Dermatophytosis is a global infection with increasing reports of resistance among its causative agents in recent years. As a result of this issue, new therapeutic options are needed. The calcineurin-calmodulin pathway is critical for fungi. Inhibitors of this pathway, such as tacrolimus in combination with antifungal drugs, may serve as alternative treatments. Nanoformulation is another method to address challenges in dermatophytosis treatment. Thirty dermatophyte isolates were included in this study. Antidermatophyte activities of terbinafine, itraconazole, posaconazole, nanoposaconazole, and tacrolimus were investigated using the third edition of the CLSIM38 protocol. In vitro interactions between tacrolimus and the antifungal drugs were studied using a checkerboard method. The isolates included Trichophyton indotineae (n = 14), Trichophyton tonsurans (n = 9), Trichophyton interdigitale (n = 6), and Microsporum canis (n = 1). Tacrolimus demonstrated moderate inhibitory effects against all species. Itraconazole had the strongest activity; however, based on EUCAST epidemiological cutoff values, one T. indotineae isolate was non-wildtype to this drug. Additionally, 10 out of 14 (71.42%) isolates of this species were non-wild type to terbinafine. Nanoposaconazole showed superior antifungal activity compared to posaconazole. Regarding drug combinations, the highest and lowest synergistic rates were observed for combinations of tacrolimus with nanoposaconazole (15/30, 50%) and itraconazole (4/30, 13.33%), respectively. The high rate of non-wildtype T. indotineae isolates to terbinafine underscores the necessity of precise identification to prevent treatment failure. Itraconazole proved to be the most effective antifungal. Combining tacrolimus with antifungal drugs, particularly nanoposaconazole, shows promise and warrants further investigation.

The current work aimed to investigate the therapeutic potential of Pluchea lanceolata (Rasna) in the management of rheumatoid arthritis (RA) using in silico, in vitro, and in vivo studies. After administering Rasna (aqueous and ethanolic extracts), physical parameters such as paw volume and arthritic score were found suppressed in rats (in Freund's complete adjuvant-induced model). Also, radiography and histopathological findings revealed that joint deformities, pannus formation, and tissue swelling of the ankle joint improved when compared with standard and arthritis-induced after 4 weeks. Simultaneously, ELISA results revealed that the serum levels of IL-1β, IL-6, TNF-α, C-reactive protein (CRP), and COL2A1 were lowered when compared with the standard group. An in silico study revealed that quercetin, isorhamnetin, and linalool were the potential active phytoconstituents and showed promising binding affinity toward targets such as KDR (VEGFR2), matrix metalloproteinase (MMPs), ALOX5, IL-1β, IL-6, TNF-α, CRP, and COL2A1. The biological mechanism of Rasna includes several molecular and cellular functions involving the downregulation of angiogenesis through the vascular endothelial growth factor signaling pathway, the MAPK signaling pathway, PI3K-Akt signaling pathway, and the reduction of cytokines and anti-collagen II antibodies. Rasna inhibits the activation of the abovementioned pathways and mRNA expression of IL-1β, IL-6, and TNF-α in RA. The study suggested the potential use of Rasna in managing arthritis treatment over the conventional therapy in immunocompromised patients.

Colon cancer ranks among the most prevalent malignancies worldwide and contributes substantially to cancer-related mortality. This study employed an integrated approach to evaluate the chemopreventive effects of Boeravinone B (BB) and Resveratrol (REV), administered individually and in combination, in the azoxymethane (AOM)-induced rat model of colon cancer, with particular emphasis on cytokine signaling pathways and mitochondrial regulation of apoptosis. The combination of BB (15 mg/kg) and REV (8 mg/kg) exhibited greater efficacy than either treatment alone. These combined treatments (BB + REV) significantly reduced pro-inflammatory cytokines (IL-1β, IL-6, tumor necrosis factor-alpha [TNF-α]), nitro-oxidative stress indicators (NO, iNOS), and histological damage, while promoting mitochondria-mediated apoptosis via modulation of BAX and BCL2. Network analysis revealed that centrality metrics (betweenness, closeness, degree, and stress centrality), identified STAT3, SOCS3, JAK2, BAX, and BCL2 as key hub proteins involved in cytokine signaling and apoptotic pathways. These nodes exhibited the highest centrality values (betweenness: 0.046667 for STAT3/SOCS3/JAK2; degree: 10 for all five proteins), indicating their pivotal roles as therapeutic targets. Molecular docking revealed favorable binding affinities of BB for SOCS3 (-9.0 kcal/mol), BAX (-9.0 kcal/mol), JAK2 (-8.1 kcal/mol), and STAT3 (-7.8 kcal/mol). In comparison, REV exhibited its highest binding affinities for SOCS3 (-7.2 kcal/mol) and BAX (-7.0 kcal/mol). These findings identify SOCS3, BAX, JAK2, and STAT3 as potential molecular targets mediating the combined treatment's anti-inflammatory and pro-apoptotic effects. This integrated in vivo and in silico study showed that combined BB and REV exerted a stronger chemopreventive effect against AOM-induced colon cancer via complementary mechanisms: restoring mitochondrial adenosine triphosphate synthase (ATPase) activity, suppressing biomarkers of inflammation, nitro-oxidative stress, and apoptosis, with strong binding affinities. These findings support repurposing BB and REV as a multitargeted combination therapy against colon cancer.

