Multi-target Mechanism Research Articles (Page 3)

Astaxanthin mitigates dibutyl phthalate-induced thyroid hormone disruption in zebrafish larvae via multi-target regulation.

Osteoporosis (OP) has imposed a heavy burden on global health. Current treatments often come with side effects, which has spurred interest in dietary bioactive compounds with preventive potential. Flavonoids, typical representatives of both medicine and food, possess nutritional and pharmacological properties related to bone health. However, the key active components and mechanisms of action of their anti-OP effects still require systematic research. Data from the National Health and Nutrition Examination Survey and the Food and Nutrient Database for Dietary Studies were integrated. The flavonoid intake and OP status of 5789 American adults (aged ≥50) were analyzed. Five machine-learning algorithms (Boruta, LassoCV, RFECV, mRMR, and ReliefF) were employed to screen flavonoid sub-classes, followed by ADMET (absorption, distribution, metabolism, excretion, toxicity) analysis. The XGBoost model was used to predict the risk of OP and was validated through the area under the receiver operating characteristic curve and SHapley Additive exPlanations analysis. Network pharmacology was used to identify the common targets of OP and flavonoids, and the binding stability was verified by molecular docking and molecular dynamics simulation. Eleven key flavonoids were identified by machine learning. Five compounds with high bioavailability and low toxicity were prioritized through ADMET screening: daidzein, quercetin, catechin, apigenin, and kaempferol. Five core targets related to the pathogenesis of OP were identified through network pharmacology and protein-protein interaction network: signal transducer and activator of transcription 3, estrogen receptor 1, carbonic anhydrase 2, androgen receptor (AR), and estrogen receptor 2. Molecular docking confirmed strong binding between the 5 screened flavonoids and the core targets, especially the binding between apigenin and AR. Molecular dynamics simulation further indicated excellent stability of the AR-apigenin complex. Daidzein, quercetin, catechin, apigenin, and kaempferol may inhibit bone resorption and promote bone formation by regulating signal transducer and activator of transcription 3, estrogen receptor 1, carbonic anhydrase 2, AR, and estrogen receptor 2. The high stability of the AR-apigenin complex supports the potential of flavonoids as therapeutic agents for OP through a multi-target mechanism and their value in nutritional intervention.

Traditional Chinese medicine, especially Bushen Huoxue decoction, has demonstrated good therapeutic effects in the treatment of intervertebral disc degeneration and osteoarthritis, but its mechanism of action in osteoporosis remains unclear. This study aimed to explore its potential mechanisms against osteoporosis. Active components of Bushen Huoxue decoction were identified through searching the TCM databases. Osteoporosis-related genes were retrieved from three disease databases. Common targets were used to construct a PPI network. Functional enrichment analyses (GO and KEGG), molecular docking, molecular dynamics simulations, and literature validation were performed. A total of 112 active compounds and 343 potential targets were identified. Key bioactive ingredients included quercetin, luteolin, kaempferol, wogonin, and baicalein. The decoction appeared to act via multiple pathways, such as TNF, NF-κB, MAPK, PI3K/Akt, Wnt/β-catenin, HIF-1, FoxO, AMPK, mTOR, and VEGF, affecting inflammation, metabolism, cell proliferation, survival, and angiogenesis. Bushen Huoxue decoction likely exerted anti-osteoporotic effects through a multi-component, multi-target, and multi-pathway approach, consistent with current understanding of osteoporosis mechanisms. However, as this study was based on network pharmacology and computational analysis, experimental validation is needed. Bushen Huoxue decoction showed promise as a potential treatment for osteoporosis through complex regulatory mechanisms. The findings provided a theoretical basis for further pharmacological research and TCM-based drug development.

