Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma.

The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of ß2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.

Identifying the active ingredients of carbonized Typhae Pollen by spectrum-effect relationship combined with MBPLS, PLS, and SVM algorithms.

Typhae Pollen (TP) and its carbonized product (carbonized Typhae Pollen, CTP), as cut-and-dried herbal drugs, have been widely used in the form of slices in clinical settings. However, the two drugs exhibit a great difference in terms of their clinical efficacy, for TP boasts an effect of removing blood stasis and promoting blood circulation, while CTP typically presents a hemostatic function. Since the active ingredients of CTP, so far, still remain unclear, this study aimed at identifying the active ingredients of CTP by spectrum-effect relationship approach coupled with multi-block partial least squares (MBPLS), partial least squares (PLS), and support vector machine (SVM) algorithms. In this study, the chemical profiles of a series of CTP samples which were stir-fried for different duration (denoted as CTP0∼CTP9) were firstly characterized by UHPLC-QE-Orbitrap MS. Then the hemostatic effect of the CTP samples was evaluated from the perspective of multiple parameters-APTT, PT, TT, FIB, TXB2, 6-keto-PGF1α, PAI-1 and t-PA-using established rat models with functional uterine bleeding. Subsequently, MBPLS, PLS and SVM were combined to perform spectrum-effect relationship analysis to identify the active ingredients of CTP, followed by an in vitro hemostatic bioactivity test for verification. As a result, a total of 77 chemical ingredients were preliminarily identified from the CTP samples, and the variations occurred in these ingredients were also analyzed during the carbonizing process. The study revealed that all the CTP samples, to a varying degree, showed a hemostatic effect, among which CTP6 and CTP7 were superior to the others in terms of the hemostatic effect. The block importance in the projection (BIP) indexes of MBPLS model indicated that flavonoids and organic acids made more contributions to the hemostatic effect of CTP in comparison to other ingredients. Consequently, 9 bioactive ingredients, including quercetin-3-O-glucoside, kaempferol-3-O-rutinoside, quercetin, kaempferol, isorhamnetin, 2-methylenebutanedioic acid, pentanedioic acid, benzoic acid and 3-hydroxybenzoic acid, were further identified as the potential active ingredients based on PLS and SVM models as well as the in vitro verification. This study successfully revealed the bioactive ingredients of CTP associated with its hemostatic effect, and also provided a scientific basis for further understanding the mechanism of TP processing. In addition, it proposed a novel path to identify the active ingredients for Chinese herbal medicines.

The roles of natural triterpenoid saponins against Alzheimer's disease.

The aging of the world population and increasing stress levels in life are the major cause of the increased incidence of neurological disorders. Alzheimer's disease (AD) creates a huge burden on the lives and health of individuals and has become a big concern for society. Triterpenoid saponins (TS), representative natural product components, have a wide range of pharmacological bioactivities such as anti-inflammation, antioxidation, antiapoptosis, hormone-like, and gut microbiota regulation. Notably, some natural TS exhibited promising neuroprotective activity that can intervene in AD progress, especially in the early stage. Recently, studies have indicated that TS play a pronounced positive role in the prevention and treatment of AD. This review discusses the recent research on the neuroprotection of TS and proceeds to detail the action mechanisms of TS against AD, hoping to provide a reference for drug development for anti-AD.

Combined Metabolite Analysis and Network Pharmacology to Elucidate the Mechanisms of Therapeutic Effect of Melastoma dodecandrum Ellagitannins on Abnormal Uterine Bleeding.

The abnormal uterine bleeding (AUB) is complex and usually leads to severe anemia. Melastomadodecandrum (MD) is clinically used for the treatment of metrorrhagia bleeding. The MD ellagitannins (MD-ETs) had been evidenced being effective at hemorrhage, and exerts biological activities upon their metabolites including ellagic acid and urolithins. In this study, the blood-permeated metabolites from theMD-ETs were analyzed using LC-MS approach, and 19 metabolites including ellagic acid and urolithin A derivatives were identified. Furthermore, a network pharmacology analysis including the target prediction analysis, AUB target analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted to reveal the relationships between "metabolites-targets-pathways", which was further verified by molecular docking analysis. The results showed that methyl ellagic acid, urolithin A and isourolithin A produced from MD-ETs can be absorbed into the blood, and might act on the core targets of VEGFA, SRC, MTOR, EGFR and CCND1. And the hemostatic effects were exerted through PI3K-Akt, endocrine resistance and Rap 1 signaling pathways. These results implied the potential effective constituents and action mechanism of MD-ETs in the therapy of AUB, which will promote the application of MD-ETs as natural agent for the treatment of gynecological bleeding diseases.

