Zhilong Huoxue Tongyu Capsule regulates the macrophage polarization and inflammatory response via the let-7i/TLR9/MyD88 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhilong Huoxue Tongyu Capsule (ZL) is clinically prescribed for acute ischemic stroke (AIS). However, only a few studies have addressed the mechanisms of ZL in treating AIS. AIM OF THE STUDY: To explore the underlying mechanism of macrophage polarization and inflammation mediated by ZL, and to provide a reference for AIS treatment. MATERIALS AND METHODS: Sixteen SD rats were fed with different dose of ZL (0, 0.4, 0.8, and 1.6 g/kg/d) for 4 days to prepare ZL serum. After 500 ng/mL lipopolysaccharide (LPS) stimulation, RAW264.7 cells were administrated with ZL serum. Then, experiments including ELISA, flow cytometry, real-time quantitative PCR and Western blot were performed to verify the effects of ZL on macrophage polarization and inflammation. Next, let-7i inhibitor was transfected in RAW264.7 cells when treated with LPS and ZL serum to verify the regulation of ZL on the let-7i/TLR9/MyD88 signaling pathway. Moreover, the interaction between let-7i and TLR9 was confirmed by the dual-luciferase assay. RESULTS: ZL serum significantly decreased the expression of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), and increased the expression of IL-10 and transforming growth factor ß1 (TGF-ß1) of LPS stimulated-macrophages. Furthermore, ZL serum polarized macrophages toward M2, decreased the expressions of TLR9, MyD88, and iNOS, as well as increased the expressions of let-7i, CHIL3, and Arginase-1. It is worth mentioning that the effect of ZL serum is dose-dependent. However, let-7i inhibitor restored all the above effects in LPS stimulated-macrophages. In addition, TLR9 was the target of let-7i. CONCLUSIONS: ZL targeted let-7i to inhibit TLR9 expression, thereby inhibiting the activation of the TLR9/MyD88 pathway, promoting the M2 polarization, and inhibiting the development of inflammation in AIS.

Guanxin V alleviates ventricular remodeling by promoting transforming growth factor-beta 1-mediated proteasomal degradation of Vimentin.

More and more studies have demonstrated that proteasomal degradation occurs in the development of various diseases, including ventricular remodeling, which is a cardiac pathological change and seriously makes patient outcomes worse. Our preliminary results showed that Guanxin V, an effective and safe complementary and alternative medicine for ventricular remodeling, reverses ventricular hypertrophy by transforming growth factor-beta 1 (TGF-ß1), but the specific mechanism needs to be explored. The left anterior descending coronary artery was ligated to build a ventricular remodeling model. Cardiac function and histopathology were measured. Fibrosis-related indicators were detected. Moreover, cardiomyocytes were exposed to hydrogen peroxide to construct an in vitro model of ventricular remodeling. The stability of the Vimentin protein was assessed with cycloheximide and MG132. Endogenous and exogenous TGF-ß1-Vimentin interactions were detected by co-immunoprecipitation. Guanxin V significantly eased heart function and improved fibrosis in ventricular remodeling. Mechanistically, Guanxin V promoted TGF-ß1-mediated proteasomal degradation of Vimentin and reduced the TGF-ß1-Vimentin interaction. Here, we reported a completely new mechanism, Guanxin V alleviates ventricular remodeling by promoting and targeting TGF-ß1-mediated proteasomal degradation of Vimentin, which provides a new target for the management of ventricular remodeling and lays the foundation for the further clinical promotion of Guanxin V.

Guanxin V Relieves Ventricular Remodeling by Inhibiting Inflammation: Implication from Virtual Screening, Systematic Pharmacology, Molecular Docking, and Experimental Validation.

