Variation of antibacterial and antioxidant secondary metabolites and volatiles in leaf and callus extracts of Phulai (Acacia Modesta Wall.).

BACKGROUND: Acacia species are economically significant as medicinal plants that have been utilized since ancient times. Acacia modesta has been reported to possess potent antibacterial and antioxidant properties, but its growth rate is slow. In this study, we hypothesized that inducing callus in vitro from A. modesta could enhance the production of antibacterial and antioxidant secondary metabolites, thereby circumventing the issues of slow growth and excessive harvesting of the plant. RESULTS: The callus was induced from axillary buds on MS medium supplemented with 1 mg/L of 2,4-D and 1 mg/L of BAP. The secondary metabolites, volatile compounds, antibacterial activity, and antioxidant activity of the callus and parent plant leaf extracts were evaluated. The results revealed that the content of phenolics and flavonoids, the number of volatile compounds, and the antibacterial and antioxidant activities of the callus extract were significantly enhanced (P ≤ 0.05) compared to the leaf extract. The antibacterial and antioxidant effects were strongly correlated with the total phenolic and flavonoid content in the extracts. CONCLUSIONS: Our findings suggest that in vitro callus culture increases the production of phenolics, flavonoids, and volatile compounds. This subsequently enhances the antibacterial and antioxidant properties of A. modesta.

Medical education and the epidemics: How educational technology responded.

The global disruption created by the Coronavirus Disease 2019 (COVID-19) pandemic in medical education and healthcare institutions is unparalleled. Consequently, it is essential to evaluate the usability of forms of educational technology and to identify their viability and suitability for medical education. The objective of the investigation was to present an assessment of the state of medical education during the COVID-19 epidemic and to identify the obstacles faced by educators while introducing online learning systems for medical students. Two cross-sectional surveys were conducted with 200 medical students and 75 staff members from Saudi Arabia's University of Health. A descriptive method was used to focus on the mechanisms of analysis, foresight, and comprehension of reality. The most significant findings were the obstacles posed by instructors' most urgent requirements for educational technology training and its applications in order to activate distance education in medical education. In addition to a detailed description of the academic and technological concerns and obstacles encountered by students and faculty of health colleges during the pandemic, this report includes a discussion of the pandemic itself. Several prospective recommendations for the use of online and blended learning in health colleges post-pandemic were also made. Additionally, the requirement to activate learning via virtual professional learning groups.

La perturbation mondiale créée par la pandémie de maladie à coronavirus 2019 (COVID-19) dans les établissements d'enseignement médical et de soins de santé est sans précédent. Par conséquent, il est essentiel d'évaluer l'utilisabilité des formes de technologie éducative et d'identifier leur viabilité et leur adéquation à l'enseignement médical. L'objectif de l'enquête était de présenter une évaluation de l'état de l'enseignement médical pendant l'épidémie de COVID-19 et d'identifier les obstacles rencontrés par les éducateurs lors de l'introduction de systèmes d'apprentissage en ligne pour les étudiants en médecine. Deux enquêtes transversales ont été menées auprès de 200 étudiants en médecine et de 75 membres du personnel de l'Université de la Santé d'Arabie Saoudite. Une méthode descriptive a été utilisée pour se concentrer sur les mécanismes d'analyse, de prospective et de compréhension de la réalité. Les résultats les plus significatifs ont été les obstacles posés par les besoins les plus urgents des instructeurs en matière de formation en technologie éducative et ses applications afin d'activer l'enseignement à distance en médecine. éducation. En plus d'une description détaillée des préoccupations et des obstacles académiques et technologiques rencontrés par les étudiants et les professeurs des collèges de santé pendant la pandémie, ce rapport comprend une discussion sur la pandémie elle-même. Plusieurs recommandations prospectives concernant l'utilisation de l'apprentissage en ligne et mixte dans les établissements de santé après la pandémie ont également été formulées. À cela s'ajoute l'obligation d'activer l'apprentissage via des groupes d'apprentissage professionnel virtuels.

Genetic assessment of litter size, body weight, carcass traits and gene expression profiles in exotic and indigenous rabbit breeds: a study on New Zealand White, Californian, and Gabali rabbits in Egypt.

