Systems Pharmacology Dissection of Mechanisms of Dengzhan Xixin Injection against Cardiovascular Diseases.

Dengzhan Xixin injection (DZXXI), a herbal product prepared from a Chinese herb called Erigeron breviscapus, is a classical and traditional therapeutic for cadiovascular diseases (CVDs), including coronary heart disease (CHD), angina, and stroke, etc. However, its potential pharmacology mechanism against CVDs remains unclear. In this paper, a systems pharmacology-based strategy is presented for predicting drug targets and understanding therapeutic mechanisms of DZXXI against CVDs. The main ingredients were identified by HPLC-diode array detector (DAD). The target fishing was performed on the PharmMapper Server (http://lilab-ecust.cn/pharmmapper/). Potential targets were confirmed by two molecular docking tools, Sybyl-X 1.3 and Ledock to ensure the accuracy. The resulting target proteins were applied as baits to fish their related diseases and pathways from the molecular annotation system (MAS 3.0, http://bioinfo.capitalbio.com/mas3/) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database (http://www.genome.jp/kegg/). Network generation and topological analysis were performed in Cytoscape 3.6.0. 15 main ingredients from DZXXI were identified. Forty five putative drug targets and 50 KEGG pathways, which have highly relevance to the therapeutic effects of DZXXI against CVDs, were then obtained. The systems analysis suggested that DZXXI could attenuate cardiac fibrosis, regulate cardiac contractility, and preserve heart function in adverse cardiac remodeling; meanwhile DZXXI also could have the function of activating blood circulation and dilating blood vessels. DZXXI exerts its therapeutic effects on CVDs possibly through multi-targets including CMA1, epidermal growth factor receptor (EGFR), phenylalanine-4-hydroxylase (PAH), SRC, F7, etc., and multi-pathways including Focal adhesion, mitogen-activated protein kinase (MAPK) signaling pathway, complement and coagulation cascades, Wnt signaling pathway, vascular endothelial growth factor (VEGF) signaling pathway, Renin-angiotensin system, etc.

Antioxidative and Cardioprotective Effects of Schisandra chinensis Bee Pollen Extract on Isoprenaline-Induced Myocardial Infarction in Rats.

Oxidative stress plays an important role in the pathogenesis of myocardial infarction (MI). Schisandra chinensis bee pollen extract (SCBPE) possesses powerful antioxidant capacity. This study aimed to further explore the antioxidative and cardioprotective effects of SCBPE on acute MI induced by isoprenaline (ISO) in rats. The rats were intragastrically administrated with SCBPE (600, 1200, or 1800 mg/kg/day) and Compound Danshen dropping pills (270 mg/kg/day) for 30 days, then subcutaneously injected with ISO (65 mg/kg/day) on the 29th and 30th day. Compared with the model group, pretreatment with middle and high doses of SCBPE significantly reduced serum aspartate transaminase, lactate dehydrogenase, and creatine kinase activities and increased myocardial superoxide dismutase, glutathione peroxidase, and catalase activities. The histopathologic aspects showed that pathological heart change was found in the model group and reduced to varying degrees in the SCBPE groups. Moreover, the protein expression of nuclear factor-erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1), and Bcl2 in the heart increased in the SCBPE groups, while that of Bax decreased compared to the model group. Besides this, uridine was isolated from S. chinensis bee pollen for the first time. This study could provide a scientific basis for using Schisandra chinensis bee pollen as a functional food for the prevention of MI.

A comprehensive review of recent studies on pharmacokinetics of traditional Chinese medicines (2014-2017) and perspectives.

Traditional Chinese medicines (TCMs) have a long history for safely treating human diseases. Unlike western medicine, TCMs usually contain multiple components synergistically and holistically acting on the diseases. It remains a big challenge to represent rationally the in vivo process of multiple components of TCMs for understanding the relationship between administration and therapeutic effects. For years, efforts were always made to face the challenge, and the achievements were obvious. Here, we give an comprehensive overview of the recent investigation progress (from 2015 to 2017, except the part of 'integrated pharmacokinetics of TCMs' from 2014 to 2017 and the part of 'reverse pharmacokinetics in drug discovery from natural medicines' in 2014) on pharmacokinetics of TCMs, mainly referring to the following six aspects: (1) classical pharmacokinetic studies on TCMs; (2) absorbed components and metabolites identification of TCMs; (3) pharmacokinetic herb-drug interactions and herb-herb interactions with TCMs; (4) integrated pharmacokinetics of TCMs; (5) pharmacokinetic and pharmacodynamic combination studies to dissect the action mechanisms of TCMs; and (6) reverse pharmacokinetics in drug discovery from natural medicines. Finally, based on the insights from the recent progress and our latest efforts, we propose new perspectives on the integrated pharmacokinetics of TCMs.

