Nuciferol C, a new sesquineolignan dimer from Cocos nucifera L.: bioactivity and theoretical investigation.

Nuciferol C (NC), an undescribed dimer of nuciferol B (NB), was isolated from the endocarp of Cocos nucifera L. The planar structure of NC was determined using 1D- and 2D-NMR spectroscopy as well as high resolution MS spectrometry. The absolute configuration was concluded based on analysis of NOESY spectra. NC showed cytotoxic activity against colon cancer cells (CaCo-2) with an IC50 value of 76 µM, and significantly decreased the expression of human epidermal growth factor receptor (EGFR) and tumor necrosis factor alpha (TNF-α) in CaCo-2 as compared with untreated cells by 39% and 33%, respectively (p < 0.05). In addition, NC exhibited anti-herpes simplex virus (HSV-I) activity with an IC50 value of 23 µM. In silico study of NC was implemented at three levels: density functional theory (DFT) was used to study its electronic properties, molecular mechanics was used to estimate the docking results, and finally, molecular dynamic simulation was used to study the behavior and stability of NC inside the active site of the target protein of HSV-1.

In vivo determination of analgesic and anti-inflammatory activities of isolated compounds from Cleome amblyocarpa and molecular modelling for the top active investigated compounds.

Cleome amblyocarpa Barr. and Murb. from the family Cleomaceae is used in folk medicine as it has analgesic, anti-inflammatory, antibacterial and antioxidant activities. In this study, ten compounds from the whole plant of C. amblyocarpa, a wild plant that grows in the Sinai Peninsula of Egypt, were isolated. Six compounds, ß-sitosterol 3-O-ß-d-glucoside 2, calycopterin 5, rhamnocitrin 6, 17α-hydroxycabraleahy-droxylactone 7, cleogynol 8, and ß-sitosterol 10 were first isolated from this species. In addition, four previously reported compounds, kaempferol-3, 7-dirhamnoside 1, 15α-acetoxycleomblynol A 3, and 11-α-acetylbrachy-carpone-22(23)-ene 4, as well as cleocarpanol 9, were isolated and identified. Isolated compounds were evaluated to determine their analgesic properties utilizing a hot-plate test method, and their anti-inflammatory effects utilizing rat paw edema. In a hot-plate test, compounds 3, 4, 7, 8, and 9 showed significant pain inhibition in latency time as compared to the normal group. Compounds 3-9 exhibited a significant inhibition of carrageenan-induced inflammation. According to the results of this work, compounds 3 and 4 (Dammarane triterpenoid) have the strongest analgesic/anti-inflammatory activity as compared to the other tested compounds. These results give support to the medicinal benefits of the plant as an analgesic along with an anti-inflammatory agent in traditional therapy. Molecular modelling studies of the isolated compounds 3 and 4 assessed the molecular affinity and binding interaction patterns for these compounds towards COX-2 as compared to specific COX-2 inhibitors and in relation to COX-1 isozyme. Compound 3 revealed extended accommodation across COX-2's hydrophobic sub-pockets and preferential thermodynamic stability across molecular dynamics simulations.

Dual SARS-CoV-2 and MERS-CoV inhibitors from Artemisia monosperma: isolation, structure elucidation, molecular modelling studies, and in vitro activities.

The COVID-19 pandemic has spread throughout the whole globe, so it is imperative that all available resources be used to treat this scourge. In reality, the development of new pharmaceuticals has mostly benefited from natural products. The widespread medicinal usage of species in the Asteraceae family is extensively researched. In this study, compounds isolated from methanolic extract of Artemisia monosperma Delile, a wild plant whose grows in Egypt's Sinai Peninsula. Three compounds, stigmasterol 3-O-ß-D-glucopyranoside 1, rhamnetin 3, and padmatin 6, were first isolated from this species. In addition, five previously reported compounds, arcapillin 2, jaceosidin 4, hispidulin 5, 7-O-methyleriodictyol 7, and eupatilin 8, were isolated. Applying molecular modelling simulations revealed two compounds, arcapillin 2 and rhamnetin 3 with the best docking interactions and energies within SARS-CoV-2 Mpro-binding site (-6.16, and -6.70 kcal mol-1, respectively). The top-docked compounds (2-3) were further evaluated for inhibitory concentrations (IC50), and half-maximal cytotoxicity (CC50) of both SARS-CoV-2 and MERS-CoV. Interestingly, arcapillin showed high antiviral activity towards SARS-CoV-2 and MERS-CoV, with IC50 values of 190.8 µg mL-1 and 16.58 µg mL-1, respectively. These findings may hold promise for further preclinical and clinical research, particularly on arcapillin itself or in collaboration with other drugs for COVID-19 treatment.