OBJECTIVE: To reveal the anti-inflammatory mechanism of Guanxin V, which is prescribed for ventricular remodeling in clinical practice. METHODS: Guanxin V-, ventricular remodeling-, and inflammation-related targets were obtained through an integrated strategy of virtual screening and systematic pharmacology, and then the shared targets were visualised with a Venn diagram. Guanxin V network and the protein-protein interaction network were drawn, and enrichment analysis was conducted. Finally, the main results obtained from the integrated strategy were validated by molecular docking and in vivo experiments. RESULTS: A total of 251, 11,425, and 15,246 Guanxin V-, ventricular remodeling-, and inflammation-related targets were acquired, respectively. Then, 211 shared targets were considered to contribute to the mechanism of ventricular remodeling treated by Guanxin V. Guanxin network and the protein-protein interaction network were drawn, and enrichment analysis showed some cardiovascular-related biological processes and signaling pathways. Molecular docking revealed that the Guanxin V-derived compounds could align with key targets. Final in vivo experiments proved that Guanxin V reverses ventricular remodeling by inhibiting inflammation. CONCLUSION: Guanxin V relieves ventricular remodeling by regulating inflammation, which provides new ideas for the anti-ventricular remodeling mechanism of Guanxin V.

Zhilong Huoxue Tongyu Capsule attenuates hemorrhagic transformation through the let-7f/TLR4 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Hemorrhagic transformation after acute ischemic stroke is a life-threatening disease that currently has no effective chemotherapy. Zhilong Huoxue Tongyu Capsule (ZL) is an empirical prescription of traditional Chinese medicine that is used to prevent and treat cardiovascular and cerebrovascular diseases in China. However, only a few studies have addressed the mechanisms of ZL in treating hemorrhagic transformation. AIM OF THE STUDY: To evaluate the anti-inflammatory effects of ZL on hemorrhagic transformation model rats and lipopolysaccharide (LPS)-induced RAW264.7 macrophages and to explore the underlying molecular mechanisms. MATERIALS AND METHODS: Murine RAW264.7 cells were treated with ZL and LPS (1 µg/mL), and cell viability was detected by cell counting kit-8 assay. RT-qPCR was used to detect the expression of inflammatory chemokines, microRNA let-7a/e/i/f, toll like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa-B (NF-κB) p65. The protein expression levels of TLR4, MyD88, NF-κB p65, and apoptosis related molecules were determined by Western blotting. The apoptosis rate of RAW264.7 macrophages was detected by Annexin V-FITC/PI double staining. A hemorrhagic transformation model in rats was established by intraperitoneal injection of high glucose solution combined with thread embolization. Then, the model rats were observed behaviourally, pathologically, and molecularly. The gene expression of TLR4, MyD88, and NF-κB p65 was measured by RT-qPCR and used to evaluate the protective effect of ZL against hemorrhagic transformation in rats. RESULTS: ZL (5, 20, 40 µg/mL) was beneficial in cell proliferation. LPS (1 µg/mL) stimulated the production of inflammatory chemokines and inhibited the production of let-7a/e/i/f, with let-7f being influenced most strongly. Moreover, overexpression of let-7f decreased the gene and protein levels of TLR4, MyD88, and NF-κB p65, downregulated TLR4, and inhibited its transcriptional activity. ZL (5, 20, and 40 µg·mL-1) inhibited the production of TLR4, MyD88, and NF-κB p65 and promoted the production of let-7f in a concentration-dependent manner. Furthermore, the blockade of TLR4 antagonized the promoting effects of TLR4 pathway activation in cell inflammation and apoptosis by downregulating let-7f. Critically, it was confirmed in vivo and in vitro that ZL upregulated the expression of let-7f and inhibited the gene expression of TLR4, MyD88, and NF-κB p65 to reduce inflammatory cell infiltration, which determined the occurrence of hemorrhagic transformation. CONCLUSIONS: ZL can reduce inflammatory response by upregulating let-7f and subsequently inhibiting the TLR4 signaling pathway, thereby decreasing the occurrence of hemorrhagic transformation.

Tongue diagnostic parameters-based diagnostic signature in coronary artery disease patients with clopidogrel resistance after percutaneous coronary intervention.

