Integration of virtual screening and proteomics reveals potential targets and pathways for ginsenoside Rg1 against myocardial ischemia.

Background: Ginsenoside Rg1 (Rg1) is one of the main active components in Chinese medicines, Panax ginseng and Panax notoginseng. Research has shown that Rg1 has a protective effect on the cardiovascular system, including anti-myocardial ischemia-reperfusion injury, anti-apoptosis, and promotion of myocardial angiogenesis, suggesting it a potential cardiovascular agent. However, the protective mechanism involved is still not fully understood. Methods: Based on network pharmacology, ligand-based protein docking, proteomics, Western blot, protein recombination and spectroscopic analysis (UV-Vis and fluorescence spectra) techniques, potential targets and pathways for Rg1 against myocardial ischemia (MI) were screened and explored. Results: An important target set containing 19 proteins was constructed. Two target proteins with more favorable binding activity for Rg1 against MI were further identified by molecular docking, including mitogen-activated protein kinase 1 (MAPK1) and adenosine kinase (ADK). Meanwhile, Rg1 intervention on H9c2 cells injured by H2O2 showed an inhibitory oxidative phosphorylation (OXPHOS) pathway. The inhibition of Rg1 on MAPK1 and OXPHOS pathway was confirmed by Western blot assay. By protein recombination and spectroscopic analysis, the binding reaction between ADK and Rg1 was also evaluated. Conclusion: Rg1 can effectively alleviate cardiomyocytes oxidative stress injury via targeting MAPK1 and ADK, and inhibiting oxidative phosphorylation (OXPHOS) pathway. The present study provides scientific basis for the clinical application of the natural active ingredient, Rg1, and also gives rise to a methodological reference to the searching of action targets and pathways of other natural active ingredients.

Cooperation of TGF-ß and FGF signalling pathways in skin development.

The skin is a multi-layered structure composed of the epidermis, dermis and hypodermis. The epidermis originates entirely from the ectoderm, whereas the dermis originates from various germ layers depending on its anatomical location; thus, there are different developmental patterns of the skin. Although the regulatory mechanisms of epidermal formation are well understood, mechanisms regulating dermis development are not clear owing to the complex origin. It has been shown that several morphogenetic pathways regulate dermis development. Of these, transforming growth factor-ß (TGF-ß) and fibroblast growth factor (FGF) signalling pathways are the main modulators regulating skin cell induction, fate decision, migration and differentiation. Recently, the successful generation of human skin by modulating TGF-ß and FGF signals further demonstrated the irreplaceable roles of these pathways in skin regeneration. This review provides evidence of the role of TGF-ß and FGF signalling pathways in the development of different skin layers, especially the disparate dermis of different body regions. This review also provides new perspectives on the distinct developmental patterns of skin and explores new ideas for clinical applications in the future.

Recent progress (2015-2020) in the investigation of the pharmacological effects and mechanisms of ginsenoside Rb1, a main active ingredient in Panax ginseng Meyer.

Ginsenoside Rb1 (Rb1), one of the most important ingredients in Panax ginseng Meyer, has been confirmed to have favorable activities, including reducing antioxidative stress, inhibiting inflammation, regulating cell autophagy and apoptosis, affecting sugar and lipid metabolism, and regulating various cytokines. This study reviewed the recent progress on the pharmacological effects and mechanisms of Rb1 against cardiovascular and nervous system diseases, diabetes, and their complications, especially those related to neurodegenerative diseases, myocardial ischemia, hypoxia injury, and traumatic brain injury. This review retrieved articles from PubMed and Web of Science that were published from 2015 to 2020. The molecular targets or pathways of the effects of Rb1 on these diseases are referring to HMGB1, GLUT4, 11ß-HSD1, ERK, Akt, Notch, NF-κB, MAPK, PPAR-γ, TGF-ß1/Smad pathway, PI3K/mTOR pathway, Nrf2/HO-1 pathway, Nrf2/ARE pathway, and MAPK/NF-κB pathway. The potential effects of Rb1 and its possible mechanisms against diseases were further predicted via Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and disease ontology semantic and enrichment (DOSE) analyses with the reported targets. This study provides insights into the therapeutic effects of Rb1 and its mechanisms against diseases, which is expected to help in promoting the drug development of Rb1 and its clinical applications.

Deciphering the potential anti-COVID-19 active ingredients in Andrographis paniculata (Burm. F.) Nees by combination of network pharmacology, molecular docking, and molecular dynamics.

