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The interaction between the tumor suppressor protein p53 and its negative regulator, the MDM2 oncogenic protein, has gained significant attention in cancer drug discovery. In this study, 120 lignans reported from Ferula sinkiangensis and Justicia procumbens were assessed for docking simulations on the active pocket of the MDM2 crystal structure bound to Nutlin-3a. The docking analysis identified nine compounds with higher docking scores than the co-crystallized reference. Subsequent AMDET profiling revealed satisfactory pharmacokinetic and safety parameters for these natural products. Three compounds, namely, justin A, 6-hydroxy justicidin A, and 6′-hydroxy justicidin B, were selected for further investigation due to their strong binding affinities of −7.526 kcal/mol, −7.438 kcal/mol, and −7.240 kcal/mol, respectively, which surpassed the binding affinity of the reference inhibitor Nutlin-3a (−6.830 kcal/mol). To assess the stability and reliability of the binding of the candidate hits, a molecular dynamics simulation was performed over a duration of 100 ns. Remarkably, the thorough analysis demonstrated that all the hits exhibited stable molecular dynamics profiles. Based on their effective binding to MDM2, favorable pharmacokinetic properties, and molecular dynamics behavior, these compounds represent a promising starting point for further refinement. Nevertheless, it is essential to synthesize the suggested compounds and evaluate their activity through in vitro and in vivo experiments.

Cyclin-dependent kinase 5 (CDK5) plays a crucial role in various biological processes, including immune response, insulin secretion regulation, apoptosis, DNA (deoxyribonucleic acid) damage response, epithelial−mesenchymal transition (EMT), cell migration and invasion, angiogenesis, and myogenesis. Overactivation of CDK5 is associated with the initiation and progression of cancer. Inhibiting CDK5 has shown potential in suppressing cancer development. Despite advancements in CDK5-targeted inhibitor research, the range of compounds available for clinical and preclinical trials remains limited. The marine environment has emerged as a prolific source of diverse natural products with noteworthy biological activities, including anti-cancer properties. In this study, we screened a library of 47,450 marine natural compounds from the comprehensive marine natural product database (CMNPD) to assess their binding affinity with CDK5. Marine compounds demonstrating superior binding affinity compared to a reference compound were identified through high-throughput virtual screening, standard precision and extra-precision Glide docking modes. Refinement of the selected molecules involved evaluating molecular mechanics–generalized born surface area (MM/GBSA) free binding energy. The three most promising compounds, (excoecariphenol B, excoecariphenol A, and zyzzyanone B), along with the reference, exhibiting favorable binding characteristics were chosen for molecular dynamics (MD) simulations for 200 nanoseconds. These compounds demonstrated interaction stability with the target during MD simulations. The marine compounds identified in this study hold potential as effective CDK5 inhibitors and warrant subsequent experimental validation.

Background Laparoscopic cholecystectomy is a popular abdominal surgery and the most common problem for patients undergoing laparoscopic cholecystectomy is the postoperative pain, and associated side effects due to opioids use for pain management and multimodal analgesia is suggested to reduce postoperative pain and need for postoperative opioids. This controlled clinical trial compares the effects of multimodal analgesia and pregabalin as unimodal analgesia on postoperative pain management, postoperative opioids consumption, and reduction of opioids accompanied adverse effects in patients undergoing laparoscopic cholecystectomy where large multicenter studies evaluating specific analgesic combinations are lacking. Method This comparison randomized controlled trial between multimodal analgesia approach and pregabalin as unimodal analgesia included 95 laparoscopic cholecystectomy patients that were randomly allocated to three groups using a simple randomization method where multimodal and pregabalin groups included 30 patients in each and the drugs was administered orally one hour before the incision and control group included 35 patients that did not receive any preoperative analgesia. Multimodal analgesic therapy included acetaminophen 1 g, pregabalin 150 mg and celecoxib 400 mg while pregabalin group received pregabalin 150 mg only. Results Multimodal group showed a significantly lower need for total opioid analgesics mean ± SD (1.33 ± 1.918) as compared to the control group mean ± SD (3.31 ± 2.784) with p-value 0.014. Pregabalin and multimodal groups showed significantly lower postoperative visual analogue scale used for pain assessment mean ± SD (3.50 ± 2.543) and mean ± SD (3.70 ± 2.231), respectively, compared to the control group mean ± SD (5.89 ± 2.857) with p-value 0.001. Conclusion Multimodal analgesia reduced postoperative opioids consumption more than pregabalin alone when used preoperatively in laparoscopic cholecystectomy and consequently reduced opioids associated adverse effects, but they have the same efficacy in reducing postoperative pain, so pregabalin can be used alone preoperatively in patients with contraindications for using some analgesics included in multimodal analgesia protocol. The study was registered retrospectively in clinical trials; Trial registration ID: NCT05547659.