Simultaneous Determination of Five Phenolic Acids and Four Flavonoid Glycosides in Rat Plasma Using HPLC-MS/MS and Its Application to a Pharmacokinetic Study after a Single Intravenous Administration of Kudiezi Injection.

This study has developed a reliable and precise high performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of five phenolic acids and four flavonoid glycosides in rat plasma after a single intravenous administration of Kudiezi injection (KI). Chromatographic separation was carried out on an Ultimate®XB-C18 column (4.6 × 100 mm, 3.5 µm) using a gradient elution program with a mobile phase consisting of water containing 0.5% acetic acid and acetonitrile at a flow rate of 0.6 mL/min. Detection was performed on a triple-quadrupole tandem mass spectrometry using multiple reaction monitoring in negative electrospray ionization mode. The calibration curves of all analytes showed good linearity (R² > 0.990). The results of selectivity, intra-day and inter-day precisions, extraction recoveries, matrix effects and stability were satisfactory. Pharmacokinetic parameters showed that luteolin-7-O-ß-d-gentiobioside, luteolin-7-O-ß-d-glucuronide, luteolin-7-O-ß-d-glucoside and apigenin-7-O-ß-d-glucuronide were eliminated quickly (0.07 h < t1/2 < 0.66 h), whereas 5-caffeoylquinic acid, caftaric acid, chlorogenic acid, 4-caffeoylquinic acid and caffeic acid were eliminated relatively slowly (2.22 h < t1/2 < 6.09 h) in rat blood. The pharmacokinetic results would be valuable to identify bioactive constituents, elucidate mechanisms of pharmacological actions or adverse drug reactions and guide the rational clinical use of KI.

DPPH·-luminol chemiluminescence system and its application in the determination of scutellarin in pharmaceutical injections and rat plasma with flow injection analysis.

In this article, a DPPH·-luminol chemiluminescence (CL) system was reported and the CL mechanism was discussed according to the CL kinetic properties after sequence injecting DPPH· into the DPPH·-luminol reaction mixture. It was observed that scutellarin could inhibit the CL response of the DPPH·-luminol system. Based on this observation, a simple and rapid flow injection CL method was developed for the determination of scutellarin using the inhibition effect in alkaline medium. The optimized chemical conditions for the CL reaction were 5 × 10-6  mol/L DPPH· and 1.0 × 10-4  mol/L luminol in 0.01 mol/L NaOH. Under optimized conditions, the CL intensity was inversely proportional to the concentration of scutellarin over the ranges 5-2000 and 40-3200 ng/ml in pharmaceutical injection and rat plasma, respectively. The limits of detection (S/N = 3) were 5 and 40 ng/ml in preparations and rat plasma, respectively. Furthermore, the precision, recovery and stability of the validated method were acceptable for the determination of scutellarin in both pharmaceutical injections and rat plasma. The presented method was successfully applied in the determination of scutellarin in pharmaceutical injections and real rat plasma samples.

Analysis of the Total Biflavonoids Extract from Selaginella doederleinii by HPLC-QTOF-MS and Its In Vitro and In Vivo Anticancer Effects.

Selaginella doederleinii Hieron has been traditionally used as a folk antitumor herbal medicine in China. In this paper, the phytochemical components of the total biflavonoids extract from S. doederleinii were studied by using high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC-ESI-QTOF MS/MS) in negative ion mode, and their in vitro and in vivo anticancer effects were evaluated. Four types of biflavonoids from S. doederleinii, including IC3'-IIC8'', IC3'-IIC6'', IC3'-IIC3''', and C-O linked biflavonoids were examined originally using QTOF MS/MS. The fragmentation behavior of IC3'-IIC3''' linked biflavonoids was reported for the first time. A total of twenty biflavonoids were identified or tentatively characterized and eight biflavonoids were found from S. doederleinii for the first time. Furthermore, the 3-(4,5-Dimethyl-2-thizolyl)-2,5-diphenyltertazolium bromide (MTT) assay and xenograft model of mouse lewis lung cancer(LLC) in male C57BL/6 mice revealed favorable anticancer properties of the total biflavonoids extracts from S. doederleinii. The results of this work could provide useful knowledge for the identification of biflavonoids in herbal samples and further insights into the chemopreventive function of this plant.