Rabbits are essential for commercial meat production due to their efficient growth and productivity, breeds like New Zealand White (NZW), Californian (CAL), and Gabali (GAB) rabbits offer unique genetic traits in litter, growth, and carcass traits. This study aimed to evaluate heritability (h2), genetic and phenotypic correlations (rg and rp) for litter size, body weight and carcass traits across California (CAL), New Zealand white (NZW) and Gabali (GA) rabbits. Along with exploring gene expression profiles of TBC1D1, NPY, AGRP, POMC, Leptin, GH, GHR, IGF-1, CAA, GPR, ACC, CPT1, FAS, and CART in the brain, liver, and meat tissues of different rabbit breeds. The breed genotype had a significant impact on litter size (LS), litter weight (LW), body weight at 12 weeks (BW12), and daily weight gain (DWG) traits. NZW rabbits displayed superior performance in terms of litter size and litter weight, while CAL rabbits recorded the highest values for BW12 and DWG. Heritability estimates (h2) were generally low for litter size (ranging from 0.05 to 0.12) and medium for body weight (ranging from 0.16 to 0.31). Both genetic (rg) and phenotypic (rp) correlations for litter size were positive and moderate (ranging from 0.08 to 0.48), while correlations for body weight ranged from 0.21 to 0.58. Additionally, CAL rabbits exhibited higher carcass traits compared to NZW and GA rabbits. In terms of breed-specific gene expression patterns, New Zealand White (NZW) rabbits displayed the highest expression levels of key genes related to energy metabolism (TBC1D1), appetite regulation (NPY, AGRP, POMC), nutrient transport (CAA), and G protein-coupled receptors (GPR) in both brain and liver tissues. Californian (CAL) rabbits exhibited superior gene expression of the ACC gene in brain tissue and GH, GHR, and IGF-1 genes in brain and meat tissues. Gabali (GAB) rabbits demonstrated the highest expression levels of TBC1D1, NPY, AGRP, GPR, and ACC genes in meat tissues. These breed-specific gene expression differences, combined with genetic evaluation efforts, have the potential to enhance reproductive and productive performance in rabbits, offering valuable insights for rabbit breeding programs and genetic selection.

Production of bioactive ß-carotene by the endophytic bacterium Citricoccus parietis AUCs with multiple in vitro biological potentials.

BACKGROUND: Although microalgae and plants are traditionally used for obtaining natural pigments, overexploitation and overharvesting threaten them. Bacteria represent a superior alternative for the production of pigments due to their ability to produce greater amounts in a short time without seasonal restrictions; furthermore, bacterial pigments have a wide range of uses and are safe and biodegradable. This study is the first on the production of ß-carotene as a promising bioactive agent from endophytic bacteria. RESULTS: The yellow pigment produced by the endophytic bacterium Citricoccus parietis AUCs (NCBI accession number: OQ448507.1) was extracted by methanol and then purified and identified. One band was obtained by TLC analysis, which was identified as ß-carotene based on its spectroscopic and chromatographic characteristics. The pigment exhibited remarkable antibacterial, antioxidant and antidiabetic activities. CONCLUSIONS: This research may serve as a valuable starting point for exploiting C. parietis AUCs as a potent source of ß-carotene for biomedical therapies. To validate the findings of this research, in vivo studies must be performed.

Phytotoxic Interference of Culture Filtrates of Endophytic Bacteria Associated with Nerium oleander Leaf Against Seed Germination of the Invasive Noxious Weed Cenchrus echinatus.

Weeds cause destructive agricultural losses, so weed control is an urgent challenge facing agriculture. The extensive use of synthetic chemical herbicides has detrimental environmental impacts and promotes the emergence of resistant species. Therefore, in this study we tried to find a new natural weed control that can ensure biosafety and eco-sustainability. The phytotoxic potential of culture filtrates of the endophytes Bacillus inaquosorum NL1 and Bacillus safensis NL2 isolated from Nerium oleander leaf against the invasive harmful weed species Cenchrus echinatus was evaluated. Culture filtrates of both bacterial species exhibited potent phytotoxic activity, which resulted in 100% germination inhibition of C. echinatus. The chemical analysis of culture filtrates revealed high contents of total phenolics and n-alkanes that have phytotoxic effects against seed germination. According to the findings of this study the endophytic bacteria associated with N. oleander leaf can be used in the future to develop a sustainable bio-herbicide formulation.

Navel orange peel hydroethanolic extract as a phytogenic feed supplement: impacts on growth, feed intake, nutrient digestibility, and serum metabolites of heat stressed growing rabbits.

