Natural 7,8-secolignans from Schisandra sphenanthera fruit potently inhibit SARS-CoV-2 3CLpro and inflammation.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), turned into a global pandemic, and there remains an urgent demand for specific/targeted drugs for the disease. The 3C-like protease (3CLpro) is a promising target for developing anti-coronavirus drugs. Schisandra sphenanthera fruit is a well-known traditional Chinese medicine (TCM) with good antiviral activity. This study found that the ethanolic extract displayed a significant inhibitory effect against SARS-CoV-2 3CLpro. Forty-four compounds were identified in this extract using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Combining molecular docking and in vitro experiments, we found that two epimeric 7,8-secolignans, rel-(1S,2R)-1-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutyl-3,4-dimethoxybenzoate (2) and rel-(1S,2S)-1-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutyl-3,4-dimethoxybenzoate (4), potently inhibited 3CLpro with IC50 values of 4.88 ± 0.60 µM and 4.75 ± 0.34 µM, respectively. Moreover, in vivo and in vitro experiments indicated that compounds 2 and 4 were potent in regulating the inflammatory response and preventing lung injury. Our findings indicate that compounds 2 and 4 may emerge as promising SARS-CoV-2 inhibitors via 3CLpro inhibition and anti-inflammatory mechanisms.

Polydatin from Polygoni Cuspidati Rhizoma et Radix regulates glucolipid metabolism in the liver of diabetic rats: Multiscale analysis of network pharmacology and multiomics.

BACKGROUND: Polygoni Cuspidati Rhizoma et Radix (Huzhang in Chinese), refers to the root and rhizome of Polygonum cuspidatum Sieb. et Zucc. Huzhang is commonly used in clinical practice for the prevention and treatment of diabetes and its complications, but its active components and regulatory mechanisms have not yet been thoroughly analyzed. PURPOSE: The network pharmacology combined with multi-omics analysis will be employed to dissect the substance basis and action mechanism of Huzhang in exerting its anti-diabetic activity. METHODS: This study employed phenotypic indicators for baseline assessment, followed by integrated analysis using network pharmacology, metabolomics, transcriptomics, and qPCR technology to elucidate the active components and pharmacological mechanisms of Huzhang. RESULTS: The analysis of network pharmacology revealed that polydatin is a potential active component responsible for the anti-T2DM pharmacological effects of Huzhang. In vivo experimental results demonstrated that polydatin significantly regulates blood glucose, lipid levels, liver function, and liver pathological damage in diabetic rats. Analysis results from transcriptomics, metabolomics, and qPCR validation showed that polydatin comprehensively regulates glucose and lipid metabolism in T2DM by modulating bile acid metabolism, fatty acid oxidation, and lipogenesis. CONCLUSION: Polydatin is a key component of Huzhang in treating T2DM, and its regulatory mechanisms are diverse, indicating significant development potential.

TFEB activator tanshinone IIA and derivatives derived from Salvia miltiorrhiza Bge. Attenuate hepatic steatosis and insulin resistance.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bge. (SMB) is an herbal medicine extensively used for improving metabolic disorders, including Nonalcoholic fatty liver disease (NAFLD). However, the potential material basis and working mechanism still remained to be elucidated. AIM OF THE STUDY: To find potential ingredients for therapy of NAFLD by high content screening and further verify the efficacy on restoring hepatic steatosis and insulin resistance, and clarify the potential working mechanism. MATERIALS AND METHODS: The mouse transcription factor EB (Tfeb) in preadipocytes was knocked out by CRISPR-Cas9 gene editing. High content screening of TFEB nuclear translocation was performed to identify TFEB activators. The effect of candidate compounds on reducing lipid accumulation was evaluated using Caenorhabditis elegans (C. elegans). Then the role of Salvia miltiorrhiza extract (SMB) containing Tanshinone IIA and the derivatives were further investigated on high-fat diet (HFD) fed mice. RNA-seq was performed to explore potential molecular mechanism of SMB. Finally, the gut microbiota diversity was evaluated using 16S rRNA sequencing to investigate the protective role of SMB on regulating gut microbiota homeostasis. RESULTS: Knockout of Tfeb led to excessive lipid accumulation in adipocytes while expression of TFEB homolog HLH-30 in C. elegans (MAH240) attenuated lipid deposition. Screening of TFEB activators identified multiple candidates from Salvia miltiorrhiza, all of them markedly induced lysosome biogenesis in HepG2 cells. One of the candidate compounds Tanshinone IIA significantly decreased lipid droplet deposition in HFD fed C. elegans. Administration of SMB on C57BL/6J mice via gastric irrigation at the dose of 15 g/kg/d markedly alleviated hepatic steatosis, restored serum lipid profile, and glucose tolerance. RNA-seq showed that gene expression profile was altered and the genes related to lipid metabolism were restored. The disordered microbiome was remodeled by SMB, Firmicutes and Actinobacteriotawere notably reduced, Bacteroidota and Verrucomicrobiota were significantly increased. CONCLUSION: Taken together, the observations presented here help address the question concerning what were the main active ingredients in SMB for alleviating NAFLD, and established that targeting TFEB was key molecular basis for the efficacy of SMB.