BACKGROUND: Credible diagnostic stratification remains a challenge for coronary artery disease patients with clopidogrel resistance after percutaneous coronary intervention. Tongue diagnostic parameters-based diagnostic signatures might predict clopidogrel resistance. METHODS: Clinical and tongue diagnostic parameters data were obtained from coronary artery disease patients with clopidogrel resistance after percutaneous coronary intervention patients and then analyzed. Tongue diagnostic parameters-based diagnostic signatures were developed through univariate and multivariate logistic regression analysis. The diagnostic prediction was assessed using a receiver operating characteristic curve. RESULTS: A total of 101 patients were consecutively identified. Then, tongue diagnostic parameters were identified as significantly associated with clopidogrel resistance diagnosis and were combined with risk factors to develop a model. The receiver operating characteristic curve analysis showed that tongue diagnostic parameters-based diagnostic signatures performed well in diagnosing clopidogrel resistance with an area under the receiver operating characteristic curve value of 0.819. CONCLUSIONS: This study identified a novel tongue diagnostic parameters-based diagnostic signature to reliably distinguish clopidogrel resistance diagnosis in coronary artery disease patients undergoing percutaneous coronary intervention. Further larger, multicenter prospective studies are desired to validate this model.

Exploratory study of sea buckthorn enhancing QiangGuYin efficacy by inhibiting CKIP-1 and Notum activating the Wnt/ß-catenin signaling pathway and analysis of active ingredients by molecular docking.

Background: Sea buckthorn (SBT) is a traditional Chinese medicine (TCM), rich in calcium, phosphorus, and vitamins, which can potentially prevent and treat osteoporosis. However, no research has been conducted to confirm these hypotheses. QiangGuYin (QGY) is a TCM compound used to treat osteoporosis. There is a need to investigate whether SBT enhances QGY efficacy. Objectives: The aim of this study was to explore whether SBT enhances QGY efficacy by inhibiting CKIP-1 and Notum expression through the Wnt/ß-catenin pathway. The study also aimed to explore the active components of SBT. Methods: Experimental animals were divided into control, model, QGY, SBT, SBT + Eucommia ulmoides (EU), and SBT + QGY groups. After treatment, bone morphometric parameters, such as estrogen, PINP, and S-CTX levels, and Notum, CKIP-1, and ß-catenin expression were examined. Screening of SBT active components was conducted by molecular docking to obtain small molecules that bind Notum and CKIP-1. Results: The results showed that all the drug groups could elevate the estrogen, PINP, and S-CTX levels, improve femoral bone morphometric parameters, inhibit Notum and CKIP-1 expression, and promote ß-catenin expression. The effect of SBT + EU and SBT + QGY was superior to the others. Molecular docking identified that SBT contains seven small molecules (folic acid, rhein, quercetin, kaempferol, mandenol, isorhamnetin, and ent-epicatechin) with potential effects on CKIP-1 and Notum. Conclusion: SBT improves bone morphometric performance in PMOP rats by inhibiting CKIP-1 and Notum expression, increasing estrogen levels, and activating the Wnt/ß-catenin signaling pathway. Furthermore, SBT enhances the properties of QGY. Folic acid, rhein, quercetin, kaempferol, mandenol, isorhamnetin, and ent-epicatechin are the most likely active ingredients of SBT. These results provide insight into the pharmacological mechanisms of SBT in treating osteoporosis.

Guanxin V alleviates acute myocardial infarction by restraining oxidative stress damage, apoptosis, and fibrosis through the TGF-ß1 signalling pathway.

BACKGROUND: Oxidative stress, apoptosis, and fibrosis have important roles in acute myocardial infarction, which is the main cause of global morbidity and mortality. Guanxin V significantly ameliorates acute myocardial infarction, the underlying mechanism, however, is still unclear. PURPOSE: In this study, we detected the anti-oxidative, anti-apoptotic, and anti-fibrosis effects of Guanxin V on acute myocardial infarction. METHODS: We used left anterior descending coronary artery ligation to construct an acute myocardial infarction model. Cardiac function, heart weight, infarction size, and histopathology were measured. Cardiomyocytes were treated with hydrogen peroxide to build an in vitro model. Cell apoptosis, fibrosis, and reactive oxygen species-related markers were tested. We observed the mitochondrial ultrastructure through transmission electron microscopy. The levels of collagens and TGF-ß1 signalling were measured. The lentiviral vector containing the full-length TGF-ß1 sequence was administered to investigate the rescue role of Guanxin V. RESULTS: Guanxin V significantly decreased apoptosis and inhibited oxidative stress damage and fibrosis in acute myocardial infarction. Hydrogen peroxide could stimulate cardiomyocytes to produce reactive oxygen species and Guanxin V could significantly reverse hydrogen peroxide-induced cell damage, inhibit oxidative stress damage, apoptosis, and fibrosis, and enhance mitochondrial dynamic balance. Mechanistically, Guanxin V attenuated oxidative stress damage, apoptosis, and fibrosis induced by the TGF-ß1 signalling pathway activation. CONCLUSIONS: Guanxin V effectively relieved apoptosis, oxidative stress damage, and fibrosis through down-regulating the TGF-ß1 signalling pathway, which enhances the knowledge of the cellular and molecular mechanism of Guanxin V in treating acute myocardial infarction.