Currently, coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 has posed an enormous threat to public health worldwide. An andrographolide sulfonates preparation, named Xiyanping injection in Chinese, which was prepared from the aqueous extract of Andrographis paniculata (Burm. F.) Nees, showed favorable therapeutic effectiveness on COVID-19, suggesting A. paniculata could contain powerful therapeutic ingredients against COVID-19. In this study, to search for the potential drug candidates for COVID-19 in the herb, 68 potential target proteins and 24 active ingredients from A. paniculata were screened out using TCMSP, STP, Genecards and TTD databases firstly. A. paniculata-Compound-Target network constructed by cytoscape software showed that the protein targets PTGS2, EGFR, MAPK14, etc. had a high network relevance value. GO and KEGG enrichment analysis indicated that the 24 compounds in A. paniculata might exert their therapeutic effects by the biological processes, cellular response to biotic stimulus, response to lipopolysaccharide, response to molecule of bacterial origin, etc. And AGE-RAGE signaling pathway in diabetic complications (hsa04933), Kaposi sarcoma-associated herpesvirus infection (hsa05167), Human cytomegalovirus infection (hsa05163), etc. were predicted as the most significant effect pathways. Andrographidine C (MOL008223) and andrographolide (MOL008232) were found with strong binding affinity to the target active sites of the potential targets by molecular docking. Ultimately, the application of molecular dynamics simulations demonstrated that andrographidine C could bind well to the ACE2 and PIK3CG proteins. This research identified novel molecules against COVID-19 for developing natural medicines from A. paniculate and also provides a possible explanation for the molecular mechanisms of Xiyanping Injection against COVID-19.

Traditional Chinese medicine for restless legs syndrome: A study protocol for a network meta-analysis.

BACKGROUND: Restless legs syndrome (RLS) is a sensory motor disorder. It mainly manifests as indescribable pain in the lower limbs at night or at rest, and the symptoms are reduced after activity or beating, which seriously affects the patients sleep. Nowadays, a large number of randomized controlled clinical studies have shown that Chinese medicine has the advantages of good curative effect and high safety in the treatment of RLS. However, due to the various treatment methods of Chinese medicine, its relative effectiveness and safety have not been verified. Therefore, this study will use a network meta-analysis method to verify the effectiveness and safety of different types of TCM therapies in the treatment of RLS. METHODS: Computer retrieval was conducted in PubMed, Cochrane Library, Web of Science, Embase, SinoMed, CNKI, WanFang-database, VIP. The retrieval period was until September 9, 2020, and all randomized controlled trials of TCM treatment of RLS were collected. To avoid omissions, we will manually search relevant references and conference papers. According to the inclusion and exclusion criteria, we conduct quality assessment and risk assessment of all retrieved documents. Methodological quality assessment and risk of bias will be assessed using Cochrane bias risk tool. All data analysis will use Revman5.3, WinBUGS 1.4.3, and Stata14.2 software. RESULTS: This study will directly or indirectly compare the effectiveness of different interventions on RLS outcome indicators, and rank the effectiveness. The main outcome indicators include total effective rate (total effective rate = rocovery + obvious effective + effective/total number of cases × 100%), International Restless Legs Syndrome Score Scale, secondary outcome indicators include visual analog scale, Pittsburgh sleep quality indicators and adverse events. CONCLUSION: Provide a basis for evidence-based medicine, and provide a basis for clinical researchers to choose more effective Chinese medicine treatment of RLS.

An Integrated Pharmacokinetic Study of an Acanthopanax senticosus Extract Preparation by Combination of Virtual Screening, Systems Pharmacology, and Multi-Component Pharmacokinetics in Rats.

