Network Pharmacology Analysis Research Articles

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and cholinergic dysfunction. This study evaluated the neuroprotective potential of Ficus microcarpa leaf extract via a multidisciplinary approach that integrates phytochemical profiling, in silico analysis, and in vivo validation. LC‒MS analysis revealed key bioactive compounds, including fortunellin, thalsimine, and vocalristine, which are flavonoids, alkaloids, and terpenoids, that are known for their neuroprotective effects. Drug-likeness and toxicity evaluations via SwissADME and ProTox-II revealed favorable pharmacokinetic properties. Network pharmacology and KEGG enrichment analyses identified AChE, APP, and GSK3β as central AD-related targets. Molecular docking (AutoDock 4.2) revealed strong binding affinities of fortunellin (-9.2kcal/mol) and donepezil (-9.0kcal/mol) with AChE, which was supported by active site interactions. Molecular dynamics (200ns, GROMACS) confirmed the complex stability via RMSD, RMSF, SASA, and hydrogen bond analyses. The MM-PBSA calculations further validated the binding stability. In vivo studies revealed that F. microcarpa (100 and 200mg/kg, po) and donepezil (3mg/kg, po) administered for 21 days significantly reversed scopolamine-induced (2mg/kg, ip) memory deficits in Wistar rats, as assessed by the Morris water maze, elevated plus maze, and novel object recognition tests. Biochemical analysis revealed reduced oxidative stress, increased antioxidant enzyme levels, and the restoration of cholinergic function. Histopathological studies revealed that the integrity of the hippocampus was preserved. Overall, these findings support F. microcarpa, particularly fortunellin, as a promising multitarget candidate for AD therapy, meriting further pharmacological investigation.

Exploring the anti-Helicobacter pylori activity and mechanism of Shouhui Tongbian through chemical composition analysis and network pharmacology.

Intervertebral disc degeneration (IVDD) is a complex and multifactorial condition characterized by the progressive deterioration of the intervertebral discs. Ginsenoside Rg1, a bioactive compound isolated from Panax ginseng C.A.Mey., that has demonstrated promising therapeutic potential in the treatment of IVDD. This study employed a multi-faceted approach to investigate the therapeutic effects of ginsenoside Rg1 on IVDD. Initially, histopathology, magnetic resonance imaging (MRI) were performed in clinical IVDD patients. Subsequently, histopathology, safranin green staining, X-ray, and MRI were utilized to evaluate the efficacy of ginsenoside Rg1 in alleviating in a rat model in vivo. Transcriptomics and gene set enrichment analysis (GESA) were conducted, and a network pharmacology visualization of ginsenoside Rg1-ferroptosis key targets-pathways-IVDD was constructed, along with molecular docking of ginsenoside Rg1 and targets, to identify the signaling pathways and proteins associated with the therapeutic effects of ginsenoside Rg1 on alleviating IVDD. Additionally, an Hydrogen peroxide (H2O2)-induced degeneration model of nucleus pulposus cells (NP cells) was used to evaluate the efficacy of ginsenoside Rg1 in alleviating IVDD in vitro. Methods including lipid-reactive oxygen species (ROS) detection, enzyme-linked immunosorbent assay (ELISA), FerroOrange staining, and transmission electron microscopy were employed to validate the effect and mechanism of ginsenoside Rg1 on alleviating IVDD in vivo and in vitro. ML385, a nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor, was used to reverse the effect of ginsenoside Rg1 in mitophagy and ferroptosis, respectively. The expression of proteins was assessed on immunochemical, immunofluorescence, and western blotting techniques. Significant ferroptosis was observed in the NP tissue of IVDD patients, with more effects in patients with higher imaging grades. Ginsenoside Rg1 significantly mitigated IVDD in rats and promoted intervertebral disc repair. Network pharmacology and transcriptomics analyses indicated the key targets of ginsenoside Rg1 for the treatment of IVDD, including NRF2, glutathione peroxidase 4 (GPX4), solute carrier family 7a member 11 (SLC7A11), and ferritin light chain 1 (FTL1). Molecular docking exhibited that ginsenoside Rg1 had good binding ability between ginsenoside Rg1 and these ferroptosis key targets. Ginsenoside Rg1 reduced the expression of ROS and malondialdehyde (MDA), decreased Fe2+ content, increased the expression of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), and upregulated the expression of ferroptosis key proteins NRF2, GPX4, FTL1, and SLC7A11 in intervertebral disc tissues and NP cells. Treatment with ML385 attenuated the ginsenoside Rg1-induced upregulation of these proteins in NP cells, thereby promoting ferroptosis and reversing the protective effects of ginsenoside Rg1. Ginsenoside Rg1 can mitigate IVDD by inhibiting ferroptosis in NP cells. The NRF2/GPX4 pathway was validated as the key ferroptosis pathway through which ginsenoside Rg1 exerts its therapeutic effects on IVDD.

