Current Pharmaceutical Design - Online First

Acute Lung Injury (ALI) is a serious complication of many diseases and can progress to Acute Respiratory Distress Syndrome (ARDS) without intervention. The current study aimed to determine the effect of Maxing Kugan Decoction (MXKGD) on an Oleic Acid (OA)-induced rat model of ALI while also exploring the regulatory effects of MXKGD on the PI3K/AKT signaling pathway and gut microbiota.

Ultra-Performance Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry (UPLC-QTOF/MS) was employed to determine the chemical ingredients of MXKGD. The therapeutic effects of different doses of MXKGD in treating OA-induced ALI were investigated using histopathology, ELISA assays, and immunofluorescence analysis. Additionally, network pharmacology and 16S rRNA sequencing were utilized to explore the underlying mechanisms of MXKGD in ALI treatment.

Through UPLC-QTOF/MS analysis, a total of 104 compounds were identified in MXKGD, including flavonoids, alkaloids, triterpenoids, glycosides, organic acids, and cyclic peptides. Pharmacodynamic results demonstrated that MXKGD could mitigate histomorphological changes in OA-induced ALI, suppress inflammation and oxidative stress, while promoting the proliferation and differentiation of alveolar type II (AT II) cells to repair the alveolar epithelial-microvascular endothelial barrier. Network pharmacology, molecular docking, and subsequent experimental validation revealed that MXKGD upregulates the expression of p-PI3K and p-AKT proteins, thereby activating the PI3K/AKT signaling pathway. Furthermore, MXKGD rebalanced the disturbance of gut microbiota and associated metabolic levels of short-chain fatty acids (SCFAs) to regulate the inflammatory response.

This study suggests that MXKGD exerts anti-inflammatory effects and protects the alveolar epithelial-microvascular endothelial barrier in ALI models by activating the PI3K/AKT signaling pathway and modulating the abundance of beneficial gut bacteria. However, further metabolomic experiments are required to confirm its precise mechanism of action.

The data indicate that MXKGD can effectively inhibit the development of ALI by reducing inflammation and regulating the balance of intestinal microbiota. MXKGD may serve as a potential new therapeutic option for treating ALI.

Obesity represents a significant health and lifestyle issue worldwide. White and brown adipocytes, which originate from resident mesenchymal stem cells (MSCs), are critically involved in the process of adipogenesis.

Human umbilical cord-derived mesenchymal stem cells (hUCMSCs) were utilized to investigate epigenetic modifications associated with adipogenic differentiation. Briefly, histone acetylation and/or methylation pattern of hUCMSCs were evaluated with histone deacetylase inhibitor Trichostatin A (TSA) for cell viability, death rate, and adipogenic commitment.

Inhibition of histone deacetylation was accompanied by a reduction of the global methylation pattern compared to the baseline levels in untreated cells. These changes decreased cell viability at 36 hrs, while reciprocally increasing the rate of cell death from 24 hrs. Most importantly, TSA-treated cells demonstrated diminished adipogenic differentiation compared to normal cells post-induction.

Epigenetic remodeling triggered by inhibition of histone deacetylase led to reduced DNA methylation. The increased cytotoxicity, impairing cell survival due to alteration in chromatin state, reduced adipogenic differentiation potential in TSA-treated cells, promoting disruption of normal lineage commitment pathways.

Taken together, the results show a possible anti-obesity effect of histone deacetylation inhibitors (HDCAs) in MSCs, resulting in depletion and restriction of their adipogenic differentiation.

This study employed network pharmacology and molecular docking to investigate the mechanism of Inula helenium in treating liver cancer.

Active compounds and their targets were identified from Inula helenium using HERB and Swiss Target Prediction. After standardizing target names via UniProt, liver cancer-related genes were collected from GeneCards and OMIM. Venny 2.1 analysis yielded 57 overlapping targets. A PPI network was constructed with STRING 11.5, and functional enrichment analyses were conducted using DAVID. GO analysis revealed multiple biological processes, cellular components, and molecular functions, while KEGG analysis highlighted key pathways including chemical carcinogenesis, IL-17, and NF-κB signaling. Thirteen core targets (e.g., TNF, IL1B, PTGS2, GSK3B, and MAPK14) were identified, and molecular docking confirmed their strong binding with active compounds.

