Multi-target Mechanism Research Articles (Page 1)

Puerarin demonstrates therapeutic potential in alleviating chronic postoperative pain (CPSP) through multi-target mechanisms. While previous studies established its ferroptosis-inhibiting and anti-inflammatory properties via lipid peroxidation reduction and iron-mediated apoptosis regulation, its specific efficacy in CPSP remained unexplored. This study integrated network pharmacology with experimental validation using a skin/muscle incision-retraction (SMIR) rat model. Protein-protein interaction network analysis, Gene Ontology annotation, and KEGG pathway enrichment revealed puerarin's dual action pathway: modulating Th17 cell differentiation and regulating the HIF1 signaling axis. Molecular docking confirmed high-affinity binding between puerarin and five core targets: HIF1A, PTGS2, mTOR, RELA, and GSK3β. In vivo validation showed puerarin significantly elevated mechanical pain thresholds in SMIR rats while downregulating mRNA expression of these targets via qPCR. The compound's multimodal mechanism involves coordinated suppression of inflammatory signaling cascades and hypoxia-responsive pathways. These findings establish a robust methodology combining computational prediction with biological validation for herbal compound research.

Morphine remains a first-line analgesic for both acute and chronic pain. However, its prolonged use often results in the development of tolerance, diminishing its analgesic efficacy and limiting its long-term clinical utility. Emerging evidence highlights the pivotal role of microglial activation in the central nervous system as a key contributor to morphine tolerance. Phytochemicals, natural metabolites derived from plants, have garnered attention for their multi-target mechanisms, low toxicity, and broad biological activities, positioning them as promising candidates for mitigating morphine tolerance. This review systematically explores the key receptors and signaling pathways involved in microglial activation during morphine tolerance, and elucidates how various phytochemicals modulate these pathways to attenuate tolerance. Furthermore, it discusses the translational challenges associated with phytochemical-based interventions and outlines future directions for their clinical application. The aim is to provide a theoretical framework to support translational research and the development of novel adjunct therapies for opioid analgesia.

The central nervous system is a highly complex and specialized network that regulates essential physiological and behavioral functions. Owing to its limited regenerative capacity, it is particularly susceptible to pathological insults such as trauma, ischemia, and neurodegenerative diseases. In this sense, the search for effective therapies to prevent and repair damage to this system remains a major biomedical challenge. The present study comprises a comprehensive literature search conducted in PubMed database, covering peer-reviewed articles published in English between January 2015 and May 2025. The search combined the reference term "natural compounds" with the keywords "central nervous system, oxidative stress, neuroinflammation, regeneration, and neuroprotection," employing the Boolean operator "AND." Articles were selected according to their relevance to the scope of this work, encompassing both original experimental studies (in vivo and in vitro) as well as literature reviews. Natural compounds derived from plants, fungi, and other biological sources exhibit promising neuroprotective and regenerative properties by modulating multiple cellular and molecular pathways. Key classes of bioactive compounds, such as polyphenols, terpenes, saponins, and alkaloids, as well as standardized plant extracts, are highlighted, emphasizing their multitarget mechanisms and translational potential. These include enhancement of antioxidant defenses (nuclear factor erythroid 2-related factor 2/antioxidant response element), suppression of inflammatory signaling (nuclear factor-kappaB), regulation of apoptosis (Bcl-2 and caspases), promotion of neurotrophic activity (brain-derived neurotrophic factor and nerve growth factor), and restoration of autophagic flux (mammalian target of rapamycin and AMP-activated protein kinase). Current challenges, such as low bioavailability and scarcity of high-quality clinical validation, are also discussed, alongside future perspectives for incorporating natural compounds into central nervous system-directed therapeutic strategies. Altogether, the present work underscores the potential of natural agents to promote neuroprotection and regeneration and supports further investigation into their clinical applicability.