Currently, using agricultural wastes in animal production has gained worldwide interest. Hence, herein, an eight-week trial was performed to explore the effects of supplemental navel orange peel extract (NPE) on the growth, feed utilization, nutrient digestibility, antioxidant, and hematological parameters of heat-stressed rabbits. In total, 75 weaned rabbits were randomly assigned into five groups. The first group was reared in the winter (mild weather) and fed an untreated pelleted diet (W-NPE-0; control). The other four groups were reared in the summer (hot climate) and fed the control diet fortified with 0 (S-NPE-0), 250 (S-NPE-250), 500 (S-NPE-500), or 1000 (S-NPE-1000) mg NPE/kg diet. The results indicated that thermal-stressed rabbits (S-NPE-0) had significantly lower feed intake, growth performance, hematological indices, serum lipid profile, and antioxidative status, but higher lipid peroxidation compared to the W-NPE-0 group. However, the highest final weight and feed intake were recorded in the S-NPE-1000 group compared with the S-NPE-0 group. Also, supplemental NPE in the growing rabbit diet, especially the S-NPE-1000 group, enhanced the hematological and antioxidative indicators. In conclusion, NPE supplementation in growing rabbit diets could be used to efficiently mitigate the detrimental effects of chronic temperature stress on performance, hematobiochemical features, and oxidative stability.

Factorial validity of the self-compassion scale among female University students: A comparative study between Saudi and Egyptian cultures.

The study aims to verify the factorial structure of the self-compassion scale across different cultural contexts. The sample included 1039 students, divided into 521 students from Zagazig University (ZU) and 518 from Princess Nourah University (PNU) in the Kingdom of Saudi Arabia (KSA), which were chosen randomly. Exploratory factor analysis was used to test the stability of items on the dimensions. The results showed stability along with kindness with self, isolation, common humanity, and self-judgment factors. On the other hand, confirmatory factor analysis demonstrated that the results of this study yielded the best fit for the total sample. Then factor analysis across the two groups was used to verify the existence of differences between Saudi and Egyptian cultures. The analysis results revealed that the Egyptian environment model is superior to its Saudi counterpart and that there are no differences between the two cultures using the factorial differences indicators RMSEA, NNFI, GFI, and SRMR. This study's outcomes can have global implications for promoting self-compassion as a tool for improving mental health and well-being across cultures.

Phenotypical changes of hematopoietic stem and progenitor cells in COVID-19 patients: Correlation with disease status.

Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) play a crucial role in the context of viral infections and their associated diseases. The link between HSCs and HPCs and disease status in COVID-19 patients is largely unknown. This study aimed to monitor the kinetics and contributions of HSCs and HPCs in severe and non-severe COVID-19 patients and to evaluate their diagnostic performance in differentiating between healthy and COVID-19 patients as well as severe and non-severe cases. Peripheral blood (PB) samples were collected from 48 COVID-19 patients, 16 recovered, and 27 healthy controls and subjected to deep flow cytometric analysis to determine HSCs and progenitor cells. Their diagnostic value and correlation with C-reactive protein (CRP), D-dimer, and ferritin levels were determined. The percentages of HSCs and common myeloid progenitors (CMPs) declined significantly, while the percentage of multipotent progenitors (MPPs) increased significantly in COVID-19 patients. There were no significant differences in the percentages of megakaryocyte-erythroid progenitors (MEPs) and granulocyte-macrophage progenitors (GMPs) between all groups. Severe COVID-19 patients had a significantly low percentage of HSCs, CMPs, and GMPs compared to non-severe cases. Contrarily, the levels of CRP, D-dimer, and ferritin increased significantly in severe COVID-19 patients. MPPs and CMPs showed excellent diagnostic performance in distinguishing COVID-19 patients from healthy controls and severe from non-severe COVID-19 patients, respectively. Collectively, our study indicated that hematopoietic stem and progenitor cells are significantly altered by COVID-19 and could be used as therapeutic targets and diagnostic biomarkers for severe COVID-19.

Unusual pattern of thrombotic events in young adult non-critically ill patients with COVID-19 may result from an undiagnosed inherited and acquired form of thrombophilia.

