The mechanism of Zhenzhu Pills treating intracerebral hemorrhage secondary injury based on network pharmacology and molecular docking
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SUBMITTER: Wu G
PROVIDER: S-EPMC10869077 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Project description:BackgroundDiabetic nephropathy (DN) is a common and serious complication of diabetes, but without a satisfactory treatment strategy till now. Liuwei Dihuang pills (LDP), an effective Chinese medicinal formula, has been used to treat DN for more than 1000 years. However, its underlying mechanism of action is still vague.MethodsActive compounds and corresponding targets of LDP were predicted from the TCMSP database. DN disease targets were extracted from the OMIM, GeneCards, TTD, DisGeNET, and DrugBank databases. Subsequently, the "herbal-compound-target" network and protein-protein interaction (PPI) network were constructed and analyzed via the STRING web platform and Cytoscape software. GO functional and KEGG pathway enrichment analyses were carried out on the Metascape web platform. Molecular docking utilized AutoDock Vina and PyMOL software.Results41 active components and 186 corresponding targets of LDP were screened out. 131 common targets of LDP and DN were acquired. Quercetin, kaempferol, beta-sitosterol, diosgenin, and stigmasterol could be defined as five crucial compounds. JUN, MAPK8, AKT1, EGF, TP53, VEGFA, MMP9, MAPK1, and TNF might be the nine key targets. The enrichment analysis showed that common targets were mainly associated with inflammation reaction, oxidative stress, immune regulation, and cell apoptosis. AGE-RAGE and IL-17 were the suggested two significant signal pathways. Molecular docking revealed that the nine key targets could closely bind to their corresponding active compounds.ConclusionThe present study fully reveals the multicompound's and multitarget's characteristics of LDP in DN treatment. Furthermore, this study provides valuable evidence for further scientific research of the pharmacological mechanisms and broader clinical application.
| S-EPMC8452392 | biostudies-literature
Project description:Intracerebral hemorrhage (ICH) can be divided into a primary and secondary phase. In the primary phase, hematoma volume is evaluated and therapies are focused on reducing hematoma expansion. In the secondary, neuroprotective phase, complex systemic inflammatory cascades, direct cellular toxicity, and blood-brain barrier disruption can result in worsening perihematomal edema that can adversely affect functional outcome. To date, all major randomized phase 3 trials for ICH have targeted primary phase hematoma volume and incorporated clot evacuation, intensive blood pressure control, and hemostasis. Reasons for this lack of clinical efficacy in the major ICH trials may be due to the lack of therapeutics involving mitigation of secondary injury and inflexible trial design that favors unilateral mechanisms in a complex pathophysiology. Potential pathophysiological targets for attenuating secondary injury are highlighted in this review and include therapies increasing calcium, antagonizing microglial activation, maintaining macrophage M1 versus M2 balance by decreasing M1 signaling, aquaporin inhibition, NKCCl inhibition, endothelin receptor inhibition, Sur1-TRPM4 inhibition, matrix metalloproteinase inhibition, and sphingosine-1-phosphate receptor modulation. Future clinical trials in ICH focusing on secondary phase injury and, potentially implementing adaptive trial design approaches with multifocal targets, may improve insight into these mechanisms and provide potential therapies that may improve survival and functional outcome.
