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Background: The search for effective painkillers has led to intensive research, with a particular focus on the transient receptor potential vanilloid-1 (TRPV1) channel as a possible target., Methods: One promising candidate is ononin, which is investigated for its binding with TRPV1 through a 200-ns molecular dynamic simulation and analysed via root-meansquare deviation (RMSD), root-mean-square fluctuation (RMSF), hydrogen-bond interactions, radius of gyration (RadGyr), and MM-PBSA energy calculations. The results were further validated experimentally via calcium imaging studies., Results: Molecular dynamics revealed that the ononin-TRPV1 complex achieved stable binding within a remarkably short time of approximately 38 ns while maintaining the degree of compactness of the receptor throughout a 200 ns simulation period. In contrast, the capsazepine-TRPV1 complex displayed more significant structural deviations during the whole simulation. Moreover, MM-PBSA energy calculations showed a relatively strong binding affinity between ononin and TRPV1, mainly attributed to favourable hydrophobic interactions. Pre-incubation of dorsal root ganglia (DRG) neurons with ononin (1 and 10 μM) or capsazepine (10 μM) for 4 min prior to stimulation with capsaicin significantly reduced capsaicin-evoked calcium responses. No significant difference between capsazepine and ononin was found at a concentration of 10 μM., Conclusion: Overall, this research demonstrates the potential of ononin as a potential antagonist for developing analgesics targeting TRPV1. Hence, and to our best knowledge, this study represents the first report of ononin's antagonistic activity towards TRPV1., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The combination of clopidogrel and acetylsalicylic acid is the standard treatment for atherosclerotic cardiovascular disease. Nonetheless, there is a pressing need for more potent P2Y 12 receptor inhibitors with quicker onset, especially for early intervention in acute myocardial infarction. Integrating computational modeling, i.e. pharmacophore modeling, molecular docking, and dynamics, with empirical data guides the development of effective antiplatelet therapies. This multidisciplinary study employs computational modeling and in-vitro experimental analysis, demonstrating significant inhibition of P2Y 12 activity by two NCI compounds namely: NSC380324 and NSC618163. Both NSC380324 and NSC618163 exhibited a platelet reactivity index (%PRI) of 30.0% and 34.0%, respectively compared to cangrelor that demonstrated superior activity, with a %PRI of 11.0% in platelet vasodilator-stimulated phosphoprotein (VASP) assay. Molecular docking simulations show strong binding affinities of both compounds, along with strong binding interactions at the P2Y 12 binding site. Importantly, molecular dynamics simulations highlight the influence of receptor dynamics on practical efficacy, suggesting that NSC380324, a promising P2Y 12 antagonists indicated by its excellent stability profiles at the binding pocket of P2Y 12 , its hydrogen-bond interactions occupancies and the average MM-PBSA total binding energy of -38.17 kcal/mol, require further structural optimization and in-vivo studies to realize their full potential for clinical application.