Design and synthesis of chromene-1,2,3-triazole benzene sulfonamide hybrids as potent carbonic anhydrase-IX inhibitors against prostate cancer.

Considering the promising effects of molecular hybridization on drug discovery in recent years and the ongoing endeavors to develop bioactive scaffolds tethering the 1,2,3-triazole core, the present study sought to investigate whether the 1,2,3-triazole-linked chromene and benzene sulfonamide nucleus could exhibit activity against the human breast cancer cell line MCF-7 and prostate cancer cell line PC-3. To this end, three focused bioactive series of mono- and -bis-1,2,3-triazoles were effectively synthesized via copper-assisted cycloaddition of mono- and/or di-alkyne chromenone derivatives 2a and b and 9 with several sulfa drug azides 4a-d and 6. The resulting molecular derivatives were tested for cytotoxicity against prostate and breast cancer cells. Among the derivatives, 10a, 10c, and 10e exhibited potent cytotoxicity against PC-3 cells with IC50 values of 2.08, 7.57, and 5.52 µM compared to doxorubicin (IC50 = 2.31 µM) with potent inhibition of CA IX with IC50 values of 0.113, 0.134, and 0.214 µM. The most active compound, 10a, was tested for apoptosis-induction; it induced apoptosis by 31.9-fold cell cycle arrest at the G1-phase. Further, the molecular modeling approach highlighted the relevant binding affinity for the top-active compound 10a against CA IX as one of the most prominent PC-3 prostate cancer-associated biotargets.

Assessing Soil Quality, Wheat Crop Yield, and Water Productivity under Condition of Deficit Irrigation.

Wheat is one of the most important cereal crops in Egypt and all over the world. Its productivity is adversely affected by drought due to deficient irrigation to provide nutrients required for plant growth. In a field experiment, silicon foliar applications at concentrations of 0, 200, and 400 mg L-1 were performed at different irrigation rates ranging from 1000 to 4000 m3 ha-1 to assess water irrigation productivity and wheat crop yield in a calcareous soil under arid climate conditions. Increased irrigation rates led to a significant increase in soil nutrient dynamics, as well as in the number and weight of grains per spike, leaf area index, grain yield, straw yield, and biological yield, with the exception of the weight of 1000 grains. Spraying with sodium silicate had a significant impact on grain yield and harvest index but did not significantly impact the other traits. Furthermore, the interaction between irrigation and silicate application rates showed significance only for grain yield, the number of spikes/m2, and the harvest index. Applying three times irrigation could produce the highest nutrient retention, wheat yield, and water irrigation productivity. No significance was observed between 3000 m3 ha-1 and 4000 m3 ha-1 irrigation, indicating a saving of 25% of applied irrigation water. It can be concluded that applying irrigation at 3000 m3 ha-1 could be a supplemental irrigation strategy. High wheat grain yield can be achieved under deficit irrigation (3000 m3 ha-1) on the northwestern coast of Egypt with an arid climate by spraying crops with sodium silicate at a rate of 400 mg L-1.

Chitosan decorated oleosomes loaded propranolol hydrochloride hydrogel repurposed for Candida albicans-vaginal infection.

Aim: Our investigation aims to estimate the antifungal effect of propranolol hydrochloride (PNL). Methods: Oleosomes (OLs) were fabricated by thin-film hydration and evaluated for entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and amount of drug released after 6 h Q6h (%). Results: The optimal OL showed a rounded shape with optimum characteristics. The ex-vivo permeation and confocal laser scanning microscopy verified the prolonged release and well deposition of PNL-loaded OLs-gel. The in-silico assessment demonstrated the good stability of PNL with OLs' ingredients. In vivo evaluations for PNL-loaded OLs-gel showed a good antifungal impact against Candida albicans with good safety. Conclusion: This work highlights the potential of PNL-loaded OLs-gel as a potential treatment for candida vaginal infection.