Electrochemical monitoring of TMZ derivative release from a novel chitosan-modified polymeric carrier for targeted glioma therapy

Background Osteoporosis (OP), as a systemic bone disorder, has a complex pathogenesis and faces significant challenges in clinical treatment. Oligomeric proanthocyanidin (OPC), a type of natural polyphenolic flavonoid compound, demonstrates outstanding therapeutic potential due to its excellent antioxidant and anti-inflammatory properties and good safety. The breakthrough advances in single-cell RNA sequencing (scRNA-seq) technology have provided a powerful research tool for elucidating the multitarget mechanisms of OPC in the treatment of OP. Methods This study first screened the active components of OPC leveraging the TCMSP database. The protein–protein interaction network of OPC target proteins was generated through the STRING database, and visual analysis was accomplished using the Cytoscape software. The ClusterProfiler R package and ClueGO plugin were employed for functional enrichment analysis and network visualization. At the same time, scRNA-seq data from the GEO database were integrated, and cell-type identification was attained using the Seurat tool. The differentiation trajectories of subtypes were inferred using Monocle and Slingshot software. The cell communication network was analyzed using CellChat. Results This study utilized scRNA-seq to identify C2 NR4A1 + MSCs with distinct metabolic features and differentiation potential in the bone microenvironment during the early stage of OP, namely, osteopenia. The natural component OPC can precisely target this subtype and exert therapeutic effects through two mechanisms: inhibiting the transcriptional activity of NR4A1 to suppress the expression of PTGS2 in MSCs and simultaneously activating the β-catenin-dependent NR4A1 – Runx2 signaling axis to promote osteogenesis and inhibit osteoclastogenesis. These findings establish a new therapeutic paradigm of “targeting cell subtypes–multipathway regulation,” providing an important basis for the development of novel anti-OP drugs. Conclusion Our research integrated multilevel approaches, including single-cell transcriptomics, network pharmacology, cellular experiments, and animal models, to systematically reveal the dual mechanism of OPC in treating OP. This discovery not only established C2 NR4A1 + MSCs as key mediators in the pathological process of OP but also clarified the molecular mechanism of multitarget synergy of natural active compounds in restoring bone homeostasis, providing a theoretical basis and practical guidance for the development of new OP therapies.

2,4-Dichlorophenoxyacetic acid (2,4-D) is a widely used herbicide, yet its potential to induce hepatorenal injury via oxidative stress and apoptosis raises significant health concerns. Lycium barbarum polysaccharides (LBP) possess recognized antioxidant and anti-apoptotic properties, but their protective mechanisms against 2,4-D toxicity, particularly through a multi-target network, remain inadequately explored. This study aimed to systematically investigate the mechanisms of 2,4-D-induced hepatorenal injury and the protective efficacy of LBP by integrating network toxicology, molecular docking, and experimental validation. An integrated approach was employed. Core targets and pathways were identified via network toxicology. Molecular docking predicted interactions between 2,4-D and these targets. In vivo validation was conducted on Sprague-Dawley rats treated with 2,4-D (75 mg/kg) and/or LBP (50 mg/kg) for 28 days, assessing histopathology, serum oxidative stress markers superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA) and cellular apoptosis (TUNEL staining). Network analysis identified PPARG, NFKB1, PPARA, NFE2L2, and SERPINE1 as core targets, with molecular docking confirming strong binding affinities (binding energies: −5.1 to −6.3 kcal·mol−1) and KEGG enrichment implicating cAMP, Ca2+, and PPAR signaling pathways. Experimentally, 2,4-D exposure induced significant histopathological damage, suppressed SOD/GSH-Px activities (p < 0.001), elevated MDA levels (p < 0.001), and markedly increased renal apoptosis (p < 0.01). Crucially, LBP intervention substantially mitigated these alterations, ameliorating tissue injury, restoring antioxidant defenses, increasing SOD/GSH-Px (p < 0.01), reducing MDA (p < 0.001) and significantly decreasing renal apoptosis (p < 0.05). This study elucidates a multi-target mechanism for 2,4-D-induced hepatorenal injury centered on oxidative stress–apoptosis dysregulation and demonstrates that LBP confers significant protection likely via modulation of this network. These findings underscore the potential of LBP as a natural protective agent against pesticide-induced organ damage and highlight the utility of integrated network approaches in toxicological research.

Jinzhen oral liquid in pediatric respiratory diseases: Multi-Target mechanisms, quality control, and clinical translation

Intelligent technology leads the transformation of traditional Chinese medicine: Large models and virtual cells aid modern analysis of stroke treatment.

The multifaceted mechanism of action of quinoline thiosemicarbazone based on disruption of iron homeostasis and selective IGF1R inhibition leading to oxidative stress induction.

Methyl-2,4-dihydroxybenzoate induces transcriptomic reprogramming in Fusarium oxysporum f. sp. cubense and defense gene responses in Kadali banana.