In this paper, the integrated pharmacokinetics (PK) of an Acanthopanax senticosus extract preparation (ASEP, named as Ciwujia injection in clinic in China) was explored by combining with multi-component PK in rats, virtual screening, systems pharmacology and molecular docking. Firstly, the ingredients in ASEP with high contents and detectable property in rat plasma were selected. Next, the PK study of the resulted ingredients was performed in rats (1.76 ml/kg and 3.52 ml/kg of 5 times concentrated ASEP, single i.v.). Meanwhile, the drug targets for the ingredients screened out were predicted by using a target fishing online server, PharmMapper (http://www.lilab-ecust.cn/pharmmapper/) with a fit filtration threshold of z'-score >0. Next, the network pharmacology, molecular docking, diseases ontology (DO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed respectively for the predicted targets. Finally, the supporting evidences were obtained to characterize the PK markers and carry out the integrated PK study with "plasma-drug concentration sum" or "plasma-drug AUC weighted" methods. As a result, 6 ingredients, involving 5-caffeoylquinic acid (5-CQA), 3-CQA, 4-CQA, protocatechuic acid, eleutheroside B, and gentiopicroside were selected, and their PK profiles were elucidated. The 6 ingredients were highly related to arteriosclerotic cardiovascular disease and atherosclerosis and could mainly interact with similar targets, e.g., GSK3B, PDPK1, PLAU, etc., or pathways, e.g., Insulin, VEGF, FoxO, etc, providing the basis for integrating plasma drug concentration. Ultimately, the 6 ingredients were considered as PK markers and the whole in vivo process of ASEP were characterized. Our study would enhance understanding of the therapeutic effects and mechanisms of ASEP against cardiovascular diseases, and provided useful insights for future integrated PK study on anti-cardiovascular diseases TCM injections.

Different acupuncture therapies for spastic paralysis after stroke: A protocol for systematic review and network meta-analysis.

BACKGROUND: Stroke is emerging as a significant health issue that threatens human health worldwide and as a common sequela of stroke spastic paralysis after stroke (SPAS) has received wide attention. Currently, several systematic reviews have suggested that the commonly used acupuncture therapy (electroacupuncture, fire acupuncture, warm acupuncture, and filiform needle acupuncture) has achieved significant efficacy in the treatment of SPAS. In this study, network meta-analysis will be used to analyze the results of different clinical trials and evaluate the differences in the efficacy of different acupuncture treatments for SPAS. METHODS: Only randomized controlled trials will be included and all patients were diagnosed as spastic paralysis after stroke. A computer-based retrieval will be conducted at CNKI, WanFang databases, VIP, Sinoed, Pubmed, Embase, Web of Science, and the Cochrane library. The search period limit is from the time the date of database establishment to April 17, 2020. To avoid omissions, we will manually retrieve relevant references and conference papers. The risk of bias in the final included studies will be evaluated based on the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. All data analysis will be conducted by Revman5.3, WinBUGS 1.4.3, and Stata14.2. RESULTS: This study quantified the effectiveness of each intervention for different outcome indicators. The primary outcomes include the Fugl-Meyer Assessment score, the modified Ashworth scale for the assessment of spasticity, and Barthel Index. The secondary outcomes include clinical effectiveness and adverse reactions. CONCLUSION: It will provide evidence-based medical evidence for clinicians to choose more effective acupuncture therapy for SPAS.

Acupotomy therapy for cervical vertigo: A protocol for a systematic review and meta-analysis.

BACKGROUND: Acupotomy has been widely used to relieve cervical vertigo (CV). However, the efficacy of acupotomy for CV is uncertain. The purpose of this study is to evaluate the efficacy and safety of the acupotomy for CV. METHODS: The following electronic databases will be searched to identify relevant randomized controlled trials (RCTs) for inclusion in the review from inception to April 2020: PubMed, the Cochrane Library, Embase, the China National Knowledge Infrastructure, Wanfang Database, Chinese Science and Technology Periodical Database, and Chinese Biomedical Literature Database. Two researchers will independently select studies, collect data, and assess the methodology quality by the Cochrane risk of bias tool. Meta-analysis will be completed by RevMan V.5.3 software. RESULTS: This systematic review will provide an assessment of the current state of acupotomy for CV, aiming to assess the efficacy and safety of acupotomy for Patients with CV. CONCLUSION: This systematic review will provide a credible Evidence-based for the clinical treatment of CV with acupotomy.PROSPERO registration number: CRD42019134712.

Traditional Chinese medicine for myasthenia gravis: Study protocol for a network meta-analysis.

