Exploring the Molecular Mechanisms of Xuefu Zhuyu Pills in Treating Antipsychotic-Induced Hyperprolactinemia: An Integrated Approach Based on Plasma Component Analysis, Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulations.
This study preliminarily revealed the components in human plasma of XFZY in HPRL treatment and their potential pharmacological mechanism, providing a scientific basis for clinical studies.
Abstract
INTRODUCTION
Antipsychotic-induced hyperprolactinemia (HPRL) is a prevalent and troubling side effect that impairs treatment adherence. Xuefu Zhuyu Pills (XFZY), a traditional Chinese medicine formula, have shown efficacy in clinical practice; however, their active components and mechanisms of action remain unknown.
Methods
We identified the components of XFZY in human plasma by UPLC-Q-TOF-MS/MS and performed network pharmacology analysis to screen key targets and core active components through topological analysis. Intersecting targets were subjected to GO and KEGG enrichment analyses on Metascape, followed by molecular docking and molecular dynamics simulations to assess binding stability between core active components and key targets.
Results
A total of 67 absorbed components were found in human plasma. Based on the network pharmacology results, we identified seven core targets (AKT1, ESR1, IL6, TNF, ERBB2, CTNNB1, and MAOA) and three potential active ingredients (Makisterone B, 3-O-beta-Dglucopyranosylplatycodigenin, and 4',5,6,7-Tetramethoxyflavone). GO and KEGG suggested that hormone level regulation, the neuroactive ligand-receptor interaction, the apelin signaling pathway, and the cGMP-PKG signaling pathway may play key roles in treating HPRL caused by antipsychotic drugs.
Discussion
Molecular docking results showed that the core active ingredient binds well with the key targets, and molecular dynamics simulations further verified their stability.
Conclusion
This study preliminarily revealed the components in human plasma of XFZY in HPRL treatment and their potential pharmacological mechanism. These findings provide a scientific basis for clinical studies.
BACKGROUND
Rosacea is a chronic inflammatory skin disorder with limited therapeutic options. Puhuaiyin (PHY), a traditional Chinese medicinal formula, shows clinical efficacy, but its multi-component mechanisms remain unclear.
METHODS
Chemical constituents of PHY were identified by UPLC-Q-TOF-MS. Network pharmacology was used to predict potential targets, which were intersected with rosacea-associated genes. Bioinformatics analyses (differential expression, WGCNA, and machine learning) were applied to the GEO dataset GSE65914 to refine core targets. Molecular docking and molecular dynamics simulations were conducted to validate the binding modes and stability between key active constituents and the core targets.
RESULTS
A total of 59 chemical constituents were identified in PHY, with five key active components subsequently screened: quercetin, emodin, kushenol N, physcion, and palmitic acid. Network pharmacology analysis revealed 44 intersecting targets, which were significantly enriched in inflammation-related pathways, such as MAPK, NF-κB, and JAK-STAT signaling. Integrated bioinformatics and machine learning approaches identified MMP9 and IL1B as core targets, both of which were markedly upregulated in rosacea lesions and demonstrated prominent diagnostic value (AUC = 0.999 for MMP9, 0.964 for IL1B). Molecular docking indicated strong binding affinity between the core components and MMP9/IL1B. Molecular dynamics simulations confirmed stable complex conformations over 200 ns, with MM/PBSA binding free energies of -15.54 Kcal/mol (quercetin-MMP9) and -15.57 Kcal/mol (quercetin- IL1B).
DISCUSSION
This study, through a multidisciplinary approach, systematically elucidates the "multi-component, multi-target, and multi-pathway" mode of action of PHY in the treatment of rosacea. However, the computational predictions remain to be further validated by in vivo and in vitro experiments. Future research should focus on verifying its therapeutic efficacy in animal or cellular models, as well as elucidating the regulatory effects of key active components on the MMP9 and IL1B targets.