| S-EPMC8521409 | biostudies-literature
Project description:ImportanceIntracerebral hemorrhage (ICH) contributes significantly to the global burden of disease.ObjectiveTo examine the association of ICH and secondary injury with disability-adjusted life-years (DALYs) for the individual patient.Design, setting, and participantsThis cohort study was conducted using data from the Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage study. Consecutive patients admitted to a single tertiary care center from January 1, 2006, to December 31, 2015, were included. The sample comprised patients with oral anticoagulation-associated ICH (OAC-ICH) or primary spontaneous ICH (non-OAC-ICH). Statistical analysis was conducted from October 1 to December 31, 2020.ExposuresICH occurrence and secondary injury.Main outcomes and measuresDALYs, years of life lost (YLL), and years lived with disability (YLD) were analyzed by hematoma location, ICH volume, and secondary injury (ie, hematoma expansion [HE], intraventricular hemorrhage [IVH], and perihemorrhagic edema [PHE]).ResultsAmong 1322 patients with ICH, 615 (46.5%) were women and the mean (SD) age at hospital admission was 71 (13) years; ICH was associated with a mean (SD) of 9.46 (8.08) DALYs, 5.72 (8.29) YLL, and 3.74 (5.95) YLD. There were statistically significant differences in mean (SD) DALYs by extent of hematoma volume (< 10 mL ICH: 7.05 [6.79] DALYs; 10-30 mL ICH: 9.91 [8.35] DALYs; >30 mL ICH: 12.42 [8.47] DALYs; P < .001) and ICH location (deep location: 10.60 [8.35] DALYs; lobar location: 8.18 [7.63] DALYs; cerebellum: 8.14 [6.80] DALYs; brainstem: 12.63 [9.21] DALYs; P < .001). Regarding population-level disease burden of secondary injuries after ICH, there was a statistically significant difference in mean (SD) by injury type, with 0.94 (3.19) DALYs for HE, 2.45 (4.16) DALYs for IVH, and 1.96 (2.66) DALYs for PHE (P < .001) among the entire ICH cohort. Regarding individual-level exposure to secondary injuries after ICH, there were a mean (SD) 7.14 (6.62) DALYs for HE, 4.58 (4.75) DALYs for IVH, and 3.35 (3.28) DALYs for PHE among patients with ICH affected by secondary injuries.Conclusions and relevanceThese findings suggest that there is a high burden of disability associated with ICH and secondary injuries, and the findings may guide public health strategies. The study findings further suggest that IVH and PHE may be relevant for the overall outcome of patients with ICH, that DALYs may represent a viable outcome parameter for studies to evaluate treatment outcomes in ICH research, and that IVH and PHE may represent potential treatment targets.
| S-EPMC8290300 | biostudies-literature
Project description:Intracerebral hemorrhage (ICH) is a major cerebrovascular illness that causes substantial neurological sequelae and dysfunction caused by secondary brain injury (SBI), and there are no effective therapies to mitigate the disability. Microglia, the brain-resident macrophage, participates in the primary inflammatory response, and activation of microglia to an M1-like phenotype largely takes place in the acute phase following ICH. A growing body of research suggests that the pathophysiology of SBI after ICH is mediated by an inflammatory response mediated by microglial-pyroptotic inflammasomes, while inhibiting the activation of microglial pyroptosis could suppress the inflammatory cascade reaction, thus attenuating the brain injury after ICH. Pyroptosis is characterized by rapid plasma membrane disruption, followed by the release of cellular contents and pro-inflammatory mediators. In this review, we outline the molecular mechanism of microglial pyroptosis and summarize the up-to-date evidence of its involvement in the pathological process of ICH, and highlight microglial pyroptosis-targeted strategies that have the potential to cure intracerebral hemorrhage. This review contributes to a better understanding of the function of microglial pyroptosis in ICH and assesses it as a possible therapeutic target.
| S-EPMC9507402 | biostudies-literature
Project description:A collection of chronic central motor, postural, and activity restriction symptoms are referred to as cerebral palsy (CP). Previous research suggests that a number of perinatal variables, including hypoxia, may be linked to CP. And the pathophysiological process that causes brain injury in growing fetuses is mostly caused by amniotic fluid infection and intra-amniotic inflammation. Still, there is still much to learn about the molecular mechanism of CP. The goal of this study was to identify the molecular mechanism of Liuwei Dihuang pill (LWDHP) in the treatment of CP using network pharmacology and bioinformatics. The Chinese medicine database provided the LWDHP components and targets, the CP illness gene data set was gathered from a disease, and the expression profile of children with CP was chosen from anther database. Using the Kyoto Encyclopedia of Genes and Genomes and gene ontology databases, a network of interactions between proteins was created, and functional enrichment analysis was carried out. Analysis of traditional Chinese medicine found that the key active ingredients of LWDHP are quercetin, Stigmasterol and kaempferol. Through enrichment analysis, it was found that the hub genes for LWDHP treatment of CP are CXCL8, MMP9, EGF, PTGS2, SPP1, BCL2L1, MMP1, and AR. K EGG analysis found that LWDHP treatment of CP mainly regulates PI3K-Akt signaling pathway, IL-17 signaling pathway, Jak-STAT signaling pathway, NF-kappa B signaling pathway, etc. To summarize, LWDHP regulates immunological and inflammatory variables through a variety of components, targets, and signaling pathways, which plays a significant role in the development and management of CP.
