Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes that severely impairs quality of life. The Yi-Qi-Bu-Shen Recipe (YQBS) alleviates diabetic complications, but its mechanism against DPN remains unclear. This study aimed to explore the underlying mechanism of YQBS against DPN using network pharmacology and to verify its effects on peripheral nerve injury and modulation of the AGE-RAGE/NF-κB signaling pathway in vivo. Active components of YQBS were computationally screened via the TCMSP database, potential targets were predicted using GeneCards and OMIM, and key pathways were analyzed by KEGG enrichment. Molecular docking was performed to assess binding affinities. In animal experiments, streptozotocin-induced DPN rats were randomized into control, model, low-dose YQBS, and high-dose YQBS groups. After 12 weeks, nerve conduction velocity, sciatic nerve pathology, nerve repair-related proteins, and RAGE/NF-κB p65 phosphorylation were evaluated. Network pharmacology predicted quercetin, β-sitosterol, and formononetin as major active components, PTGS2 and NOS2 as core targets, and AGE-RAGE/PI3K-Akt as key pathways. Molecular docking predicted favorable binding affinities. Animal experiments confirmed that YQBS significantly improved nerve conduction, alleviated nerve damage, upregulated repair proteins, and inhibited RAGE expression and NF-κB p65 phosphorylation. In conclusion, YQBS ameliorates DPN in rats, with suppression of AGE-RAGE/NF-κB pathway activation.

Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus. Circadian rhythm disorders are related to the pathogenesis of LN. This study aims to identify the core circadian rhythm-related genes in LN and identify the potential natural active compounds for LN treatment. In the present study, cyclin A2 (CCNA2) and cyclin-dependent kinase inhibitor 3 (CDKN3) were identified as the core targets most related to the circadian rhythm of LN. Both of them were upregulated in blood and kidney tissue samples in LN and had high diagnostic efficacy. Deguelin had strong binding capabilities with CCNA2 and CDKN3 proteins. Deguelin could dose-dependently alleviate lipopolysaccharide-induced human kidney-2 (HK-2) cell damage, inhibit cell apoptosis and the release of inflammatory factors, downregulate the mRNA and protein expression levels of core genes CCNA2 and CDKN3, and inhibit the activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. The protective effect of deguelin could be reversed by AKT activator SC79 treatment. In summary, CCNA2 and CDKN3 are core genes related to the circadian rhythm in LN. Deguelin probably alleviates renal tubular epithelial cell injury by modulating the expression levels of core genes CCNA2 and CDKN3, inhibiting the activation of the PI3K/Akt signaling pathway, and thus has the potential to become a therapeutic agent for LN.

Mitochondrial protein import is essential for overall cellular homeostasis, yet scalable approaches to systematically interrogate mitochondrial protein import and identify modulators of this process remain limited. Here, we describe a yeast-based, gain-of-growth (GoG), high-throughput screening assay for the identification of small-molecule modulators of mitochondrial protein import. In this system, truncated human proteins that contain N-terminal mitochondrial targeting sequences (MTSs) are expressed in S. cerevisiae, where mitochondrial protein import is coupled to an auxotrophic growth readout. Disruption of import leads to cytosolic accessibility of the URA3 reporter, producing a GoG phenotype under selective conditions. As a proof of concept, we applied this model to PTEN-induced kinase 1 (PINK1), a mitochondrial imported regulator of mitochondrial quality control. Using this approach, we demonstrate the ability to monitor PINK1 import and identify candidate compounds that modulate this process. Collectively, this work establishes a scalable and reproducible platform for interrogating mitochondrial protein import and identifying compounds for downstream validation in mammalian systems.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by the deposition of amyloid-β plaques in the hippocampus, leading to cognitive and behavioral impairments. This study investigated the neuroprotective outcome of Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor primarily used for glycemic control, which also exhibits notable anti-inflammatory, antioxidant, and neuroprotective properties. Using an aluminum chloride (AlCl3)-induced rat model of AD, the research evaluates behavioral, biochemical, and neuroinflammatory changes, particularly focusing on the nuclear factor kappa-B protein (NF-κB) signaling pathway. Rats were orally administered AlCl3 to induce AD-like pathology, followed by DAPA treatment (1 and 2 mg/kg, p.o.) over a 28-day period. Behavioral assessments, including the Morris water maze and Elevated Plus Maze, were used to evaluate spatial memory and anxiety. On day 29, hippocampal tissues were collected to assess neurotransmitter levels, oxidative stress markers (LPO, GSH, nitrite), and inflammatory cytokines (interleukin-1 beta, interleukin-6), along with the expression of NF-κB. AlCl3 exposure led to significant alterations in neurotransmitter balance (AChE, GABA, and glutamate), heightened oxidative stress, and increased neuroinflammatory responses. DAPA treatment significantly mitigated these changes, notably downregulating NF-κB, which correlated with decreased amyloid beta and expression in the hippocampus. These findings suggest that beyond its antidiabetic action, DAPA offers promising neuroprotection against AlCl3-induced neurotoxicity, potentially via modulation of the NF-κB signaling pathway.