Silver nanoparticles (AgNPs) are spherical particles with a number of specific and unique physical (such as surface plasmon resonance, high electrical conductivity and thermal stability) as well as chemical (including antimicrobial activity, catalytic efficiency and the ability to form conjugates with biomolecules) properties. These properties allow AgNPs to exhibit desired interactions with the biological system and make them prospective candidates for use in antibacterial and anticancer activities. AgNPs have a quenching capacity, which produces reactive oxygen species and disrupts cellular processes (such as reducing the function of the mitochondria, damaging the cell membrane, inhibiting DNA replication and altering protein synthesis). In addition, sponge extracts contain biologically active substances with therapeutic effects. Therefore, the concurrent use of these agents may present a potential for the development of novel antitumor and antimicrobial drugs. The present study investigated the cytotoxic effects of AgNPs combined with the extracts from sponge species, Stylissa carteri or Amphimedon chloros , against various cancer cell lines and pathogenic bacterial strains. The present study was novel as it provided a further understanding of the cytotoxicity and underlying mechanisms of AgNPs. Alterations in the properties, such as size, charge and polydispersity index, of the AgNPs were demonstrated after lyophilization. Scanning electron microscopy revealed submicron-sized particles. The cytotoxic potential of AgNPs across various cancer cell lines such as lung, colorectal, breast and pancreatic cancer cell lines, was demonstrated, especially when the AgNPs were combined with sponge extracts, which suggested a synergistic effect. Analysis using liquid chromatography-mass spectrometry revealed key chemical components in the extracts, and molecular docking simulations indicated potential inhibition interactions between a number of the extract components and the epidermal growth factor receptor and tyrosine kinase receptor A. Synergistic antibacterial effects against several bacterial species such as Staphylococcus xylosus , Klebsiella oxytoca , Enterobacter aerogenes , Micrococcus spp. and Escherichia coli , were observed when AgNPs were combined with sponge ethyl acetate extracts. The results of the present study suggested a potential therapeutic application of marine-derived compounds and nanotechnology in combating cancer and bacterial infections. Future research should further elucidate the mechanistic pathways and investigate the in vivo therapeutic efficacy., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2025 Alqaraleh et al.)

The P2Y 12 receptor is an important member of the purinergic receptor family, known for its critical role in platelet activation and thrombosis. In our previously published study, the acridinone analogue NSC618159 was identified as a potent antagonist of P2Y 12 . In this work, we investigate the conformational changes in P2Y 12 when bound to NSC618159 using molecular dynamics simulations on the receptor's active and inactive forms (4PXZ and 4NTJ, respectively). It was observed that it took the systems about 7 ns and 12 ns to stabilise when NSC618159 was in complex with the active and inactive forms of P2Y 12 , respectively. Additionally, the binding pocket of the crystal structure 4PXZ expanded from 172.34 Å 3 to an average of 661.55 Å 3 when bound to NSC618159, with a maximum pocket volume of 820.49 Å 3 . This expansion was attributed to the pulled away transmembrane (TM) helices and the adoption of a more open conformation by extracellular loop 2 (EL2). In contrast, 4NTJ's pocket volume was mostly consistent and had an average of 1203.82 Å 3 . Moreover, the RMSF profile of the NSC618159-4PXZ complex showed that residues of TM-I and TM-VII had similar fluctuations to the 4NTJ crystal structure, representing the inactive form of P2Y 12 . Finally, the energy components and binding affinities of NSC618159 towards the active and inactive forms of P2Y 12 were predicted using the MM-PBSA approach. According to the results, the binding affinity of NSC618159 towards both active (4PXZ) and inactive (4NTJ) forms of P2Y 12 was found to be almost identical, with values of -43.52 and -41.68 kcal/mol, respectively. In conclusion, our findings provide new insights into the conformational changes of P2Y 12 upon binding to NSC618159 and may have implications for the development of new P2Y 12 antagonists with enhanced potency and specificity.

Milk is a rich source of miRNA packaged in exosomes. Evidence for the systemic uptake and tissue distribution of milk exosomes was reported in newborn and adult humans and animals. Breastfeeding in infants was associated with a reduced risk of obesity. Numerous adipogenesis-related miRNAs have been detected in human milk exosomes. It has been demonstrated that ingested exosomal milk miRNAs may alter gene expression in offspring to regulate their metabolism and growth. In humans, consumption of other species' milk, such as cows and goats, is continued through adulthood. Since miRNAs are conserved, the concern of cross-species transfer of adipogenic miRNA has been raised in recent years, and the increase in obesity worldwide was attributed partially to dairy milk consumption by humans. However, evidence is still weak. Research emphasizes the need for an adequate number of exosomal milk's miRNAs to reach the target cell for biological action to be achieved. It was reported that obese women's milk had less miRNA-148a and miRNA-30b, which may affect the fat acquisition of their babies. Some exosomal milk miRNAs, such as miRNA-29, miRNA-148, miRNA-30b and miRNA-125b, may have epigenetic effects on milk recipients. Moreover, the ability of milk exosomes to cross the gastrointestinal barrier makes them a promising oral drug delivery tool. Yet, exosomes may also be tagged with specific ligands which target certain tissues. Thus, milk exosomes can be engineered and loaded with certain miRNAs responsible for adipocyte differentiation, conversion, or browning. Modifications in the miRNA cargo of exosomes can benefit human health and be an alternative to traditional drugs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