Inula helenium may treat liver cancer by modulating targets such as TNF, PTGS2, GSK3B, and MAPK14, as well as pathways like IL-17, NF-κB, and hepatitis B, thereby suppressing tumor growth and apoptosis.

The findings support the anti-hepatocellular carcinoma effect of Inula helenium and suggest potential mechanisms, though further clinical validation is needed due to inherent limitations of network pharmacology.

This study offers a theoretical basis for the clinical use of Inula helenium in liver cancer treatment and encourages further investigation.

This study elucidates molecular mechanisms underlying sanguinarine (SAN)-mediated inhibition of Lung Adenocarcinoma (LUAD) progression.

Potential targets for SAN and LUADwere obtainedfrom public databases. A Protein-Protein Interaction (PPI) network was constructed, and core targets were visualized using Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed with DAVID, while Reactome, WikiPathways, and MSigDB Hallmark analyses utilized Enrichr. Core targets expression and immune infiltration in LUAD were validated using The Cancer Genome Atlas (TCGA). Molecular docking assessed binding affinity between SAN and core targets, and in vitro experiments confirmed SAN's suppression of LUAD progression via the TGF-β1/Smad3 pathway.

Ten core targets of SAN in LUAD were identified. GO analysis revealed biological processes including proliferation, apoptosis, and signal transduction. Significantly enriched cancer-related pathways included PI3K-Akt, MAPK, Ras, and TGF-β signaling, the latter of which was significantly enriched across KEGG, Reactome, WikiPathways, and MSigDB Hallmark analyses. Molecular docking demonstrated a strong binding affinity between SAN and core targets. In vitro, SAN suppressed proliferation and autophagy in A549 cells while promoting apoptosis by inhibiting the TGF-β1/Smad3 signaling pathway.

The results demonstrate SAN's multi-target action against LUAD, notably through the inhibition of TGF-β1/Smad3, providing a mechanistic basis within oncogenic networks. Limitations include reliance on in vitro models and the preclinical focus. Future work requires in vivo validation and clinical translation.

This study identifies key targets and pathways for SAN's inhibition of LUAD progression, validating its effect through the suppression of TGF-β1/Smad3 and providing experimental evidence for clinical application in LUAD therapy.

Intestinal permeability plays a crucial role in drug absorption, as it varies across different gastrointestinal regions, affecting the bioavailability of orally administered drugs. This variability, combined with dose-dependent absorption, influences the overall efficacy and pharmacokinetics of the drug.

This study aimed to investigate the impact of three intestinal regions (jejunum, ileum, and colon) along with two different doses of amlodipine (AML) (5 mg and 10 mg) on its permeability.

An optimized HPLC method was developed and validated for the simultaneous quantification of AML, metoprolol (MTP), and phenol red (PR), while a modified single-pass intestinal perfusion (SPIP) was used to assess AML permeability across different intestinal segments.

Net Water Flux (NWF) showed significant fluctuations, with high positive values in the colon, indicating distinct physiological responses in this region. The effective permeability (Peff) of AML varied across different intestinal segments and doses. In the jejunum and ileum, the Peff of AML decreased with increasing doses from 5 mg to 10 mg, while in the colon, Peff remained relatively stable. Peff values ranged from 
3.50 × 10⁻⁴ cm/s for the 5 mg dose to 1.80 × 10⁻⁴ cm/s for the 10 mg dose in the jejunum, from 3.30 × 10⁻⁴ cm/s (5 mg) to 2.41 × 10⁻⁴ cm/s (10 mg) in the ileum, and from 6.65 × 10⁻⁴ cm/s (5 mg) to 6.79 × 10⁻⁴ cm/s (10 mg) in the colon.

This study demonstrated significant segmental and dose-dependent variations in the intestinal permeability of AML using the SPIP model in rats.