Osteoarthritis (OA) is widely recognized as a common degenerative joint disease that imposes a significant burden on patients and society. Gujian Tiaosui Decoction (GTD), an empirical formula from Zhejiang Provincial Hospital of Traditional Chinese Medicine, has demonstrated clinical efficacy in treating OA. However, the therapeutic mechanisms underlying GTD’s effects on OA remain unclear. Potential targets of GTD and OA-related targets were identified using the TCMSP, OMIM, and GeneCards databases. A visual network of “GTD–compounds–key targets–pathways–OA” was constructed. Gene ontology and Kyoto encyclopedia of genes and genomes analyses were performed to explore biological processes and pathways. Key targets were further screened using Mendelian randomization and expression analyses. Molecular docking was conducted between key bioactive compounds and targets to identify signaling pathways and proteins associated with GTD’s therapeutic effects on OA. A total of 160 compounds with 575 unique targets related to GTD were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and 185 overlapping targets between GTD and OA were identified. Protein–protein interaction network analysis revealed core targets including AKT serine/threonine kinase 1, hypoxia-inducible factor-1α (HIF1A), estrogen receptor 1, SRC proto-oncogene, non-receptor tyrosine kinase, epidermal growth factor receptor, mitogen-activated protein kinase 3, matrix metalloproteinase 9, and signal transducer and activator of transcription 3. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses indicated that relevant biological processes involved in GTD’s anti-OA effects may include inflammatory response, positive regulation of protein kinase B signaling, protein phosphorylation, integral component of membrane, and protein serine/threonine/tyrosine kinase activity. Mendelian randomization analysis suggested a positive causal relationship between OA and 2 genes: HIF1A and IMPDH2. Molecular docking of 5 active ingredients with HIF1A and inosine-5′-monophosphate dehydrogenase 2 showed strong binding affinity. This study reveals the multicomponent, multi-target, and multi-pathway mechanism of GTD in the treatment of OA, providing a foundation for further experimental validation and suggesting new research directions.

This study investigates the multi-target mechanisms of Atractylodes macrocephala (AM) and its main active component, Atractylenolide III (ATR-III), in mitigating central nervous system (CNS) inflammatory responses in pediatric epilepsy via modulation of the nuclear factor kappa-B (NF-κB) signaling pathway. Network pharmacology identified AM’s active components and their targets, which were integrated with pediatric epilepsy-related targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed potential mechanisms, while molecular docking assessed the binding capacity of ATR-III to key targets. In vitro, an LPS-induced microglial inflammation model was used, with CCK-8 assays, Western blot, qPCR, and JC-1 staining evaluating ATR-III’s effects on cell viability, NF-κB activation, inflammatory cytokine expression, and mitochondrial function. Network pharmacology showed AM’s targets overlap with pediatric epilepsy targets, enriched in neuroinflammation pathways. Molecular docking confirmed ATR-III’s strong binding to NF-κB targets. In vitro, ATR-III significantly suppressed NF-κB activation, reduced p65 and IκBα phosphorylation, decreased inflammatory cytokines, and improved LPS-induced mitochondrial dysfunction by restoring membrane potential and upregulating PGC-1α and COX4. This study elucidates AM and ATR-III’s mechanisms in reducing CNS inflammation and improving mitochondrial function, offering a theoretical basis for AM’s use in pediatric epilepsy and highlighting ATR-III’s potential as a natural anti-inflammatory drug.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-19492-8.

ObjectiveAnemarrhenae Rhizoma (AR) is a traditional Chinese medicine widely used for the treatment of type 2 diabetes mellitus (T2DM). However, the specific bioactive constituents responsible for its in vivo effects and their underlying mechanisms of action remain unclear. We hypothesise that serum-absorbed and metabolised AR components modulate key metabolic and inflammatory pathways in T2DM. To test this hypothesis, this study employs an integrated strategy combining metabolomics with serum-urine pharmacochemistry and network pharmacology to systematically identify AR’s active constituents and elucidate their multi-target mechanisms in T2DM management.MethodsUHPLC-Q-TOF-MS coupled with multivariate statistical analysis was employed to identify the AR-derived constituents in serum and urine of T2DM rats. Network pharmacology was utilised to predict the targets of the AR’s active components, while biochemical assays, liver histopathology, and metabolomics were performed to evaluate its therapeutic effects. Molecular docking and molecular dynamics (MD) simulations were conducted to assess the binding affinities between key components and their targets.Results77 AR components were identified, among which 47 prototypes and 11 metabolites were detected in serum and urine. The key bioactive constituents included sarsasapogenin, markogenin/neogitogenin, digitogenin, norathyriol, and mangiferin. AR treatment significantly reduced blood glucose and lipid levels, ameliorated insulin resistance, attenuated inflammation, and modulated the PPAR and NF-κB signalling pathways. Serum metabolomics analysis revealed 35 differential metabolites, with linoleic acid metabolism and PPAR signalling identified as the predominant metabolic pathways. Molecular docking and MD simulations demonstrated strong binding affinity between core components and key targets (PPARA, NFKB1, IL6, AKT1, IL1B). Pharmacological validation confirmed AR’s therapeutic efficacy in T2DM through regulation of these core targets.ConclusionAR ameliorates T2DM by suppressing NF-κB signalling and activating PPAR pathways, thereby improving metabolic dysregulation.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine-metabolic disorder affecting reproductive-aged women and is characterized by hyperandrogenemia, ovulatory dysfunction, and polycystic ovaries. Astragaloside IV (AS-IV), an active compound derived from Astragalus membranaceus, shows promise in the treatment of metabolic disorders. However, the precise molecular targets and mechanisms of action in PCOS remain unclear. This study aimed to elucidate the therapeutic effects and underlying mechanisms of AS-IV in PCOS. AS-IV's therapeutic effects of AS-IV were assessed in a rat model of PCOS. Potential AS-IV targets were predicted using the PharmMapper and SwissTargetPrediction databases and expanded using STRINGdb. PCOS-related differentially expressed genes (DEGs) were identified from Gene Expression Omnibus (GEO)datasets, and weighted gene co-expression network analysis (WGCNA) revealed the disease-associated gene modules. Overlapping drug-disease targets were analyzed using protein-protein interaction (PPI) network, Gene Ontology (GO), and KEGG pathway enrichment. The core targets were validated using molecular docking. In vitro, qPCR was used to assess key gene expression in the control, DHT model, AS-IV, EP300 inhibitor (C646), and Nrf2 inhibitor (ML385) groups. A total of 371 potential AS-IV targets were identified. Analysis of GEO data yielded 2286 DEGs, with WGCNA identifying key PCOS-related modules and hub genes. The intersection revealed 31 key targets, including five core genes. In vivo, AS-IV improved ovarian pathology, increased antioxidant enzyme levels, reduced inflammatory cytokine, testosterone, and LH levels, and increased estradiol levels. In vitro, the PCOS, EP300, and Nrf2 inhibitor groups showed decreased EP300, NFE2L2, HMOX1, and AKT1 expression and increased MMP9 expression compared to the controls and AS-IV group. AS-IV ameliorated endocrine and ovarian abnormalities in PCOS by modulating the EP300/Nrf2/HMOX1/MMP9 axis, demonstrating multi-target antioxidant, anti-inflammatory, and hormone-regulatory effects, supporting its potential as a therapeutic agent for PCOS.