Mechanism analysis of essential oil from Radix Bupleuri for the treatment of asthma through regulation of ectopic olfactory receptor.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Bupleuri is the root of Bupleurum chinense DC. (BC) and a classic aromatic traditional Chinese medicine. The traditional pharmacological effects of Radix Bupleuri are alleviating bronchial spasms, dilating airways, and promoting the resolution of respiratory inflammation, thereby reducing asthma symptoms. AIM OF THE STUDY: Studies have demonstrated the efficacy of water extracts from BC in asthma treatment. However, the potential role of volatile oil, another active constituent in BC, remains unexplored with asthma. Notably, volatile oil is renowned for its ease of absorption and direct targeting of affected areas, offering distinct advantages in alleviating airway inflammation. This study aims to explain the anti-asthmatic mechanism of BC-oil through in vivo and in vitro pharmacological experiments. MATERIALS AND METHODS: Firstly, the OVA-induced SD rat asthma model was utilized to evaluate the pharmacological effect of BC-oil by lung function monitoring, HE staining, flow cytometry, ELISA, and RT-qPCR. The anti-asthmatic mechanism was further analyzed by combining transcriptomic analysis of lung tissue from rat model and airway smooth muscle tissue from public database. Initially, GC-MS was used to analyze the components of BC-oil. The anti-asthmatic activity was evaluated in 16-HBE, RBL-2H3, and ASMC cells using CAMKII inhibitors to explore of the critical signal transduction regulated by BC-oil. Furthermore, molecular docking and calcium flow assay were utilized to screen and identify the active components from BC-oil. RESULTS: Oral administration of BC-oil significantly enhanced pulmonary function in asthmatic SD rats by reducing airway resistance and elastic resistance. Additionally, BC-oil inhibited inflammatory cytokines, including serum IL-2, pulmonary Il1b, Tnf, and Cxcl13, demonstrating potent anti-inflammatory and immunomodulatory effects. In this study, we analyzed the significant role of OR2W3 in asthma using public transcriptomic data. Furthermore, we indicated that BC-oil regulated the expression of Olr1433 and GNAL in rat lung tissue. BC-oil reduced degranulation and inhibited gene expression of Il3 and Tnf in RBL-2H3 cells and suppressed gene expression of IL8 and TNF in 16-HBE cells. BC-oil also attenuated airway smooth muscle cell proliferation and expression of Acta2 and Ccnd1. Furthermore, BC-oil regulates asthma-related cellular processes by activating CAMKII. GC-MS analysis identified 11 components of BC-oil, and n-hexadecanoic acid, linoleic acid and oleic acid from BC-oil were identified to interact with OR2W3 by molecular docking. The calcium flow assay revealed linoleic acid as a significant activator of OR2W3 and indicated that BC-oil alleviated asthma through the ectopic olfactory signaling pathway. CONCLUSIONS: The mechanism of BC-oil in treating asthma through signal transduction of OR2W3 is revealed at the molecular and cellular levels.

SYSTCM: A systemic web platform for objective identification of pharmacological effects based on interplay of "traditional Chinese Medicine-components-targets".