Quality assessment of Rheum species cultivated in Japan by focusing on M2 polarization of microglia.

In traditional Japanese medicine, Rhei Rhizoma is used as a purgative, blood stasis-resolving and antipsychotic drug. The latter two properties are possibly related to anti-inflammatory effects. Microglia regulate inflammation in the central nervous system. M1 microglia induce inflammation, while M2 microglia inhibit inflammation and show neurotrophic effects. This study investigated the effects from water extracts of roots of cultivated Rheum species in Nagano Prefecture, Japan (strain C, a related strain to a Japanese cultivar, 'Shinshu-Daio'; and strain 29, a Chinese strain) and 3 kinds of Rhei Rhizoma available in the Japanese market, and also examined their constituents on the polarization of cultured microglia. All extracts significantly decreased M1 microglia, and strains C and 29 significantly increased M2 microglia. Furthermore, the extracts of both strains significantly increased the M2/M1 ratio. Among the constituents of Rhei Rhizoma, ( +)-catechin (2), resveratrol 4'-O-ß-D-(6″-O-galloyl) glucopyranoside (5), isolindleyin (8), and physcion (15) significantly increased the M2/M1 ratio. The contents of the constituents in water extract of each strain were quantified using HPLC. The extracts of strains C and 29 contained relatively large amounts of 2 and 5; and 2, 8, and 15, respectively. This study showed the water extracts of roots of cultivated Rheum strains in Japan had the effects of M2 polarization of microglia, suggesting that these strains become the candidate to develop anti-inflammatory Rhei Rhizoma. Moreover, the suitable chemical composition to possess anti-inflammatory activity in the brain was clarified for the future development of new type of Rhei Rhizoma.

Molecular networking-assisted systematical profiling and the in vivo neuroprotective effect of ellagitannins from the Melastoma dodecandrum Lour.

BACKGROUND: Ellagitannins (ETs) are a major classification of natural tannins, with relatively large and complex structures. ETs from medicinal plants are focused increasingly due to urolithins, a kind of intestinal metabolite of ETs, which showed promising anti-Alzheimer's disease (AD) effects. Melastoma dodecandrum (MD), a widely used traditional Chinese medicine is rich in ETs, but their chemistry and potential neuroprotective effects have not been investigated. PURPOSE: This study aimed to identify the chemical composition of ETs in the crude extract of MD and to investigate their neuroprotective effects in vivo. METHODS: UPLC-QTOF-MS-based molecular networking (MN) and structural characterization were applied to targeted profiling of the MD-ETs. Animal behavior experiments, including the novel object recognition test (NOR), open field test (OFT), and Morris water maze test (MWM), were conducted to assess the memory improvement effects of MD-ETs in AD model mice. RESULTS: A total of 70 ETs, ranging from monomers to tetramers, were tracked and characterized in the MD extract using MN-guided targeted profiling, with 59 of them reported for the first time in this species. MD-ETs significantly improved memory impairment in AD mice, as indicated by decreased escape latency, increased number of crossings and target quadrant distance in MWM, increased rearing number in OFT, and increased preference index in NOR. CONCLUSION: This study systematically characterized the composition and structural features of ETs in MD using targeted LC-MS profiling, expanding the chemical information of ETs in MD. Furthermore, the results demonstrate that MD-ETs have significant effects on improving impaired memory in AD mice, suggesting their potential as alternative natural medicines for the treatment of neurodegenerative diseases.