Patients often suffer from hypertension, hyperlipidemia, and diabetes, requiring long-term polypharmacy. These drugs may alter gut microbiota composition, leading to adverse effects, but the underlying mechanisms are unclear. We selected 23 common drugs from ChEMBL, identified their metabolites via DrugBank, and used TargetNet and GeneCardsSuite to find drug targets and human proteins. Cross-analysis revealed 15 shared human side-effect protein targets. Molecular docking and Structure-activity relationship analyses assessed interactions with human and bacterial proteins. Eight compounds, including metabolites of amlodipine, metoprolol, glipizide, and fenofibrate, showed significant binding to human and gut bacterial proteins. Based on our in silico models, we predict that specific structural modifications could potentially enhance efficacy while minimizing microbial disruption and adverse reactions. Molecular dynamics simulations suggest that these modified drugs might computationally maintain therapeutic interactions while reducing gut microbiota disruption. Our findings highlight the impact of these drugs on gut microbiota and side effects via shared protein targets. Supported by in silico models and preliminary in vitro assays, we think that precision medicine, probiotic co-administration, or drug structure modifications could potentially serve as future strategies to mitigate complications and side effects in elderly patients, warranting further in vivo and clinical validation.

Amyloidosis comprises a spectrum of protein misfolding disorders characterized by the aggregation of diverse amyloidogenic proteins into cytotoxic fibrillar structures. Due to the conserved β-sheet-rich architecture of fibrils across various amyloid species, pan-amyloid therapeutics present a promising strategy for simultaneously targeting multiple amyloidogenic proteins. In this study, four representative amyloidogenic proteins-amyloid β, serum amyloid A1, islet amyloid polypeptide, and transthyretin-were selected as targets. From a library of 10,272 small molecules, five functional groups were identified as critical contributors to high-affinity binding. Utilizing these functional groups, potential compounds capable of binding to all four amyloidogenic proteins were further screened. This functional group-based screening workflow not only validates the effectiveness of functional group-driven screening in multitarget drug discovery but also facilitates the efficient identification of candidate pan-amyloid binding compounds. Furthermore, these findings provide valuable insights into the development of pan-amyloid therapeutic strategies.

Despite embelin's (EB) promising biological activities including the hepatoprotective effect, its clinical use is constrained by inadequate solubility and low oral bioavailability, which restrict its therapeutic effectiveness. The current study aimed to address this gap by developing EB-loaded glycerosomes (GLSMs), an advanced vesicular system designed to improve oral bioavailability and enhance drug delivery to the liver. EB-loaded GLSMs were prepared using a thin-film hydration method and optimized via a 3[2] Box-Behnken design. The concentrations of soy lecithin and glycerol, along with the probe sonication cycle, were chosen as independent variables to study their effect on vesicle size and percentage drug entrapment. The prepared formulation was tested for vesicle size and its distribution, surface charge (zeta potential), and drug release and was also assessed in vivo. The optimized formulation exhibited a vesicle size of 214.41 ± 2.12 nm, a polydispersity index of 0.145 ± 0.02, a zeta potential of -30 ± 1.14 mV, and an entrapment efficiency (EE) of 94.74% ± 0.056%. Transmission electron microscopy images confirmed the presence of uniform, spherical vesicles with no signs of aggregation. The sustained-release properties of the GLSM formulation were evident, with 99% of EB released from the pure drug suspension within 2 h, compared with the same amount released from the EB-loaded GLSMs over 12 h. In vivo pharmacokinetic studies showed a significantly higher plasma maximum concentration (Cmax), AUC0-t, and AUC0-∞ values for optimized EB-loaded GLSMs compared with aqueous EB suspension (p < 0.01), resulting in approximately 2.5-fold greater plasma bioavailability. Furthermore, rats treated with the optimized EB-loaded GLSMs showed significantly lower serum triglyceride and total cholesterol levels compared with those treated with the aqueous EB suspension. The developed EB-loaded GLSMs exhibited promising lipid-lowering and hepatoprotective effects, suggesting their potential as a therapeutic approach for liver diseases.

