derivatives is their reported anti-angiogenic and anti-cancer properties. Furthermore, they possessed a low molecular weight and a low toxicity profile. In the current investigation, the pharmacophore model-based drug design, facilitates the filtering of curcumin derivatives as VEGFR2 interfacial inhibitors. Initially, the Axitinib scaffold was used to build a pharmacophore query model against which curcumin derivatives were screened. Then, top hits from pharmacophore virtual screening were subjected to in-depth computational studies such as molecular docking, density functional theory (DFT) studies, molecular dynamics (MD) simulations, and ADMET property prediction. The findings of the current investigation revealed the substantial chemical reactivity of the compounds. Specifically, compounds S8, S11, and S14 produced potential molecular interactions against all four selected protein kinases. Docking scores of -41.48 and -29.88 kJ/mol for compounds S8 against VEGFR1 and VEGFR3, respectively, were excellent. Whereas compounds S11 and S14 demonstrated the highest inhibitory potential against ERBB and VEGFR2, with docking scores of -37.92 and -38.5 kJ/mol against ERBB and -41.2 and -46.5 kJ/mol against VEGFR-2, respectively. The results of the molecular docking studies were further correlated with the molecular dynamics simulation studies. Moreover, HYDE energy was calculated through SeeSAR analysis, and the safety profile of the compounds was predicted through ADME studies.

Synthesis and Antiproliferative Potential of Thiazole and 4-Thiazolidinone Containing Motifs as Dual Inhibitors of EGFR and BRAFV600E.

Thiazole and thiazolidinone recur in a wide range of biologically active compounds that reach different targets within the context of tumors and represent a promising starting point to access potential candidates for treating metastatic cancer. Therefore, searching for new lead compounds that show the highest anticancer potency with the fewest adverse effects is a major drug-discovery challenge. Because the thiazole ring is present in dasatinib, which is currently used in anticancer therapy, it is important to highlight the ring. In this study, cycloalkylidenehydrazinecarbothioamides (cyclopentyl, cyclohexyl, cyclooctyl, dihydronapthalenylidene, flurine-9-ylidene, and indolinonyl) reacted with 2-bromoacetophenone and diethylacetylenedicarboxylate to yield thiazole and 4-thiazolidinone derivatives. The structure of the products was confirmed by using infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and single-crystal X-ray analyses. The antiproliferative activity of the newly synthesized compounds was evaluated. The most effective inhibitory compounds were further tested in vitro against both epidermal growth factor receptor (EGFR) and B-Raf proto-oncogene, serine/threonine kinase (BRAFV600E) targets. Additionally, molecular docking analysis examined how these molecules bind to the active sites of EGFR and BRAFV600E.

New potent ciprofloxacin-uracil conjugates as DNA gyrase and topoisomerase IV inhibitors against methicillin-resistant Staphylococcus aureus.

A series of ciprofloxacin-uracil conjugates 5a-t were synthesized and identified by 1H NMR, 13C NMR, mass spectroscopy and elemental analyses. The antibacterial results revealed that the new derivatives exhibited better activity against Gram-positive than the Gram-negative strains; most of the target compounds exhibited good activities against S. aureus ATCC 6538. Compounds 5b and 5g possess the highest activities with MICs of 1.25 and 2.37 µM, respectively, which are more potent than the parent drug ciprofloxacin, MIC, 7.58 µM. In addition, they also exhibited potent activities against MRSA AUMC 261 with MICs, 0.031 and 0.046 µM respectively, higher than ciprofloxacin with MIC, 0.57 µM. Moreover, compounds 5b and 5g showed potent inhibitory activities against DNA gyrase (IC50 = 1.72 and 5.72 µM) and topoisomerase IV (4.36 and 7.77 µM) compared to ciprofloxacin with IC50 values 0.66 and 8.16 µM, respectively. The molecular docking study revealed that compounds 5b and 5g may formed stable interaction with the active sites of DNA gyrase and topoisomerase IV similar to ciprofloxacin. Hence, 5b and 5g are considered promising antibacterial candidated against MRSA AUMC 261 strains that requires further optimization.