Pharmacokinetics, Tissue Distribution and Protein Binding Studies of Chrysocauloflavone I in Rats.

Chrysocauloflavone I, an unfrequent biflavonoid, was purified from Selaginella doederleinii in this study. It showed cytotoxic effects on three human cancer cells, NCI-H1975, A549, and HepG-2, in vitro. In silico assessment of the physicochemical properties was performed for predicting the permeability and intestinal absorption of the tested compound. Subsequently, a rapid, sensitive, and specific high-performance liquid chromatography method was developed for determination of the compound in different biological samples to ascertain the pharmacokinetics, tissue distribution, and protein binding profiles of this active ingredient in rats. After intravenous dosing of chrysocauloflavone I at different levels (10 and 20 mg/kg), the elimination half-life was approximately 85 min, and the AUC0-∞ increased with the dose from 148.52 mg/L × min for 10 mg/kg to 399.01 mg/L × min for 20 mg/kg. After single intravenous dosing (20 mg/kg), chrysocauloflavone I was detected in all tissues studied with higher levels in the heart, blood, and lungs. The results of equilibrium dialysis indicated a very high protein binding degree (over 97%) for chrysocauloflavone I. After intragastric administration of 100 mg/kg chrysocauloflavone I to rats, no parent drug was detected in the rat plasma. This is the first report of the favorable bioactivities, plasma pharmacokinetics, tissue distribution, and protein binding profiles of the rare biflavone chrysocauloflavone I.

Metabolism and plasma pharmacokinetics of isoorientin, a natural active ingredient, in Sprague-Dawley male rats after oral and intravenous administration.

1. Several pharmacological effects have been revealed on isoorientin, suggesting its potential medicinal prospects. The metabolic and plasma pharmacokinetic profiles of isoorientin were investigated in rats. 2. For intra-gastric gavage, parent drug and three metabolites were detected in urine and feces by HPLC-MS/MS, but only one metabolite was found in plasma and identified as isoorientin 3'- or 4'-O-sulfate (M1) according to MS and UV absorbance spectra. 3. After a single i.v. administration of isoorientin (5, 10, or 15 mg/kg B.W.) in rats, linear pharmacokinetic property was observed with favorable terminal half-lives (1.67 ± 1.32-2.07 ± 0.50 h). After a single p.o. administration of isoorientin (150 mg/kg B.W.) in rats, plasma isoorientin concentration was low, but the concentration of M1 was comparatively high. Low systemic exposure of oral isoorientin in rats could result from its low aqueous solubility and extensive first-pass metabolism, and plasma concentration of M1 can be used as a biomarker of isoorientin intake. Isoorientin showed low oral bioavailability (8.98 ± 1.07%), and had about 6% or 45% dose recovery in urine or feces, respectively, 72 h after intra-gastric gavage. 4. These studies are the first to describe the pharmacokinetics of isoorientin via i.v. or p.o. dosing, providing important information for understanding its process in vivo.

Honey reduces blood alcohol concentration but not affects the level of serum MDA and GSH-Px activity in intoxicated male mice models.

BACKGROUND: For a long time, honey was purportedly helpful to prevent drunkenness and relieve hangover symptoms. However, few of the assertions have experienced scientific assessment. The present study examined the effects of honey on intoxicated male mice. METHODS: Low or high doses of lychee flower honey (2.19 or 4.39 g/kg body weight, respectively) were single orally administrated 30 min before the ethanol intoxication of mice, followed by recording the locomotor activity by autonomic activity instrument and observing the climbing ability after alcohol. On the other hand, 2.19 g/kg honey was single orally administrated 5 min after the ethanol intoxication of mice, followed by determining the ethanol concentration in mice blood. In addition, subacute alcoholism mice models were developed and after the treatment of 2.19 g/kg honey s.i.d for successive three days, the level of serum malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) activity were detected in the models. RESULTS: Both of the two doses of honey increased the autonomic activity of alcoholized mice. Furthermore, the treatment of 2.19 g/kg honey could decrease significantly the blood ethanol concentration in intoxicated mice. The anti-intoxication activity of honey could be due to the effect of the fructose contained in the honey. Meanwhile, honey could not affect the serum MDA level and GSH-Px activity in alcoholism mice models. CONCLUSION: Honey indeed possesses anti-intoxication activity.

Schisandra chinensis Bee Pollen Extract Inhibits Proliferation and Migration of Hepatocellular Carcinoma HepG2 Cells via Ferroptosis-, Wnt-, and Focal Adhesion-Signaling Pathways.