In 145 previously healthy non-critically ill young adults, coronavirus disease 2019 (COVID-19)-related symptoms, risk factors for thrombosis, coagulation and inflammatory parameters were compared, with 29 patients reporting unusual thrombotic events (UTEs) and 116 not having thrombotic events. The inflammatory indices, coagulation and prothrombotic platelet phenotype (PTPP) were significantly higher in patients with UTEs versus those without. Patients with UTEs were categorised according to detection of thrombophilic genes (TGs), coagulation and inflammatory markers to the non-TG and TG subcohort. A total of 38 UTEs were identified, which included splanchnic vein thrombosis (SVT; 11), stroke (six), cerebral vein thrombosis (five), thrombotic microangiopathy (four), limb ischaemia and inferior vena cava thrombosis (three each), ST-segment elevation myocardial infarction (two), superior vena cava thrombosis (two), upper limb deep venous thrombosis and retinal vein thrombosis, one each. We found a 55% prevalence of TGs mainly heterozygous coagulation factor II, thrombin (FII)-G20210A, Janus kinase 2 (JAK2)-V617F, protein-S, and antithrombin III deficiency with a high (76·9%) prevalence of venous UTEs, multiple vessels thrombosis, and recurrence rate among the TG versus non-TG subcohort. The presence of JAK2-V617F, and FII-G20210A mutations was linked with SVT. Thrombosis in the non-TG subcohort was associated with more haemorrhagic problems, thrombosis progression and a significantly higher level of inflammatory markers, PTPP, mean platelet volume, von Willebrand factor, and factor VIII, which remained high for up to 6 months, as well as elevated D-dimer. Acquired and inherited thrombophilia with endotheliopathy appeared to be a relevant mechanism to explain the occurrence of UTEs that are not correlated to COVID-19 severity.

The endophyte Stenotrophomonas maltophilia EPS modulates endogenous antioxidant defense in safflower (Carthamus tinctorius L.) under cadmium stress.

Cadmium (Cd) pollution in agricultural soils induces oxidative stress in plants that in turn is the foremost limiting factor for agricultural productivity. In past few decades, plant-metal-microbe interaction is of great interest as an emerging environmentally friendly technology that can be exploited to alleviate metal stress in plants. Considering these, in the present study an endophytic bacterium strain EPS has been isolated from the roots of common bean. The present strain was identified as Stenotrophomonas maltophilia based on 16S rRNA gene sequence. The strain showed Cd tolerance and Cd-adsorption potentials. The inoculation of strain EPS in safflower seeds significantly enhanced the antioxidant defense of plants under Cd-stress conditions through increasing the levels of antioxidant molecules like phenolics, flavonoids and carotenoids as well as improving the activities of the antioxidative enzymes including guaiacol peroxidase (POX), ascorbate peroxidase (APX) and superoxide dismutase (SOD). The output of this study is that strain EPS inoculation mitigates Cd-induced oxidative stress and consequently it may be beneficial, especially in Cd-contaminated crop fields.

Cabergoline versus calcium infusion in the prevention of ovarian hyperstimulation syndrome: a randomised controlled study.

The aim of this study was to compare the efficacy of calcium infusion versus cabergoline in the prevention of ovarian hyperstimulation syndrome (OHSS) in IVF patients at high risk for OHSS. One hundred and seventy patients who were stimulated using the long luteal GnRH agonist protocol and at high risk for developing OHSS were randomised in a 1:1 ratio to cabergoline group and calcium gluconate group. In cabergoline group, 0.5 mg of cabergoline was administered once daily p.o. for eight days starting on the day of HCG administration. In calcium gluconate group, intravenous calcium gluconate (10%, 10 ml in 200 ml of physiologic saline) was administered daily for four days starting on the day of ovum pickup. Six patients in cabergoline group and eight patients in calcium gluconate group developed moderate OHSS. One patient in each group developed severe OHSS. The incidence of moderate/severe OHSS was comparable between both groups (8.24% vs. 10.59%, p value = .599, OR = 0.76, 95% CI [0.269-2.138]). The implantation, clinical and ongoing pregnancy rates were similar in the two groups (16.91% vs. 15.84%, p = .771, 35.29% vs. 32.94%, p = .746, and 30.59% vs. 28.24%, p = .736, respectively). In conclusion, calcium infusion and cabergoline have comparable effectiveness in the prevention of OHSS. Both drugs are well tolerated, cheap and have no adverse effects on the reproductive outcomes of IVF cycle.Clinical trial registration: The trial was registered on clinical trials.gov database [NCT02875587].Impact StatementWhat is already known on this subject? The effectiveness of cabergoline in the prevention of OHSS in IVF patients at high risk for OHSS is confirmed by overwhelming scientific evidence. Calcium infusion is a novel strategy for prevention of OHSS. Few studies reported the use of calcium infusion in the prevention of OHSS. A retrospective study and a randomised controlled study revealed that calcium infusion reduces the incidence of OHSS. Moreover, a quasi-randomised study revealed that calcium infusion is as effective as cabergoline in the prevention of OHSS.What the results of this study add? Calcium infusion and cabergoline have comparable effectiveness in the prevention of OHSS. Both drugs are well tolerated, cheap and have no adverse effects on the reproductive outcomes of IVF cycle.What the implications are of these findings for clinical practice and/or further research? Calcium infusion should be used to minimise the incidence of OHSS in IVF patients at high risk for OHSS.