Mechanism analysis is essential for the use and promotion of Traditional Chinese Medicine (TCM). Traditional methods of network analysis relying on expert experience lack an explanatory framework, prompting the application of deep learning and machine learning for objective identification of TCM pharmacological effects. A dataset was used to construct an interacted network graph between 424 molecular descriptors and 465 pharmacological targets to represent the relationship between components and pharmacological effects. Subsequently, the optimal identification model of pharmacological effects (IPE) was established through convolution neural networks of GoogLeNet structure. The AUC values are greater than 0.8, MCC values are greater than 0.7, and ACC values are greater than 0.85 across various test datasets. Subsequently, 18 recognition models of TCM efficacy (RTE) were created using support vector machines (SVM). Integration of pharmacological effects and efficacies led to the development of the systemic web platform for identification of pharmacological effects (SYSTCM). The platform, comprising 70,961 terms, including 636 Traditional Chinese Medicines (TCMs), 8190 components, 40 pharmacological effects, and 18 efficacies. Through the SYSTCM platform, (1) Total 100 components were predicted from TCMs with anti-inflammatory pharmacological effects. (2) The pharmacological effects of complete constituents were predicted from Coptidis Rhizoma (Huang Lian). (3) The principal components, pharmacological effects, and efficacies were elucidated from Salviae Miltiorrhizae radix et rhizome (Dan Shen). SYSTCM addresses subjectivity in pharmacological effect determination, offering a potential avenue for advancing TCM drug development and clinical applications. Access SYSTCM at http://systcm.cn.

Effects of diarylbutane lignans from Schisandra chinensis fruit on SARS-CoV-2 3CLpro and PLpro and their in vitro anti-inflammatory properties.

Background: Schisandra chinensis fruit is a well-known traditional Chinese medicine (TCM), whose extract has a potent inhibitory effect on the severe acute respiratory syndrome-coronavirus-2 (SARS­CoV­2) 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro). Purpose: This work aims to find the active components from the fruit of S. chinensis against SARS­CoV­2 3CLpro and PLpro. Materials and methods: The chemical constituents of the fruit of S. chinensis were retrieved based on the electronic databases, such as Web of Science, PubMed, Medline Plus, and CNKI. Molecular docking was used to screen the active components against SARS­CoV­2 3CLpro and PLpro. Potential hit compounds were further evaluated by enzymatic activity assay. Furthermore, the anti-inflammatory activities of the active compounds were further explored using the phorbol-12-myristate-13-acetate (PMA)-induced THP1 cells model. Results: In this work, we retrieved 75 components of S. chinensis fruit, including 62 dibenzocyclooctadiene-type lignans, 3 diarylbutane-type lignans, 2 tetrahydrofuran-type lignans, and 8 nortriterpenoids. Combining molecular docking study and in vitro experiments, we found that pregomisin (63), meso­dihydroguaiaretic acid (64), and nordihydroguaiaretic acid (65) could potently inhibit 3CLpro with IC50 values of 3.07 ± 0.38, 4.12 ± 0.38, and 6.06 ± 0.62 µM, respectively, and inhibit PLpro with IC50 values of 5.23 ± 0.33, 4.24 ± 0.46, and 16.28 ± 0.54 µM, respectively. Interestingly, compounds 63, 64, and 65 also have potent activities of regulating the inflammatory response in vitro. Conclusion: Our results suggest that compounds 63, 64, and 65 may be promising SARS-CoV-2 3CLpro and PLpro inhibitors and anti-inflammatory.

Wenshenyang recipe treats infertility through hormonal regulation and inflammatory responses revealed by transcriptome analysis and network pharmacology.

The Wenshenyang recipe (WSYR) has the effect of treating infertility, but the mechanisms underlying this activity have not been fully elucidated. In this study, network pharmacology and RNA sequencing were combined, with database-based "dry" experiments and transcriptome analysis-based "wet" experiments used conjointly to analyse the mechanism of WSYR in the treatment of infertility. In the dry analysis, 43 active compounds in WSYR and 44 therapeutic targets were obtained through a database search, 15 infertility pathways were significantly enriched, and key targets, such as ESR1, TP53, AKT1, IL-6, and IL-10 were identified. Then the wet experiments were performed to detect the expression changes of the 412 genes from 15 infertility pathways identified by dry analysis. HK-2 cells were treated with the three herbs of WSYR and subjected to targeted RNA sequencing. Based on the results, 92 of the 412 genes in 15 infertility pathways were identified as DEGs. Additionally, key targets, such as ESR2, STAT1, STAT3, and IL6, were also identified in the wet experiments. RT-qPCR experiments further verified that WSYR played an anti-inflammatory role by upregulating IL-4 and IL-10 and Epimedium brevicornu Maxim (Yinyanghuo) showed broader effect than Drynaria fortunei (Kunze) J. Sm (Gusuibu) and Cistanche deserticola Y.C.Ma (Roucongrong). By screening compounds of WSYR using molecular docking models of ESR1 and ESR2, it was further found that xanthogalenol in Gusuibu, arachidonate in Roucongrong, and anhydroicaritin in Yinyanghuo had good affinity for estrogen receptors. These findings provide evidence for an estrogen-regulating role of the three herbs in WSYR.