Lippia nodiflora leaves have been traditionally used by healers in Silent Valley, Palakkad district of Kerala, for treating wounds. This study aimed to scientifically validate the wound-healing potential of the methanol extract of L. nodiflora leaves (MELN) to support its ethnopharmacological claims. Phytochemical profiling using UPLC-QTOF-MS identified key constituents, and network pharmacology analysis revealed potential pathways and targets involved in wound healing. These findings were further supported by molecular docking, in vitro, in vivo, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analyses. No toxicity was observed in either in vitro or in vivo models. Network pharmacology indicated that MELN may act through the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance pathway. Core compounds such as quercetin, 3-methylherbacetin, eupafolin, 6-hydroxyluteolin 3'-methyl ether 7-sulfate, and syringic acid beta-glucopyranosyl ester likely contribute to the wound-healing activity, as supported by docking studies. RT-qPCR analysis demonstrated upregulation of genes related to cell migration and proliferation. In vitro assays showed enhanced cell proliferation and migration, indicating pro-healing properties. In vivo excision wound models confirmed significant wound closure, complete epithelialization, and improved histopathological features in MELN-treated groups. Overall, this study provides scientific evidence supporting the ethnopharmacological claim of L. nodiflora in wound management and establishes MELN as a potential herbal formulation for wound healing.

Background:Diabetic kidney disease (DKD) is a major cause of end-stage renal disease. Although metformin is widely prescribed, the mechanisms underlying its renoprotective effects remain incompletely understood.Methods:We integrated multi-omics approaches—including network pharmacology, phosphoproteomics, and targeted metabolomics—in both db/db mice (male) and human patients. Analyses were performed on blood and kidney tissue from mice and paired blood/urine samples from DKD patients to identify conserved therapeutic targets and metabolic pathways.Results:Metformin treatment improves glycemic control and renal function (reduced creatinine and urea nitrogen) in DKD mice. Network pharmacology and phosphoproteomic analyses reveal metformin’s engagement with the MAPK pathway, specifically through MAPK1 and MAPK3. Targeted metabolomics identifies four carbohydrate metabolites (mannitol, D-arabitol, D-mannose, and D-xylose) associated with DKD risk in humans. Cross-species validation in mice supports D-Xylose as a potential key biomarker for metformin’s therapeutic effects in DKD, with proximal tubule bicarbonate reclamation and alanine, aspartate and glutamate metabolism as key metabolic pathways.Conclusions:Metformin alleviates DKD through multi-modal mechanisms, modulating the MAPK signaling pathway and carbohydrate metabolites—notably D-xylose. As far as we are aware, these findings provide new mechanistic insights and suggest potential biomarker-driven strategies for DKD management.