Macroalga-associated bacterial endophyte bioactive secondary metabolites twinning: Cystoseira myrica and its associated Catenococcus thiocycli QCm as a model.

Marine ecosystems represent the largest biome on the earth. Until now, the relationships between the marine microbial inhabitants and the macroalgal species unclear, and the previous studies are insufficient. So, more research is required to advance our understanding of macroalgal- microbial interactions. In this study, we tried to investigate the relationship between the brown marine macroalga, Cystoseira myrica and its associated bacterial endophyte, Catenococcus thiocycli, as the first study concerning the production of bioactive secondary metabolites from a macroalgal species comparing with its associated endophytic bacteria. Secondary metabolites were extracted from alga and its bacterial endophyte with ethyl acetate and methanol. All extracts contained significant quantities of phenolics, flavonoids, tannins, and saponins. Strikingly, extracts possess antioxidant, anti-inflammatory and antimicrobial activities which were significantly correlated to phenolic and flavonoid contents.

Drought-tolerant Sphingobacterium changzhouense Alv associated with Aloe vera mediates drought tolerance in maize (Zea mays).

Drought severity and duration are expected to increase as a result of ongoing global climate change. Therefore, finding solutions to help plants to deal with drought stress and to improve growth in the face of limited water resources is critical. In this study, a drought tolerant- plant growth promoting endophytic bacterium was isolated from Aloe vera roots. It was identified as Sphingobacterium changzhouense based on 16S rRNA gene sequencing and was deposited into NCBI database with accession number (ON944028). The effect of S. changzhouense inoculation on maize growth under drought stress was investigated. The results revealed that inoculation significantly (p ≤ 0.05) enhanced root and shoot elongation by 205 and 176.19% respectively. Photosynthesis rate, stomatal conductance and water use efficiency were improved in inoculated plants. interestingly, inoculation resulted in significant increase in total chlorophyll, total carbohydrates, proline, total proteins, total phenolics and total flavonoids by 64, 31.5, 25.1, 75.07, 83.7 and 65.4% respectively. Total antioxidant capacity of inoculated plants (51.2 mg/g FW) was higher than that of non-inoculated plants (11.87 mg/g FW), which was found to be positively correlated to the levels of phenolics and flavonoids. Our finding suggests that S. changzhouense could be used to improve crop growth and assist plants to resist drought stress in arid agricultural lands.

Design, synthesis and anti-inflammatory activity of imidazol-5-yl pyridine derivatives as p38α/MAPK14 inhibitor.

P38α/MAPK14 is intracellular signalling regulator involved in biosynthesis of inflammatory mediator cytokines (TNF-α, IL-1, IL-6, and IL-1b), which induce the production of inflammatory proteins (iNOS, NF-kB, and COX-2). In this study, drug repurposing strategies were followed to repositioning of a series of B-RAF V600E imidazol-5-yl pyridine inhibitors to inhibit P38α kinase. A group 25 reported P38α kinase inhibitors were used to build a pharmacophore model for mapping the target compounds and proving their affinity for binding in P38α active site. Target compounds were evaluated for their potency against P38α kinase, compounds 11a and 11d were the most potent inhibitors (IC50 = 47 nM and 45 nM, respectively). In addition, compound 11d effectively inhibited the production of proinflammatory cytokinesTNF-α, 1L-6, and 1L-1ß in LPS-induced RAW 264.7 macrophages with IC50 values of 78.03 nM, 17.6 µM and 82.15 nM, respectively. The target compounds were tested for their anti-inflammatory activity by detecting the reduction of Nitric oxide (NO) and prostaglandin (PGE2) production in LPS-stimulated RAW 264.7 macrophages. Compound 11d exhibited satisfied inhibitory activity of the production of PGE2 and NO with IC50 values of 0.29 µM and 0.61 µM, respectively. Molecular dynamics simulations of the most potent inhibitor 11d were carried out to illustrate its conformational stability in the binding site of P38α kinase.