Astaxanthin (AST) is a potent xanthophyll carotenoid that is well known for its extraordinary therapeutic and antioxidant properties. However, its weak water solubility and low bioavailability limit its application in pharmaceuticals. The present study aimed to enhance the solubility, stability, and sustained release of AST by developing an AST-chitosan (AST-CHT) nanoplex via green polyelectrolyte complexation. The nanoplex was lyophilized to obtain a stable dry powder and systematically characterized for its physicochemical properties. Comprehensive evaluations, including particle size analysis, entrapment efficiency, zeta potential, Fourier-transform infrared spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and transmission electron microscopy, confirmed successful nanoplex formation with improved solubility and amorphous transformation. Molecular docking studies revealed stable electrostatic and hydrophobic interactions between AST and CHT, thereby supporting the complex's stability. The optimized formulation, F5 (AST:CHT = 1.48:1% w/w), was selected based on its high entrapment efficiency (71.8%), appropriate particle size (420.1 nm, polydispersity index of 0.465), drug loading (0.79), and moderate zeta potential (-12.87 mV), which together ensured optimal stability and sustained release performance. In vitro release studies indicated sustained release following zero-order and Korsmeyer-Peppas kinetics (correlation coefficient of 0.9759). Stability analysis confirmed stability for 2 months. Overall, the developed AST-CHT nanoplex offers a promising, eco-friendly, and mechanistically supported nanodelivery system for improving the therapeutic performance and bioavailability of AST.

Despite the significant progress made in developing different in silico methodology for structure activity research over the past few decades. The ability to predict correlation structure activity (CSA) from absorption distribution metabolism excretion (ADME) descriptors to select indolizine compounds for human papilloma virus (HPV) anticancer activity continues to pose a challenge. This study employed five machine learning (ML) algorithms for classification, viz., stochastic gradient descent (SGD), random forest (RF), support vector machine (SVM), convolutional neural network (CNN), and logistic regression (LR), to perform the classification based on ADME-related physiochemical descriptors of 8,900 indolizine compounds to predict the CSA. The present study focuses on 26 well-known parameters to optimize the results, which are utilized for ML models SGD, RF, SVM, CNN, and LR for classification. The CNN achieved the best results with the highest overall accuracy and average loss values of 98.33% and 0.16, respectively. On the other hand, the SGD, RF, SVM, and LR recorded the accuracy values of 95.32%, 93.23%, 96.03%, 94.03%, and loss values of 0.046, 0.067, 0.039, and 0.059, respectively. It is stated that from the obtained results, the CNN is performing better compared to other methods. The cross-validation and results are done with the relationship of descriptors, viz., accuracy, correlation, distribution, area under the receiver operating characteristic, area under the precision recall curve, and bootstrap error analysis. This study demonstrated the utility of ML to facilitate early prediction of indolizine compounds for HPV anticancer activity in preclinical development.

The therapeutic efficacy of ellagic acid could be improved by developing suitable carrier system. The present research was to develop ellagic acid-loaded microsponges impregnated with chitosan-guar gum hydrogel and evaluate its potential as novel carrier system for wound therapy. Ellagic acid-loaded microsponges were fabricated using ethyl cellulose by the quasi-emulsion solvent diffusion method and incorporated into chitosan and guar gum hydrogel. Prepared microsponges were found to be spherical, non-aggregated particles ranging in size from 100 to 300 µm. The hydrogel formulation was assessed for pharmaceutical characteristics, rheology, drug release, antioxidant and antimicrobial activities. FTIR confirmed that the bioactive and the excipients used are chemically compatible. Spreadability data confirm precise and easy dosage application of microsponge hydrogel in the skin. Results of rheological studies revealed that microsponge-loading considerably increased elastic strength, while frequency and temperature sweep tests demonstrated viscoelastic stability at 25°C. A sustained ellagic acid release for 12 h following the Higuchi kinetics model (R[2] = 0.987) was noticed with microsponge loaded chitosan-guar gum hydrogel. The good antioxidant activity exhibited at doses (50-100 µg/mL) by the developed hydrogel implies that the formulation successfully preserves bioactive antioxidant properties. Developed hydrogel retained antimicrobial activity against the test organisms and showed notable inhibition against Pseudomonas aeruginosa at low concentration (12.5 µg/mL). This study establishes an effective topical formulation of ellagic acid-loaded microsponges with potential antioxidant and antimicrobial efficacy, highlighting its possibility to be used for wound healing.