A simple, rapid, sensitive, and stability-indicating reverse-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the quantitative determination of promethazine hydrochloride (HCl) in pharmaceutical formulations. Chromatographic separation was achieved using a SunFire® C18 column (4.6 × 250 mm, 5 µm) with a mobile phase consisting of acetonitrile and 0.1% orthophosphoric acid in water (80:20, v/v) at a flow rate of 1.0 mL/min. Detection was performed at 249 nm using a photodiode array detector. The developed method was validated according to the International Council for Harmonisation Q2 guidelines with respect to specificity, linearity, precision, accuracy, robustness, limit of detection, and limit of quantitation.The method exhibited good linearity over the concentration range of 2-64 µg/mL with a correlation coefficient (R[2]) of 0.9993. The percentage relative standard deviation for precision studies was below 2%, indicating satisfactory repeatability and reproducibility. Forced degradation studies were performed under acidic, alkaline, neutral, oxidative, and thermal stress conditions to evaluate the stability indicating capability of the method. Additional chromatographic peaks corresponding to degradation products were observed in acid, base, neutral, and oxidative stress conditions, while minimal degradation was observed under thermal stress. Furthermore, liquid chromatography-mass spectrometry (LC-MS) analysis was carried out to characterize the degradation products formed during stress studies. LC-MS results indicated that alkaline stress produced the highest degree of degradation, whereas thermal stress generated only minor residual impurities, confirming the relative stability of promethazine HCl under thermal conditions. The developed RP-HPLC method was found to be suitable for routine quality control analysis and stability assessment of promethazine HCl in pharmaceutical formulations.

In the last few decades, diabetes mellitus has become an increasingly prevalent global health crisis. Both type 1 and type 2 diabetes are associated with a wide range of complications, including diabetic retinopathy, neuropathy, nephropathy, cardiovascular disease, and a higher risk of gastrointestinal, liver, and pancreatic cancers. In managing such conditions, drug delivery systems with enhanced therapeutic efficacy and specific tissue targets have received significant attention. Development of thiolated natural gums, which are polysaccharides that have been covalently modified with thiol groups, has paved the way for biomaterial-based drug delivery. These modified polymers are also prominent choices for controlled delivery of active pharmaceutical ingredients in topical application, dry powder inhalation, or oral administration. Additionally, they can enclose hydrophilic macromolecular drugs, peptides, RNA, and biomacromolecules, namely insulin, FGF, and siRNA. This article explores the potential of thiolated natural gums in drug delivery for the treatment of diabetes and diabetes-associated carcinoma. The properties of thiolated gums, their mechanisms of drug release, and their advantages over conventional drug delivery systems are also discussed here. Furthermore, the article delves into various applications for diabetes and diabetes-associated breast, liver, and colorectal cancers. The article also discusses the challenges and future prospects of thiolated natural gums in the pharmaceutical arena.

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.