BACKGROUND: Myasthenia gravis (MG) is a disease that is difficult to cure, mainly manifested in the affected skeletal muscle weakness and morbid fatigue, which seriously affects the patients' daily life and work. A large number of randomized controlled trial have shown that Traditional Chinese medicine (TCM) has a good effect in treating MG. However, due to the variety of TCM treatment methods, its relative effectiveness and safety have not been verified. Therefore, this study will use a network meta-analysis method to verify the effectiveness and safety of different types of TCM in the treatment of MG. METHODS: We will search the following databases from inception to June 2020: the China National Knowledge Infrastructure, Wanfang Database, Chinese Science and Technology Periodical Database, Chinese Biomedical Literature Database, Pubmed, Embase, Web of Science, and the Cochrane library. Collect all randomized controlled trial of TCM for the treatment of MG, The 2 authors will independently select studies and extract data based on pre-designed inclusion and exclusion criteria. Methodological quality assessment and risk of bias will be assessed using Cochrane bias risk tool. All data analysis will be conducted using Revman5.3, WinBUGS 1.4.3, and Stata14.2 software. RESULTS: This study will directly and indirectly compare the different outcome indicators of various studies, and rank the effectiveness of different TCM methods. The main outcome indicators include effectiveness, remission rate (no drug symptoms), relapse rate, clinical absolute score, and relative score. Secondary outcome indicators: including any related adverse reactions, the concentration of acetylcholine receptor antibody in serum. CONCLUSION: The conclusion of this systematic review will provide credible Evidence-based for the relative advantages of different TCM treatment methods for MG.

Potential mechanism of action of Ixeris sonchifolia extract injection against cardiovascular diseases revealed by combination of HPLC-Q-TOF-MS, virtual screening and systems pharmacology approach.

Ixeris sonchifolia extract injection, a Chinese medicine preparation named as Kudiezi injection (KDZI) in China, has been widely used for the treatment of cardiovascular diseases (CVDs) in recent years. Owing to the component complexity of the preparation, the study on the effect mechanism of the herbal medicine against CVDs is a big challenge. In this research, HPLC-Q-TOF-MS was used to analyze the constituents of the preparation, disclosing that the KDZI mainly consists of 10 ingredients, namely 3-caffeoylquinic acid (KDZI-1), 4-caffeoylquinic acid (KDZI-2), 5-caffeoylquinic acid (KDZI-3), apigenin-7-O-ß-d-glucuronide (KDZI-4), caffeic acid (KDZI-5), chicoric acid (KDZI-6), caftaric acid (KDZI-7), luteolin-7-O-ß-d-gentiobioside (KDZI-8), luteolin-7-O-ß-d-glucopyranoside (KDZI-9) and luteolin-7-O-ß-d-glucuronide (KDZI-10). Afterwards, target fishing and an integrated systems pharmacology approach combined with molecular docking (Sybyl 1.3 and AutoDock Vina) were adopted to predict the potential targets and pathways for the main ingredients in KDZI. As results, 39 protein targets and 9 KEGG pathways, possessing high relevance to the therapeutic effects of the ingredients of KDZI against CVDs, were screened out reasonably. The integrated pharmacology analysis suggested that KDZI could exert its therapeutic effects against CVDs possibly via multi-targets including EGFR, MAPK10, and SRC and multi-pathways referring to MAPK, focal adhesion, complement and coagulation cascades, etc. This research provides insights into understanding the comprehensive therapeutic effect and mechanism of the KDZI on CVDs.

[Effects of Early Goal-directed Therapy Combined with Yiqi Fumai Lyophilized Powder on P(cv-a) CO2 and S(cv)O2 in Patients with Septic Shock].

OBJECTIVE: To explore the effect of early goal-directed therapy (EGDT) combined with Yiqi Fumai Lyophilized Powder (YFLP) on central venous-arterial carbon dioxide difference [P(cv-a)CO2] and central venous oxygen saturation (S(cv)O2) in patients with septic shock. METHODS: Totally 50 patients with septic shock were assigned to the control group and the treatment group according to random digit table, 25 cases in each group. Patients in the control group received treatment according to EGDT principle. Those in the treatment group were intravenously injected with YFLP (5.2 g adding in 500 mL normal saline) additionally. Changes of P(cv-a)CO2, S(cv)O2, lactic acid, central venous pressure (CVP), mean arterial pressure (MAP), and APACHE II score were observed in the two groups before and after treatment. The 6-h success rate and 28-day mortality were also observed. RESULTS: Compared with before treatment in the same group, lactic acid and APACHE II score decreased, levels of S(cv)O2, MAP, CVP increased in the two groups after treatment (P < 0.01). P(cv-a)CO2 decreased more obviously after treatment in the treatment group, and lower than that in the control group after treatment (P < 0. 05, P < 0. 01). The 6-h success rate was 48% (12/25) in the control group and 76% (19/25) in the treatment group (P < 0.05). The 28-day mortality was 36% (9/25) in the control group and 12% (3/25) in the treatment group (P < 0.05). CONCLUSION: EGDT combined with YFLP could significantly elevate S(cv)O2, decrease P(cv-a)CO2 and mortality in patients with septic shock, and obviously improve the clinical effect.