Doxorubicin (DOX), a widely used chemotherapeutic agent, is effective against various malignancies, but its clinical application is limited by cumulative dose-dependent cardiotoxicity. The objective of this review is to systematically explore the molecular mechanisms involved in DOX-induced cardiotoxicity (DIC) and evaluate the cardioprotective potential of plant-derived bioactive compounds.

A comprehensive literature search was conducted using databases, such as PubMed, Scopus, and Web of Science, focusing on studies published in the last two decades. Emphasis was placed on experimental and preclinical models that investigated molecular pathways of DIC and the therapeutic role of phytochemicals.

DOX-induced cardiotoxicity is mediated through a cascade of molecular events, including excessive oxidative and nitrosative stress, mitochondrial damage, apoptosis, impaired autophagy, and altered activity of signaling pathways, such as AMPK, Nrf2, TGF-β1/Smad2, and HIF-1α. Epigenetic dysregulation also contributes to myocardial injury. Phytochemicals, such as flavonoids, polyphenols, and alkaloids, have shown significant cardioprotective effects. These compounds exert their actions by modulating redox homeostasis, preserving mitochondrial function, regulating apoptotic markers, and restoring signaling imbalances.

The pleiotropic nature of phytocompounds enables them to target multiple pathological mechanisms associated with DIC. Despite promising in vitro and in vivo evidence, limitations, such as poor bioavailability, lack of standardized dosing, and inadequate clinical data, hinder their translational potential. Novel delivery systems and well-controlled clinical trials are necessary to overcome these challenges.

Plant-derived bioactive compounds show potential in mitigating doxorubicin-induced cardiotoxicity, as supported by preclinical evidence. However, further translational studies are warranted to validate these findings, optimize pharmacokinetics, and evaluate their feasibility in clinical oncology settings.

Metallic nanoparticles are of interest for their potent bactericidal and anti-biofilm effects within a favorable therapeutic index. This study reports the green synthesis of bimetallic nickel-iron (Ni-Fe) nanoparticles using Eugenia jambolana extract and evaluates their antimicrobial, anti-biofilm, anti-inflammatory, and antioxidant activities.

Ni-Fe nanoparticles were synthesized using E. jambolana extract and characterized for crystalline structure, size, stability, zeta potential, and functional groups. Antimicrobial activity was tested against Gram-positive (Bacillus subtilis, Staphylococcus aureus), Gram-negative (Escherichia coli, Pseudomonas aeruginosa), and Candida albicans. Anti-biofilm potential was assessed via inhibition and dispersion assays, EPS quantification, and in situ visualization. Anti-inflammatory activity was measured through protein denaturation and nitric oxide scavenging assays, while antioxidant capacity was determined using DPPH and H2O2 scavenging tests.

Crystalline, stable Ni-Fe nanoparticles with favorable functional groups were obtained. At 200 µg/mL, they showed broad-spectrum antimicrobial activity. Biofilm formation was reduced by 50% at 250 µg/mL, and dispersion occurred at 10-50 µg/mL, with S. aureus most susceptible. EPS inhibition at 50 µg/mL was 78% (E. coli), 70% (P. aeruginosa), 73% (B. subtilis), and 91% (S. aureus). Visualization confirmed strong adherence to biofilms. At 250 µg/mL, protein denaturation inhibition reached 45%, nitric oxide scavenging 42.6%, DPPH scavenging 44%, and H2O2 scavenging 49%.

Ni-Fe nanoparticles exhibit strong antimicrobial, anti-biofilm, anti-inflammatory, and antioxidant activities, notably against S. aureus. High EPS inhibition and biofilm dispersion suggest potential against biofilm-associated, drug-resistant infections.

Green-synthesized Ni-Fe nanoparticles from E. jambolana show multifunctional bioactivities, offering promise for therapeutic applications targeting resistant and biofilm-related infections.

This study aimed to synthesize and characterize copper oxide nanoparticles (CuO NPs) using Rhus punjabensis extract and chemical methodologies. The comparative nephrotoxicity of green-synthesized CuO NPs (G-CuO-NPs) and chemically synthesized CuO NPs (C-CuO NPs) were examined in Sprague-Dawley rats and their offspring following oral administration during pregnancy and lactation.