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Nanocomposite alginate hydrogel loaded with propranolol hydrochloride kolliphor® based cerosomes as a repurposed platform for Methicillin-Resistant Staphylococcus aureus-(MRSA)-induced skin infection; in-vitro, ex-vivo, in-silico, and in-vivo evaluation.

Nanocomposite alginate hydrogel containing Propranolol hydrochloride (PNL) cerosomes (CERs) was prepared as a repurposed remedy for topical skin Methicillin-Resistant Staphylococcus aureus (MRSA) infection. CERs were formed via an ethanol injection technique using different ceramides, Kolliphores® as a surfactant, and Didodecyldimethylammonium bromide (DDAB) as a positive charge inducer. CERs were optimized utilizing 13. 22 mixed-factorial design employing Design-Expert® software, the assessed responses were entrapment efficiency (EE%), particle size (PS), and zeta potential (ZP). The optimum CER, composed of 5 mg DDAB, ceramide VI, and Kolliphor® RH40 showed tubular vesicles with EE% of 92.91 ± 0.98%, PS of 388.75 ± 18.99 nm, PDI of 0.363 ± 0.01, and ZP of 30.36 ± 0.69 mV. Also, it remained stable for 90 days and manifested great mucoadhesive aspects. The optimum CER was incorporated into calcium alginate to prepare nanocomposite hydrogel. The ex-vivo evaluation illustrated that PNL was permeated in a more prolonged pattern from PNL-loaded CERs nanocomposite related to PNL-composite, optimum CER, and PNL solution. Confocal laser scanning microscopy revealed a perfect accumulation of fluorescein-labeled CERs in the skin. The in-silico investigation illustrated that the PNL was stable when mixed with other ingredients in the CERs and confirmed that PNL is a promising candidate for curing MRSA. Moreover, the PNL-loaded CERs nanocomposite revealed superiority over the PNL solution in inhibiting biofilm formation and eradication. The PNL-loaded CERs nanocomposite showed superiority over the PNL-composite for treating MRSA infection in the in-vivo mice model. Histopathological studies revealed the safety of the tested formulations. In conclusion, PNL-loaded CERs nanocomposite provided a promising, safe cure for MRSA bacterial skin infection.

Unveiling the Multifaceted Capabilities of Endophytic Aspergillus flavus Isolated from Annona squamosa Fruit Peels against Staphylococcus Isolates and HCoV 229E-In Vitro and In Silico Investigations.

Recently, there has been a surge towards searching for primitive treatment strategies to discover novel therapeutic approaches against multi-drug-resistant pathogens. Endophytes are considered unexplored yet perpetual sources of several secondary metabolites with therapeutic significance. This study aims to isolate and identify the endophytic fungi from Annona squamosa L. fruit peels using morphological, microscopical, and transcribed spacer (ITS-rDNA) sequence analysis; extract the fungus's secondary metabolites by ethyl acetate; investigate the chemical profile using UPLC/MS; and evaluate the potential antibacterial, antibiofilm, and antiviral activities. An endophytic fungus was isolated and identified as Aspergillus flavus L. from the fruit peels. The UPLC/MS revealed seven compounds with various chemical classes. The antimicrobial activity of the fungal ethyl acetate extract (FEA) was investigated against different Gram-positive and Gram-negative standard strains, in addition to resistant clinical isolates using the agar diffusion method. The CPE-inhibition assay was used to identify the potential antiviral activity of the crude fungal extract against low pathogenic human coronavirus (HCoV 229E). Selective Gram-positive antibacterial and antibiofilm activities were evident, demonstrating pronounced efficacy against both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA). However, the extract exhibited very weak activity against Gram-negative bacterial strains. The ethyl acetate extract of Aspergillus flavus L exhibited an interesting antiviral activity with a half maximal inhibitory concentration (IC50) value of 27.2 µg/mL against HCoV 229E. Furthermore, in silico virtual molecular docking-coupled dynamics simulation highlighted the promising affinity of the identified metabolite, orienting towards three MRSA biotargets and HCoV 229E main protease as compared to reported reference inhibitors/substrates. Finally, ADME analysis was conducted to evaluate the potential oral bioavailability of the identified metabolites.

