Antifungal potential of multi-drug-resistant Pseudomonas aeruginosa: harnessing pyocyanin for candida growth inhibition.

Introduction: Pseudomonas aeruginosa is notorious for its multidrug resistance and its involvement in hospital-acquired infections. In this study, 20 bacterial strains isolated from soil samples near the Hindan River in Ghaziabad, India, were investigated for their biochemical and morphological characteristics, with a focus on identifying strains with exceptional drug resistance and pyocyanin production. Methods: The isolated bacterial strains were subjected to biochemical and morphological analyses to characterize their properties, with a particular emphasis on exopolysaccharide production. Strain GZB16/CEES1, exhibiting remarkable drug resistance and pyocyanin production. Biochemical and molecular analyses, including sequencing of its 16S rRNA gene (accession number LN735036.1), plasmid-curing assays, and estimation of plasmid size, were conducted to elucidate its drug resistance mechanisms and further pyocynin based target the Candida albicans Strain GZB16/CEES1 demonstrated 100% resistance to various antibiotics used in the investigation, with plasmid-curing assays, suggesting plasmid-based resistance gene transmission. The plasmid in GZB16/CEES1 was estimated to be approximately 24 kb in size. The study focused on P. aeruginosa's pyocyanin production, revealing its association with anticandidal activity. The minimum inhibitory concentration (MIC) of the bacterial extract against Candida albicans was 50 µg/ml, with a slightly lower pyocyanin-based MIC of 38.5 µg/ml. Scanning electron microscopy illustrated direct interactions between P. aeruginosa strains and Candida albicans cells, leading to the destruction of the latter. Discussion: These findings underscore the potential of P. aeruginosa in understanding microbial interactions and developing strategies to combat fungal infections. The study highlights the importance of investigating bacterial-fungal interactions and the role of pyocyanin in antimicrobial activity. Further research in this area could lead to the development of novel therapeutic approaches for combating multidrug-resistant infections.

Quest for Anti-SARS-CoV-2 antiviral therapeutics: in-silico and in-vitro analysis of edible mushroom- Cordyceps militaris.

BACKGROUND: The emergence and evolution of SARS-CoV-2 resulted a severe threat to public health globally. Due to the lack of an effective vaccine with durable immunity, the disease transited into the endemic phase, necessitating potent antiviral therapy including a scientific basis for current traditional herbal medicine. OBJECTIVE: This study aimed to conduct a pharmacoinformatic analysis of selected chemical ingredients and in-vitro evaluation of Cordyceps militaris extract against SARS-CoV-2. MATERIALS AND METHODS: C. militaris, the widely used fungus in conventional herbal medicine, was subjected to computational investigation using molecular docking, molecular dynamic simulation and network pharmacology analysis followed by the in-vitro assay for evaluating its anti-SARS-CoV-2 potential. RESULTS: The molecular docking analysis of C. militaris revealed the Cordycepin's highest affinity (-9.71 kcal/mol) than other molecules, i.e., Cicadapeptin-I, Cicadapeptin-II, Cordycerebroside-B, and N-Acetyl galactosamine to the receptor binding domain of the SARS-CoV-2 spike protein. C. militaris aqueous extract could reduce the SARS-CoV-2 viral copy numbers by 50.24% using crude extract at 100 µg/mL concentration. CONCLUSION: These findings suggest that C. militaris has promising anti-SARS-CoV-2 activity and may be explored as traditional medicine for managing the COVID-19 surge in the endemic phase.

Phytoconstituents of Nymphaea rubra flowers and their anti-diabetic metabolic targets.