Design, synthesis, and biological evaluation of novel imidazole derivatives possessing terminal sulphonamides as potential BRAFV600Einhibitors.

BRAFV600E mutation has been detected in various malignant tumours. Developing of potent BRAFV600E inhibitors is considered a leading step in the way to cure different cancer types. In the current work, a series of 38 4-(1H-imidazol-5-yl)pyridin-2-amine derivatives was designed and synthesized using Dabrafenib as a lead compound for structural-guided optimization. The target compounds were evaluated as potential anticancer agents against NCI 60 human cancer cell lines. In 5-dose testing mode, two compounds 14h and 16e were tested to determine their IC50 values over each of the 60 cell lines. The selected candidates exhibited promising activity with mean IC50 values of 2.4 µM and 3.6 µM, respectively. Melanoma cancer cell lines exhibited the highest sensitivity after the treatment with the tested compounds 14h and 16e. The mean IC50 values of compounds 14h and 16e against Melanoma cancer cell lines are 1.8 µM and 1.88 µM, respectively. In addition, BRAFV600E kinase inhibitory activity was determined for each derivative. Compounds 15i, 15j, 16a, and 16d were the most potent inhibitors against BRAFV600E with IC50 76 nM, 32 nM, 35 nM, and 68 nM. The newly developed compounds represent a therapeutically promising approach for the treating various cancer types.

Assessment of the potential of non-thermal atmospheric pressure plasma discharge and microwave energy against Tribolium castaneum and Trogoderma granarium.

This study was carried out to investigate the efficacy of the non-thermal atmospheric pressure plasma produced with dielectric barrier discharge (APPD) using air as a processing gas and microwave energy to control Tribolium castaneum and Trogoderma granarium adults and larvae in wheat grains. Insects' mortality was found to be power and time-dependent. The results indicated that non-thermal APPD and the microwave have enough insecticidal effect on the target pests. From the bioassay, LT50's and LT90's levels were estimated, T. granarium larvae appeared more tolerant to non-thermal APPD and the microwave energy than adults 7 days post-exposure. The germination percentage of wheat grains increased as the time of exposure to the non-thermal APPD increased. On the contrary, the germination percentage of wheat grains decreased as the time of exposure to the microwave increased. In addition, changes in antioxidant enzyme activities, catalase (CAT), glutathione S-transferase (GST) and peroxidase, in adults and larvae were examined after 24 h post-treatment to non-thermal APPD at 15.9 W power level, which caused 50% mortality. The activity of CAT, GST and lipid peroxide in the treated larvae showed a significant increase post-exposure to the non-thermal APPD at 15.9 W power level. On the other hand, no significant change in GSH-Px activity was observed. Reductions in the level of glutathione (GSH) and protein content occurred in treated larvae in comparison with the control.

Scaffold Repurposing of In-House Small Molecule Candidates Leads to Discovery of First-in-Class CDK-1/HER-2 Dual Inhibitors: In Vitro and In Silico Screening.

Recently, multitargeted drugs are considered a potential approach in treating cancer. In this study, twelve in-house indole-based derivatives were preliminary evaluated for their inhibitory activities over VEGFR-2, CDK-1/cyclin B and HER-2. Compound 15l showed the most inhibitory activities among the tested derivatives over CDK-1/cyclin B and HER-2. Compound 15l was tested for its selectivity in a small kinase panel. It showed dual selectivity for CDK-1/cyclin B and HER-2. Moreover, in vitro cytotoxicity assay was assessed for the selected series against nine NCI cell lines. Compound 15l showed the most potent inhibitory activities among the tested compounds. A deep in silico molecular docking study was conducted for compound 15l to identify the possible binding modes into CDK-1/cyclin B and HER-2. The docking results revealed that compound 15l displayed interesting binding modes with the key amino acids in the binding sites of both kinases. In vitro and in silico studies demonstrate the indole-based derivative 15l as a selective dual CDK-1 and HER-2 inhibitor. This emphasizes a new challenge in drug development strategies and signals a significant milestone for further structural and molecular optimization of these indole-based derivatives in order to achieve a drug-like property.

Indomethacin can induce cell death in rat gastric parietal cells through alteration of some apoptosis- and autophagy-associated molecules.