Unveiling Pharmacokinetics and Drug Interaction of Linagliptin and Pioglitazone HCl in Rat Plasma Using LC-MS/MS.

The linagliptin (LIN) and pioglitazone HCl (PIO) combination, currently undergoing phase III clinical trials for diabetes mellitus treatment, demonstrated significant improvements in glycemic control. However, the absence of an analytical method for simultaneous determination in biological fluids highlights a crucial gap. This underscores the pressing need for sensitive bioanalytical methods, emphasizing the paramount importance of developing such tools to advance diabetes management strategies and enhance patient care. Herein, a sensitive reverse-phase high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method was developed for simultaneous determination of LIN and PIO in rat plasma using alogliptin as an internal standard. Chromatographic separation was performed on an Agilent Eclipse Plus C18 (4.6 × 100 mm, 3.5 µm) using an isocratic mobile phase system consisting of ammonium formate (pH 4.5) and methanol using an acetonitrile-induced protein precipitation technique for sample preparation. Multiple reaction monitoring in positive ion mode was used for quantitation of the precursor to production at m/z 473.2 → 419.9 for LIN, 357.1 → 134.2 for PIO, and 340.3 → 116.1 for ALO. The linearity range was 0.5 to 100 and 1 to 2000 ng/mL for LIN and PIO, respectively. The developed method was validated as per US-FDA guidelines and successfully applied to clinical pharmacokinetic and drug-drug interaction studies with a single oral administration of LIN and PIO in rat plasma. Pharmacokinetic parameters of LIN were significantly influenced by the concomitant administration of PIO and vice versa. Molecular modeling revealed the significant interaction of LIN and PIO with P-glycoprotein. Therefore, the drug-drug interaction between LIN and PIO deserves further study to improve drug therapy and prevent dangerous adverse effects.

Green innovation in analytical chemistry: A sustainable densitometric HPTLC approach for the distinctive separation and quantification of structurally related abused drugs - tramadol, tapentadol, and venlafaxine - in seized pharmaceutical dosage forms.

An innovative ecofriendly high-performance thin layer chromatographic (HPTLC) method with spectrophotometric detection for simultaneous determination of Tramadol (TMD), Tapentadol (TAP), and Venlafaxine (VEN) in seized dosage forms was presented. Our method was conducted to achieve separation following the optimal conditions: pre-coated silica gel plates using a green mobile phase (heptane: acetone: ammonia, 7:3:0.5 v/v), with absorbance scanning at 272 nm. The validation of the method was done following International Conference on Harmonization (ICH) guidelines, demonstrates linearity, accuracy, precision, selectivity, robustness, and system suitability. Separation was achieved with a detection limit of 0.34, 0.16, and 0.084 (ug/band) for TMD, TAP, and VEN, respectively, the method successfully analyzes seized samples. Trueness is confirmed through a high degree of similarity between HPTLC and gas chromatography results. The study's ecofriendly approach, simplicity, and selectivity position it as a promising method for efficient, on-site monitoring of seized samples.

The Anti-Virulence Activities of the Antihypertensive Drug Propranolol in Light of Its Anti-Quorum Sensing Effects against Pseudomonas aeruginosa and Serratia marcescens.