Nymphaea rubra (N. rubra) flowers are prevalent in subtropical regions for both dietary and traditional medicinal purposes, attributing to their beneficial properties in supporting overall health. This study first time provides descriptions of the antidiabetic and dyslipidemic properties employing STZ induced high fat diet fed diabetic rats and inhibition of α-amylase enzyme activity first by in vitro analyses, followed by a confirmatory in silico study to create a stronger biochemical rationale. Furthermore, in 3 T3-L1 cells, this extract promoted the suppression of adipogenesis. GC-MS investigation of the ethyl acetate fraction of ethanolic extract of N. rubra flowers revealed the presence of marker compounds of N. rubra, Nuciferine, and Apomorphine, which were the focus of molecular docking studies. The acquired concentrations of Nuciferine (22.39%) and 10, 11-dimethoxy-Apomorphine (1.47%) were detected. Together with other alkaloids identified by GC-MS analysis from this extract, mechanistically suggested that it might be caused by the synergistic impact of these bioactive chemicals. Molecular docking has been done to check the binding affinities of various isolated phytochemicals with HPAA, the dose-response effect of 100 mg/kg and 250 mg/kg of flower extract after 30 days showed a significant effect on body weight, food, water intake, serum insulin, FBG, OGTT, lipid profile, glycated haemoglobin, liver and kidney function test. Kidney histopathology results show a significant effect. These findings offer a strong foundation for the potential application of the ethyl acetate fraction of ethanolic extract from Nymphaea rubra flowers and its bioactive constituent in an in vivo system for the treatment and control of diabetes and its associated condition dyslipidemia.

Understanding the interactions between repurposed drugs sertindole and temoporfin with receptor for advanced glycation endproducts: Therapeutic implications in cancer and metabolic diseases.

CONTEXT: In the pursuit of novel therapeutic possibilities, repurposing existing drugs has gained prominence as an efficient strategy. The findings from our study highlight the potential of repurposed drugs as promising candidates against receptor for advanced glycation endproducts (RAGE) that offer therapeutic implications in cancer, neurodegenerative conditions and metabolic syndromes. Through careful analyses of binding affinities and interaction patterns, we identified a few promising candidates, ultimately focusing on sertindole and temoporfin. These candidates exhibited exceptional binding affinities, efficacy, and specificity within the RAGE binding pocket. Notably, they displayed a pronounced propensity to interact with the active site of RAGE. Our investigation further revealed that sertindole and temoporfin possess desirable pharmacological properties that highlighted them as attractive candidates for targeted drug development. Overall, our integrated computational approach provides a comprehensive understanding of the interactions between repurposed drugs, sertindole and temoporfin and RAGE that pave the way for future experimental validation and drug development endeavors. METHODS: We present an integrated approach utilizing molecular docking and extensive molecular dynamics (MD) simulations to evaluate the potential of FDA-approved drugs, sourced from DrugBank, against RAGE. To gain deeper insights into the binding mechanisms of the elucidated candidate repurposed drugs, sertindole and temoporfin with RAGE, we conducted extensive all-atom MD simulations, spanning 500 nanoseconds (ns). These simulations elucidated the conformational dynamics and stability of the RAGE-sertindole and RAGE-temoporfin complexes.

Synergistic adsorption and photocatalytic degradation of tetracycline using a Z-scheme kaolin/g-C3N4/MoO3 nanocomposite: A sustainable approach for water treatment.

This research focuses on the synthesis and application of a novel kaolin-supported g-C3N4/MoO3 nanocomposite for the degradation of tetracycline, an important antibiotic contaminant in water systems. The nanocomposite was prepared through a facile and environmentally friendly approach, leveraging the adsorption and photocatalytic properties of kaolin, g-C3N4 and MoO3 nanoparticles, respectively. Comprehensive characterization of the nanocomposite was conducted using techniques such as X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR) and optical spectra. The surface parameters were studied using N2 adsorption-desorption isotherm. The elemental composition was studied using X-ray photoelectron spectroscopy. The efficiency of the developed nanocomposite in tetracycline degradation was evaluated and the results revealed an efficient tetracycline degradation exhibiting the synergistic effects of adsorption and photocatalytic degradation in the removal process. The tetracycline degradation was achieved in 60 min. Kinetic studies and thermodynamic analyses provided insights into the degradation mechanism, suggesting potential applications for the nanocomposite in wastewater treatment. Additionally, the recyclability and stability of the nanocomposite were investigated, demonstrating its potential for sustainable and long-term application in water treatment.

Identification of potential marine bioactive compounds from brown seaweeds towards BACE1 inhibitors: molecular docking and molecular dynamics simulations approach.