CONCLUSION
These computational predictions suggest that PHY may exert therapeutic effects against rosacea via quercetin and other components targeting MMP9 and IL1B, thereby modulating MAPK, NF-κB, and JAK-STAT pathways. The proposed mechanisms include inhibition of inflammation, regulation of the immune microenvironment, attenuation of vascular dilation, and promotion of skin barrier recovery. These findings provide a theoretical basis for future experimental validation.
Dan Sun, Na-Na Yang, Yi-Ding Zhao et al.· Current Computer - Aided Dru...· 0 citations
INTRODUCTION
The global prevalence of Alcoholic Liver Disease (ALD) is rising, presenting a significant public health challenge. Taraxacum, a medicinal-food homologous plant, demonstrates hepatoprotective properties, yet its mechanisms remain unclear. This study aimed to identify the core bioactive components of Taraxacum and validate their mechanisms and therapeutic efficacy in ALD mice.
METHODS
In this study, comprehensive compositional analysis of Taraxacum was performed utilizing ultra-performance liquid chromatography coupled with UPLC-QE-MS. Active components of Taraxacum and their associated targets relevant to ALD were identified through integration of public databases. Subsequently, a Protein-Protein Interaction (PPI) network and a "Drug-components-targets" network were constructed. Key targets and key bioactive components were screened from these networks. The core component was further determined via molecular docking simulations, and its therapeutic efficacy was evaluated in the ALD mouse model by examining pertinent biochemical markers and conducting histopathological examination.
RESULTS
50 chemical components were identified from Taraxacum using UPLC-QE-MS analysis, with organic acids and flavonoids predominating. Subsequent screening via network pharmacology yielded 10 key components and 9 key targets, predominantly associated with inflammatory pathways. GO and KEGG enrichment analyses indicated significant involvement of oxidative stress responses and the HIF-1 signaling pathway, among others. Molecular docking results suggested that isorhamnetin may represent the primary active constituent against ALD, exhibiting the strongest binding affinity with MAPK3. An experiment in mouse models of alcohol-induced liver injury demonstrated that isorhamnetin significantly reduced the activities of hepatic injury markers, attenuated histopathological damage and the release of pro-inflammatory cytokines, while concurrently inhibiting oxidative stress and protecting hepatocytes.
DISCUSSION
Taraxacum therapy for ALD has the advantage of multi-component, multi-- target, and multi-pathway synergistic regulation. Comprehensive analysis demonstrated that its core component, isorhamnetin, alleviates ALD through synergistic multi-pathway mechanisms involving metabolic regulation, antioxidant defense, and anti-inflammatory effects.
CONCLUSION
This study systematically characterized the bioactive components of Taraxacum, elucidating the therapeutic efficacy of the core component, isorhamnetin, against ALD. These findings provide a scientific foundation for the development of plant- derived therapeutics targeting ALD.
Mingyu Liu, Changqing Qin, Chuanguo Liu et al.· Current Medicinal Chemistry· 0 citations
This study integrated UPLC-QE Orbitrap-MS/MS, network pharmacology, and experimental validation to investigate the chemical profile and therapeutic mechanisms of the Yueju pill (YJP) in the treatment of alcoholic liver disease (ALD). Chemical analysis identified 91 compounds in the YJP. After SwissADME screening, 45 active ingredients were predicted as potential bioactive compounds. By overlapping the targets of these compounds with ALD-related targets, a "component-target-disease" network was constructed, revealing 183 common targets. Enrichment analysis indicated that YJP exerts its therapeutic effects through multiple pathways, including the HIF-1 signaling pathway. In animal experiments, an ALD mouse model was established using the Lieber-DeCarli ethanol liquid diet. YJP intervention significantly reduced serum TG, AST, and ALT levels, alleviated hepatic lipid deposition and collagen deposition, improved liver mitochondrial homeostasis, and decreased hepatic HIF-1α expression. Moreover, the YJP improved intestinal barrier integrity and upregulated intestinal HIF-1α and occludin expression, reflecting a therapeutic mechanism involving coordinated regulation of the gut-liver axis.