The rising global obesity rates and related health problems have led to more studies focusing on dietary interventions. Anthocyanins have become a subject of great interest as a bioactive compound. This study employs a comprehensive bibliometric analysis of 945 publications from the Web of Science Core Collection (WoSCC) (2003-2024) to map the evolving research landscape linking anthocyanins to obesity management. Analysis using VOSviewer, CiteSpace, and R-bibliometrix revealed a substantial increase in the cumulative number of publications in the field, with the USA and China dominating in terms of research output. Keyword analysis identified current main research themes in the field: “anthocyanins”, “obesity”, “insulin resistance”, “oxidative stress” and “antioxidant activity” reflecting current mechanistic investigations into metabolic regulation and inflammatory pathways. The focus of research has shifted from initial compositional studies to molecular mechanisms and interactions, including intestinal flora regulation, metabolic and inflammatory regulation. This reveals a shift in research trends from phenomenal observations to precise interventions. Emerging frontiers emphasize interdisciplinary integration. In the future, anthocyanin and obesity research is expected to advance precision nutrition strategies as disciplines such as metabolomics and genetic engineering are integrated. Anthocyanin-rich formulations are expected to be adjunctive therapeutic agents for personalized obesity therapies. This highlights the dual role of anthocyanins as functional food ingredients and therapeutic agents. At the same time, it also maps out the critical path for future research including bioavailability optimization and the clinical validation of multi-target mechanisms. These findings provide new ideas and insights for interdisciplinary collaboration and innovation in the development of functional foods for metabolic health.

Breaking barriers in antimicrobial therapy: resistance mechanisms and novel antimicrobial strategies.

Osteomyelitis is a severe bone infection caused by bacterial pathogens, involving inflammation and tissue destruction. Shikonin, a naphthoquinone compound extracted from the traditional Chinese medicinal herb Lithospermum erythrorhizon, exhibits anti-inflammatory, antibacterial, antitumor, and wound-healing properties. Nonetheless, the efficacy and specific mechanisms of shikonin in treating osteomyelitis remain unexplored. In this study, the potential mechanism of shikonin in the treatment of osteomyelitis was systematically explored using network pharmacology, molecular docking, molecular dynamics simulation, and experimental validation in a Staphylococcus aureus (S. aureus) -induced mouse osteomyelitis model. Microcomputed tomography and Hematoxylin-Eosin staining demonstrated that shikonin alleviated bone destruction and inflammatory infiltration. Through network pharmacology, eight potential core targets of shikonin were identified: MET, MMP9, EGFR, SRC, PTGS2, CASP3, MMP2, and CCND1. Molecular docking and dynamics simulations indicated that shikonin had high binding affinity and stable interactions with MET, MMP9, and EGFR, with binding energies of -9.18kcal/mol, -9.73kcal/mol, and -9.58kcal/mol, respectively. Furthermore, Western blot analysis confirmed that shikonin significantly downregulated the expression of MMP9 and EGFR. KEGG enrichment analysis suggested that shikonin may exert anti-inflammatory and antibacterial effects via pathways such as PI3K-Akt, VEGF, chemokine, and Toll-like receptor signaling. These findings reveal the multi-target mechanism of shikonin against osteomyelitis and provide a theoretical basis for its further therapeutic development.

Exercise and the blood-brain barrier: Mechanistic insights and therapeutic implications.

Unraveling the active ingredients and molecular mechanisms of Qinghua Changyan granule against irritable bowel syndrome with diarrhea: Effects on gut microbiota and glutamine transport via an integrative approach combining UHPLC-MS/MS and experimental verification.

iCAM-Net: Interpretable herb-disease association prediction via cross-channel attention and molecular interaction signals.

Bridging traditional knowledge and modern science: A systematic review of Ampelopsis japonica with emphasis on novel anti-cancer compounds, polypharmacology and clinical translation potential.