In clinical medicine, indomethacin (IND, a non-steroidal anti-inflammatory drug) is used variously in the treatment of severe osteoarthritis, rheumatoid arthritis, gouty arthritis or ankylosing spondylitis. A common complication found alongside the therapeutic characteristics is gastric mucosal damage. This complication is mediated through apoptosis and autophagy of the gastrointestinal mucosal epithelium. Apoptosis and autophagy are critical homeostatic pathways catalysed by caspases downstream of the gastrointestinal mucosal epithelial injury. Both act through molecular signalling pathways characterized by the initiation, mediation, execution and regulation of the cell regulatory cycle. In this study we hypothesized that dysregulated apoptosis and autophagy are associated with IND-induced gastric damage. We examined the spectra of in vivo experimental gastric ulcers in male Sprague-Dawley rats through gastric gavage of IND. Following an 18-hour fast, IND was administered to experimental rats. They were sacrificed at 3-, 6- and 12-hour intervals. Parietal cells (H+ , K+ -ATPase ß-subunit assay) and apoptosis (TUNEL assay) were determined. The expression of apoptosis-signalling caspase (caspases 3, 8, 9 and 12), DNA damage (anti-phospho-histone H2A.X) and autophagy (MAP-LC3, LAMP-1 and cathepsin B)-related molecules in gastric mucosal cells was examined. The administration of IND was associated with gastric mucosal erosions and ulcerations mainly involving the gastric parietal cells (PCs) of the isthmic and upper neck regions and a time-dependent gradual increase in the number of apoptotic PCs with the induction of both apoptotic (upregulation of caspases 3 and 8) cell death and autophagic (MAP-LC3-II, LAMP-1 and cathepsin B) cell death. Autophagy induced by fasting and IND 3 hours initially prompted the degradation of caspase 8. After 6 and 12 hours, damping down of autophagic activity occurred, resulting in the upregulation of active caspase 8 and its nuclear translocation. In conclusion we report that IND can induce time-dependent apoptotic and autophagic cell death of PCs. Our study provides the first indication of the interactions between these two homeostatic pathways in this context.

Free Testosterone and Prolactin Levels and Sperm Morphology and Function Among Male Patients With Tramadol Abuse: A Case-Control Study.

BACKGROUND/PURPOSE: Tramadol abuse has become a crisis in Egypt and many other Middle Eastern countries. Tramadol abuse is associated with sexual dysfunction and male infertility, according to recent animal and human studies. The objective of this study was to compare tramadol abuse patients and healthy controls regarding free testosterone and prolactin levels and semen analysis. METHODS: Sixty patients with opiate use disorders attributed to tramadol (OUD-T) based on Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) diagnostic criteria and 30 healthy controls were included in the study. Sociodemographic and clinical data and urine, blood, and semen samples were collected from patients and controls for assessment. RESULTS: Compared with controls, OUD-T patients had higher prolactin and lower free testosterone levels. Patients with OUD-T were more likely to have lower sperm count and higher abnormal motility and forms of sperms compared with controls. CONCLUSIONS: Patients with OUD-T were found to be more likely to have lower free testosterone levels and lower sperm counts and vitality, and higher prolactin levels and sperm abnormal forms compared with controls.

Modification of imidazothiazole derivatives gives promising activity in B-Raf kinase enzyme inhibition; synthesis, in vitro studies and molecular docking.

B-Raf mutation was identified as a key target in cancer treatment. Based on structural features of dabrafenib (potent FDA approved B-Raf inhibitor), the design of new NH2-based imidazothiazole derivatives was carried out affording new highly potent derivatives of imidazothiazole-based scaffold with amino substitution on the terminal phenyl ring as well as side chain with sulfonamide group and terminal substituted phenyl ring. In vitro enzyme assay was investigated against V600E B-Raf kinase. Compounds 10l, 10n and 10o showed higher inhibitory activities (IC50 = 1.20, 4.31 and 6.21 nM, respectively). In vitro cytotoxicity evaluation was assessed against NCI-60 cell lines. Most of tested derivatives showed cytotoxic activities against melanoma cell line. Compound 10k exhibited most potent activity (IC50 = 2.68 µM). Molecular docking study revealed that the new designed derivatives preserved the same binding mode of dabrafenib with V600E B-Raf active site. It was investigated that the new modification in the synthesized derivatives (substituted with NH2) had a significant inhibitory activity towards V600E B-Raf. This core scaffold is considered a key compound for further structural and molecular optimization.