This study demonstrates through an integrated computational and experimental approach that classical calcium channel blockers (CCBs) from four distinct structural classes possess previously unrecognized Mu-opioid receptor (MOR) activation capabilities. Virtual screening revealed stable binding modes between the investigated compounds (verapamil, cinnarizine, diltiazem, and flunarizine) and the 7SBF protein target, with cinnarizine exhibiting the most favorable interaction profile through strong hydrogen bonding with TYR-236 and GLN-124. Molecular dynamics simulations confirmed binding stability, particularly for cinnarizine, which maintained a root-mean-square deviation below 0.3 nm. Experimental validation via cAMP inhibition assays demonstrated significant MOR activation by all compounds, with cinnarizine showing superior potency (IC50 = 21.4 ± 1.5 nM) and efficacy (Imax = 70% ± 2%). The conserved MOR activation across structurally diverse CCBs supports a polypharmacological mechanism where these drugs concurrently modulate both calcium channels and opioid receptors. These findings not only elucidate a novel aspect of CCB pharmacology but also suggest new avenues for drug repurposing and the development of multi-target cardiovascular therapeutics.

Huxinkang tablets (HXKT) is the formula prescription of Traditional Chinese Medicine for treating atherosclerosis (AS), but its underlying mechanisms remain unclear. Network pharmacology and experimental verification were integrated to explore the therapeutic effects and key targets of HXKT in macrophage-associated genes in vulnerable AS plaques. Our findings indicated that a total of 75 candidate targets of HXKT against vulnerable AS were acquired. Furthermore, five core targets were identified including STAT3, HIF1A, EGFR, ESR1, and BCL2. KEGG pathway analysis demonstrated that these targets participated in the advanced glycation end product - receptor for advanced glycation end-product (AGE-RAGE) signaling pathway associated with diabetic complications, lipid metabolism, AS, and human cytomegalovirus infection. Molecular docking results indicated that the ESR1-miltirone complex exhibited the highest binding affinity. In vitro experiments demonstrated that HXKT inhibited oxidized low-density lipoprotein-induced macrophage injury, reversed abnormal expression of key targets, and reduced inflammation and lipid accumulation. Overexpression of STAT3 partially attenuated the protective effects of HXKT, confirming its role as a critical target while underscoring the multi-target mechanism of HXKT. In conclusion, HXKT stabilizes vulnerable atherosclerotic plaques by regulating macrophage function through a multi-component, multi-target mechanism, with STAT3 signaling playing a pivotal role.

Neonates are particularly susceptible to a range of adverse reactions when administered antimicrobial drugs, including allergic reactions, gastrointestinal discomfort, and hepatic or renal dysfunction. These adverse reactions can have significant long-term impacts on neonatal health. This study aimed to investigate the common molecular targets associated with these adverse reactions using reverse target identification and molecular dynamics (MD) simulations, and to experimentally assess the inhibitory effects of selected drugs on these targets. We initially identified adverse reactions associated with commonly used antimicrobial drugs such as Ceftazidime, Meropenem, Levofloxacin, Cefdinir, and Avibactam through DrugBank. Potential targets for these drugs were predicted using SwissTargetPrediction software, and common targets were identified using a Venn diagram. Molecular docking and MD simulations were conducted to assess the binding affinity and stability of the drug-target interactions. Finally, the inhibitory potential of selected antimicrobial drugs on the target proteins was evaluated through in vitro bioactivity assays. The study identified AKR1B1 and Neprilysin as common potential off-targets. Bioactivity assays confirmed that the tested antimicrobial drugs exhibited significant inhibitory effects on these two proteins, with inhibitory concentration at 50% (IC50) values generally in the micromolar range. MD simulations indicated that the complexes of these drugs with the target proteins maintained relatively stable root mean square deviation (RMSD) values throughout the simulation period. Analysis of intermolecular forces revealed key attractive charge interactions and hydrogen bonds between the drugs and target proteins. This study systematically analyzed the molecular targets associated with antimicrobial drug adverse reactions in neonates by integrating computational and experimental approaches. The findings suggest that these drugs may cause adverse reactions by affecting the function of specific off-target proteins. This discovery provides valuable molecular insights into the mechanisms of adverse reactions and establishes a scientific basis for the rational design of safer drug analogs and for informing future antimicrobial treatment research for neonates.