The development of bacterial resistance is an increasing global concern that requires discovering new antibacterial agents and strategies. Bacterial quorum sensing (QS) systems play important roles in controlling bacterial virulence, and their targeting could lead to diminishing bacterial pathogenesis. In this context, targeting QS systems without significant influence on bacterial growth is assumed as a promising strategy to overcome resistance development. This study aimed at evaluating the anti-QS and anti-virulence activities of the ß-adrenoreceptor antagonist propranolol at sub-minimal inhibitory concentrations (sub-MIC) against two Gram-negative bacterial models Pseudomonas aeruginosa and Serratia marcescens. The effect of propranolol on the expression of QS-encoding genes was evaluated. Additionally, the affinity of propranolol to QS receptors was virtually attested. The influence of propranolol at sub-MIC on biofilm formation, motility, and production of virulent factors was conducted. The outcomes of the propranolol combination with different antibiotics were assessed. Finally, the in vivo protection assay in mice was performed to assess propranolol's effect on lessening the bacterial pathogenesis. The current findings emphasized the significant ability of propranolol at sub-MIC to reduce the formation of biofilms, motility, and production of virulence factors. In addition, propranolol at sub-MIC decreased the capacity of tested bacteria to induce pathogenesis in mice. Furthermore, propranolol significantly downregulated the QS-encoding genes and showed significant affinity to QS receptors. Finally, propranolol at sub-MIC synergistically decreased the MICs of different antibiotics against tested bacteria. In conclusion, propranolol might serve as a plausible adjuvant therapy with antibiotics for the treatment of serious bacterial infections after further pharmacological and pharmaceutical studies.

Unraveling Extremely Damaging IRAK4 Variants and Their Potential Implications for IRAK4 Inhibitor Efficacy.

Interleukin-1-receptor-associated kinase 4 (IRAK4) possesses a crucial function in the toll-like receptor (TLR) signaling pathway, and the dysfunction of this molecule could lead to various infectious and immune-related diseases in addition to cancers. IRAK4 genetic variants have been linked to various types of diseases. Therefore, we conducted a comprehensive analysis to recognize the missense variants with the most damaging impacts on IRAK4 with the employment of diverse bioinformatics tools to study single-nucleotide polymorphisms' effects on function, stability, secondary structures, and 3D structure. The residues' location on the protein domain and their conservation status were investigated as well. Moreover, docking tools along with structural biology were engaged in analyzing the SNPs' effects on one of the developed IRAK4 inhibitors. By analyzing IRAK4 gene SNPs, the analysis distinguished ten variants as the most detrimental missense variants. All variants were situated in highly conserved positions on an important protein domain. L318S and L318F mutations were linked to changes in IRAK4 secondary structures. Eight SNPs were revealed to have a decreasing effect on the stability of IRAK4 via both I-Mutant 2.0 and Mu-Pro tools, while Mu-Pro tool identified a decreasing effect for the G198E SNP. In addition, detrimental effects on the 3D structure of IRAK4 were also discovered for the selected variants. Molecular modeling studies highlighted the detrimental impact of these identified SNP mutant residues on the druggability of the IRAK4 ATP-binding site towards the known target inhibitor, HG-12-6, as compared to the native protein. The loss of important ligand residue-wise contacts, altered protein global flexibility, increased steric clashes, and even electronic penalties at the ligand-binding site interfaces were all suggested to be associated with SNP models for hampering the HG-12-6 affinity towards IRAK4 target protein. This given model lays the foundation for the better prediction of various disorders relevant to IRAK4 malfunction and sheds light on the impact of deleterious IRAK4 variants on IRAK4 inhibitor efficacy.

Deciphering Molecular Aspects of Potential α-Glucosidase Inhibitors within Aspergillus terreus: A Computational Odyssey of Molecular Docking-Coupled Dynamics Simulations and Pharmacokinetic Profiling.