IntroductionColorectal carcinoma (CRC) is a leading cause of gastrointestinal malignancy worldwide. Its development is closely linked to aberrant activation of NF-κB and Akt signaling pathways. This study aimed to evaluate the inhibitory effects of Compound Sini Decoction (SND), a traditional Chinese medicine, on CRC and clarify its molecular mechanisms.MethodsAn AOM/DSS-induced mouse CRC model was used to assess the in vivo effects of SND. Network pharmacology identified potential targets, while molecular docking and kinetic simulations evaluated binding interactions. In vitro, SND-containing mouse serum was applied to HCT116 and SW480 cells to examine proliferation, migration, apoptosis, ROS production, and signaling pathway modulation.ResultsSND significantly reduced tumor burden, alleviated symptoms, and decreased body weight loss in mice. Network analysis highlighted NFKB1, CASP3, and AKT1 as key targets, suggesting regulation of NF-κB, Caspase-3, and Akt pathways. In vitro, SND inhibited cell proliferation and migration, induced apoptosis, promoted ROS accumulation, suppressed NF-κB and AKT1 phosphorylation, and enhanced CASP3 cleavage. Molecular docking showed Glyuranolide had the strongest binding affinity, particularly with NFKB1 and AKT1, indicating it as a likely effector compound.ConclusionSND exerts anti-CRC effects through multi-target synergistic mechanisms involving NF-κB/Akt signaling and Caspase-3-mediated apoptosis. Glyuranolide may represent its key active molecule. These findings provide preliminary evidence supporting SND or its derivatives as potential candidates for precision CRC therapy and suggest a strategy to overcome resistance to single-target treatment. Further studies are warranted to confirm the clinical translational value of SND and the specific role of Glyuranolide.

Intervertebral disc degeneration (IVDD) serves as a central pathological mechanism in the development of spinal degenerative disorders. Its progression is closely associated with the dysregulated activation of various programmed cell death (PCD) pathways, including apoptosis, pyroptosis, necroptosis, ferroptosis, and autophagy. Recent investigations have highlighted the potential of natural products to modulate these cell death processes through multitarget mechanisms, making them promising candidates for IVDD intervention. In this study, a comprehensive literature search was conducted using the PubMed database (up to 2025), applying a dual search strategy to systematically identify relevant publications. Following the screening of titles and abstracts and the removal of non-original publications, a total of 194 eligible studies were retained, covering 134 distinct natural products. The analysis revealed that these products are capable of targeting multiple PCD pathways in intervertebral disc cells and exhibit considerable therapeutic potential. These findings offer a theoretical framework and methodological reference for the development of novel treatments for IVDD. Nevertheless, limitations remain regarding natural products, particularly in terms of bioavailability and safety. Future efforts should focus on optimizing screening platforms and drug delivery strategies to enhance therapeutic efficacy while minimizing potential toxicity.