Comparative study between topical methotrexate 1% gel and minoxidil 5% gel in the treatment of localized alopecia areata.

Alopecia areata (AA) is an autoimmune disease that results in non-scarring hair loss. Topical minoxidil 5% gel and methotrexate (MTX) 1% gel are important modalities used in the treatment of many dermatological diseases. We aimed to evaluate the efficacy of MTX 1% gel versus topical minoxidil 5% gel in the treatment of localized AA both clinically and dermoscopically. A total of 50 patients were randomly divided into two groups of 25 each; the first was treated with topical minoxidil 5% gel and the second was with MTX 1% gel. Dermoscopic and photographic pictures were used to follow up at baseline, 3, 6, and 12 weeks. By comparing the two therapies, we noticed that minoxidil has a statistically significant higher frequency of broken hair and black dots after 6 weeks than MTX. After 12 weeks, dermoscopic revealed that the minoxidil group had a lower frequency of vellus hair than the MTX group. Clinically after 6 weeks, minoxidil showed significantly more excellent improvement than MTX (16% vs. 0%), after 12 weeks, minoxidil and MTX showed excellent improvement (52% and 36%), respectively. There was no significant difference in side effects (erythema and itching) between the MTX and minoxidil groups. Both topical MTX 1% gel and topical minoxidil 5% gel had high efficacy in treating localized AA, with no significant differences between them as evaluated by clinical and dermoscopic examination.

A high-volume ERCP service led by surgeons is associated with good outcomes and meets national key performance indicators: results from a British district general hospital.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a common, but technically challenging procedure used in the management of hepatopancreaticobiliary (HPB) disease. It is traditionally performed by medical gastroenterologists. In 2014, the British Society of Gastroenterology (BSG) proposed key performance indicators to evaluate and set standards of ERCP practice. This study aimed to compare our ERCP outcomes against these targets, in a centre where ERCP is exclusively performed by surgeons. METHODS: A retrospective analysis of all ERCPs undertaken over a 38 months in a District General Hospital in the United Kingdom (UK), by three Upper Gastrointestinal Surgeons. Study outcomes were based upon, and compared against, BSG key performance indicators, including number of ERCPs per annum, proportion of successful cannulations of bile duct and stone clearance, ERCP-specific complications and mortality. RESULTS: The unit's caseload over this period was 1324, equating to approximately 418 per annum (BSG minimum 200 per unit). Management of bile duct stones was the commonest indication for ERCP. Overall, 95% (1253/1324) of bile ducts were cannulated and 92% (645/698) for those undergoing their first ERCP. Bile duct clearance was achieved in 80% of patients (BSG recommend > 75%) and the successful stenting of extra-hepatic strictures in 94% (BSG recommend > 80%). The overall complication rate was 4.3% (BSG standard < 6%). Procedure-specific mortality was 0.3% (4/1324) where death was either caused by pancreatitis or sepsis. CONCLUSION: A high-volume ERCP service led and performed exclusively by surgeons meets all BSG performance indicators, with good procedural and patient outcomes. Formal training pathways should be developed to encourage more surgical centres to provide an ERCP service and deal with what are common surgical pathologies.

A review on the synthesis of heteroannulated quinolones and their biological activities.

The quinoline scaffold has become an important construction motif for the development of new drugs. The quinolones and their heteroannulated derivatives have high importance due to their diverse spectrum of biological activities as antifungal, anti-inflammatory, anti-diabetes, anti-Alzheimer's disease, antioxidant and diuretic activities. This review summarizes the various new, efficient and convenient synthetic approaches to synthesize diverse quinolone-based scaffolds and their biological activities. We also dealt with the important mechanism, the route and type of reactions of the obtained products. The biological activities of some heteroannulated quinolones were also discussed.