The protective effects and mechanism of Ruyi Zhenbao Pill, a Tibetan medicinal compound, in a rat model of osteoarthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ruyi Zhenbao Pill (RZP) is a prescribed Tibetan formulation for the treatment of white-pulse-disease, yellow-water-disease as well as pain-related disease. RZP is composed of 30 medicinal materials including herbal medicine, animal medicine and mineral medicine. They are widely used in the Tibetan area to treat cerebrovascular disease, hemiplegia, rheumatism, and pain diseases for centuries. AIM OF THE STUDY: The aim of the present study was to evaluate the anti-osteoarthritis function of RZP and to clarify the underlying mechanisms. MATERIALS AND METHODS: The active components in RZP were identified using HPLC methods. Osteoarthritis (OA) animal model was established via intra-articular injection of papain in rat knees. After the administration of RZP (0.45, 0.9 g/kg) for 28 days, the clinical observation was conducted, and pathological changes as well as serum biochemical indexes were detected. Moreover, therapeutic targets and pathways of RZP were discussed. RESULTS: The results showed that RZP could suppress knee joint swelling and arthralgia, thus relieving joint pain and inflammation in OA rats. Microcomputed tomography (µCT)-based physiological imaging and staining pictures confirmed the therapeutic effects of RZP on OA symptoms including knee joint swelling and structural changes with progressive inflammation in OA rats. RZP could promote the synthesis or inhibit the degradation of COLⅡ, attenuate OA-induced OPN up-regulation and thus relieve the OA symptom. Furthermore, RZP (0.45-0.9 g/kg) could all ameliorate the imbalance of biomarkers related to OA such as MMP1, TNF-α, COX2, IL-1ß and iNOS in knee joints or serum. CONCLUSION: In conclusion, RZP could effectively relieve inflammatory reaction induced by OA injury and the formulation could be applied to the treatment of OA therapy.

MS/MS molecular networking-guided in-depth profiling of triterpenoid saponins from the fruit of Eleutherococcus senticosus and their neuroprotectivity evaluation.

INTRODUCTION: Eleutherococcus senticosus fruit (ESF) is a natural health supplement resource that has been extensively applied as a tonic for the nervous system. The structures and neural bioactivities of triterpenoid saponins (TS), which are the major constituents of ESF, have not been comprehensively analyzed thus far. OBJECTIVE: We conducted a complete in-depth MS/MS molecular networking (MN)-based targeted analysis of TS from the crude extract of ESF and investigated its neuroprotective value. METHODS: An MS/MS MN-guided strategy was used to rapidly present a series of precursor ions (PIs) of TS in a compound cluster as TS-targeted information used in the discovery and characterization of TS. In addition, a prepared TS-rich fraction of ESF was assayed for its restraining effects on ß-amyloid-induced inhibition of neurite outgrowth. RESULTS: A total of 87 TS were discovered using a PI tracking strategy, 28 of which were characterized as potentially undescribed structures according to their high-resolution MS values. Furthermore, the TS-rich fraction can significantly reduce ß-amyloid-induced damage to neural networks by promoting the outgrowth of neurites and axons. CONCLUSION: Our findings reveal the richness of TS in ESF and will accelerate their application in the treatment of neurodegenerative diseases.

Identification and localization of morphological feature-specific metabolites in Reynoutria multiflora roots.

Reynoutria multiflora roots are a classical herbal medicine with unique nourishing therapeutic effects. Anomalous vascular bundle (AVB) forming "cloudy brocade patterns" is a typical morphological feature of R. multiflora roots and has been empirically linked to its quality classification. However, scientific evidence, especially for AVB-specific specialised metabolites, has not been comprehensively revealed thus far. Herein, desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) analysis was applied to carry out an in situ analysis of specialised metabolites distributed specifically at the AVB and cork of R. multiflora roots. To enlarge the scope of compounds by DESI detection, various solvent systems including acetone, acetonitrile, methanol, and water were used to assist in the discoveries of 40 specialised metabolites with determined localization. A series of bioactive constituents including stilbenes, flavonoids, anthraquinones, alkaloids, and naphthalenes were found specifically around the brocade patterns. Notably, phospholipids were detected from R. multiflora roots by in situ analysis for the first time and were found mainly in the phloem of AVB (PAB). This is the first study to use gradient solvent systems in DESI-MSI analysis to locate the specialised metabolites distribution. The discovery of feature-specific compounds will bridge the empirical identification to precision quality control of R. multiflora roots.

Pharmacological effects of Eleutherococcus senticosus on the neurological disorders.