| S-EPMC11521014 | biostudies-literature
Project description:BackgroundParkinson's disease (PD) is a common neurodegenerative disease in middle-aged and elderly people. Liuwei Dihuang (LWDH) pills have a good effect on PD, but its mechanism remains unclear. Network pharmacology is the result of integrating basic theories and research methods of medicine, biology, computer science, bioinformatics, and other disciplines, which can systematically and comprehensively reflect the mechanism of drug intervention in disease networks.MethodsThe main components and targets of herbs in LWDH pills were obtained through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Its active components were screened based on absorption, distribution, metabolism, and excretion (ADME); the PD-related targets were obtained from the Genecards, OMIM, TTD, and DRUGBANK databases. We used R to take the intersection of LWDH- and PD-related targets and Cytoscape software to construct the drug-component-target network. Moreover, STRING and Cytoscape software was used to analyze protein-protein interactions (PPI), construct a PPI network, and explore potential protein functional modules in the network. The Metascape platform was used to perform KEGG pathway and GO function enrichment analyses. Finally, molecular docking was performed to verify whether the compound and target have good binding activity.ResultsAfter screening and deduplication, 210 effective active ingredients, 204 drug targets, 4333 disease targets, and 162 drug-disease targets were obtained. We consequently constructed a drug-component-targets network and a PPI-drug-disease-targets network. The results showed that the hub components of LWDH pills were quercetin, stigmasterol, kaempferol, and beta-sitosterol; the hub targets were AKT1, VEGFA, and IL6. GO and KEGG enrichment analyses showed that these targets are involved in neuronal death, G protein-coupled amine receptor activity, reactive oxygen species metabolic processes, membrane rafts, MAPK signaling pathways, cellular senescence, and other biological processes. Molecular docking showed that the hub components were in good agreement with the hub targets.ConclusionLWDH pills have implications for the treatment of PD since they contain several active components, target multiple ligands, and activate various pathways. The hub components possibly include quercetin, stigmasterol, kaempferol, and beta-sitosterol and act through pairing with hub targets, such as AKT1, VEGFA, and IL6, to regulate neuronal death, G protein-coupled amine receptor activity, reactive oxygen species metabolic process, membrane raft, MAPK signaling pathway, and cellular senescence for the treatment of PD.
| S-EPMC8568527 | biostudies-literature
Project description:To explore the mechanism of the Zhenbao pill (ZBP) in treating spinal cord injury (SCI). The TCMSP Database, HERB Database and literature search were used to screen the effective ingredients and targets of ZBP; SCI-related genes were searched in GeneCards, OMIM, PharmGkb, TTD and DrugBank databases; the potential targets of ZBP for treating SCI were predicted and Venn diagrams were drawn, and the "herb-ingredient-target" network was constructed by Cytoscape software. The PPI network was constructed by STRING software, and the core targets were screened by cytoNCA plug-in; GO enrichment and KEGG pathway analysis were performed on the predicted targets using the DAVID Platform, and visualized with the Microbiology Network Platform. The molecular docking between the key ingredients and the core target was carried out by AutoDockVina software. 391 active ingredients and 836 action targets were obtained from ZBP and there are 1557 SCI related genes in 5 disease databases. The top 5 active ingredients were Quercetin, Camptothecin, Kaempferol, Ethyl iso-allocholate, and Ethyl linoleate, and 5 core genes were SRC, CTNNB1, TP53, AKT1, and STAT3. GO enrichment analysis showed that the core targets were involved in 1206 biological processes, 120 cellular components and 160 molecular functions; KEGG enrichment analysis showed that the core targets involved 183 pathways, including PI3K-Akt signaling pathway and other signaling pathways. Molecular docking indicated that CTNNB1, SRC, TP53, AKT1 and STAT3 showed good binding ability with the active ingredients quercetin, kaempferol and ethyl isobutyric acid. ZBP improves SCI through multi-components, multi-targets and multi-pathways.
| S-EPMC10869052 | biostudies-literature
Project description:BackgroundChinese medicine usually acts as "multi-ingredients, multi-targets and multi-pathways" on complex diseases, and these action modes reflect the coordination and integrity of the treatment process with traditional Chinese medicine (TCM). System pharmacology is developed based on the cross-disciplines of directional pharmacology, system biology, and mathematics, has the characteristics of integrity and synergy in the treatment process of TCM. Therefore, it is suitable for analyzing the key ingredients and mechanisms of TCM in treating complex diseases. Intracerebral Hemorrhage (ICH) is one of the leading causes of death in China, with the characteristics of high mortality and disability rate. Bring a significant burden on people and society. An increasing number of studies have shown that Chinese medicine prescriptions have good advantages in the treatment of ICH, and Ditan Decoction (DTT) is one of the commonly used prescriptions in the treatment of ICH. Modern pharmacological studies have shown that DTT may play a therapeutic role in treating ICH by inhibiting brain inflammation, abnormal oxidative stress reaction and reducing neurological damage, but the specific key ingredients and mechanism are still unclear.MethodsTo solve this problem, we established PPI network based on the latest pathogenic gene data of ICH, and CT network based on ingredient and target data of DTT. Subsequently, we established optimization space based on PPI network and CT network, and constructed a new model for node importance calculation, and proposed a calculation method for PES score, thus calculating the functional core ingredients group (FCIG). These core functional groups may represent DTT therapy for ICH.ResultsBased on the strategy, 44 ingredients were predicted as FCIG, results showed that 80.44% of the FCIG targets enriched pathways were coincided with the enriched pathways of pathogenic genes. Both the literature and molecular docking results confirm the therapeutic effect of FCIG on ICH via targeting MAPK signaling pathway and PI3K-Akt signaling pathway.ConclusionsThe FCIG obtained by our network pharmacology method can represent the effect of DTT in treating ICH. These results confirmed that our strategy of active ingredient group optimization and the mechanism inference could provide methodological reference for optimization and secondary development of TCM.