Sarcopenia (SP) associated with functional impairment is highly prevalent; however, therapeutic strategies addressing this condition remain limited. Inflammation and oxidative stress are the key contributors. Suitably, formononetin (FMN) offers diverse benefits, including antioxidant, anti-apoptotic, and anti-inflammatory properties. Therefore, this study used network pharmacology to identify 81 potential target genes for FMN to alleviate SP. Serine/threonine-protein kinase 1 (AKT1), epidermal growth factor receptor (EGFR), and sirtuin 1 (SIRT1) as the core targets. Kyoto Encyclopedia of Genes and Genome analysis indicated that FMN primarily affects SP via the interleukin (IL)-17, PI3K-Akt and FoxO signalling pathways. Cell studies revealed that FMN reduces IL-6 release and boosts superoxide dismutase activity, thereby enhancing C2C12 skeletal muscle cell vitality. FMN intervention also enhanced AKT1 and SIRT1 gene and protein expression, decreased muscle-specific RING finger protein-1 gene expression, and increased EGFR protein expression. This suggests its anti-inflammatory and antioxidant effects in dexamethasone-treated C2C12 cells, potentially preventing muscle atrophy by inhibiting protein breakdown. These findings highlight the promising multi-target role and molecular mechanism of FMN in the treatment of SP and suggest future clinical applications.Graphical

Dopamine receptor agonist (DA)-resistant prolactinoma presents a significant clinical challenge, highlighting the need for novel therapeutic strategies. Deguelin is a rotenoid compound derived from several plant species with unique antitumor effects. In this study we investigated the efficacy of deguelin on DA-resistant prolactinoma and elucidated its antitumor mechanisms. We showed that deguelin concentration-dependently inhibited cell viability, proliferation and prolactin secretion, and promoted apoptosis and cell cycle arrest in two prolactinoma tumor cell lines GH3 and MMQ. In CCK-8 assay, the IC50 values of deguelin for GH3 and MMQ were 0.1518 and 0.2381 µM, respectively. Network pharmacology analysis predicted that ornithine decarboxylase (ODC), a rate-limiting enzyme in the de novo synthesis of polyamine and responsible for converting ornithine into putrescine, was the target of deguelin. We demonstrated that deguelin directly interacted with ODC, competitively inhibiting putrescine production, and thereby reducing the levels of active Rac1. Transcriptomic analysis of deguelin-treated GH3 cells identified the PI3K/AKT signaling pathway as a crucial mediator of the action of deguelin with the inhibition of CREB3L1 playing a central role. In GH3 xenograft nude mice, administration of deguelin (4 mg/kg, i.p., every other day for two weeks) significantly inhibited tumor growth with significant reduction in both AKT phosphorylation and CREB3L1 levels in deguelin-treated xenografts. These results suggest that deguelin can be considered a therapeutic option for treating DA-resistant prolactinoma and serve as a basis for developing novel treatment approaches.

Betulinaldehyde regulates VSMC phenotypic transition to alleviate vascular hyperplasia through PPARγ/mitochondria/ROS axis.

Frititaipaines A-O, undescribed cevanine-type isosteroidal alkaloids from the bulbs of Fritillaria taipaiensis and their anti-neuroinflammatory and AChE inhibitory activities.

Fibroblast activation protein-α drives rheumatoid arthritis inflammation through the AKT/mTOR signaling pathway and its therapeutic effect by Wangbi granules.

A multi-index decision analysis method for saposhnikoviae radix based on biological-chemical integrative evaluation.

Protection against stroke-induced blood-brain barrier disruption by Guanxinning injection and its active-component combination via TLR4/NF-κB/MMP9-mediated neuroinflammation.