The drug target protein ß-secretase 1 (BACE1) is one of the promising targets in the design of the drugs to control Alzheimer's disease (AD). Patients with neurodegenerative diseases are increasing in number globally due to the increase in the average lifetime. Neuro modulation is the only remedy for overcoming these age related diseases. In recent times, marine bioactive compounds are reported from Phaeophyceae (Brown Algae), Rhodophyta (Red Algae) and Chlorophyta (Green Algae) for neuro-modulation. Hence, an important attempt is made to understand the binding and stability of the identified bioactive compounds from the above marine algae using BACE1 as the molecular target. The docking study shows that the bioactive compound Fucotriphlorethol A ( - 17.27 kcal/mol) has good binding affinity and energy compared to other compounds such as Dieckol ( - 16.77 kcal/mol), Tetraphlorethol C ( - 15.12 kcal/mol), 2-phloroeckol ( - 14.98 kcal/mol), Phlorofucofuroeckol ( - 13.46 kcal/mol) and the co-crystal ( - 8.59 kcal/mol). Further, molecular dynamics simulations studies had been carried out for ß-secretase 1 complex with Fucotriphlorethol A and Phlorofucofuroeckol for 100 ns each. Results are compared with that of the co-crystal inhibitor. Molecular dynamics simulations studies also support the stability and flexibility of the two bioactive compounds Fucotriphlorethol A and Phlorofucofuroeckol with BACE1. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00210-7.

Interplay of precision therapeutics and MD study: Calocybe indica's potentials against cervical cancer and its interaction with VEGF via octadecanoic acid.

The evolving landscape of personalized medicine necessitates a shift from traditional therapeutic interventions towards precision-driven approaches. Embracing this paradigm, our research probes the therapeutic efficacy of the aqueous crude extract (ACE) of Calocybe indica in cervical cancer treatment, merging botanical insights with advanced molecular research. We observed that ACE exerts significant influences on nuclear morphology and cell cycle modulation, further inducing early apoptosis and showcasing prebiotic attributes. Characterization of ACE have identified several phytochemicals including significant presence of octadeconoic acid. Simultaneously, utilizing advanced Molecular Dynamics (MD) simulations, we deciphered the intricate molecular interactions between Vascular Endothelial Growth Factor (VEGF) and Octadecanoic acid to establish C.indica's role as an anticancer agent. Our study delineates Octadecanoic acid's potential as a robust binding partner for VEGF, with comprehensive analyses from RMSD and RMSF profiles highlighting the stability and adaptability of the protein-ligand interactions. Further in-depth thermodynamic explorations via MM-GBSA calculations reveal the binding landscape of the VEGF-Octadecanoic acid complex. Emerging therapeutic innovations, encompassing proteolysis-targeting chimeras (PROTACs) and avant-garde nanocarriers, are discussed in the context of their synergy with compounds like Calocybe indica P&C. This convergence underscores the profound therapeutic potential awaiting clinical exploration. This study offers a holistic perspective on the promising therapeutic avenues facilitated by C. indica against cervical cancer, intricately woven with advanced molecular interactions and the prospective integration of precision therapeutics in modern oncology.

Decoding dynamic interactions between EGFR-TKD and DAC through computational and experimental approaches: A novel breakthrough in lung melanoma treatment.

In the quest for effective lung cancer treatments, the potential of 3,6-diaminoacridine-9-carbonitrile (DAC) has emerged as a game changer. While DAC's efficacy against glioblastoma is well documented, its role in combating lung cancer has remained largely untapped. This study focuses on CTX-1, exploring its interaction with the pivotal EGFR-TKD protein, a crucial target in lung cancer therapeutics. A meticulous molecular docking analysis revealed that CTX-1 exhibits a noteworthy binding affinity of -7.9 kcal/mol, challenging Erlotinib, a conventional lung cancer medication, which displayed a binding affinity of -7.3 kcal/mol. For a deeper understanding of CTX-1's molecular mechanics, this study employed rigorous 100-ns molecular dynamics simulations, demonstrating CTX-1's remarkable stability in comparison with erlotinib. The Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method further corroborated these results, with CTX-1 showing a free binding energy of -105.976 ± 1.916 kJ/mol. The true prowess of CTX-1 was tested against diverse lung cancer cell lines, including A549, Hop-62 and H-1299. CTX-1 not only significantly outperformed erlotinib in anticancer activity but also exhibited a spectrum of therapeutic effects. It effectively diminished cancer cell viability, induced DNA damage, halted cell cycle progression, generated reactive oxygen species (ROS), impaired mitochondrial transmembrane potential, instigated apoptosis and successfully inhibited EGFR-TKD. This study not only underscores the potential of CTX-1 a formidable contender in lung cancer treatment but also marks a paradigm shift in oncological therapeutics, offering new horizons in the fight against this formidable disease.

