Quercetin Attenuates Vocal Fold Fibrosis via PI3K/AKT and MAPK Pathways: An Integrative Network Pharmacology and Experimental Study.

Molecular and metabolic mechanisms of quercetin in liver fibrosis: an integrated network pharmacology, metabolomics, and molecular dynamics study

Liver fibrosis, a severe chronic liver injury sequela, lacks effective therapies. Quercetin, a natural flavonoid, exhibits multi-target anti-fibrotic potential. This study integrated network pharmacology,metabolomics, molecular docking, and molecular dynamics simulations to investigate its mechanisms. Network analysis identified 203 overlapping targets, with core targets including protein kinase B (AKT1), interleukin-6 (IL6), tumor protein p53 (TP53), and tumor necrosis factor (TNF), which were enriched in PI3K-Akt and TNF signaling pathways. In CCl4- induced rats (quercetin 50 mg/kg/day), quercetin alleviated pathological damage, significantly reduced collagen area by 43.1% (P = 0.006), and lowered serum alanine aminotransferase, aspartate aminotransferase, and type III procollagen levels. Metabolomics revealed 32 differential metabolites, implicating multiple metabolic pathways including lipid and amino acid metabolism. Molecular docking showed strong binding to AKT1 (5.8 kcal/mol) and TNF (7.2 kcal/ mol), with stable complexes over 100 ns simulations. QPCR was used to detect the expression of PI3K/AKT1 core targets in liver tissue, and experimental verification confirmed the predicted key targets. This multi-faceted study elucidates quercetin’s anti-fibrotic mechanism, laying a foundation for its therapeutic development.

Silybin protects against ethanol-induced acute gastric ulcer in rats with PI3K/AKT-associated phosphorylation changes.

Apigenin Alleviates Ligamentum Flavum Ossification by Dual-Targeting CA9 and CDK6 and Modulating Calcium/PI3K-Akt Signaling.

While apigenin shows therapeutic potential for bone-related disorders like osteoporosis and osteoarthritis, its mechanisms in regulating ligamentum flavum ossification (OLF) are unclear. An integrated computational strategy combining network pharmacology, machine learning, and molecular docking was used to study apigenin's therapeutic potential for OLF. First, differential gene expression profiling was done using the GSE113212 dataset to find OLF-related differentially expressed genes. At the same time, apigenin's putative targets and bioactive components were collected from pharmacological databases and literature. Common targets between apigenin and OLF-related genes were identified by Venn diagram analysis. Then, the Metascape platform was used to analyze the functional enrichment of these overlapping targets, including Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analyses. The results showed significant involvement in bone-metabolism and inflammatory-response biological processes and signaling pathways, especially the calcium and PI3K-Akt signaling pathways. A protein-protein interaction network was built with the STRING database and refined by machine-learning algorithms to find central therapeutic targets. Molecular docking analysis showed binding energies of <-5 kcal/mol between apigenin and core target proteins, indicating strong binding. Molecular dynamics simulations supported the stability and binding reliability of apigenin-target complexes. Overall, these results offer initial insights into how apigenin may modulate OLF, highlighting new therapeutic strategies and potential targets for OLF treatment.

Exploring the Molecular Mechanisms of SB216763 in the Therapeutic Intervention of Pulmonary Fibrosis Based on Macrophage Functional Plasticity‌.

BACKGROUND SB216763 has demonstrated efficacy in treating pulmonary fibrosis in animal models, but its underlying mechanisms remain poorly understood. This study used network pharmacology, molecular docking, and molecular dynamics simulations to explore the molecular mechanisms by which SB216763 exerts therapeutic effects on pulmonary fibrosis. METHODS The targets of SB216763 were screened using the PharmMapper database, while pulmonary fibrosis-related targets were obtained from GeneCards and OMIM databases. A Venn diagram generated from these datasets highlighted overlapping targets. Protein-protein interaction networks were constructed using the STRING database and Cytoscape software to assess target importance. GO and KEGG enrichment analyses using the Metascape database revealed relevant biological functions and signaling pathways of SB216763 in the treatment of pulmonary fibrosis. Molecular docking investigated the binding affinity and binding mode of SB216763 with GSK-3β. Molecular dynamics simulations further confirmed the stability of the complex formed by SB216763 and GSK-3β. Finally, Western blotting, Griess assays, and ELISA were employed to validate the effect of SB216763 on macrophage functional plasticity in pulmonary fibrosis. RESULTS Network pharmacology analysis identified the following three key targets of SB216763 in pulmonary fibrosis: AKT1, GSK3B, and TGFBR1, along with the PI3K-AKT signaling pathway. Molecular docking and dynamics simulations revealed that SB216763 primarily interacts with GSK-3β through hydrogen bonds and hydrophobic interactions. In vitro validation demonstrated significant anti-inflammatory and antifibrotic effects of SB216763. Additionally, SB216763 exhibited good safety in macrophages. CONCLUSIONS This study provided new insights into the mechanisms of SB216763 in the treatment of pulmonary fibrosis.