Eleutherococcus senticosus is a medicinal plant widely used in traditional medicine and edible remedies with effects on anti-fatigue, sleep improvement, and memory enhancement. Recently, the application of E. senticosus to neurological disorders has been a focus. However, its overall pharmacological effect on neural diseases and relevant mechanisms are needed in an in-depth summary. In this review, the traditional uses and the therapeutic effect of E. senticosus on the treatment of fatigue, depression, Alzheimer's disease, Parkinson's disease, and cerebral ischemia were summarized. In addition, the underlying mechanisms involved in the anti-oxidative damage, anti-inflammation, neurotransmitter modulation, improvement of neuronal growth, and anti-apoptosis were discussed. This review will accelerate the understanding of the neuroprotective effects brought from the E. senticosus, and impetus its development as a phytotherapy agent against neurological disorders.

(20R)-Panaxadiol as a Natural Active Component with Anti-Obesity Effects on ob/ob Mice via Modulating the Gut Microbiota.

Obesity is an important cause of diseases such as type 2 diabetes, non-alcoholic fatty liver and atherosclerosis. The use of ingredients extracted from traditional Chinese medicine for weight loss is now receiving more and more attention. Ginseng has been recorded since ancient times for the treatment of diabetes. The (20R)-Panaxadiol (PD) belongs to the ginseng diol type compounds, which are moderately bioavailable and may remain in the intestinal tract for a longer period of time. This study investigated the potential positive effect of PD in ob/ob mice and evaluated its effect against obesity. The ob/ob mice were administered PD for ten weeks. Our study showed that PD could improve obesity, glucose tolerance disorder, as well as gut dysbiosis. Panaxadiol decreased ob/ob mice's Firmicutes/Bacteroidetes (F/B). Furthermore, 16S rRNA gene sequencing of the fecal microbiota suggested that PD changed the composition of the gut microbiota in ob/ob mice and modulated specific bacteria such as lactobacillus, prevotellace and so on. Moreover, PD improved the intestinal wall integrity. In conclusion, our results suggest that (20R)-Panaxadiol, as an active ingredient of the traditional Chinese medicinal herb ginseng, may improve obesity to some extent via improving gut microbiota.

Memory enhancement effect of saponins from Eleutherococcus senticosus leaves and blood-brain barrier-permeated saponins profiling using a pseudotargeted monitoring strategy.

Dried Eleutherococcus senticosus leaves (ESL), also known as Siberian ginseng tea, are beneficial for human neural disorders. Our previous studies showed that the aqueous extract of ESL enhanced memory in mice, and its saponin fraction (ESL-SAP) exhibited promising neuroprotective activities in vitro; however, the in vivo neurally related effect, bioactive material basis, and possible mechanism of action of ESL-SAP have not been investigated. Here, a series of memory and learning tests were carried out, and the results evidenced a significant enhancement effect of ESL-SAP. Furthermore, an in vivo saponin library-guided pseudotargeted strategy was established to support the rapid monitoring of 26 blood-brain barrier (BBB)-permeated saponins from ESL-SAP-administered rats. A further network pharmacology analysis was conducted on BBB-permeated compounds, which indicated that the in vivo mechanism of ESL-SAP might be effective through multiple targets and pathways, such as the AGE-RAGE signaling pathway and PI3K-Akt signaling pathway, to exert neuroprotective effects. Moreover, the molecular docking experiments demonstrated that key BBB-transferred saponins primarily interacted with targets HRAS, MAPK1, and MAPK8 to produce the neuroprotective effect.

LC-MS-based identification and antioxidant evaluation of small molecules from the cinnamon oil extraction waste.

Cinnamon oil is obtained by steam distillation from cinnamon leaves and is usually considered highly cost-effective compared to bark oil, however, which results in tons of waste cinnamon leaves (WCL) discarded annually. By using MS/MS molecular networking (MN) assisted profiling, six main chemical diversities including flavonols and flavones, phenolic acids, lactones, terpenoids, phenylpropanoids and flavanols were rapid revealed from WCL aqueous extract. 101 compounds were tentatively identified by assigning their MS/MS fragments within typical pathways under ESI-MS/MS dissociation. The featured phenolic acids, terpenoids and their glycosides in cinnamon species were recognized as the main constituents of WCL. The hydrophilic lactones, lignans and flavanols were reported for the first time in cinnamon leaves. Furthermore, ABTS and FRAP assays integrated with MN analysis were conducted to uncover an antioxidant fraction, from which 40 potential antioxidant compounds were rapidly annotated. This fundamental information will help expand the utilization of WCL from cinnamon oil industry.

Drug affinity responsive target stability (DARTS) accelerated small molecules target discovery: Principles and application.