Purpose: Bee pollen possesses favorable anticancer activities. As a medicinal plant source, Schisandra chinensis bee pollen (SCBP) possesses potential pharmacological properties, such as reducing cisplatin-induced liver injury, but its anti-liver cancer effect is still rarely reported. This paper aims to investigate the effect and mechanism of SCBP extract (SCBPE) on hepatocellular carcinoma HepG2 cells. Methods: The effect of SCBPE on cell proliferation and migration of HepG2 cells was evaluated based on MTT assay, morphology observation, or scratching assay. Furthermore, tandem mass tag-based quantitative proteomics was used to study the effect mechanisms. The mRNA expression levels of identified proteins were verified by RT-qPCR. Results: Tandem mass tag-based quantitative proteomics showed that 61 differentially expressed proteins were obtained in the SCBPE group compared with the negative-control group: 18 significantly downregulated and 43 significantly upregulated proteins. Bioinformatic analysis showed the significantly enriched KEGG pathways were predominantly ferroptosis-, Wnt-, and hepatocellular carcinoma-signaling ones. Protein-protein interaction network analysis and RT-qPCR validation revealed SCBPE also downregulated the focal adhesion-signaling pathway, which is abrogated by PF-562271, a well-known inhibitor of FAK. Conclusion: This study confirmed SCBPE suppressed the cell proliferation and migration of hepatocellular carcinoma HepG2 cells, mainly through modulation of ferroptosis-, Wnt-, hepatocellular carcinoma-, and focal adhesion-signaling pathways, providing scientific data supporting adjuvant treatment of hepatocellular carcinoma using SCBP.

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.

Lotus Bee Pollen Extract Inhibits Isoproterenol-Induced Hypertrophy via JAK2/STAT3 Signaling Pathway in Rat H9c2 Cells.

Bee pollen possesses an anti-cardiomyocyte injury effect by reducing oxidative stress levels and inhibiting inflammatory response and apoptosis, but the possible effect mechanism has rarely been reported. This paper explores the effect of the extract of lotus bee pollen (LBPE) on cardiomyocyte hypertrophy (CH) and its mechanism. The main components of LBPE were identified via UPLC-QTOF MS. An isoproterenol-induced rat H9c2 CH model was subsequently used to evaluate the protection of LBPE on cells. LBPE (100, 250 and 500 µg∙mL-1) reduced the surface area, total protein content and MDA content, and increased SOD activity and GSH content in CH model in a dose-dependent manner. Meanwhile, quantitative real-time PCR trials confirmed that LBPE reduced the gene expression levels of CH markers, pro-inflammatory cytokines and pro-apoptosis factors, and increased the Bcl-2 mRNA expression and Bcl-2/Bax ratio in a dose-dependent manner. Furthermore, target fishing, bioinformatics analysis and molecular docking suggested JAK2 could be a pivotal target protein for the main active ingredients in the LBPE against CH. Ultimately, Western blot (WB) trials confirmed that LBPE can dose-dependently inhibit the phosphorylation of JAK2 and STAT3. The results show that LBPE can protect against ISO-induced CH, possibly via targeting the JAK2/STAT3 pathway, also suggesting that LBPE may be a promising candidate against CH.

Identification of pharmacokinetic markers for safflower injection using a combination of system pharmacology, multicomponent pharmacokinetics, and quantitative proteomics study.

Safflower injection (SI), a water-extract preparation from safflower (Carthamus tinctorius L.), has been widely used for the treatment of cardio-cerebrovascular diseases. This work aims to develop an approach for identifying PK markers of cardiovascular herbal medicines using SI as a case study. Firstly, qualitative and quantitative analyses were performed to reveal ingredients of the preparation via HPLC-MS. Subsequently, multiple PK ingredients and integrated PK investigations were carried out to ascertain ingredients with favorable PK properties (e.g., easily detected at conventional PK time points and high system exposure) for the whole preparation. Next, ingredients against cardiovascular diseases (CVDs) in the preparation were predicted with target fishing and system pharmacology studies. Finally, ingredients with favorable PK properties, satisfactory PK representativeness for the preparation, and high relevance to CVDs were considered as potential PK markers. Their therapeutic effect was further evaluated using the H2O2-induced H9c2 cardiomyocyte-injured model and a proteomics study to identify objective PK markers. As results, it disclosed that SI mainly contains 11 ingredients. Among them, five ingredients, namely, hydroxysafflor yellow A (HSYA), syringin (SYR), p-coumaric acid (p-CA), scutellarin (SCU), and p-hydroxybenzaldehyde (p-HBA), showed favorable PK properties. HSYA, SYR, and rutin (RU) were predicted to show high relevance to CVDs and screened as potential PK markers. However, only HSYA and SYR were confirmed as therapeutic ingredients against CVDs. Combined with these findings, only HSYA demonstrated satisfactory representativeness on PK properties and therapeutic effects of multiple ingredients of the preparation, thereby indicating that HSYA is a potential PK marker for the SI. The results of this study can provide a reference for the characterization of PK markers for traditional Chinese medicines.