Berberine, the primary active compound in Coptis chinensis Franch, is well known for its anti-infective, hypoglycemic, lipid-lowering, antitumor, and anti-inflammatory effects. This review summarizes the physicochemical and pharmacokinetic characteristics of berberine, its intraintestinal pharmacology involving gut microbiota cross-talk to heart failure (gut-cardiac axis), extraintestinal pharmacology in heart failure, and network pharmacology. Berberine enhances the intestinal barrier, reducing endotoxin entry into the bloodstream. It also regulates the intestinal flora composition, notably altering the Bacillota/Bacteroidota ratio. Importantly, berberine promotes beneficial bacteria while inhibiting pathogenic bacteria. In addition, it influences gut microbiota metabolites, decreasing trimethylamine and trimethylamine N-oxide while increasing short-chain fatty acids. Berberine addresses extraintestinal direct mechanisms by mitigating heart failure risk factors such as atherosclerosis, hyperglycemia, and hyperlipidemia. It also decreases cardiac oxygen consumption, oxidative stress, and endoplasmic reticulum stress, thereby reducing chronic cardiac inflammation, apoptosis, and remodeling, while enhancing myocardial energy to improve cardiac function. Network pharmacology analysis has identified the top 10 hub genes for berberine in heart failure therapy: STAT3, TNF, MTOR, NFKB1, HIF1A, ESR1, BCL2, PTGS2, PPARG, and MMP9. Notably, TNF, HIF1A, and PPARG are key targets for berberine in heart failure with preserved ejection fraction treatment. Berberine shows promise for heart failure treatment, but its bioavailability needs improvement. In addition, the efficacy and safety of berberine in clinical heart failure management, especially in heart failure with preserved ejection fraction, require further evaluation through large-scale, multicenter clinical trials.

Mechanistic insights into baicalein's anti-inflammatory effects in COPD: Targeting oxidative stress and CD8⁺ T cell cytotoxicity.

Kaixin San in treating vascular dementia via regulating the Bcl-2/Beclin-1/LC3A/B signaling pathway via animal experiments and network pharmacology analysis

Elucidating the underlying therapeutic mechanism of Feikang prescription on chronic obstructive pulmonary disease: insights from a comprehensive analysis.

Cancer is the second leading cause of death worldwide, highlighting the urgent need for novel therapeutic strategies and targeted drug development. Oleanolic acid (OA) is a natural compound with notable antitumor activity. This study aimed to develop OA derivatives with enhanced antitumor potency through structural optimization and biological evaluation. First, modifications were introduced at the C28 carboxylic acid group of OA to generate a series of acylhydrazone derivatives. Their structures were confirmed via ¹H NMR, 13C NMR, HRMS, and X-ray single-crystal diffraction. Subsequently, the cytotoxic effects of these derivatives were assessed in tumor cell lines (A549, AGS, and K562) using the CCK-8 assay, with cisplatin as a positive control. Notably, compounds 5, 6, 9, 10, 16, 21, 27, and 28 showed stronger inhibitory activity than cisplatin. Among them, compound 28 exhibited the highest potency against A549 (IC50 = 8.34 ± 0.65 µM) and K562 cells (IC50 = 6.25 ± 0.57 µM), while derivative 16 showed the best efficacy against AGS cells (IC50 = 7.93 ± 0.81 µM). Finally, network pharmacology analysis was performed to identify the core signaling pathways and targets of compound 16 in AGS cells and compound 28 in A549 and K562 cells. Six key proteins (SRC, PLCG1, EGFR, GRB2, IL1B, and HSP90AB1) with high degree values (> 10) were identified. Molecular docking further confirmed strong binding interactions-mainly hydrogen bonds, π-π stacking, and other forces-between the active compounds and their targets. Collectively, this study offers valuable insights into the development of OA-based antitumor agents and highlights promising lead compounds for further investigation.

Corilagin alleviates cardiac ischemia-reperfusion injury by inhibiting ferroptosis via PI3K/AKT pathway.

Exploring the alleviating effect and mechanism of the diterpenoid alkaloid Polyschistine D on rheumatoid arthritis based on network pharmacology and non-targeted metabolomics.

Royal jelly acid inhibits NF-κB signaling by regulating H3 histone lactylation to alleviate IgE-mediated mast cell activation and allergic inflammation.