Network pharmacology, molecular docking, and dynamics to explore the pharmacodynamic components and mechanism of epimedium in treating skeletal diseases

Periodontitis, chronic osteomyelitis of the jaw, and osteoporosis are etiologically distinct disorders but share persistent inflammation, impaired bone remodeling, and progressive bone loss. Epimedium brevicornum Maxim. has been widely used in traditional Chinese medicine for bone-related conditions; however, its shared mechanisms across these bone-destructive diseases remain insufficiently defined. This study integrated network pharmacology, molecular docking, and molecular dynamics simulations to identify potential active compounds, targets, and pathways of Epimedium. Twenty-three active compounds were screened from Epimedium, and 539 drug-related targets were obtained. A total of 966 disease-related targets were collected from public databases, yielding 160 overlapping targets. Protein-protein interaction analysis identified JUN, TNF, IL6, and TP53 as candidate hub genes. GO and KEGG analyses suggested that the common targets were mainly associated with inflammatory regulation, stress response, immune activation, and bone-homeostasis-related signaling. In the compound-target-pathway-disease network, quercetin, kaempferol, luteolin, genistein, and anhydroicaritin showed high connectivity. Molecular docking indicated favorable binding of quercetin and kaempferol with the hub proteins, with binding energies below -5.0 kcal/mol. A 50 ns molecular dynamics simulation further suggested stable TNF-quercetin and TP53-kaempferol complexes, with RMSD values remaining approximately 0.16-0.20 nm. These findings provide a computational basis for the hypothesis that Epimedium may modulate shared inflammatory and bone-remodeling networks in these diseases, which requires further experimental validation.

Synergistic effect of resveratrol and curcumin against doxorubicin-induced cardiac injury: Network pharmacology, molecular mechanisms and in-vivo evidence

To evaluate the cardioprotective effects of resveratrol and curcumin, individually and in combination, against doxorubicin- induced cardiac toxicity and explore the underlying mechanisms via network pharmacology. In silico target prediction, enrichment analyses, and Cytoscape network modeling were performed to investigate shared molecular targets and pathways among resveratrol, curcumin and doxorubicin. Male Wistar rats ( n =6/group) received oral treatments of vehicle, nebivolol (5 mg/kg), resveratrol (20 mg/kg), curcumin (100 mg/kg), resveratrol plus curcumin for 28 d, with cardiotoxicity induced via doxorubicin (2.5 mg/kg, i.p .) on days 7 and 14. Cardioprotection was evaluated using electrocardiographic, hemodynamic, biochemical, RT-PCR, and histopathological assays. Network analysis revealed four common targets (NFE2L2/ Nrf2, TNF, CYP3A4, and MAPT) with significant protein-protein interaction enrichment ( P =0.019 6), implicating modulation of redox balance, inflammation, and xenobiotic metabolism. Concomitant therapy with resveratrol and curcumin significantly mitigated doxorubicin-induced cardiac injury by suppressing relative heart weight, reducing myocardial infarction area, reversing electrocardiographic and conduction abnormalities, attenuating dyslipidemia, and lowering serum CK-MB, LDH, and troponin I leakage ( P < 0.05). Furthermore, combination treatment was more effective in restoring cardiac antioxidants, decreasing lipid peroxidation, downregulating mRNA expressions of TNF-α and NF-κB , upregulating Nrf2 mRNA expression, and improving myocardial architecture compared with individual monotherapies. Concomitant therapy with resveratrol and curcumin confers robust cardioprotection against doxorubicin-induced cardiotoxicity in rats, likely via coordinated activation of Nrf2- mediated antioxidant defenses and suppression of TNF-α/NF- κB-driven inflammation, supporting their potential for future investigation as adjunct therapies during anthracycline treatment.