Dendrocalamus latiflorus and its component rutin exhibit glucose-lowering activities by inhibiting hepatic glucose production via AKT activation.

The potential medicinal value of Ma bamboo (Dendrocalamus latiflorus), one of the most popular and economically important bamboo species in China, has been underestimated. In the present study, we found that D. latiflorus leaf extract (DLE) reduced fasting blood glucose levels, body weight, and low-density lipoprotein cholesterol with low liver toxicity in db/db mice. In addition, gene expression profiling was performed and pathway enrichment analysis showed that DLE affected metabolic pathways. Importantly, DLE activated the AKT signaling pathway and reduced glucose production by downregulating glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1) expression. Moreover, network pharmacology analysis identified rutin as an active component in DLE through targeting insulin growth factor 1 receptor (IGF1R), an upstream signaling transducer of AKT. Due to its hypoglycemic effects and low toxicity, DLE may be considered an adjuvant treatment option for type 2 diabetes patients.

White tea and its active polyphenols lower cholesterol through reduction of very-low-density lipoprotein production and induction of LDLR expression.

Emerging in vivo and vitro data suggest that white tea extract (WTE) is capable of favourably modulating metabolic syndrome, especially by ameliorating abnormal lipid metabolism. Microarray-based gene expression profiling was performed in HepG2 cells to analyze the effects of WTE from a systematic perspective. Gene Ontology and pathway analysis revealed that WTE significantly affected pathways related to lipid metabolism. WTE significantly downregulated apolipoprotein B (APOB) and microsomal triglyceride transfer protein (MTTP) expression and thereby reduced the production of very-low-density lipoprotein. In the meanwhile, WTE stimulated low-density lipoprotein-cholesterol (LDL-c) uptake through targeting low-density lipoprotein receptor (LDLR), as a consequence of the activation of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator-activated receptor δ (PPARδ). Furthermore, WTE significantly downregulated triglycerides synthetic genes and reduced intracellular triglycerides accumulation. Besides, we demonstrated that the tea catechins epigallocatechin-3-gallate (EGCG) and epicatechin-3-gallate (ECG) are abundant in WTE and contribute to the regulation of cholesterol metabolism related genes, including LDLR, MTTP and APOB. Our findings suggest white tea plays important roles in ameliorating abnormal lipid metabolism in vitro.

[Discovery of cytochrome P450 enzymes-inhibiting components in traditional Chinese medicine].

With the widespread use of traditional Chinese medicine(TCM) and the integration of TCM and western medicine, drug-drug interaction(DDI) is considered as a major cause of therapeutic failures and side effects. Cytochrome P450 enzymes(CYPs) are responsible for large number of drug metabolism. CYP3 A4 and CYP2 D6, two important CYP isoforms, are responsible for about 80% drug metabolism of CYPs super family. The inhibition of CYPs is likely to be the most common factor leading to adverse DDI. Therefore, it is of great significance to predict potential CYP3 A4 and CYP2 D6 inhibitors to prevent the DDI. A fast and low-cost me-thod for calculating and predicting CYP inhibiting components was established in this paper, namely support vector machine(SVM) and molecular docking technology which are used to predict and screen drugs. Firstly, 12 qualitative models of two targets were established by using SVM, and the optimal model was selected to predict the compounds in traditional Chinese medicine database(TCMD). Then, molecular docking technology was used to establish docking model. By analyzing the key amino acids involved in drug-target interactions and combining with SVM model, potential inhibitors of CYP3 A4 and CYP2 D6 were found. From the computational results, astin D and epiberberine exhibited inhibition effect on CYP3 A4 and CYP2 D6, respectively. Astin D was only found in astins family from Aster tataricus, while epiberberine was considered to be the active constituent of Coptidis Rhizoma. Therefore, for the risk of DDI, extra attention should be paid to the source of these potential inhibitors, Asteris Radix et Rhizoma and Coptidis Rhizoma. This computational method provides technical support for discovering potential natural inhibitors of CYPs from Chinese herbs by using SVM and molecular docking model, and it is also helpful to recognize the CYPs-mediated DDI existing in TCM, providing research ideas for further pharmacovigilance of integrated therapy.