Revolutionizing pharmacological research of traditional Chinese medicine with single-cell omics technologies.

Mechanistic insights into Shengxian Sanren granules' effects on chronic heart failure: A synergistic study of UPLC-Q-TOF-MS/MS and network pharmacology.

UPP1 as a Potential Target for Astilbin in Ameliorating High-Fat Diet-Induced Bone Loss via MAPK Signaling: A Study Incorporating Gut Microbiota and Metabolomics.

Fetal therapies in congenital diaphragmatic hernia: a review of possibilities and practical challenges.

Psoralen alleviates ulcerative colitis by suppressing inflammation, modulating oxidative stress, and regulating ferroptosis.

Network Pharmacology and In Vivo Evaluation of Lycium barbarum Polysaccharide in Preventing Perfluorooctanoic Acid-Induced Damage in Broilers.

Unveiling the mechanisms of Inonotus hispidus against polycystic ovary syndrome: An integrated metabolomics and network pharmacology approach in vivo and vitro.

This study aimed to explore the potential target and molecular mechanism of Eclipta prostrata L-Ligustrum Lucidum Ait (EPL-LLA) in the treatment of periodontitis by using network pharmacology and molecular docking technology, and to explore its biocompatibility, regulatory effects on inflammatory factors, and antioxidant acti-vity through in vitro experiments. The active components and potential targets of EPL-LLA were screened and predicted through a variety of databases, and the intersection of EPL-LLA and periodontitis targets was selected. The protein interaction network (PPI) was analyzed by the string platform. The Metascape database was used for gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. The active ingredients from the top 6 degrees were docked with the core targets, and the results of binding energy were visualized. An in vitro cell model was established to evaluate the biocompatibility, modulation of inflammatory factors, and antioxidative effects of EPL-LLA through cell counting kit-8 (CCK-8), quantitative real-time polymerase chain reaction (qRT-PCR) and 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe assays. Screening revealed 13 active components in EPL corresponding to 220 potential targets, 10 active components in LLA corresponding to 283 potential targets, and 1 643 periodontitis-related targets, with 91 shared targets among the three. GO analysis of the shared targets yielded 5 271 entries, while KEGG enrichment analysis indicated involvement in 253 signaling pathways. Molecular docking confirmed stable binding between the top 6 active components and core targets. CCK-8 assays demonstrated good biocompatibility of EPL-LLA at concentrations 0.02 mg/mL (P<0.05). qRT-PCR showed that EPL-LLA reduced the mRNA expression of pro-inflammatory factors in macrophages stimulated by Porphyromonas gingivalis lipopolysaccharide while upregulating anti-inflammatory factor mRNA expression (P<0.05). DCFH-DA fluorescence probe assays confirmed the reactive oxygen species (ROS)-scavenging capacity of EPL-LLA (P<0.05). EPL-LLA may treat periodontitis through multi-component, multi-target, and multi-pathway mechanisms, providing a theoretical basis for further research on its therapeutic potential.

Applying click chemistry to discover the direct targets of the active components of traditional Chinese medicines.

The swift emergence of multidrug- and highly drug-resistantstrainsof Mycobacterium tuberculosis (Mtb)makes it essential to develop new agents with varied chemical structuresand multitarget mechanisms of action. In the current investigation,we have designed and synthesized 24 novel heterocyclic ring-substituted1,3,4-thiadiazole (5a-l) and 1,2,4-triazole (6a-l) hybrids to be testedagainst the H37RV strain of M. tuberculosis. Compounds 5b, 5d, 5e, 5f, 6b, 6c, 6d, and 6f showed good to moderateeffectiveness against tuberculosis, with minimum inhibitory concentration(MIC) values ranging from 4 to 64 μg/mL. Compounds 5b and 6bdisplay an MIC value of 4 μg/mL, suggesting significant antitubercularpotential and warranting further exploration as effective antitubercularagents. The chemical structures of the synthesized compounds weredetermined through spectral techniques (Fourier transform infrared(FT-IR), NMR {1H, 13C}, and mass spectroscopy).The molecular docking analysis shows that these compounds can successfullybind to the active site of the five most promising proteins for treatingtuberculosis. ADME-T, molecular dynamics (MD) simulation, and DensityFunctional Theory (DFT) analysis confirm that these compounds havegood drug-like properties and remain stable in the binding sites ofthe selected target proteins. We assessed the cytotoxicity of thechosen compounds. According to the findings, this research thoroughlyindicated that these newly created derivatives could serve as promisingand effective multitargeted antitubercular agents.

Mechanistic study of the novel peroxidase mimetic DhHP-6 in metabolic cataracts.