Guanxin V protects against ventricular remodeling after acute myocardial infarction through the interaction of TGF-ß1 and Vimentin.

BACKGROUND: Our previous study demonstrated that Guanxin V (GXV), a traditional Chinese herbal medicine, has a significant therapeutic effect on ventricular remodeling. However, the mechanistic action of GXV in ventricular remodeling warrants clarification. PURPOSE: Here, we aimed to explore the anti-ventricular remodeling contribution of GXV and to provide an experimental basis for clinical generalization. METHODS: A ventricular remodeling model after acute myocardial infarction was constructed in Syrian hamsters. The echocardiography and biochemical indices of cardiac function and remodeling were evaluated in different groups. Moreover, we built a remodeling model in cardiomyocytes and further explored the mechanism. Transmission electron microscopy was used to observe the ultrastructure of cardiomyocytes. The vital markers involved in the signaling pathway were detected by RT-qPCR and immunoblotting. Transforming growth factor beta 1 (TGF-ß1) was overexpressed with lentivirus to verify the necessity of TGF-ß1 in GXV's anti-ventricular remodeling effect. Finally, co-immunoprecipitation was conducted to test the interaction of TGF-ß1 and Vimentin. RESULTS: In hamster cardiac remodeling induced by acute myocardial infarction, GXV alleviated apoptosis, cardiac hypertrophy, and cardiac remodeling, and even improved cardiac function. Mechanistically, GXV inhibited the remodeling process by directly targeting TGF-ß1. Overexpression of TGF-ß1 exacerbated the ventricular remodeling, whereas GXV reversed this dysregulation. GXV also decreased the up-regulated Vimentin level in pathological ventricular remodeling. Moreover, the interaction of Vimentin and TGF-ß1 was confirmed by co-immunoprecipitation, and GXV impeded this interaction. CONCLUSION: We showed that the interaction of Vimentin and TGF-ß1 may be a novel target for ventricular remodeling and that GXV might be a new agent to fight against ventricular remodeling by targeting TGF-ß1 and impeding its interaction with Vimentin.

Cellular and Molecular Mechanism of Traditional Chinese Medicine on Ventricular Remodeling.

Ventricular remodeling is related to the renin-angiotensin-aldosterone system, immune system, and various cytokines involved in inflammation, apoptosis, and cell signal regulation. Accumulated studies have shown that traditional Chinese medicine can significantly inhibit the process of ventricular remodeling, which may be related to the mechanism mentioned above. Here, we conducted a system overview to critically review the cellular and molecular mechanism of traditional Chinese medicine on ventricular remodeling. We mainly searched PubMed for basic research about the anti-ventricular remodeling of traditional Chinese medicine in 5 recent years, and then objectively summarized these researches. We included more than 25 kinds of Chinese herbal medicines including Qi-Li-Qian-Xin, Qi-Shen-Yi-Qi Pill, Xin-Ji-Er-Kang Formula, and Yi-Qi-Wen-Yang Decoction, and found that they can inhibit ventricular remodeling effectively through multi-components and multi-action targets, which are promoting the clinical application of traditional Chinese medicine.

Potential Mechanism of Dingji Fumai Decoction Against Atrial Fibrillation Based on Network Pharmacology, Molecular Docking, and Experimental Verification Integration Strategy.