Marine-derived fungi are renowned as a source of astonishingly significant and synthetically appealing metabolites that are proven as new lead chemicals for chemical, pharmaceutical, and agricultural fields. Aspergillus sydowii is a saprotrophic, ubiquitous, and halophilic fungus that is commonly found in different marine ecosystems. This fungus can cause aspergillosis in sea fan corals leading to sea fan mortality with subsequent changes in coral community structure. Interestingly, A. sydowi is a prolific source of distinct and structurally varied metabolites such as alkaloids, xanthones, terpenes, anthraquinones, sterols, diphenyl ethers, pyrones, cyclopentenones, and polyketides with a range of bioactivities. A. sydowii has capacity to produce various enzymes with marked industrial and biotechnological potential, including α-amylases, lipases, xylanases, cellulases, keratinases, and tannases. Also, this fungus has the capacity for bioremediation as well as the biocatalysis of various chemical reactions. The current work aimed at focusing on the bright side of this fungus. In this review, published studies on isolated metabolites from A. sydowii, including their structures, biological functions, and biosynthesis, as well as the biotechnological and industrial significance of this fungus, were highlighted. More than 245 compounds were described in the current review with 134 references published within the period from 1975 to June 2023.

Background Data on the best norepinephrine bolus dose for management of hypotension are limited. The aim of this study was to compare the efficacy and safety of two norepinephrine bolus doses in the rescue management of maternal hypotension during cesarean delivery. Methods This randomized, controlled trial included mothers scheduled for cesarean delivery with spinal anesthesia with a prophylactic norepinephrine infusion. Following spinal anaesthesia administration, a participant was considered hypotensive if systolic blood pressure was ≤80% compared to the baseline reading. Participants were allocated to receive either 6 mcg or 10 mcg norepinephrine bolus for the management of hypotensive episodes. The hemodynamic response after administration of norepinephrine bolus was recorded. The episode was considered successfully managed if systolic blood pressure returned to within 80% from the baseline reading within 2 min after norepinephrine bolus administration, and did not drop again within 6 min after the norepinephrine bolus. The primary outcome was the incidence of successful management of the first hypotensive episode. Other outcomes included systolic blood pressure, heart rate, incidence of maternal bradycardia, and reactive hypertension. Results One hundred and ten mothers developed hypotensive episodes and received norepinephrine boluses for management. The number of successfully managed first hypotensive episodes was 50/57 (88%) in the 6 mcg-treated episodes and 45/53 (85%) in the 10 mcg-treated episodes ( p  = 0.78). Systolic blood pressure was comparable after administration of either bolus dose. Heart rate was lower after administration of 10 mcg bolus compared to 6 mcg bolus, without significant bradycardia requiring atropine administration. The incidence of reactive hypertension was comparable between both groups. Conclusion In mothers undergoing elective cesarean delivery under prophylactic norepinephrine infusion at 0.05 mcg/kg/min, there was no advantage to the use of 10 mcg norepinephrine bolus over 6 mcg norepinephrine bolus for the rescue management of first hypotensive episode. Neither of the 2 bolus doses reached a 100% success rate. The incidences of bradycardia and reactive hypertension were comparable between both norepinephrine doses. Trial registration At clinicaltrial.gov registry system on January 4, 2019 Clinical trial identifier: NCT03792906 .

Fungi are of considerable importance due to their capacity to biosynthesize various secondary metabolites with bioactive properties that draw high attention in new drug discovery with beneficial uses for improving human well-being and life quality. Aspergillus genus members are widespread and cosmopolitan species with varying economic significance in the fields of industry, medicine, and agriculture. Its species are renowned for their biosynthesis of secondary metabolites, characterized by both potent biological activity and structural novelty, making them a substantial reservoir for the development of new pharmaceuticals. The current work aimed at focusing on one species of this genus, Aspergillus wentii Wehmer, including its reported secondary metabolites in the period from 1951 to November 2023. A total of 97 compounds, including nitro-compounds, terpenoids, anthraquinones, xanthones, benzamides, and glucans. A summary of their bioactivities, as well as their biosynthesis was highlighted. Additionally, the reported applications of this fungus and its enzymes have been discussed. This review offers a useful reference that can direct future research into this fungus and its active metabolites, as well as their possible pharmacological and biotechnological applications.

The Aurora kinases play crucial roles in regulating mitotic progression and have implications in various diseases, including cancer. In this study, we explored the potential of depsidone analogues as inhibitors of Aurora A kinase through computational methods. A molecular docking studies of 260 depsidone molecules against Aurora A kinase, were conducted using extra precision docking mode of Glide. Three molecules, parmosidone A, chaetosidone A, and parmosidone E, showed promising docking scores compared to the reference inhibitor. These compounds exhibited strong interactions with the binding site of Aurora A kinase, involving hydrogen bonds and hydrophobic interactions. To further evaluate the stability of these interactions, we performed molecular dynamics simulations for 100 nanoseconds. RMSD analysis indicated that all compounds maintained relatively stable interactions with the protein throughout the simulation period. Notably, parmosidone A and chaetosidone A exhibited minimal fluctuations after an initial equilibration phase. RMSF analysis revealed that certain protein residues showed high fluctuations but were not crucial for inhibitor binding. Protein-ligand interaction analysis demonstrated that water bridges and hydrogen bonds played significant roles in the interactions between the compounds and Aurora A kinase. Overall, our computational assessments suggest that depsidone analogues, particularly parmosidone A and chaetosidone A, have potential as inhibitors of Aurora A kinase. These findings provide insights into the molecular interactions of these compounds and open new avenues for targeting Aurora A kinase in cancer therapy.