This work aimed to develop and assess terpene encapsulated polycaprolactone (PCL) nanoparticles for topical delivery of hydrocortisone (HC). Formulations were designed to investigate the effect of terpene/PCL ratio and concentration of surfactant on physicochemical characteristics. Structural analyses were studied using differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy techniques. Ex vivo skin permeation and anti-inflammatory activity of HC were also appraised. Results showed that the physicochemical characteristics were particularly influenced by terpene/PCL ratio and concentration of surfactant. The selected formulation (F6) showed core-shell structure and good encapsulation of HC in less crystalline state. Higher skin flux (366.11 ± 32.8 µg/cm[2]/h) and permeability coefficient (17.57 ± 2.6 × 10[2] cm/h) of HC from gel based on F6 were observed when compared with crude drug gel. Anti-inflammatory activity of HC was significantly improved and showed sustained therapeutic action when using gel based on F6. Collectively, these findings suggest that terpene encapsulated PCL nanoparticles can potentially deliver HC through the skin.

Circadian rhythms orchestrate a wide array of physiological processes that critically influence drug absorption, distribution, metabolism, and excretion. Misalignment between drug administration and biological timing can compromise therapeutic efficacy, increase adverse effects, and lead to therapeutic failure in diseases with established diurnal variation. Chronotherapy seeks to align pharmacologic interventions with these endogenous rhythms; however, traditional drug delivery systems lack the ability to adapt dynamically to circadian cues. Recent advances in nanotechnology have enabled the development of spatiotemporal nanocarrier systems capable of both anatomical targeting and time-synchronized drug release. These smart nanocarriers leverage internal stimuli (e.g., pH, redox state, enzyme activity) or external triggers (e.g., light, temperature, magnetic fields) to optimize therapeutic action at specific circadian windows. This review provides a comprehensive analysis of circadian biology relevant to drug delivery, current clinical applications of chronotherapy, and emerging preclinical evidence for chrono-responsive nanosystems, enabling technologies such as wearable biosensors, organ-on-chip platforms, and artificial intelligence. We also discuss the translational barriers and future directions in realizing patient-specific, feedback-controlled chrono-nanomedicine. The convergence of circadian pharmacology and intelligent nanocarrier design represents a transformative approach toward achieving precision medicine that targets not only the right site but also the right time.

Ischemic stroke (IS) is an important disease leading to high disability and mortality, and the current clinical treatment is limited. Tongnao Decoction (TND) is a traditional Chinese herbal formula for treating IS, but its pharmacological mechanism remains unclear. This study aims to elucidate the molecular mechanism through network pharmacology, molecular docking, and related experimental verification. First, the bioactive components of TND, along with their potential targets and IS-related gene targets, were identified through multiple databases. Subsequently, an "herb-active component-disease gene target" network and a protein-protein interaction (PPI) network were constructed. Combined with enrichment analysis, key biological processes and signaling pathways were identified. Following this, molecular docking experiments were conducted to preliminarily validate drug-target interactions. Finally, the efficacy of the relevant pathway targets was validated in a photochemically induced mouse cerebral ischemia model. A total of 90 active compounds and 615 target genes were screened. PPI network analyses suggested that TP53, EGFR, STAT3, AKT1, and IL-6 were the hub targets. TND significantly modulates inflammatory biological processes and the PI3K-Akt signaling pathway during IS treatment. Molecular docking analysis indicated that the primary components of TND may exhibit favorable binding affinity to multiple hub target proteins, including TP53, EGFR, STAT3, AKT1, and IL-6. Further in vivo experiments showed that TND dramatically improved neurological function, reduced neuronal damage, and decreased IL-6 expression in brain tissue. In addition, TND stimulated the PI3K/Akt/GSK-3β pathway. These findings imply that TND and its key bioactive components, coryincine, dihydrocapsaicin, and 4 (4'-hydroxybenzyloxy)benzyl methylether exert therapeutic effects on IS through the IL-6/PI3K/Akt/GSK-3β pathway.