P2Y 12 has a key role in platelet aggregation and thrombus formation via an ADP-induced platelet activation mechanism. Recently, P2Y 12 antagonists have become of great interest in the clinical management of antithrombotic therapy. In light of this, we explored the pharmacophoric space of P2Y 12 using structure-based pharmacophore modelling. Subsequently, genetic algorithm and multiple linear regression analyses were conducted to select the best combination of physicochemical descriptors and pharmacophoric models to create useful predictive quantitative structure-activity relationship (QSAR) equation ( r 2 = 0.9135, r (adj) 2 = 0.9147, r (PRESS) 2 = 0.9129, LOF = 0.3553). One pharmacophoric model emerged in the QSAR equation and was validated by analysing receiver operating characteristic (ROC) curves. The model was then used to screen 200 000 compounds from the National Cancer Institute (NCI) database. The top-ranked hits were in vitro tested, where their IC 50 's range between 4.20 to 35.00 μM when measured via the electrode aggregometry assay. Whilst, the VASP phosphorylation assay showed 29.70% platelet reactivity index for NSC618159, which is superior to that of ticagrelor., Competing Interests: The authors have no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

According to the World Health Organisation (WHO), as of week 23 of 2022, there were more than 1,311 cases of dengue in Malaysia, with 13 deaths reported. Furthermore, there was an increase of 65.7% during the same period in 2021. Despite the increase in cumulative dengue incidence, there is no effective antiviral drug available for dengue treatment. This work aimed to evaluate several nitro-benzylidene phenazine compounds, especially those that contain 4-hydroxy-3,5- bis ((2-(4-nitrophenyl)hydrazinylidene)-methyl)benzoate through pharmacophore queries selection method as potential dengue virus 2 (DENV2) NS2B-NS3 protease inhibitors. Herein, molecular docking was employed to correlate the energies of selected hits' free binding and their binding affinities. Pan assay interference compounds (PAINS) filter was also adopted to identify and assess the drug-likeness, toxicity, mutagenicity potentials, and pharmacokinetic profiles to select hit compounds that can be considered as lead DENV2 NS2B-NS3 protease inhibitors. Molecular dynamics assessment of two nitro-benzylidene phenazine derivatives bearing dinitro and hydroxy groups at the benzylidene ring showed their stability at the main binding pocket of DENV2 protease, where their MM-PBSA binding energies were between -22.53 and -17.01 kcal/mol. This work reports those two nitro-benzylidene phenazine derivatives as hits with 52-55% efficiency as antiviral candidates. Therefore, further optimisation is required to minimise the lead compounds' toxicity and mutagenicity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Salin, Hariono, Khalili, Zakaria, Saqallah, Mohamad Taib, Kamarulzaman, Wahab and Khawory.)