Mechanisms of inhibition of advanced glycation end-products (AGEs) and α-glucosidase by Heliotropium bacciferum: Spectroscopic and molecular docking analysis.

Diabetes mellitus is characterized by hyperglycemia that makes insulin more prone to glycation and form advanced glycation end products (AGEs). Here, we report the effect of glyoxal (GO) on the formation of AGEs using human insulin as model protein and their structural modifications. The present investigation also reports the anti-AGE potential of Heliotropium bacciferum (Leaf) extracts. The phytochemical analysis of H. bacciferum revealed that free phenolic extract contains higher amount of total phenolic (3901.58 ± 17.06 mg GAE/100 g) and total flavonoid content (30.41 ± 0.32 mg QE/100 g) when compared to bound phenolic extract. Naringin and caffeic acid were identified as the major phenolic ingredients by UPLC-PAD method. Furthermore, bound phenolics extract showed significantly higher DPPH and superoxide radicals scavenging activity (IC50 17.53 ± 0.36 µg/mL and 0.306 ± 0.038 mg/ mL, respectively) (p ≤ 0.05). Besides, the bound phenolics extract also showed significant (p ≤ 0.05) chelating power (IC50 0.063) compared to free phenolic extract. In addition, bound phenolic extract could efficiently trap GO under physiological conditions. Spectroscopic investigation of GO-modified insulin illustrated changes in the tertiary structure of insulin and formation of AGEs. On the other hand, no significant alteration in secondary structure was observed by far UV-CD measurement. Furthermore, H. bacciferum extract inhibited α-glucosidase activity and AGEs formation implicated in diabetes. Molecular docking analysis depicted that GO bind with human insulin in both chains and forms a stable complex with TYR A: 14, LEU A:13, ASN B:3, SER A:12 amino acid residues with binding energy of - 2.53 kcal/mol. However, caffeic acid binds to ASN A:18 and GLU A:17 residues of insulin with lower binding energy of -4.67 kcal/mol, suggesting its higher affinity towards human insulin compared to GO. Our finding showed promising activity of H. bacciferum against AGEs and its complications. The major phenolics like caffeic acid, naringin and their derivatives could be exploited for the drug development for management of AGEs in diabetes.

Targeted inhibition of colorectal cancer proliferation: The dual-modulatory role of 2,4-DTBP on anti-apoptotic Bcl-2 and Survivin proteins.

The anti-apoptotic proteins, Bcl-2 and Survivin, are consistently overexpressed in numerous human malignancies, notably in colorectal cancer. 2,4-Di-tert-butylphenol (2,4-DTBP) is a naturally occurring phenolic compound known for its diverse biological activities, including anti-cancer properties. The mechanism behind 2,4-DTBP-induced inhibition of cell proliferation and apoptosis in human colorectal cancer cells, specifically regarding Bcl-2 and Survivin, remains to be elucidated. In this study, we employed both in silico and in vitro methodologies to underpin this interaction at the molecular level. Molecular docking demonstrated a substantial binding affinity of 2,4-DTBP towards Bcl-2 (ΔG = -9.8 kcal/mol) and Survivin (ΔG = -5.6 kcal/mol), suggesting a potential inhibitory effect. Further, molecular dynamic simulations complemented by MM-GBSA calculations confirmed the significant binding of 2,4-DTBP with Bcl-2 (dGbind = -54.85 ± 6.79 kcal/mol) and Survivin (dGbind = -32.36 ± 1.29 kcal/mol). In vitro assays using HCT116 colorectal cancer cells revealed that 2,4-DTBP inhibited proliferation and promoted apoptosis in both a dose- and time-dependent manner. Fluorescence imaging and scanning electron microscopy illustrated the classical features associated with apoptosis upon 2,4-DTBP exposure. Cell cycle analysis through flow cytometry highlighted a G1 phase arrest and apoptosis assay demonstrated increased apoptotic cell population. Notably, western blotting results indicated a decreased expression of Bcl-2 and Survivin post-treatment. Considering the cytoprotective roles of Bcl-2 and Survivin through the inhibition of mitochondrial dysfunction, our findings of disrupted mitochondrial bioenergetics, characterized by reduced ATP production and oxygen consumption, further accentuate the functional impairment of these proteins. Overall, the integration of in silico and in vitro data suggests that 2,4-DTBP holds promise as a therapeutic agent targeting Bcl-2 and Survivin in colorectal cancer.