Marine-derived fungi are renowned as a source of astonishingly significant and synthetically appealing metabolites that are proven as new lead chemicals for chemical, pharmaceutical, and agricultural fields. Aspergillus sydowii is a saprotrophic, ubiquitous, and halophilic fungus that is commonly found in different marine ecosystems. This fungus can cause aspergillosis in sea fan corals leading to sea fan mortality with subsequent changes in coral community structure. Interestingly, A. sydowi is a prolific source of distinct and structurally varied metabolites such as alkaloids, xanthones, terpenes, anthraquinones, sterols, diphenyl ethers, pyrones, cyclopentenones, and polyketides with a range of bioactivities. A. sydowii has capacity to produce various enzymes with marked industrial and biotechnological potential, including α-amylases, lipases, xylanases, cellulases, keratinases, and tannases. Also, this fungus has the capacity for bioremediation as well as the biocatalysis of various chemical reactions. The current work aimed at focusing on the bright side of this fungus. In this review, published studies on isolated metabolites from A. sydowii, including their structures, biological functions, and biosynthesis, as well as the biotechnological and industrial significance of this fungus, were highlighted. More than 245 compounds were described in the current review with 134 references published within the period from 1975 to June 2023.

Agriculture has significantly aided in meeting the food needs of growing population. In addition, it has boosted economic development in irrigated regions. In this study, an assessment of the groundwater (GW) quality for agricultural land was carried out in El Kharga Oasis, Western Desert of Egypt. Several irrigation water quality indices (IWQIs) and geographic information systems (GIS) were used for the modeling development. Two machine learning (ML) models (i.e., adaptive neuro-fuzzy inference system (ANFIS) and support vector machine (SVM)) were developed for the prediction of eight IWQIs, including the irrigation water quality index (IWQI), sodium adsorption ratio (SAR), soluble sodium percentage (SSP), potential salinity (PS), residual sodium carbonate index (RSC), and Kelley index (KI). The physicochemical parameters included T°, pH, EC, TDS, K+, Na+, Mg2+, Ca2+, Cl−, SO42−, HCO3−, CO32−, and NO3−, and they were measured in 140 GW wells. The hydrochemical facies of the GW resources were of Ca-Mg-SO4, mixed Ca-Mg-Cl-SO4, Na-Cl, Ca-Mg-HCO3, and mixed Na-Ca-HCO3 types, which revealed silicate weathering, dissolution of gypsum/calcite/dolomite/ halite, rock–water interactions, and reverse ion exchange processes. The IWQI, SAR, KI, and PS showed that the majority of the GW samples were categorized for irrigation purposes into no restriction (67.85%), excellent (100%), good (57.85%), and excellent to good (65.71%), respectively. Moreover, the majority of the selected samples were categorized as excellent to good and safe for irrigation according to the SSP and RSC. The performance of the simulation models was evaluated based on several prediction skills criteria, which revealed that the ANFIS model and SVM model were capable of simulating the IWQIs with reasonable accuracy for both training “determination coefficient (R2)” (R2 = 0.99 and 0.97) and testing (R2 = 0.97 and 0.76). The presented models’ promising accuracy illustrates their potential for use in IWQI prediction. The findings indicate the potential for ML methods of geographically dispersed hydrogeochemical data, such as ANFIS and SVM, to be used for assessing the GW quality for irrigation. The proposed methodological approach offers a useful tool for identifying the crucial hydrogeochemical components for GW evolution assessment and mitigation measures related to GW management in arid and semi-arid environments.

This study explores the influence of digital leadership (DL) on sustainable competitive advantage (SCA) in tourism and hospitality businesses, focusing on green absorptive capability (GAC) and eco-innovation (EI) as mediators. This study focused on middle-line management in travel agencies and hotels in Saudi Arabia. A total of 323 valid responses were collected and analyzed using WarpPLS 7.0, a PLS-SEM analysis tool. DL positively affected SCA, GAC, and EI. In addition, SCA was positively impacted by GAC and EI. Furthermore, this study found that GAC and EI significantly mediated the DL→SCA relationship. This study enhances the Dynamic Capabilities Theory, offering valuable insights for tourism and hospitality managers to utilize digital strategies and environmental initiatives for eco-conscious market competitiveness.