Dengue virus (DENV) is an arbovirus widespread through tropical and subtropical areas. It is transmitted to humans through Aedes mosquitoes. Infections with DENV can lead to a series of complications, including dengue fever, dengue haemorrhagic fever, or dengue shock syndrome, which might manifest through secondary infections because of a vulnerable immune system. To date, only one tetravalent DENV vaccine is approved to be administered to children whom have been previously DENV-infected and between 9 and 16 years of age. One of the key targets in discovering DENV antiviral agents is the NS2b/NS3 protease. This protease is a crucial enzyme complex for the proteolytic and cleavage activities of the translated polyprotein during DENV life cycle. Several studies were conducted to discover potential antivirals from natural sources or synthetic compounds and peptides. In this review, we describe the recent studies from the past five years dealing with isolated natural products as potential inhibitors of DENV with a greater focus on inhibiting the NS2b/NS3 protease. This review describes recent discoveries in anti-DENV potential of isolated phytochemicals belonging to different groups including fatty acids, glucosides, terpenes and terpenoids, flavonoids, phenolics, chalcones, acetamides, and peptides. Curcumin, quercetin, and myricetin were found to act as non-competitive inhibitors for the NS2b/NS3 protease enzyme. In some studies, the molecular targets of some of these compounds are yet to be identified using in-silico and in-vitro approaches. So far, none of the isolated natural products was tested clinically for the management of DENV infections. The discussed studies demonstrate that natural products are a rich source of potential anti-DENV compounds. However, not all of these compounds were studied for their kinetic molecular mechanism and type of inhibition. In-silico studies provided an ample number of phytochemical hits to be tested experimentally as DENV protease inhibitors. In conclusion, derivatives of these natural products can be designed and synthesised, which could enhance their specificity and efficacy towards the protease. Other sources of natural products, such as fungi, bacterial toxins, marine organisms, and animals, should also be explored towards discovering more potential and effective DENV NS2b/NS3 protease inhibitors., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Extensive attention has been focused on herbal medicine for the treatment of different endocrine disorders. In fact, compelling scientific evidence indicates that natural compounds might act as endocrine modulators by mimicking, stimulating, or inhibiting the actions of different hormones, such as thyroid, sex, steroidal, and glucose regulating hormones. These potentials might be effectively employed for therapeutic purposes related to the endocrine system as novel complementary choices. Nevertheless, despite the remarkable therapeutic effects, inadequate targeting efficiency and low aqueous solubility of the bioactive components are still essential challenges in their clinical accreditation. On the other hand, nanotechnology has pushed the wheels of combining inorganic nanoparticles with biological structures of medicinal bioactive compounds as one of the utmost exciting fields of research. Nanoparticle conjugations create an inclusive array of applications that provide greater compliance, higher bioavailability, and lower dosage. This can safeguard the global availability of these wealthy natural sources, regardless of their biological occurrence. This review inspects future challenges of medicinal plants in various endocrine disorders for safe and alternative treatments with examples of their nanoparticle formulations., Competing Interests: The authors declare no conflict of interest., (© 2022 Published by Elsevier Ltd.)

Background: Antirrhinum majus (Snapdragon) is a perennial Mediterranean-native plant that is commonly used for mass display. Few reports acknowledged the traditional use of A. majus for its medicinal and therapeutic effects. Herein, we assess the impact of A. majus 's sample preparation and extraction methods on the plant-aerial parts' phytochemical contents and antimicrobial activity. Furthermore, the microbial targets of the extracts' secondary metabolites are inspected using molecular docking simulations., Methods: The leaves and flowers of A. majus were prepared as fresh and air-dried samples, then extracted using cold maceration and hot reflux, respectively. Extracts with the best phytochemical profiles were selected to test their antimicrobial activities against Bacillus subtilis, Staphylococcus aureus, Enterobacter aerogenes, Escherichia coli and Candida albicans . Besides, molecular docking of 66 reported isolated compounds was conducted against various microbial targets., Results: The dried-refluxed samples revealed a massive deterioration in their phytochemical profiles, whereas the macerated flowers extract exhibited the highest total phenolic content and antimicrobial activity against all tested bacterial strains. However, both flowers and leaves extracts showed similar minimum inhibitory and lethal concentrations against C. albicans . Molecular docking studies revealed that chlorogenic acid, chalcononaringenin 4'-glucoside, 3,4,2',4',6'-pentahydroxy-chalcone 4'-glucoside, apigenin-7-glucuronide, and luteolin-7-glucuronide were the lead compounds in expressing the antimicrobial activity. Yet, A. majus 's compounds could neither inhibit the 30S ribosomal subunit nor muramyl ligase E., Conclusion: Our results suggest that cold maceration of A. majus fresh aerial parts gave higher flavonoid and phenolic content contributing to its antimicrobial properties. These flavonoids and phenolic compounds are predicted to have a crucial role in inhibiting fungal sterol 14-demethylase, and bacterial dihydropteroate synthase and gyrase B subunit proteins., Competing Interests: The authors declare no conflict of interest., (© 2022 Published by Elsevier Ltd.)