Aldosterone, Methylglyoxal, and Glycated Albumin Interaction with Macrophage Cells Affects Their Viability, Activation, and Differentiation.

BACKGROUND: The inflammatory response in diabetes is strongly correlated with increasing amounts of advanced glycation end products (AGEs), methylglyoxal (MGO), aldosterone (Aldo), and activation of macrophages. Aldo is known to be associated with increased pro-inflammatory responses in general, but its significance in inflammatory responses under glycated circumstances has yet to be understood. In the current work, the aim of our study was to study the macrophage immune response in the presence of AGEs, MGO, and Aldo to comprehend their combined impact on diabetes-associated complications. METHODS AND RESULTS: The viability of macrophages upon treatment with glycated HSA (Gly-HSA) promoted cell growth as the concentration increased from 100 to 500 µg/mL, whereas MGO at a high concentration (≥300 µM) significantly hampered cell growth. At lower concentrations (0.5-5 nM), Aldo strongly promoted cell growth, whereas at higher concentrations (50 nM), it was seen to inhibit growth when used for cell treatment for 24 h. Aldo had no effect on MGO-induced cell growth inhibition after 24 h of treatment. However, compared to MGO or Aldo treatment alone, an additional decrease in viability could be seen after 48 h of treatment with a combination of MGO and Aldo. Treatment with Aldo and MGO induced expression of TNF-α independently and when combined. However, when combined, Aldo and MGO significantly suppressed the expression of TGF-ß. Aldo, Gly-HSA, and MGO strongly induced the transcription of NF-κB and RAGE mRNA and, as expected, also promoted the formation of reactive oxygen species. Also, by inducing iNOS and MHC-II and suppressing CD206 transcript expression, Gly-HSA strongly favored the differentiation of macrophages into M1 type (pro-inflammatory). On the other hand, the combination of Aldo and MGO strongly induced the expression of MHC-II, CD206, and ARG1 (M2 macrophage marker). These findings suggest that Gly-HSA, MGO, and Aldo differently influence macrophage survival, activation, and differentiation. CONCLUSIONS: Overall, this study gives an insight into the effects of glycated protein and MGO in the presence of Aldo on macrophage survival, activation, differentiation, and inflammatory response.

Betulinic Acid Potentiates Mast Cell Degranulation by Compromising Cell Membrane Integrity and Without Involving Fcεri Receptors.

Mast cells play important role in acquired and natural immunity making these favorable therapeutic targets in various inflammatory diseases. Here we observed that, pentacyclic tri terpenoid betulinic acid (BA) treatment resulted in a significantly high number (9%) of cells positive for Hoechst and negative for annexin-V indicating that BA could interfere with plasma membrane integrity. The degranulation of both activated and non-activated mast cells was enhanced upon treatment with BA. The pre-treatment of BA had remarkable effect on calcium response in activated mast cells which showed increased calcium influx relative compared to untreated cells. The results also showed potentially less migration of BA treated mast cells signifying the possible effect of BA on cell membrane. BA treatment resulted in a significant increase in mRNA levels of IL-13 while as mRNA levels of other target cytokines, IL-6 and TNF-α seem to be not affected. Moreover, there was global Increase in phosphorylation of signaling proteins and no significant change in phosphorylation of FcεRI receptors indicating that the effect of BA was independent of signaling cascade or FcεRI receptor mediated mast cell aggregation. Overall, these results portray BA potentiates mast cell effector functions by compromising the membrane integrity and independent of FcεRI involvement.