Hyperglycemia, as a hallmark of the metabolic malady diabetes mellitus, has been an overwhelming healthcare burden owing to its high rates of comorbidity and mortality, as well as prospective complications affecting different body organs. Available therapeutic agents, with α-glucosidase inhibitors as one of their cornerstone arsenal, control stages of broad glycemia while showing definitive characteristics related to their low clinical efficiency and off-target complications. This has propelled the academia and industrial section into discovering novel and safer candidates. Herein, we provided a thorough computational exploration of identifying candidates from the marine-derived Aspergillus terreus isolates. Combined structural- and ligand-based approaches using a chemical library of 275 metabolites were adopted for pinpointing promising α-glucosidase inhibitors, as well as providing guiding insights for further lead optimization and development. Structure-based virtual screening through escalating precision molecular docking protocol at the α-glucosidase canonical pocket identified 11 promising top-docked hits, with several being superior to the market drug reference, acarbose. Comprehensive ligand-based investigations of these hits' pharmacokinetics ADME profiles, physiochemical characterizations, and obedience to the gold standard Lipinski's rule of five, as well as toxicity and mutagenicity profiling, proceeded. Under explicit conditions, a molecular dynamics simulation identified the top-stable metabolites: butyrolactone VI (SK-44), aspulvinone E (SK-55), butyrolactone I 4''''-sulfate (SK-72), and terrelumamide B (SK-173). They depicted the highest free binding energies and steadiest thermodynamic behavior. Moreover, great structural insights have been revealed, including the advent of an aromatic scaffold-based interaction for ligand-target complex stability. The significance of introducing balanced hydrophobic/polar moieties, like triazole and other bioisosteres of carboxylic acid, has been highlighted across docking, ADME/Tox profiling, and molecular dynamics studies for maximizing binding interactions while assuring safety and optimal pharmacokinetics for targeting the intestinal-localized α-glucosidase enzyme. Overall, this study provided valuable starting points for developing new α-glucosidase inhibitors based on nature-derived unique scaffolds, as well as guidance for prospective lead optimization and development within future pre-clinical and clinical investigations.

Integration of Chemoinformatics and Multi-Omics Analysis Defines ECT2 as a Potential Target for Cancer Drug Therapy.

Epithelial cell transforming 2 (ECT2) is a potential oncogene and a number of recent studies have correlated it with the progression of several human cancers. Despite this elevated attention for ECT2 in oncology-related reports, there is no collective study to combine and integrate the expression and oncogenic behavior of ECT2 in a panel of human cancers. The current study started with a differential expression analysis of ECT2 in cancerous versus normal tissue. Following that, the study asked for the correlation between ECT2 upregulation and tumor stage, grade, and metastasis, along with its effect on patient survival. Moreover, the methylation and phosphorylation status of ECT2 in tumor versus normal tissue was assessed, in addition to the investigation of the ECT2 effect on the immune cell infiltration in the tumor microenvironment. The current study revealed that ECT2 was upregulated as mRNA and protein levels in a list of human tumors, a feature that allowed for the increased filtration of myeloid-derived suppressor cells (MDSC) and decreased the level of natural killer T (NKT) cells, which ultimately led to a poor prognosis survival. Lastly, we screened for several drugs that could inhibit ECT2 and act as antitumor agents. Collectively, this study nominated ECT2 as a prognostic and immunological biomarker, with reported inhibitors that represent potential antitumor drugs.

Integration of immunoinformatics and cheminformatics to design and evaluate a multitope vaccine against Klebsiella pneumoniae and Pseudomonas aeruginosa coinfection.

Introduction: Klebsiella pneumoniae (K. pneumoniae) and Pseudomonas aeruginosa (P. aeruginosa) are the most common Gram-negative bacteria associated with pneumonia and coinfecting the same patient. Despite their high virulence, there is no effective vaccine against them. Methods: In the current study, the screening of several proteins from both pathogens highlighted FepA and OmpK35 for K. pneumonia in addition to HasR and OprF from P. aeruginosa as promising candidates for epitope mapping. Those four proteins were linked to form a multitope vaccine, that was formulated with a suitable adjuvant, and PADRE peptides to finalize the multitope vaccine construct. The final vaccine's physicochemical features, antigenicity, toxicity, allergenicity, and solubility were evaluated for use in humans. Results: The output of the computational analysis revealed that the designed multitope construct has passed these assessments with satisfactory scores where, as the last stage, we performed a molecular docking study between the potential vaccine construct and K. pneumonia associated immune receptors, TLR4 and TLR2, showing affinitive to both targets with preferentiality for the TLR4 receptor protein. Validation of the docking studies has proceeded through molecular dynamics simulation, which estimated a strong binding and supported the nomination of the designed vaccine as a putative solution for K. pneumoniae and P. aeruginosa coinfection. Here, we describe the approach for the design and assessment of our potential vaccine.