| S-EPMC9912606 | biostudies-literature
Project description:Although many studies have focused on functional impairment after intracerebral hemorrhage, little is known about the relationship between secondary injuries to distal regions and neurological function. Our study aimed to evaluate the secondary injuries after intracerebral hemorrhage and explore their relationship to neurological functional outcome. Twenty-one patients with hemorrhages in supratentorial, deep locations and 10 healthy subjects were recruited. Longitudinal examinations of diffusion tensor imaging, hydrogen proton magnetic resonance spectroscopy imaging and neuropsychological assessment were performed after weeks 1 and 12 to elucidate the relationship between magnetic resonance imaging parameters and neurologic outcomes. By week 12, motor function had significantly improved, but cognitive function had deteriorated compared to week 1. Fractional anisotropy values for the ipsilateral cerebral peduncle correlated with motor function at week 1. No significant correlation between fractional anisotropy for the ipsilateral cerebral peduncle and the Fugl-Meyer Motor Scale was found at week 12. Fractional anisotropy values for the ipsilateral hippocampus were related to the Montreal Cognitive Assessment and Mini-Mental State Examination at weeks 1 and 12. Deep supratentorial hemorrhage may result in injury to distal regions, which correlate with impaired motor and cognitive function.
| S-EPMC7093199 | biostudies-literature
Project description:Background: Cisplatin is an effective anti-tumor drug. However, its usage is constrained by side effects such as nephron toxicity. Cisplatin-induced acute kidney injury (AKI) appears in approximately 20%-30% of cases. Hence, finding an effective protective strategy is necessary. San-Huang decoction (SHD) is a Chinese herbal decoction with good efficacy in treating chronic kidney disease (CKD). Nevertheless, the mechanism of SHD on AKI remains unclear. Consequently, we proposed to explore the potential mechanism of SHD against cisplatin-induced AKI. Methods: Active compounds, core target proteins, and associated signaling pathways of SHD were predicted through network pharmacology. Then confirmed by molecular docking. In vivo experiment, Cisplatin + SHD group was treated with SHD (6.5 g/kg/day) for 6 days before building the model. An AKI model was established with a single intraperitoneal injection of cisplatin at 20 mg/kg. After 72 h of cisplatin injection, all mice were sacrificed to collect blood and kidney tissues for verification of network pharmacology analysis. Results: We found that calycosin, rhein, and ginsenoside Rh2 may be SHD's primary active compounds in treating cisplatin-induced AKI, and AKT, TNF-α, IL-6, IL-1β, caspase-3, and MMP9 are the core target proteins. The relationship between the compound and target protein was further confirmed by molecular docking. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses predicted that SHD has an anti-inflammatory role through the TNF and IL-17 signaling pathway. Moreover, Western blot and immunohistochemistry validated the potential molecular mechanisms of SHD, predicted from network pharmacology analysis. The mechanism of cisplatin-induced AKI involves apoptosis and inflammation. In apoptosis, Caspase-3, caspase-8, caspase-9, and Bax proteins were down-regulated, while Bcl-2 was up-regulated by SHD. The differential expression of MMP protein is involved in the pathological process of AKI. MMP9 protects from glomerular tubule damage. MMP9 and PI3K/AKT anti-apoptosis pathway were up-regulated by SHD. In addition, we discovered that SHD alleviated AKI by inhibiting the NF-κB signaling pathway. Conclusion: SHD plays a critical role in anti-inflammation and anti-apoptosis via inhibiting the NF-κB signaling pathway and activating PI3K/AKT anti-apoptosis pathway, indicating that SHD is a candidate herbal drug for further investigation in treating cisplatin-induced AKI.
| S-EPMC9939458 | biostudies-literature