Unveiling the antibacterial and antifungal potential of biosynthesized silver nanoparticles from Chromolaena odorata leaves.

This research investigates the biogenic synthesis of silver nanoparticles (AgNPs) using the leaf extract of Chromolaena odorata (Asteraceae) and their potential as antibacterial and antifungal agents. Characterization techniques like ultraviolet-visible, Fourier transform infrared (FTIR), Dynamic light scattering and zeta potential (DLS), X-ray diffraction (XRD), transmission electron microscopy (TEM), and field emission scanning electron microscopy and energy-dispersive X-ray spectroscopy (FESEM-EDX) confirmed the formation of spherical (AgNPs). UV-vis spectroscopy reaffirms AgNP formation with a peak at 429 nm. DLS and zeta potential measurements revealed an average size of 30.77 nm and a negative surface charge (- 0.532 mV). Further, XRD analysis established the crystalline structure of the AgNPs. Moreover, the TEM descriptions indicate that the AgNPs are spherical shapes, and their sizes ranged from 9 to 22 nm with an average length of 15.27 nm. The X-ray photoelectron spectroscopy (XPS) analysis validated the formation of metallic silver and elucidated the surface state composition of AgNPs. Biologically, CO-AgNPs showed moderate antibacterial activity but excellent antifungal activity against Candida tropicalis (MCC 1559) and Trichophyton rubrum (MCC 1598). Low MIC values (0.195 and 0.390 mg/mL) respectively, suggest their potential as effective antifungal agents. This suggests potential applications in controlling fungal infections, which are often more challenging to treat than bacterial infections. Molecular docking results validated that bioactive compounds in C. odorata contribute to antifungal activity by interacting with its specific domain. Further research could pave the way for the development of novel and safe antifungal therapies based on biogenic nanoparticles.

Bioactive chitosan-citral Schiff base zinc complex: A pH-responsive platform for potential therapeutic applications.

The application of CO2 supercritical fluid (SCF) technology has developed rapidly because of its non-toxic, environmentally friendly, mild reaction conditions and safety. The SCF technology can effectively speed up the reaction process of nano-material synthesis, and maintains a high degree of controllability and repeatability. This study mainly included carboxymethyl chitosan sodium salt (CCS), citral (CT), p-coumaric acid (CA), and ZnSO4 as raw materials to prepare CCS-CT-CA-Zn complex as a pH-responsive agent and was investigated using supercritical fluid technique. The coordination structure of Bridge-CCS-CT-CH3COO-CA-Zn-Schiff base/OH and the morphology of the complex agents were verified. The prepared CCS-CT-CA-Zn complex showed good dispersion and uniformity (mean size: 852 ± 202 nm, PdI: 0.301, and mean zeta potential: -31 ± 6 mV). Also, it has a good pH responsive release in an acid environment. Besides, both of CCS-CT-CA-Zn complex (DS-B) and its decomposed mixture in acid (DS-A) demonstrated significant antioxidant and anti-vibrio activity. Moreover, both DS-B complex and DS-A mixture inhibited biofilm formation, swimming, and swarming motilities of V. parahaemolyticus in a dose-dependent manner. This work will provide a scientific basis for the further design and development of natural products derived antibacterial-antioxidant complex agents, food additives and feed additives.

In vitro and Ex vivo study targeting the development of a Lavandula stoechas L. (Ustukhuddus) loaded Unani Transdermal patch: Implication of Unani Medicine in the treatment of Nisyan (Dementia).