Discovery of Novel Multi-target Inhibitor of angiotensin type 1 receptor and neprilysin inhibitors from Traditional Chinese Medicine.

Angiotensin II type-1 receptor-neprilysin inhibitor (ARNi) is consisted of Angiotensin II type-1 receptor (AT1) antagonist and neprilysin (NEP) inhibitor, which could simultaneously increase the vasodilators of the natriuretic peptides and antagonize vasoconstrictors of Ang II. ARNi has been proved a superior effect and lower risks of death on chronic heart failure (CHF) and hypertension. In this paper, ARNi from Traditional Chinese Medicines (TCM) was discovered based on target combination of AT1 and NEP by virtual screening, biological assay and molecular dynamics (MD) simulations. Two customized strategies of combinatorial virtual screening were implemented to discover AT1 antagonist and NEP inhibitor based on pharmacophore modeling and docking computation respectively. Gyrophoric acid (PubChem CID: 135728) from Parmelia saxatilis was selected as AT1 antagonist and assayed with IC50 of 29.76 µM by calcium influx assay. And 3,5,3'-triiodothyronine (PubChem CID: 861) from Bos taurus domesticus was screened as NEP inhibitor and has a dose dependent inhibitory activity by biochemistry fluorescence assay. Combined with MD simulations, these compounds can generate interaction with the target, key interactive residues of ARG167, TRP84, and VAL108 in AT1, and HIS711 in NEP were also identified respectively. This study designs the combinatorial strategy to discover novel frames of ARNi from TCM, and gyrophoric acid and 3,5,3'-triiodothyronine could provide the clues and revelations of drug design and therapeutic method of CHF and hypertension for TCM clinical applications.

Caffeine-free hawk tea lowers cholesterol by reducing free cholesterol uptake and the production of very-low-density lipoprotein.

Medicinal plants show important therapeutic value in chronic disease treatment. However, due to their diverse ingredients and complex biological effects, the molecular mechanisms of medicinal plants are yet to be explored. By means of several high-throughput platforms, here we show hawk tea extract (HTE) inhibits Niemann-Pick C1-like 1 (NPC1L1)-mediated free cholesterol uptake, thereby inducing the transcription of low-density lipoprotein receptor (LDLR) downstream of the sterol response element binding protein 2 (SREBP2) pathway. Meanwhile, HTE suppresses hepatocyte nuclear factor 4α (HNF4α)-mediated transcription of microsomal triglyceride transfer protein (MTP) and apolipoprotein B (APOB), thereby decreasing the production of very-low-density lipoprotein. The catechin EGCG ((-)-epigallocatechin gallate) and the flavonoids kaempferol and quercetin are identified as the bioactive components responsible for the effects on the NPC1L1-SREBP2-LDLR axis and HNF4α-MTP/APOB axis, respectively. Overall, hawk tea works as a previously unrecognized cholesterol-lowering agent in a multi-target and multi-component manner.

A novel angiotensin-I converting enzyme inhibitory peptide derived from the glutelin of vinegar soaked black soybean and its antihypertensive effect in spontaneously hypertensive rats.

Vinegar soaked black soybean is a traditional Chinese food widely used for the treatment of hypertension. While its pharmacodynamic substance was not fully unveiled. It contained abundant glutelin, thus the purpose of this study was to obtain potent antihypertensive peptides from vinegar soaked black soybean. Black soybean was soaked with vinegar and then glutelin was first catalyzed by alcalase. Ultrafiltration, ion exchange chromatography and reversed-phase high performance liquid chromatography were sequentially applied to separate and purify the angiotensin-I converting enzyme (ACE) inhibitory peptides from glutelin hydrolysates. As a result, the fraction L1-4 with the highest ACE inhibitory activity (83.41%) at the final concentration of 0.01 mg/ml was obtained and five peptides were then identified. These peptides were further optimized by virtual screening combining with in silico proteolysis. Finally, a novel tetrapeptide Phe-Gly-Ser-Phe (FGSF) was obtained. FGSF exhibited high in vitro ACE inhibitory activity (IC50 = 117.11 µM) and in vivo hypotensive effect which maximally reduced systolic blood pressure of 21.95 mmHg at 20 mg/kg body weight in spontaneously hypertensive rats. Our study demonstrated that FGSF derived from vinegar soaked black soybean might be used as a promising ingredient for pharmaceuticals against hypertension and its related diseases.