Molecular and Biological Investigation of Isolated Marine Fungal Metabolites as Anticancer Agents: A Multi-Target Approach.

Cancer is the leading cause of death globally, with an increasing number of cases being annually reported. Nature-derived metabolites have been widely studied for their potential programmed necrosis, cytotoxicity, and anti-proliferation leading to enrichment for the modern medicine, particularly within the last couple of decades. At a more rapid pace, the concept of multi-target agents has evolved from being an innovative approach into a regular drug development procedure for hampering the multi-fashioned pathophysiology and high-resistance nature of cancer cells. With the advent of the Red Sea Penicillium chrysogenum strain S003-isolated indole-based alkaloids, we thoroughly investigated the molecular aspects for three major metabolites: meleagrin (MEL), roquefortine C (ROC), and isoroquefortine C (ISO) against three cancer-associated biological targets Cdc-25A, PTP-1B, and c-Met kinase. The study presented, for the first time, the detailed molecular insights and near-physiological affinity for these marine indole alkaloids against the assign targets through molecular docking-coupled all-atom dynamic simulation analysis. Findings highlighted the superiority of MEL's binding affinity/stability being quite in concordance with the in vitro anticancer activity profile conducted via sulforhodamine B bioassay on different cancerous cell lines reaching down to low micromolar or even nanomolar potencies. The advent of lengthy structural topologies via the metabolites' extended tetracyclic cores and aromatic imidazole arm permitted multi-pocket accommodation addressing the selectivity concerns. Additionally, the presence decorating polar functionalities on the core hydrophobic tetracyclic ring contributed compound's pharmacodynamic preferentiality. Introducing ionizable functionality with more lipophilic characters was highlighted to improve binding affinities which was also in concordance with the conducted drug-likeness/pharmacokinetic profiling for obtaining a balanced pharmacokinetic/dynamic profile. Our study adds to the knowledge regarding drug development and optimization of marine-isolated indole-based alkaloids for future iterative synthesis and pre-clinical investigations as multi-target anticancer agents.

Exploring the Synergistic Effect of Bergamot Essential Oil with Spironolactone Loaded Nano-Phytosomes for Treatment of Acne Vulgaris: In Vitro Optimization, In Silico Studies, and Clinical Evaluation.

The foremost target of the current work was to formulate and optimize a novel bergamot essential oil (BEO) loaded nano-phytosomes (NPs) and then combine it with spironolactone (SP) in order to clinically compare the efficiency of both formulations against acne vulgaris. The BEO-loaded NPs formulations were fabricated by the thin-film hydration and optimized by 32 factorial design. NPs' assessments were conducted by measuring entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). In addition, the selected BEO-NPs formulation was further combined with SP and then examined for morphology employing transmission electron microscopy and three months storage stability. Both BEO-loaded NPs selected formula and its combination with SP (BEO-NPs-SP) were investigated clinically for their effect against acne vulgaris after an appropriate in silico study. The optimum BEO-NPs-SP showed PS of 300.40 ± 22.56 nm, PDI of 0.571 ± 0.16, EE% of 87.89 ± 4.14%, and an acceptable ZP value of -29.7 ± 1.54 mV. Molecular modeling simulations showed the beneficial role of BEO constituents as supportive/connecting platforms for favored anchoring of SP on the Phosphatidylcholine (PC) interface. Clinical studies revealed significant improvement in the therapeutic response of BEO-loaded NPs that were combined with SP over BEO-NPs alone. In conclusion, the results proved the ability to utilize NPs as a successful nanovesicle for topical BEO delivery as well as the superior synergistic effect when combined with SP in combating acne vulgaris.

Hiring of the Anti-Quorum Sensing Activities of Hypoglycemic Agent Linagliptin to Alleviate the Pseudomonas aeruginosa Pathogenesis.