Background: Dingji Fumai Decoction (DFD), a traditional herbal mixture, has been widely used to treat arrhythmia in clinical practice in China. However, the exploration of the active components and underlying mechanism of DFD in treating atrial fibrillation (AF) is still scarce. Methods: Compounds of DFD were collected from TCMSP, ETCM, and literature. The targets of active compounds were explored using SwissTargetPrediction. Meanwhile, targets of AF were collected from DrugBank, TTD, MalaCards, TCMSP, DisGeNET, and OMIM. Then, the H-C-T-D and PPI networks were constructed using STRING and analyzed using CytoNCA. Meanwhile, VarElect was utilized to detect the correlation between targets and diseases. Next, Metascape was employed for systematic analysis of the mechanism of potential targets and protein complexes in treating AF. AutoDock Vina, Pymol, and Discovery Studio were applied for molecular docking. Finally, the main findings were validated through molecular biology experiments. Results: A total of 168 active compounds and 1,093 targets of DFD were collected, and there were 89 shared targets between DFD and AF. H-C-T-D network showed the relationships among DFD, active compounds, targets, and AF. Three functional protein complexes of DFD were extracted from the PPI network. Further systematic analysis revealed that the regulation of cardiac oxidative stress, cardiac inflammation, and cardiac ion channels were the potential mechanism of DFD in treating AF. Addtionally, molecular docking verified the interactions between active compounds and targets. Finally, we found that DFD significantly increased the level of SIRT1 and reduced the levels of ACE, VCAM-1, and IL-6. Conclusions: DFD could be utilized in treating AF through a complicated mechanism, including interactions between related active compounds and targets, promoting the explanation and understanding of the molecular biological mechanism of DFD in the treatment of AF.

An In-Silico, In-Vitro and In-Vivo Combined Approach to Identify NMNATs as Potential Protein Targets of ProEGCG for Treatment of Endometriosis.

Endometriosis is defined as endometrial tissues found outside the uterine cavity. ProEGCG is a prodrug of Epigallocatechin gallate (EGCG), a potent polyphenol found in green tea. It inhibits the development of endometriotic lesions of mouse model in vivo, with higher efficacy and more remarkable anti-oxidative ability than EGCG. Our study aims to identify the molecular binding targets and pharmacological actions of ProEGCG in treating endometriosis. Protein target interaction study is essential to fully characterize the mechanism of actions, related therapeutic effects, and side effects. We employed a combined approach, starting with an in silico reverse screening of protein targets and molecular docking, followed by in vitro cellular thermal shift assay (CESTA) to assess the stability of protein-small molecule complexes. Then microarray and immunostaining of endometriotic lesions in mice in vivo confirmed the molecular interaction of the selected targets after treatment. Our study identified enzymes nicotinamide nucleotide adenylyltransferase (NMNAT)1 and NMNAT3 as protein targets of ProEGCG in silico and in vitro and were overexpressed after ProEGCG treatment in vivo. These findings suggested that participation in nicotinate and nicotinamide metabolism potentially regulated the redox status of endometriosis via its antioxidative capacities through binding to the potential therapeutic targets of ProEGCG.

Traditional Chinese Medicine Intervenes Ventricular Remodeling Following Acute Myocardial Infarction: Evidence From 40 Random Controlled Trials With 3,659 Subjects.

Objectives: We intend to conduct a meta-analysis on the systematic evaluation of traditional Chinese medicine (TCM) in the treatment of ventricular remodeling following acute myocardial infarction (AMI). Our findings may provide certain references for the clinical treatment of ventricular remodeling. Methods: A systematic literature search was conducted in PubMed, Web of Science, Cochrane Library, Embase, CNKI, Wanfang Data, CQVIP, and CBM before 20 July 2020. Data were analyzed using a random/fixed-effect model. Primary outcomes included the effectiveness and TCM syndrome score (TCMSS). Secondary outcomes included 1) echocardiography data, including the left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic volume index (LVEDVi), left ventricular end-systolic volume index (LVESVi), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), left ventricular ejection fraction (LVEF), E/A, stroke volume (SV), and wall motion score (WMS); 2) serum indicators, including the B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP), and C-reactive protein (CRP) or high sensitivity CRP (hs-CRP); (3) major adverse cardiovascular events (MACE) and other adverse events Results: Forty RCTs involving 3,659 subjects were recruited. Our findings proved that a combination of TCM or TCM preparations with conventional Western medicine for preventing and reversing ventricular remodeling at post-AMI could remarkably enhance the total effectiveness and reduced TCMSS. Moreover, myocardial functions (LVEF, E/A, and SV), ventricular remodeling (LVEDVi, LVESVi, LVEDV, LVESV, LVEDD, LVESD, LVPWT, and WMS), serum levels of BNP and CRP, and MACE were significantly improved by the combination of TCM or TCM preparations with conventional Western medicine. Nevertheless, IVST and the incidence of other adverse events were comparable between control and experimental groups Conclusion: The combination of TCM or TCM preparations and conventional Western medicine can alleviate the process of ventricular remodeling, enhance cardiac function, and reduce the incidence of MACE in AMI patients.