A Component Formula of Chinese Medicine for Hypercholesterolemia Based on Virtual Screening and Biology Network.

Hypercholesterolemia is a risk factor to atherosclerosis and coronary heart disease II. The abnormal rise of cholesterol in plasma is the main symptom. Cholesterol synthesis pathway is an important pathway of the origin of cholesterol, which is an essential pathway for the therapy of hypercholesterolemia. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), squalene synthase (SQS), and sterol regulatory element binding protein-2 (SREBP-2) are closely connected with the synthesis of cholesterol. The inhibition of these targets can reduce the cholesterol in plasma. This study aimed to build a component formula including three Traditional Chinese Medicines (TCM) components with the inhibition activity of these targets by using virtual screening and biological network. Structure-based pharmacophore models of HMG-CoA reductase and SQS and ligand-based pharmacophore model of SREBP-2 were constructed to screen the Traditional Chinese Medicine Database (TCMD). Molecular docking was used for further screening of components of HMG-CoA reductase and SQS. Then, metabolic network was constructed to elucidate the comprehensive interaction of three targets for lipid metabolism. Finally, three potential active compounds were obtained, which are poncimarin, hexahydrocurcumin, and forsythoside C. The source plants of the compounds were also taken into account, which should have known action of lowering hyperlipidemia. The lipid-lowering effect of hexahydrocurcumin was verified by experiment in vitro. The components that originated from TCMs with lipid-lowering efficacy made up a formula with a synergistic effect through the computer aid drug design methods. The research provides a fast and efficient method to build TCM component formula and it may inspire the study of the explanation of TCM formula mechanism.

Discovery of Potential Inhibitors of Squalene Synthase from Traditional Chinese Medicine Based on Virtual Screening and In Vitro Evaluation of Lipid-Lowering Effect.

Squalene synthase (SQS), a key downstream enzyme involved in the cholesterol biosynthetic pathway, plays an important role in treating hyperlipidemia. Compared to statins, SQS inhibitors have shown a very significant lipid-lowering effect and do not cause myotoxicity. Thus, the paper aims to discover potential SQS inhibitors from Traditional Chinese Medicine (TCM) by the combination of molecular modeling methods and biological assays. In this study, cynarin was selected as a potential SQS inhibitor candidate compound based on its pharmacophoric properties, molecular docking studies and molecular dynamics (MD) simulations. Cynarin could form hydrophobic interactions with PHE54, LEU211, LEU183 and PRO292, which are regarded as important interactions for the SQS inhibitors. In addition, the lipid-lowering effect of cynarin was tested in sodium oleate-induced HepG2 cells by decreasing the lipidemic parameter triglyceride (TG) level by 22.50%. Finally. cynarin was reversely screened against other anti-hyperlipidemia targets which existed in HepG2 cells and cynarin was unable to map with the pharmacophore of these targets, which indicated that the lipid-lowering effects of cynarin might be due to the inhibition of SQS. This study discovered cynarin is a potential SQS inhibitor from TCM, which could be further clinically explored for the treatment of hyperlipidemia.

In Silico Analysis of the Association Relationship between Neuroprotection and Flavors of Traditional Chinese Medicine Based on the mGluRs.

The metabotropic glutamate receptors (mGluRs) are known as both synaptic receptors and taste receptors. This feature is highly similar to the Property and Flavor theory of Traditional Chinese medicine (TCM), which has the pharmacological effect and flavor. In this study, six ligand based pharmacophore (LBP) models, seven homology modeling models, and fourteen molecular docking models of mGluRs were built based on orthosteric and allosteric sites to screening potential compounds from Traditional Chinese Medicine Database (TCMD). Based on the Pharmacopoeia of the People's Republic of China, TCMs of compounds and their flavors were traced and listed. According to the tracing result, we found that the TCMs of the compounds which bound to orthosteric sites of mGluRs are highly correlated to a sweet flavor, while the allosteric site corresponds to a bitter flavor. Meanwhile, the pharmacological effects of TCMs with highly frequent flavors were further analyzed. We found that those TCMs play a neuroprotective role through the efficiencies of detumescence, promoting blood circulation, analgesic effect, and so on. This study provides a guide for developing new neuroprotective drugs from TCMs which target mGluRs. Moreover, it is the first study to present a novel approach to discuss the association relationship between flavor and the neuroprotective mechanism of TCM based on mGluRs.