Fourier Transform Infrared Spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), and X-ray Diffraction (XRD) were employed to examine the morphology, dimensions, and functional groups of the fabricated CuO NPs. To assess the relative nephrotoxicity of G-CuO-NPs and C-CuO-NPs at doses of 50 and 100 mg/kg, twenty-five rats were randomly allocated to five groups (designated as G1, G2, G3, G4, and G5), with each group comprising one male and four female animals for mating purposes. Nephrotoxicity of both parental and offspring animals was evaluated by examining their antioxidant status, total protein content, lipid peroxidation, genotoxicity, serum biochemistry, and histopathology.

FT-IR confirmed the synthesis of CuO NPs, while TEM and SEM revealed that G-CuO NPs were spherical and C-CuO NPs were oval. The XRD analysis showed that both NPs had a monoclinic structure. The crystalline dimensions of G-CuO NPs were 36.6 nm, and 32.85 nm for C-CuO NPs. C-CuO NPs showed dose-dependent toxicity in both parents and pups, causing a disturbance in the antioxidant balance, reducing protein content, and inducing lipid peroxidation and genotoxicity in the renal tissues. The morphological architecture of the parents’ kidneys and renal function were evaluated. G-CuO NPs, on the other hand, showed mild toxicity only in the parents.

The findings indicate that G-CuO NPs exhibit biocompatibility and are suitable for biological applications. This study underscores the compatibility of plant-derived metallic nanoparticles with living systems and paves the way for investigating their potential applications in contexts where toxicity limits the use of nanoparticles.

Based on these findings, the biocompatibility of green-synthesized CuO NPs was determined, and they did not induce nephrotoxicity in both parents and their offspring. In contrast, chemically synthesized CuO NPs, when administered at higher concentrations, were found to cause nephrotoxicity, which may also be transmitted to the offspring through lactation.

The COVID-19 pandemic, caused by SARS-CoV-2, has highlighted the urgent need for effective antiviral and anti-inflammatory therapies. Spiropyridine derivatives containing a chalcone moiety have shown potential in targeting key enzymes involved in viral replication and inflammation.

To evaluate the inhibitory effects of synthesized spiropyridine derivatives on SARS-CoV-2 main protease (Mpro), secreted phospholipase A2 (sPLA2), and cytosolic phospholipase A2 (cPLA2), and to assess their impact on inflammatory and oxidative stress markers in LPS-treated lung cells.

To develop novel therapeutic agents that can effectively manage COVID-19 and related inflammatory conditions.

The synthesized compounds (1-3) were tested for their inhibitory activity against SARS-CoV-2 Mpro, sPLA2, and cPLA2 using in vitro assays to determine IC50 values. Inflammatory markers (COX-2, IL-2, IL-4, TGF-1β, TNF-α) and oxidative stress markers (GSH, SOD, GR, MDA) were measured in LPS-treated lung cells. Gene expression levels of sPLA2 and cPLA2 were also assessed. Molecular docking studies were conducted to analyze the binding affinities and interactions of the compounds with the target enzymes.

Compounds 1-3 showed significant inhibitory activity against SARS-CoV-2 Mpro with IC50 values of 19.85 µM, 7.31 µM, and 3.73 µM, respectively. For comparison, baicalein's IC50 value was 13.63 µM. Additionally, these compounds inhibited sPLA2 with IC50 values of 8.36 µM, 7.31 µM, and 3.73 µM, and cPLA2 with IC50 values of 20.44 µM, 6.02 µM, and 4.61 µM, respectively. Baicalein's IC50 values for sPLA2 and cPLA2 were 11.73 µM and 5.89 µM, respectively. In LPS-treated lung cells, compounds 1-3 significantly reduced COX-2 by up to 90.12%, IL-2 by 74.19%, IL-4 by 79.51%, TGF-1β by 44.57%, and TNF-α by 68.49%. They enhanced GSH by up to 194%, SOD by 357.19%, and GR by 445.87%, while reducing MDA by 77.90%. Gene expression of sPLA2 and cPLA2 was significantly downregulated by up to 82.31% and 64.59%, respectively. Molecular docking studies revealed binding affinities of -28.20, -28.20, and -28.07 kcal/mol for SARS-CoV-2 Mpro; -16.72, -17.21, and -15.89 kcal/mol for sPLA2; and -65.66, -66.95, and -79.24 kcal/mol for cPLA2, respectively.