Traditional Chinese Medicine for Coronary Artery Disease Treatment: Clinical Evidence From Randomized Controlled Trials.

Traditional Chinese medicine has a history of more than 2,000 years and has been widely used in clinical practice. However, due to the lack of a reliable scientific basis, the role of traditional Chinese medicine in the prevention and treatment of coronary artery disease is not clear. At present, the existing randomized controlled trials about traditional Chinese medicine for coronary artery disease have defects, small sample sizes, and different results, so it is difficult to make a clear conclusion on the actual advantages and disadvantages of traditional Chinese medicine. In this review, the efficacy and safety of traditional Chinese medicine in the prevention and treatment of coronary artery disease were systematically evaluated through randomized controlled trials, most of which were double-blind trials. We reviewed 17 randomized controlled trials that included a total of 11,726 coronary artery disease patients. The methodological quality of the trials was generally high, with nine (52.94%) having a modified Jadad score of 7 and only three (17.65%) having a modified Jadad score of <3. There are 16 trials (94.12%) reporting safety; the safety of traditional Chinese medicine seems not to be inferior to that of mimetic, placebo, or western medications. Moreover, the results from 17 randomized controlled trials (100.00%) showed that traditional Chinese medicine can be applied as a complementary and alternative method to the primary and secondary prevention of coronary artery disease, and only six trials (35.29%) described adverse cardiovascular events specifically. However, it is necessary to assess the safety and efficacy of traditional Chinese medicine in treating coronary artery disease with long-term hard endpoints.

Characterization of a Tumor-Microenvironment-Relevant Gene Set Based on Tumor Severity in Colon Cancer and Evaluation of Its Potential for Dihydroartemisinin Targeting.

Colon cancer (COAD) is a leading cause of cancer mortality in the world. Most patients with COAD die as a result of cancer cell metastasis. However, the mechanisms underlying the metastatic phenotype of COAD remain unclear. Instead, particular features of the tumor microenvironment (TME) could predict adverse outcomes including metastasis in patients with COAD, and the role of TME in governing COAD progression is undeniable. Therefore, exploring the role of TME in COAD may help us better understand the molecular mechanisms behind COAD progression which may improve clinical outcomes and quality of patients. Here, we identified a Specific TME Regulatory Network including AEBP1, BGN, POST, and FAP (STMERN) that is highly involved in clinical outcomes of patients with COAD. Comprehensive in silico analysis of our study revealed that the STMERN is highly correlated with the severity of COAD. Meanwhile, our results reveal that the STMERN might be associated with immune infiltration in COAD. Importantly, we show that dihydroartemisinin (DHA) potentially interacts with the STMERN. We suggest that DHA might contribute to immune infiltration through regulating the STMERN in COAD. Taken together, our data provide a set of biomarkers of progression and poor prognosis in COAD. These findings could have potential prognostic and therapeutic implications in the progression of COAD.

Integrating systematic pharmacology-based strategy and experimental validation to explore the synergistic pharmacological mechanisms of Guanxin V in treating ventricular remodeling.

BACKGROUND: Guanxin V (GXV) has been widely used to treat ventricular remodeling (VR) in clinical practice in China. However, the underlying mechanisms are currently still lack. METHODS: A systematic pharmacology-based strategy was utilized for predicting the synergistic pharmacological mechanisms of GXV in VR. The active compounds of GXV were selected and then the potential targets of these compounds contained in GXV and VR were successively identified. Then, after networks were constructed, DAVID was applied to functional enrichment. Moreover, the key findings were validated though molecular docking and molecular biology experiments. RESULTS: A total of 119 active components in GXV and 169 potential targets shared between GXV and VR were obtained. The results of functional enrichment indicated that several biological processes and signaling pathways, mainly cell apoptosis and fibrosis. Finally, we discovered GXV produced marked anti-apoptosis and anti-fibrosis effects in VR though Caspase-3 and TGF-ß1. CONCLUSION: GXV could relieve and reverse VR through anti-apoptosis and anti-fibrosis effects predicted by systematic pharmacology and validated by molecular docking and molecular experiments. Our study deepens the understanding of the molecular mechanisms of GXV in treating VR.