P2Y 12 is a platelet surface protein which is responsible for the amplification of P2Y 1 response. It plays a crucial role in platelet aggregation and thrombus formation through an ADP-induced platelet activation mechanism. Despite that P2Y 12 platelets' receptor is an excellent target for developing antiplatelet agents, only five approved medications are currently in clinical use which are classified into thienopyridines and nucleoside-nucleotide derivatives. In the past years, many attempts for developing new candidates as P2Y 12 inhibitors have been made. This review highlights the importance and the role of P2Y 12 receptor as part of the coagulation cascade, its reported congenital defects, and the type of assays which are used to verify and measure its activity. Furthermore, an overview is given of the clinically approved medications, the potential naturally isolated inhibitors, and the synthesised candidates which were tested either in-vitro, in-vivo and/or clinically. Finally, we outline the in-silico attempts which were carried out using virtual screening, molecular docking and dynamics simulations in efforts of designing novel P2Y 12 antagonists. Various phytochemical classes might be considered as a corner stone for the discovery of novel P2Y 12 inhibitors, whereas a wide range of ring systems can be deliberated as leading scaffolds in that area synthetically and theoretically., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Lung cancer (LC) is the leading cause of cancer-related deaths, responsible for approximately 18.4% of all cancer mortalities in both sexes combined. The use of systemic therapeutics remains one of the primary treatments for LC. However, the therapeutic efficacy of these agents is limited due to their associated severe adverse effects, systemic toxicity and poor selectivity. In contrast, pulmonary delivery of anticancer drugs can provide many advantages over conventional routes. The inhalation route allows the direct delivery of chemotherapeutic agents to the target LC cells with high local concertation that may enhance the antitumor activity and lead to lower dosing and fewer systemic toxicities. Nevertheless, this route faces by many physiological barriers and technological challenges that may significantly affect the lung deposition, retention, and efficacy of anticancer drugs. The use of lipid-based nanocarriers could potentially overcome these problems owing to their unique characteristics, such as the ability to entrap drugs with various physicochemical properties, and their enhanced permeability and retention (EPR) effect for passive targeting. Besides, they can be functionalized with different targeting moieties for active targeting. This article highlights the physiological, physicochemical, and technological considerations for efficient inhalable anticancer delivery using lipid-based nanocarriers and their cutting-edge role in LC treatment.

Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA-FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.

Mediterranean-native perennial plant Antirrhinum majus was scrutinized in this study for its antioxidant activity and its total phenolic content in order to test for the plant's wound-healing capability. The traditional uses of this plant to treat gum scurvy, various tumors, ulcers, and hemorrhoids were the main idea behind this study. Leaves and flowers of the A. majus were extracted by maceration. Pilot qualitative phytochemical tests were made to check the presence of various secondary metabolites. Quantitatively, the flowers' macerate indicated superlative results regarding antioxidant activity and total phenolic content. However, the in vivo wound-healing capability study was made using 30 Wistar strain albino rats. This innovative part of the study revealed that the healing power of the flowers' extract ointment (5% w / w ) was superior compared to the leaves' extract (5% w / w ) and the positive-control ointments (MEBO) (1.5% w / w ) ( p ≤ 0.001). This activity was assessed by visual examination, wound-length measurement, and estimation of hydroxyproline content. Antirrhinum majus is a promising plant to be considered for wound healing. However, further testing (including histological examination and high-performance liquid chromatography (HPLC) analysis) is necessary to understand more about its mechanisms of action.