The results demonstrate that the structural integration of a spiropyridine core with a chalcone moiety yields compounds with superior multi-target inhibitory activity. The potent antiviral, anti-inflammatory, and antioxidant effects are significantly correlated with their strong binding interactions with the active sites of Mpro, sPLA2, and cPLA2, as validated by molecular docking. These findings align with and extend current research on targeting host-inflammatory pathways alongside viral replication for COVID-19 management.

The synthesized spiropyridine derivatives containing a chalcone moiety exhibit potent antiviral, anti-inflammatory, and antioxidant properties. These findings suggest that these compounds could be promising therapeutic agents for managing COVID-19 and related inflammatory conditions. Future studies should focus on in vivo experiments, clinical trials, and structural optimization to further develop these compounds for clinical use.

Millions of people have died from zoonotic illnesses, like COVID-19 and Nipahvirus infection (NiV), throughout history. Fruit bats (Pteropus sp.) are the main reservoir host for NiV, an RNA virus belonging to the Henipavirus group, which causes extremely infectious illnesses, such as COVID-19. NiV outbreaks have posed significant public health concerns, especially in South and Southeast Asia. The Nipah virus (NiV) infection is caused by a virus that belongs to the Paramyxoviridae family's Henipavirus genus. It is the source of zoonosis, which causes respiratory and neurological symptoms.

This study has reviewed the epidemiology, pathophysiology, genetic diversity, and phylogenetics of NiV. It has explored NiV’s clinical features, cellular monitoring, infection factors, and the virus’ reservoir host.

Phylogenetic analysis has identified two circulating NiV lineages. Additionally, the study has examined the role of phytochemicals in combating viral infections. Despite the absence of a focused therapy for COVID-19, phytochemicals have been investigated for their potential antiviral properties. Evidence suggests that plants and their components may possess resistance against NiV by modulating the immune system and inhibiting viral replication.

The investigation into plant-derived compounds has offered a novel direction for NiV treatment, potentially enhancing viral resistance through immune modulation. Continued research on natural antivirals could bridge current gaps in therapeutic options for emerging zoonotic diseases.

The study has highlighted the transmission risk, detection challenges, and the potential of phytochemicals in managing NiV infections. The therapeutic potential of plants and their antiviral properties offer promising insights into future treatments for serious viral diseases, like NiV.

Wound healing is a complex and dynamic biological process involving hemostasis, inflammation, proliferation, and tissue remodeling. Conventional wound dressings provide only passive protection and fail to maintain an optimal healing microenvironment. Synthetic polymers, such as polyvinyl alcohol (PVA), polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), and polyethylene glycol (PEG), have emerged as promising materials in advanced wound care due to their tunable physicochemical properties, biocompatibility, and enhanced therapeutic functionality.

This review aims to evaluate the potential of synthetic polymers in wound healing applications, focusing on their structural and functional advantages, challenges, and opportunities in the development of next-generation wound dressings.

A comprehensive literature review was conducted on recent developments in polymer-based wound dressings. In this review, we conducted a systematic literature search across Google Scholar, ScienceDirect, Scopus, Web of Science, and PubMed for publications between 2015 and 2025. The search strategy employed keywords, such as “wound healing”, “polyvinyl alcohol”, “polycaprolactone”, “poly(lactic-co-glycolic acid)”, “polyethylene alcohol”, “physicochemical characteristics”, “drug delivery capabilities”, and ” clinical trial” to capture the research landscape.

Synthetic polymers demonstrated significant potential in overcoming limitations of natural biomaterials, such as poor mechanical strength and rapid degradation. PEG-based hydrogels exhibited excellent hydrophilicity and sustained drug release. PCL scaffolds offered mechanical durability and supported tissue regeneration. PLGA allowed controlled therapeutic release through tunable degradation, while PVA ensured prolonged wound protection due to its structural stability. Polymer modifications, including crosslinking and blending, further enhanced wound healing efficacy.