BackgroundOxidative stress has been firmly established as a pivotal contributor to the pathogenesis of inflammatory bowel disease, diabetes mellitus, Alzheimer’s disease, and other multifactorial disorders. Our previous findings have demonstrated the extracts from Sonchus brachyotus DC. (SBE) mitigates intestinal oxidative stress through interactions between the oxidative stress biomarkers and gut microbiota. However, we did not focus on the mechanism by which SBE exerts antioxidant stress effects through regulating metabolites and genes, nor the correlation between the two and gut microbiota. Therefore, this study aimed to elucidate the underlying mechanism by which SBE mitigates oxidative stress through the gut microbiota, metabolites, and genes.ResultsSupplementation with SBE exerts a promising regulatory effect on oxidative stress by modulating key oxidative stress biomarkers (e.g., GSH, SOD, etc.) in serum, intestine, liver, and brain tissues in ethanol-model mice. And the SBE treatment exhibited a notable reparative effect on intestine, liver, and brain tissue damage. Concomitantly, 16S rRNA and ITS sequencing revealed significant alterations in the composition of intestinal bacteria and fungi in SBE-treated mice, suggesting the restoration of gut microbiota homeostasis. Spearman correlation analysis further indicated significant associations (p < 0.05) between gut microbes, particularly fungal genera, and oxidative stress biomarkers. Notably, the abundance of specific fungal genera (Alternaria and Pichia), the levels of 14,15-DiHETrE, 5-Hydroxyindole-3-acetic acid, and prostaglandin C2 key metabolites of the serotonergic synapse pathway, and the expression of Fas and Tnfsf10 key genes of apoptosis signaling pathway were significantly correlated (p < 0.05) based on the constructed correlation network. This mechanism likely triggers coordinated changes in metabolites and gene expression associated with the serotonergic synapse and apoptosis signaling pathways, ultimately leading to multi-targeted amelioration of oxidative stress. Molecular docking further revealed that trigonelline, mesaconic acid, and salicylic acid, bioactive components of SBE, may exhibit considerable binding affinity with Fas and Tnfsf10, providing a potential structural basis for SBE’s regulatory effects on oxidative stress via modulation of the apoptotic signaling.ConclusionsThe antioxidant effects of SBE likely involve multi-pathway and multi-target mechanisms, consistent with the combinatorial properties of its herbs constituents. These findings lays a foundation for subsequent research.Video Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s40168-025-02221-8.

Gleditsia sinensis Fructus (GSF) exhibits anti-cancer activity and is effective against lung adenocarcinoma (LUAD). However, its underlying mechanisms remain unclear. In this study, the potential chemical components, targets, and pathways of GSF in treating LUAD were investigated using UHPLC-HRMS combined with network pharmacology analysis. These findings were subsequently verified via molecular docking, molecular dynamics simulation, and in vitro cell experiments. The results showed that a total of 61 components targeting 192 LUAD-related genes were identified, and 177 candidate targets of GSF against LUAD were obtained, among which AKT1, SRC, EGFR, IL6, and TNF may be the core targets. Enrichment analysis revealed that the mechanisms were related to various cancer-related pathways, particularly the PI3K-AKT signaling pathway. Molecular docking demonstrated that the active components of GSF, particularly luteolin, exhibited excellent binding affinity to the top five core targets. Molecular dynamics simulation results showed a similar trend. Therefore, we identified luteolin as the primary active component of GSF. The cell experiments revealed that luteolin significantly inhibited cell growth and proliferation and promoted the apoptosis of A549 cells, exhibiting effects similar to those of cisplatin. In addition, luteolin significantly upregulated the expression of Bax and cleaved-caspase3 and decreased the expression of P-AKT and BCL2. Our results demonstrate that GSF can exert anti-LUAD effects through multi-components, multi-targets, and multi-pathways. Luteolin, one of the main active components of GSF, suppressed proliferation and induced apoptosis in A549 cells, possibly through inhibiting the AKT signaling pathway.

Diabetic cardiomyopathy (DCM), a global cardiovascular complication of diabetes, is characterized by concurrent diastolic and systolic ventricular dysfunction that progressively leads to heart failure, arrhythmias, and cardiogenic shock. Despite advancements in modern therapeutics, DCM continues to exhibit high mortality rates, underscoring the critical need for novel preventive and therapeutic strategies. In recent years, Traditional Chinese Medicine (TCM) has gained prominence in DCM management due to its established safety profile and emerging evidence of clinical efficacy. Current research focuses on elucidating TCM's multi-target mechanisms, particularly its regulatory effects on metabolic homeostasis, oxidative stress, and inflammatory pathways - key pathological processes in DCM progression. This review systematically investigates the latest advancements in TCM for DCM management through three principal dimensions: First, it synthesizes the etiological understanding of DCM from both TCM theory and modern medical perspectives, highlighting their complementary mechanisms in disease pathogenesis. Second, it critically evaluates the therapeutic potential of clinically validated Chinese herbal agents, focusing on their bioactive compounds that target myocardial energy metabolism and oxidative stress pathways. Third, it systematically summarizes evidence-based TCM therapeutic strategies. By consolidating existing evidence, this review aims to provide a rigorous assessment of TCM's clinical value in DCM management, while proposing standardized frameworks to facilitate deeper integration of TCM principles with evidence-based cardiology practice.