[Pharmacological mechanism analysis of oligopeptide from Pinctada fucata based on in silico proteolysis and protein interaction network].

Pinctada fucata oligopeptide is one of key pharmaceutical effective constituents of P. fucata. It is significant to analyze its pharmacological effect and mechanism. This study aims to discover the potential oligopeptides from P. fucata and analyze the mechanism of P. fucata oligopeptide based on in silico technologies and protein interaction network(PIN). First, main protein sequences of P. fucata were collected, and oligopeptides were obtained using in silico gastrointestinal tract proteolysis. Then, key potential targets of P. fucata oligopeptides were obtained through pharmacophore screening. The protein-protein interaction(PPI) of targets was achieved and implemented to construct PIN and analyze the mechanism of P. fucata oligopeptides. P. fucata oligopeptide database was constructed based on in silico technologies, including 458 oligopeptides. Twelve modules were identified from PIN by a graph theoretic clustering algorithm Molecular Complex Detection(MCODE) and analyzed by Gene ontology(GO) enrichment. The results indicated that P. fucata oligopeptides have an effect in treating neurological diseases, such as Alzheimer's disease. In silico proteolysis could be used to analyze the protein sequences of traditional Chinese medicine(TCM). According to the combination of in silico proteolysis and PIN, the biological activity of oligopeptides could be interpreted rapidly based on the known TCM protein sequence. The study provides the methodology basis for rapidly and efficiently implementing the mechanism analysis of TCM oligopeptides.

[Prediction of ETA oligopeptides antagonists from Glycine max based on in silico proteolysis].

Oligopeptides are one of the the key pharmaceutical effective constituents of traditional Chinese medicine(TCM). Systematic study on composition and efficacy of TCM oligopeptides is essential for the analysis of material basis and mechanism of TCM. In this study, the potential anti-hypertensive oligopeptides from Glycine max and their endothelin receptor A (ETA) antagonistic activity were discovered and predicted based on in silico technologies.Main protein sequences of G. max were collected and oligopeptides were obtained using in silico gastrointestinal tract proteolysis. Then, the pharmacophore of ETA antagonistic peptides was constructed and included one hydrophobic feature, one ionizable negative feature, one ring aromatic feature and five excluded volumes. Meanwhile, three-dimensional structure of ETA was developed by homology modeling methods for further docking studies. According to docking analysis and consensus score, the key amino acid of GLN165 was identified for ETA antagonistic activity. And 27 oligopeptides from G. max were predicted as the potential ETA antagonists by pharmacophore and docking studies.In silico proteolysis could be used to analyze the protein sequences from TCM. According to combination of in silico proteolysis and molecular simulation, the biological activities of oligopeptides could be predicted rapidly based on the known TCM protein sequence. It might provide the methodology basis for rapidly and efficiently implementing the mechanism analysis of TCM oligopeptides.

[Synergistic mechanism of traditional Chinese medicine based on target combination of PepT1 and PPARα].

Synergistic effect is main pharmacological mechanism of traditional Chinese medicine(TCM). The research method based on the key targets combination is an important method to explore the synergistic effect of TCM. Peptide transporter 1 (PepT1) is an essential target for drug uptake into the bloodstream, accounting for about 50% of the total transporter protein content from the small intestine. Peroxisome proliferator-activated receptor α(PPARα) is the lipid-lowering target of fibrates, which have a good hypolipidemic effect by activating PPARα. It has been reported that PPARα could activate the gene expression of PepT1s, and PPARα agonists can promote the uptake of PepT1 substrates, indicating their synergistic effect. In this paper, PepT1 substrates and PPARα agonists from TCM were discovered, and their synergistic mechanism was also been discussed based on the target combination of PepT1 and PPARα. The support vector machine(SVM) model of PepT1 substrates was first constructed and utilized to predict potential TCM components. Meanwhile, merged pharmacophore and docking model of PPARα agonists was used to screen the potential active ingredients from TCM. According to the analysis results of two groups, the TCM combination of Panax notoginseng and Ganoderma lucidum, as well as TCM combination of P. notoginseng and Salvia miltiorrhiza were identified to have the synergistic mechanism based on target combination of PepT1 and PPARα. In this study, synergistic mechanism of TCM was analyzed for absorption and hypolipidemic effect based on target combination, which provides a new way to explore the synergetic mechanism of TCM related to pharmacokinetics.