Ustukhuddus (Lavandula stoechas L.) has been extensively used orally and topically in treating various neurological disorders, including dementia. The optimum potential of traditional dosage forms of Ustukhuddus is limited for various reasons. Transdermal drug delivery system (TDDS) is a novel means of drug delivery and is known to overcome the drawbacks associated with traditional dosage forms. The current study aimed at fabricating and evaluating Ustukhuddus hydro-alcoholic extract (UHAE) and essential oil (UEO) loaded matrix-type transdermal patches having a combination of hydrophilic - hydroxyl propyl methyl cellulose (HPMC) and hydrophobic - ethyl cellulose (EC) polymers. ATR-FTIR, DSC, XRD, and SEM analysis were carried out to study drug-polymer interactions, confirming the formation of developed patches and drug compatibility with excipients. We assessed the fabricated patches to evaluate their physicochemical properties, in vitro drug release, and permeation characteristics via ex vivo experiments. The physicochemical characteristics of patches showcased the development of good and stable films with clarity, smoothness, homogeneity, optimum flexibility and free from causing skin irritancy or sensitization. In vitro drug release and ex vivo permeation profile of developed patches were evaluated employing Franz diffusion cells. UHAE and UEO patches exhibited a cumulative drug release of 81.61 and 85.24 %, respectively, in a sustained-release manner and followed non-Fickian release mechanisms. The ex vivo permeation data revealed 66.82 % and 76.41 % of drug permeated from UHAE and UEO patches, respectively. The current research suggests that the formulated patches are more suitable for TDDS and hold potential significance in the treatment of dementia, contributing to enhanced patient compliance, thereby highlighting the implication of Unani Medicine in Nisyan (Dementia) treatment.

Identification of putative antiviral bioactive compounds derived from family Asteraceae: An in silico approach.

This computational study investigates 21 bioactive compounds from the Asteraceae family as potential inhibitors targeting the Spike protein (S protein) of SARS-CoV-2. Employing in silico methods and simulations, particularly CDOCKER and MM-GBSA, the study identifies two standout compounds, pterodontic acid and cichoric acid, demonstrating robust binding affinities (-46.1973 and -39.4265 kcal/mol) against the S protein. Comparative analysis with Favipiravir underscores their potential as promising inhibitors. Remarkably, these bioactives exhibit favorable ADMET properties, suggesting safety and efficacy. Molecular dynamics simulations validate their stability and interactions, signifying their potential as effective SARS-CoV-2 inhibitors.

Identifying repurposed drugs as potential inhibitors of Apolipoprotein E: A bioinformatics approach to target complex diseases associated with lipid metabolism and neurodegeneration.

Apolipoprotein E (ApoE), a pivotal contributor to lipid metabolism and neurodegenerative disorders, emerges as an attractive target for therapeutic intervention. Within this study, we deployed an integrated in-silico strategy, harnessing structure-based virtual screening, to identify potential compounds from DrugBank database. Employing molecular docking, we unveil initial hits by evaluating their binding efficiency with ApoE. This first tier of screening narrows our focus to compounds that exhibit a strong propensity to bind with ApoE. Further, a detailed interaction analysis was carried out to explore the binding patterns of the selected hits towards the ApoE binding site. The selected compounds were then evaluated for the biological properties in PASS analysis, which showed anti-neurodegenerative properties. Building upon this foundation, we delve deeper, employing all-atom molecular dynamics (MD) simulations extending over an extensive 500 ns. In particular, Ergotamine and Dihydroergocristine emerge as noteworthy candidates, binding to ApoE in a competitive mode. This intriguing binding behavior positions these compounds as potential candidates warranting further analysis in the pursuit of novel therapeutics targeting complex diseases associated with lipid metabolism and neurodegeneration. This approach holds the promise of catalyzing advancements in therapeutic intervention for complex disorders, thereby reporting a meaningful pace towards improved healthcare outcomes.

Comparison of binding sites and affinity of flavonol-Cu(II) complexes with the same parent nucleus: Synthesis, DFT prediction, and coordination pattern.

This study explores the coordination dynamics between dietary polyphenols, specifically kaempferol, quercetin, and myricetin, and Cu ions in aqueous environments. A novel synthesis method for flavonol-Cu(II) coordination compounds is introduced, effectively reducing interference from free metal ions. Our results reveal consistent binding patterns of Cu ions with flavonols (2:1 ratio of flavonol to Cu(II)), predominantly at the 4,5 sites. Various analytical techniques are used to validate these coordination ratios and sites. The binding affinity of the flavonols for Cu ions follows a descending sequence: myricetin > quercetin > kaempferol. Notably, coordination with Cu ions enhances the free-radical scavenging activities of these flavonols. These findings hold substantial importance for food chemistry, biology, and medicine, providing crucial insights into the way dietary flavonols form stable structures in environments similar to human body fluids and their interactions with metal ions, opening new possibilities for their application and understanding in diverse scientific domains.