Synthetic polymers provide versatile platforms for designing multifunctional wound dressings with improved healing outcomes. Future research should emphasize biodegradable, patient-specific, and smart wound dressings integrating controlled drug delivery, infection prevention, and angiogenic stimulation, thereby revolutionizing wound management practices.

Nitrergic transmission and oxidative stress are complicated factors in the seizure’s pathophysiology. Syringic acid has been revealed to exert numerous pharmacological properties, including neuroprotective effects. Hence, this research was designed to explore the anticonvulsant effects of syringic acid, focusing on its possible impact on nitrergic transmission and oxidative stress in the prefrontal cortex (PFC) in mice that underwent induction of seizure using pentylenetetrazole (PTZ).

Forty male NMRI mice were randomly divided into five groups, including mice that received saline containing Tween 80 at a concentration of 1% (10 ml/kg), syringic acid at doses of 10, 20, and 30 mg/kg, and diazepam (10 mg/kg). Syringic acid was dissolved in saline containing Tween 80 at a concentration of 1%. All drugs were injected intraperitoneally one hour before seizure induction by PTZ. Seizure threshold, total antioxidant capacity (TAC), nitrite, and malondialdehyde (MDA) levels, as well as inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) gene expressions, were assessed in the PFC.

Syringic acid increased the seizure threshold and TAC, whereas it decreased MDA and nitrite levels in the PFC samples. Furthermore, syringic acid diminished the expression of iNOS and nNOS genes in the PFC.

Oxidative/nitrosative stress, which is involved in the pathophysiology of seizure, was alleviated by syringic acid.

It was concluded that, at least partially, the anticonvulsant property of syringic acid was mediated through the mitigation of oxidative stress and nitrergic transmission in the PFC in PTZ-induced seizures in male mice.

The purpose of this research is to review and evaluate both traditional and emerging biomarkers used in the diagnosis, monitoring, and treatment of liver diseases. The study aims to highlight how these biomarkers—such as liver enzymes, microRNAs, exosomes, and fibrosis-related proteins—can improve early detection, track disease progression, and support personalized treatment strategies for better patient outcomes.

This study uses a literature review to analyze both traditional (ALT, AST, ALP, bilirubin, etc.) and emerging biomarkers (microRNAs, exosomes, CRP, IL-6, MMPs, TIMPs) in liver disease. It focuses on their role in diagnosis, disease monitoring, and personalized treatment planning.

Traditional biomarkers (ALT, AST, ALP, bilirubin, albumin) are key for liver function assessment. Emerging markers like microRNAs, exosomes, MMPs, and TIMPs improve early detection and disease monitoring. Together, they enhance diagnostic accuracy and support personalized treatment.

The combination of traditional and novel biomarkers improves early detection, accurate diagnosis, and personalized treatment of liver diseases. New biomarkers, such as microRNAs and exosomes, offer higher sensitivity and specificity, enabling non-invasive diagnostics. The findings align with current research trends that promote the use of molecular and extracellular markers. These biomarkers provide deeper insights into liver disease mechanisms, particularly in fibrosis and hepatocellular carcinoma.

Traditional biomarkers are essential for liver assessment, while new ones like microRNAs, exosomes, MMPs, and TIMPs improve early diagnosis and monitoring. They support personalized care but need further validation for routine use.

Disorders of mood and post-traumatic stress disorder (PTSD) are common after major trauma, and one of the treatments used is Tricyclic Antidepressants (TCA). These medications work by inhibiting the re-uptake of neurotransmitters like serotonin and noradrenaline. Serotonin is known to have measurable effects on bone tissue due to the presence of specific receptors on bone cells. However, there are conflicting reports about how serotonin signaling affects bone tissue and the process of fracture healing. This study aimed to evaluate the effect of TCAs on fracture healing.

Twelve skeletally mature Wistar rats were used in the study. All rats underwent intra-medullary pinning of the right tibia, and a complete mid-diaphyseal fracture was created. The rats were then randomly split into two groups: a control group and a study group. For twenty-eight days, the study group received a daily dose of 10 mg/kg of amitriptyline via intraperitoneal infusion, while the control group received an equal volume of plain saline via the same route. On day twenty-eight, five hours after the final dose, all rats were euthanized to assess fracture healing using radiological, microscopic, and histological methods.