Effects of Traditional Chinese Medication-Based Bioactive Compounds on Cellular and Molecular Mechanisms of Oxidative Stress.

The oxidative stress reaction is the imbalance between oxidation and antioxidation in the body, resulting in excessive production of oxygen free radicals in the body that cannot be removed, leading to excessive oxidation of the body, and causing damage to cells and tissues. A large number of studies have shown that oxidative stress is involved in the pathological process of many diseases, so inhibiting oxidative stress, that is, antioxidation, is of great significance for the treatment of diseases. Studies have shown that many traditional Chinese medications contain antioxidant active bioactive compounds, but the mechanisms of those compounds are different and complicated. Therefore, by summarizing the literature on antioxidant activity of traditional Chinese medication-based bioactive compounds in recent years, our review systematically elaborates the main antioxidant bioactive compounds contained in traditional Chinese medication and their mechanisms, so as to provide references for the subsequent research.

Network Pharmacology-Based Systematic Analysis of Molecular Mechanisms of Dingji Fumai Decoction for Ventricular Arrhythmia.

BACKGROUND: Dingji Fumai Decoction (DFD), a traditional herbal mixture, has been widely used to ventricular arrhythmia (VA) in clinical practice in China. However, research on the bioactive components and underlying mechanisms of DFD in VA is still scarce. METHODS: Components of DFD were collected from TCMSP, ETCM, and literature. The chemical structures of each component were obtained from PubChem. Next, SwissADME and SwissTargetPrediction were applied for compounds screening and targets prediction of DFD; meanwhile, targets of VA were collected from DrugBank and Online Mendelian Inheritance in Man (OMIM). Then, the H-C-T-D network and the protein-protein interaction (PPI) network were constructed based on the data obtained above. CytoNCA was utilized to filter hub genes and VarElect was used to analyze the relationship between genes and diseases. At last, Metascape was employed for systematic analysis on the potential targets of herbals against VA, and AutoDock was applied for molecular docking to verify the results. RESULTS: A total of 434 components were collected, 168 of which were qualified, and there were 28 shared targets between DFD and VA. Three function modules of DFD were found from the PPI network. Further systematic analysis of shared genes and function modules explained the potential mechanism of DFD in the treatment of VA; molecular docking has verified the interactions. CONCLUSIONS: DFD could be employed for VA through mechanisms, including complex interactions between related components and targets, as predicted by network pharmacology and molecular docking. This work confirmed that DFD could apply to the treatment of VA and promoted the explanation of DFD for VA in the molecular mechanisms.

Effect of Guanxin V in animal model of acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is the most serious and lethal manifestation of coronary heart disease worldwide, presenting extremely high disability and mortality. Our previous studies have shown that Guanxin V (GXV) could significantly improve the cardiac function and the blood flow dynamics, and reduce serum levels of inflammatory factors in AMI rats, thus triggering ventricular remodeling (VR) at post-AMI. METHODS: An in vivo AMI model was established in Syrian hamsters by performing the ligation of the left anterior descending coronary artery. Syrian hamsters were randomly divided into four groups, namely Sham operation group (n = 12), AMI group (n = 12), GXV group (GXV 6 g/Kg/d, n = 12), and Tranilast group (Tra 105 mg/Kg/d, n = 12). Drug intervention was conducted for consecutive 8 weeks. Relative biological indicators were measured in the 4th and 8th week, respectively. RESULTS: Cardiac functions were improved, and the infarcted size and heart weight index were limited in Syrian hamsters of GXV and Tra groups compared with those in AMI group. Furthermore, GXV was able to decrease the number of mast cells and chymase level in Syrian hamsters with AMI. Administration of GXV remarkably inactivated the renin-angiotension-aldosterone system, and alleviated myocardial fibrosis and cardiomyocyte apoptosis, thus slowing down VR at post-AMI. CONCLUSION: GXV slows down the process of VR at post-AMI by reducing chymase level and mast cells number, as well as inactivating the reninangiotension-aldosterone system..