K. Zhou, Xiaoyong Yuan, Xiaotian Fan et al.· Biomedical chromotography· 0 citations
Purpose In recent years, Suxiao Jiuxin Pill (SJP) has emerged as a potential treatment for various cardiovascular diseases, the exact molecular mechanisms remain poorly characterized. Consequently, this study seeks to investigate the target genes associated with SJP's active components in AMI, as well as the underlying biological processes, utilizing network pharmacology (NP) and Mendelian randomization (MR) analysis. Methods To unravel SJP's targets and its regulatory mechanisms against AMI, we combined NP, MR, and molecular docking strategies. A rat MI model was established by ligating the LAD coronary artery at the designated site. PCR and immunofluorescent labeling were applied to ovserve the expression of NAMPT and FOS. Results Totally 44 DE-TGs were gained by intersecting 689 DEGs and 969 predicted target genes. Next, two key target genes, NAMPT and FOS, showing markedly upregulated expression in AMI samples. Observations showed that these genes were co-enriched in the “Leishmania Infection” and “Chemokine Signaling Pathway”. Moreover, these key target genes showed robust associations with various immune cells, of which NAMPT exhibited a strong positive correlation with neutrophils (cor = 0.65). Molecular docking revealed NAMPT bound to oleic acid (−5.9 kcal/mol) and FOS bound to pentadecanol (−5.4 kcal/mol). The PCR and immunofluorescence assay results showed that FOS was consistent with the predicted results. Echocardiographic assessments and inflammatory factor expression analyses confirmed that SJP ameliorated cardiac function and alleviated the inflammatory response in MI rats. Conclusion This work further delivers a fresh conceptual framework for deciphering the mechanistic basis of SJP's clinical utility in AMI management.
Yugen Shi, Wenjing Yi, Xue Feng et al.· Frontiers in Cardiovascular...· 0 citations
This study provides experimental evidence supporting the protective effects of DSP against UC, with its actions likely mediated, at least in part, through the modulation of Th17 cell differentiation.
Yanxia Huang, Q. Lin, Min Zhu et al.· Combinatorial chemistry & hi...· 0 citations
Gouteng is a traditional Chinese medicine widely used for the clinical treatment of epilepsy, yet the specific mechanism underlying its antiepileptic has not been elucidated. Network pharmacology, bioinformatics, machine learning, molecular docking, MD simulation, and ADMET druggability analysis were performed to systematically elucidate the molecular regulatory mechanism of Gouteng against epilepsy. The results showed that 29 active components of Gouteng collectively regulated 661 potential antiepileptic targets. Through screening with machine learning-based disease diagnostic model, MDM2 and PPARG as the core target genes mediating the antiepileptic effect of Gouteng were finally identified. Immune infiltration analysis confirmed that MDM2 and PPARG synergistically reshape the immune microenvironment of epileptic lesions, restrain excessive inflammatory responses, and maintain immune homeostasis and tolerance. Molecular docking and MD simulation revealed that the four core active components, namely Angustidine, Rhynchophylline A, vincoside lactam_qt, and coryincine, target the hydrophobic pocket of MDM2, with non-polar interactions serving as the primary driving factor for their interactions. ADMET analysis indicated that vincoside lactam_qt and coryincine exhibit favorable oral bioavailability, excellent blood-brain barrier permeability, and low hepatotoxicity, which make them potential antiepileptic candidate drugs with clinical translational potential. Most importantly, Gouteng exerts antiepileptic effects by targeting and regulating the dual MDM2-MDM4/TP53 and PPARG-NCOA1/RXRA regulatory axes, thereby mediating neuroinflammation inhibition and neuronal protection. Furthermore, TFAP2C as a common upstream transcription factor of both MDM2 and PPARG was identify. This study provides theoretical basis for the development of novel MDM2/PPARG-targeted antiepileptic drugs and for the clinical application of Gouteng.
Hong-Quan Zhang, Lin Chen, Xian-Jun Yuan et al.· Neuropharmacology· 0 citations
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