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.

Pharmacological effects and mechanisms of bee venom and its main components: Recent progress and perspective.

Bee venom (BV), a type of defensive venom, has been confirmed to have favorable activities, such as anti-tumor, neuroprotective, anti-inflammatory, analgesic, anti-infectivity effects, etc. This study reviewed the recent progress on the pharmacological effects and mechanisms of BV and its main components against cancer, neurological disorders, inflammatory diseases, pain, microbial diseases, liver, kidney, lung and muscle injury, and other diseases in literature during the years 2018-2021. The related target proteins of BV and its main components against the diseases include Akt, mTOR, JNK, Wnt-5α, HIF-1α, NF-κB, JAK2, Nrf2, BDNF, Smad2/3, AMPK, and so on, which are referring to PI3K/Akt/mTOR, MAPK, Wnt/ß-catenin, HIF-1α, NF-κB, JAK/STAT, Nrf2/HO-1, TrkB/CREB/BDNF, TGF-ß/Smad2/3, and AMPK signaling pathways, etc. Further, with the reported targets, the potential effects and mechanisms on diseases were bioinformatically predicted via Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, disease ontology semantic and enrichment (DOSE) and protein-protein interaction (PPI) analyses. This review provides new insights into the therapeutic effects and mechanisms of BV and its main components on diseases.

Systematic characterisation of secondary metabolites from Ixeris sonchifolia by the combined use of HPLC-TOFMS and HPLC-ITMS.

INTRODUCTION: Ixeris sonchifolia (Bunge) Hance, a folk medicine, has been widely used in China for its anti-inflammatory and haemostatic effects. However, the miscellaneous component composition of this herbal medicine is not well known. OBJECTIVE: To develop a fast and comprehensive analytical method for the characterisation of various components from I. Sonchifolia, as a tool for the quality control of the herb and its related preparations. METHODOLOGY: Ixeris sonchifolia samples were extracted with 60% aqueous methanol, purified by solid-phase extraction and then analysed by the combinatorial use of HPLC-TOFMS and HPLC-ITMS. RESULTS: A total of six sesquiterpene lactones, six phenolic acids and seven flavonoids were identified or tentatively characterised. Five of them were reported for the first time in I. sonchifolia and, in particular, two amino acid-sesquiterpene lactone conjugates, 11,13-dihydro-13-prolyl-ixerin Z and 11,13-dihydro-13-prolyl-ixerin Z(1), that were first found in this plant source. CONCLUSION: A global profile of I. sonchifolia constituents was described, which could be useful for the quality control of this herb and its related preparations. The employed combination of HPLC-TOFMS and HPLC-ITMS could also be a promising tool for the analysis of other herbal medicines containing sesquiterpene lactones, phenolic acids or flavonoids.

Recent Research Progress (2015-2021) and Perspectives on the Pharmacological Effects and Mechanisms of Tanshinone IIA.

Tanshinone IIA (Tan IIA) is an important characteristic component and active ingredient in Salvia miltiorrhiza, and its various aspects of research are constantly being updated to explore its potential application. In this paper, we review the recent progress on pharmacological activities and the therapeutic mechanisms of Tan IIA according to literature during the years 2015-2021. Tan IIA shows multiple pharmacological effects, including anticarcinogenic, cardiovascular, nervous, respiratory, urinary, digestive, and motor systems activities. Tan IIA modulates multi-targets referring to Nrf2, AMPK, GSK-3ß, EGFR, CD36, HO-1, NOX4, Beclin-1, TLR4, TNF-α, STAT3, Caspase-3, and bcl-2 proteins and multi-pathways including NF-κB, SIRT1/PGC1α, MAPK, SREBP-2/Pcsk9, Wnt, PI3K/Akt/mTOR pathways, TGF-ß/Smad and Hippo/YAP pathways, etc., which directly or indirectly influence disease course. Further, with the reported targets, the potential effects and possible mechanisms of Tan IIA against diseases were predicted by bioinformatic analysis. This paper provides new insights into the therapeutic effects and mechanisms of Tan IIA against diseases.

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.

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.

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.