Bacteria communicate with each other using quorum sensing (QS) which works in an inducer/receptor manner. QS plays the main role in orchestrating diverse bacterial virulence factors. Pseudomonas aeruginosa is one of the most clinically important bacterial pathogens that can cause infection in almost all body tissues. Besides its efficient capability to develop resistance to different antibiotics, P. aeruginosa acquires a huge arsenal of virulence factors that are controlled mainly by QS. Challenging QS with FDA-approved drugs and natural products was proposed as a promising approach to mitigate bacterial virulence enabling the host immunity to complete the eradication of bacterial infection. The present study aims to evaluate the dipeptidase inhibitor-4 inhibitor hypoglycemic linagliptin anti-QS and anti-virulence activities against P. aeruginosa in vitro, in vivo, and in silico. The current results revealed the significant ability to diminish the production of protease and pyocyanin, motility, and biofilm formation in P. aeruginosa. Furthermore, the histopathological examination of liver and kidney tissues of mice injected with linagliptin-treated bacteria showed an obvious reduction of pathogenesis. Linagliptin downregulation to QS-encoding genes, besides the virtual ability to interact with QS receptors, indicates its anti-QS activities. In conclusion, linagliptin is a promising anti-virulence and anti-QS candidate that can be used solely or in combination with traditional antimicrobial agents in the treatment of P. aeruginosa aggressive infections.

HBD-2 variants and SARS-CoV-2: New insights into inter-individual susceptibility.

Background: A deep understanding of the causes of liability to SARS-CoV-2 is essential to develop new diagnostic tests and therapeutics against this serious virus in order to overcome this pandemic completely. In the light of the discovered role of antimicrobial peptides [such as human b-defensin-2 (hBD-2) and cathelicidin LL-37] in the defense against SARS-CoV-2, it became important to identify the damaging missense mutations in the genes of these molecules and study their role in the pathogenesis of COVID-19. Methods: We conducted a comprehensive analysis with multiple in silico approaches to identify the damaging missense SNPs for hBD-2 and LL-37; moreover, we applied docking methods and molecular dynamics analysis to study the impact of the filtered mutations. Results: The comprehensive analysis reveals the presence of three damaging SNPs in hBD-2; these SNPs were predicted to decrease the stability of hBD-2 with a damaging impact on hBD-2 structure as well. G51D and C53G mutations were located in highly conserved positions and were associated with differences in the secondary structures of hBD-2. Docking-coupled molecular dynamics simulation analysis revealed compromised binding affinity for hBD-2 SNPs towards the SARS-CoV-2 spike domain. Different protein-protein binding profiles for hBD-2 SNPs, in relation to their native form, were guided through residue-wise levels and differential adopted conformation/orientation. Conclusions: The presented model paves the way for identifying patients prone to COVID-19 in a way that would guide the personalization of both the diagnostic and management protocols for this serious disease.

Computational Analysis of Deleterious SNPs in NRAS to Assess Their Potential Correlation With Carcinogenesis.

The NRAS gene is a well-known oncogene that acts as a major player in carcinogenesis. Mutations in the NRAS gene have been linked to multiple types of human tumors. Therefore, the identification of the most deleterious single nucleotide polymorphisms (SNPs) in the NRAS gene is necessary to understand the key factors of tumor pathogenesis and therapy. We aimed to retrieve NRAS missense SNPs and analyze them comprehensively using sequence and structure approaches to determine the most deleterious SNPs that could increase the risk of carcinogenesis. We also adopted structural biology methods and docking tools to investigate the behavior of the filtered SNPs. After retrieving missense SNPs and analyzing them using six in silico tools, 17 mutations were found to be the most deleterious mutations in NRAS. All SNPs except S145L were found to decrease NRAS stability, and all SNPs were found on highly conserved residues and important functional domains, except R164C. In addition, all mutations except G60E and S145L showed a higher binding affinity to GTP, implicating an increase in malignancy tendency. As a consequence, all other 14 mutations were expected to increase the risk of carcinogenesis, with 5 mutations (G13R, G13C, G13V, P34R, and V152F) expected to have the highest risk. Thermodynamic stability was ensured for these SNP models through molecular dynamics simulation based on trajectory analysis. Free binding affinity toward the natural substrate, GTP, was higher for these models as compared to the native NRAS protein. The Gly13 SNP proteins depict a differential conformational state that could favor nucleotide exchange and catalytic potentiality. A further application of experimental methods with all these 14 mutations could reveal new insights into the pathogenesis and management of different types of tumors.