The study found a significant difference in the total volume of new bone formation between the two groups on day twenty-eight. The control group had a mean bone formation volume of 1.077 mm³, whereas the amitriptyline-treated group had a significantly higher mean volume of 1.824 mm³ (p<0.01).

The results suggest that TCAs positively influence the early phases of fracture healing. The increased new bone formation observed in the amitriptyline group indicates a potential therapeutic benefit beyond their known psychiatric effects. This finding adds to the existing literature on the complex relationship between serotonin signaling and bone metabolism, providing evidence that this class of antidepressants may enhance the process of bone repair.

Tricyclic Antidepressants, specifically amitriptyline, significantly increase new bone formation in the early stages of fracture healing in Wistar rats.

The Xianling Gubao capsule (XLGB), a traditional Chinese medicine formulation approved by the China Food and Drug Administration, has been effectively used to treat two common medical conditions: osteoarthritis (OA) and osteoporosis (OP). However, due to the complex ingredients, the molecular mechanisms underlying its therapeutic effects for OA and OP remain unknown.

This study identified XLGB-related therapeutic target genes and pathways for OA and OP by using bioinformatics and network pharmacology. Molecular docking assessed the interactions between core genes and compounds, while quantitative real-time PCR and Western blotting analyses validated the mRNA and protein expression of key target genes.

Bioinformatics analysis identified 473 unique genes common to OA and OP. Network pharmacology analysis identified 30 intersecting genes as the principal target genes for anti-OA and anti-OP effects. Ten hub genes were identified using protein-protein interaction as potential therapeutic targets. These genes were related to transcription regulation and enriched in certain signaling pathways, such as interleukin-17 and tumor necrosis factor. Molecular docking analysis revealed danshenxinkun B to exhibit a strong affinity for Ptgs2, Fos, and Tnfaip3, while miltirone displayed a strong affinity for Ptgs2. The experimental results have been verified using cellular experiments.

This study showed Ptgs2, Fos, and Tnfaip3 to be mainly enriched in interleukin-17 and tumor necrosis factor signaling pathways. Moreover, danshenxinkun B and miltirone significantly modulated the expression levels of these genes.

This study has demonstrated that danshenxinkun B and miltirone may be pivotal agents in treating OA and OP by down-regulating the expressions of Ptgs2, Fos, and Tnfaip3.

Hepatitis C virus (HCV) remains a major global health challenge, driving chronic hepatitis C (CHC) progression to severe liver diseases, including hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed HCV treatment by achieving high sustained virological response (SVR) rates. However, limitations such as resistance, reinfection, and restricted accessibility emphasize the urgent need for novel therapeutic approaches. Among HCV therapeutic targets, the NS3/4A protease is critical for viral replication and immune evasion, positioning it as a prime focus for innovative drug discovery.

A comprehensive computational approach was adopted to evaluate flavonoids, natural compounds with known antiviral and anticancer properties, as potential inhibitors of the HCV NS3/4A protease. A curated flavonoid library was subjected to virtual screening using molecular docking techniques. Top-ranked flavonoids were further assessed based on binding affinity, dissociation constants, and key protein-ligand interactions. Pharmacokinetic profiling, molecular dynamics simulations, MM/PBSA energy calculations, and principal component analysis were performed to validate the most promising candidate.

The top ten scoring flavonoids demonstrated strong binding affinities and stable interactions with key catalytic residues of the NS3/4A protease. CID 100943380 emerged as the most promising candidate, exhibiting favorable pharmacokinetic properties and sustained stability throughout molecular dynamics simulations. MM/PBSA and PCA analyses further confirmed its robust binding and conformational stability.

The findings highlight flavonoids as promising inhibitors of NS3/4A protease, supporting their potential for further antiviral development.

This investigation identifies 10 flavonoids with high potential as NS3/4A protease inhibitors, providing a basis for future biological validation and safer drug development.