Structural and accessibility studies highlight the differential binding of clemizole to TRPC5 and TRPC6.

Transient Receptor Potential Canonical 5 (T RP C5) and T RP C6 channels play critical physiological roles in various cell types. Their involvement in numerous disease progression mechanisms has led to extensive searches for their inhibitors. Although several potent T RP C inhibitors have been developed and the structure of their binding sites were mapped using cryo electron microscopy, a comprehensive understanding of the molecular interactions within the inhibitor binding site of T RP Cs remains elusive. This study aimed to decipher the structural determinants and molecular mechanisms contributing to the differential binding of clemizole to T RP C5 and T RP C6, with a particular focus on the accessibility of binding site residues. This information can help better understand what molecular features allow for selective binding, which is a key characteristic of clinically effective pharmacological agents. Using computational methodologies, we conducted an in-depth molecular docking analysis of clemizole with T RP C5 and T RP C6 channels. The protein structures were retrieved from publicly accessible protein databases. Discovery Studio 2020 Client Visualizer and Chimera software facilitated our in-silico mutation experiments and enabled us to identify the critical structural elements influencing clemizole binding. Our study reveals key molecular determinants at the clemizole binding site, specifically outlining the role of residues' Accessible Surface Area (ASA) and Relative Accessible Surface Area (RASA) in differential binding. We found that lower accessibility of T RP C6 binding site residues, compared to those in T RP C5, could account for the lower affinity binding of clemizole to T RP C6. This work illuminates the pivotal role of binding site residue accessibility in determining the affinity of clemizole to T RP C5 and T RP C6. A nuanced understanding of the distinct binding properties between these homologous proteins may pave the way for the development of more selective inhibitors, promising improved therapeutic efficacy and fewer off-target effects. By demystifying the structural and molecular subtleties of T RP C inhibitors, this research could significantly accelerate the drug discovery process, offering hope to patients afflicted with T RP C-related diseases.

Targeting PDE4A for therapeutic potential: exploiting drug repurposing approach through virtual screening and molecular dynamics.

cAMP-specific 3',5'-cyclic phosphodiesterase 4 A (PDE4A) holds a pivotal role in modulating intracellular levels of cyclic adenosine monophosphate (cAMP). Targeting PDE4A with novel therapeutic agents shows promise in addressing neurological disorders (e.g. Alzheimer's and Parkinson's diseases), mood disorders (depression, anxiety), inflammatory conditions (asthma, chronic obstructive pulmonary disease), and even cancer. In this study, we present a comprehensive approach that integrates virtual screening and molecular dynamics (MD) simulations to identify potential inhibitors of PDE4A from the existing pool of FDA-approved drugs. The initial compound selection was conducted focusing on binding affinity scores, which led to the identification of several high-affinity compounds with potential PDE4A binding properties. From the refined selection process, two promising compounds, Fluspirilene and Dihydroergocristine, emerged as strong candidates, displaying substantial affinity and specificity for the PDE4A binding site. Interaction analysis provided robust evidence of their binding capabilities. To gain deeper insights into the dynamic behavior of Fluspirilene and Dihydroergocristine in complex with PDE4A, we conducted 300 ns MD simulations, principal components analysis (PCA), and free energy landscape (FEL) analysis. These analyses revealed that Fluspirilene and Dihydroergocristine binding stabilized the PDE4A structure and induced minimal conformational changes, highlighting their potential as potent binders. In conclusion, our study systematically explores repurposing existing FDA-approved drugs as PDE4A inhibitors through a comprehensive virtual screening pipeline. The identified compounds, Fluspirilene and Dihydroergocristine, exhibit a strong affinity for PDE4A, displaying characteristics that support their suitability for further development as potential therapeutic agents for conditions associated with PDE4A dysfunction.Communicated by Ramaswamy H. Sarma.