Virtual screening and network pharmacology-based synergistic mechanism identification of multiple components contained in Guanxin V against coronary artery disease.

BACKGROUND: Guanxin V (GXV), a traditional Chinese medicine (TCM), has been widely used to treat coronary artery disease (CAD) in clinical practice in China. However, research on the active components and underlying mechanisms of GXV in CAD is still scarce. METHODS: A virtual screening and network pharmacological approach was utilized for predicting the pharmacological mechanisms of GXV in CAD. The active compounds of GXV based on various TCM-related databases were selected and then the potential targets of these compounds were identified. Then, after the CAD targets were built through nine databases, a PPI network was constructed based on the matching GXV and CAD potential targets, and the hub targets were screened by MCODE. Moreover, Metascape was applied to GO and KEGG functional enrichment. Finally, HPLC fingerprints of GXV were established. RESULTS: A total of 119 active components and 121 potential targets shared between CAD and GXV were obtained. The results of functional enrichment indicated that several GO biological processes and KEGG pathways of GXV mostly participated in the therapeutic mechanisms. Furthermore, 7 hub MCODEs of GXV were collected as potential targets, implying the complex effects of GXV-mediated protection against CAD. Six specific chemicals were identified. CONCLUSION: GXV could be employed for CAD through molecular mechanisms, involving complex interactions between multiple compounds and targets, as predicted by virtual screening and network pharmacology. Our study provides a new TCM for the treatment of CAD and deepens the understanding of the molecular mechanisms of GXV against CAD.

[Mechanism action of Chinese herbal compound and target network pharmacology of Yougui (YG) pill for the treatment of osteoporosis].

OBJECTIVE: To explore compounds, targets and mechanism of Yougui (YG) pill in treating osteoporosis based on systemic pharmacology of traditional Chinese medicine. METHODS: The known effective Chinese herbal compound of YG pill was searched from traditional Chinese medicine integrated database(TCMID). Bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine (BATMAN-TCM) was used to predict target of components;DisGeNET and artificial literature reading were used to obtain targets of osteoporosis and bone remodeling;Cytoscape 3.7.1 software and its plug-ins BiN-GO and ClueGO were used to enrich the GO annotation and pathwaysof the related targets, and validation of the predicted target of YG pill were validated by 87 differentially expressed proteins in postmenopausal osteoporosis and postmenopausal osteoporosis disease models in postmenopausal patients with normal bone mass from the previous serum proteomics data. RESULTS: Totally 392 compounds were retrieved from YG pill, including 83 sovereign drugs (monkshood, cinnamon, deerhorn gelatin), 127 ministerial drugs (prepared rehmannia root, dogwood, wolfberry fruit and Chinese yam) and 182 supplementary drugs (cuscuta chinensis, eucommia ulmoides and Chinese angelica). Among them, there were 4 same compounds between sovereign drug and ministerial drug, 1 same compound between sovereign drug and supplementary drug, and 14 same compounds between ministerial drug and supplementary drug. Totally 2 112 trusted targets were identified, included 775 sovereign drugs, 1 483 ministerial drugs and 1 491 supplementary drugs;227 targets were selected from YG pill for treating osteoporosis, which participate in nearly 20 process of metabolic process, cell differentiation and biology, and data mining revealed that the process involved bone remodeling and bone mineralization. Acting site of cell mainly inclded 9 kinds of cell which had 13 molecular function. Results of KEGG metabolic pathway enrichment analysis showed 137 signal passages were obviously enriched. Among them, classical osteoclast differentiation signal passages and relative estrogen regulates signaling pathways of menopause were widely distributed in 27 signal passages. Sixtargets were screened by target validation, such as AGT, FGA, APOE, DKK3, P4HB and RAB7A. CONCLUSION: The characteristics of multi-targets and multi-pathways of YG pill for the treatment of osteoporosis were clarified, which provided a clear direction for the in-depth research. The pharmacodynamic components of YG pill include 36 compounds, and their main action targets include FGA, AGT, APOE, DKK3, P4HB and RAB7A.