Drug affinity responsive target stability (DARTS) is a novel target discovery approach and is particularly adept at screening small molecule (SM) targets without requiring any structural modifications. The DARTS method is capable of revealing drug-target interactions from cells or tissues by tracking changes in the stability of proteins acting as receptors of bioactive SMs. Due to its simple operation and high efficiency, the DARTS method has been applied to uncover the drug-action mechanism. This review summarized analytical principles, protocols, validation approaches, applications, and challenges involved in the DARTS method. Due to the innate advantages of the DARTS method, it is expected to be a powerful tool to accelerate SM target discovery, especially for bioactive natural products with unknown mechanisms.

Phenylpropanoid conjugated iridoids with anti-malarial activity from the leaves of Morinda morindoides.

Two phenylpropanoid-conjugated iridoids, deglucosyl gaertneroside (1) and morindoidin (2), were isolated from the leaves of Morinda morindoides (Rubiaceae) by activity-guided fractionation using an anti-malarial activity assay. The known related iridoids molucidin (3) and prismatomerin (4), two lignans, abscisic acid, two megastigmanes, and two flavonol glycosides were also identified. The structures of isolated compounds were elucidated using spectroscopic analysis. The isolated compounds were evaluated for anti-malarial activity against the chloroquine/mefloquine-sensitive strains of Plasmodium falciparum together with cytotoxicity against adult mouse brain cells. Potent anti-malarial activity of 3 and 4 (IC50 of 0.96 and 0.80 µM, CC50 of 1.02 and 0.88 µM, and SI of 1.06 and 1.10, respectively) was shown, while new iridoids 1 and 2 and pinoresinol (5) displayed moderate activity (IC50 of 40.9, 20.6, and 24.2 µM) without cytotoxicity (CC50 > 50 µM). These results indicate that 1-5 may be promising lead compounds for anti-malarial drugs. In addition, our results imply the necessity of the quality control of the extract of M. morindoides leaves based on the contents of 1-5 in terms of the safety and efficacy.

A review of the traditional uses, phytochemistry and biological activities of the Melastoma genus.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Melastoma consists of approximately 100 species distributed widely in tropical and subtropical countries, and Melastoma species are often used for medicinal purposes, such as treatment for bleeding, diarrhea, diabetes, and gynecological tumors by local people, mostly in Southeast Asian countries. AIM OF THE REVIEW: The present review summarizes the traditional uses, phytochemistry and pharmacology of species belonging to Melastoma to suggest further research strategies and to facilitate the exploitation of the therapeutic potential of Melastoma species for the treatment of human disorders. MATERIALS AND METHODS: Information related to the traditional uses, phytochemistry and pharmacological activities was systematically collected by searching for the word "Melastoma" in electronic databases, including SciFinder, Web of Science, PubMed, and Google Scholar, from Apr. 1968 until Dec. 2019. RESULTS: A systematic literature survey revealed that Melastoma spp. are widely distributed in southern Asia to northern Oceania and the Pacific Islands and are traditionally used to treat bleeding, diarrhea, swelling, and gynecological tumors. Approximately 142 compounds, including flavonoids, tannins, phenylpropanoids, organic acids, terpenoids, and steroids, have been reported from Melastoma spp. Different extracts have been evaluated for their pharmacological activities, including anti-inflammatory, hemostatic, anticoagulant, cytotoxic, antibacterial, antioxidant, hepatoprotective, gastroprotective and hypoglycemic activities. CONCLUSIONS: Melastoma spp. are popularly used in Southeast Asian countries as effective herbs and are rich in flavonoids, tannins and organic acids with valuable medicinal properties. However, additional studies of the chemical constituents and the mechanism-based pharmacological activities of many members of Melastoma are still needed for developing new plant-derived drugs. In addition, studies on the clinical safety and efficacy of Melastoma are also needed.

[Screening of G-quadruplex ligands from Macleaya cordata extract by contrast ultrafiltration with liquid chromatography-mass spectrometry and molecular docking].

G-quadruplex DNA has become an important target for tumor therapy and anti-tumor development. Modern pharmacology has proved that Macleaya cordata has anti-inflammatory, antibacterial, anti-tumor and other pharmacological effects. Affinity ultrafiltration method can screen active ingredients from compounds rapidly, but G-quadruplex DNA ligands are difficult to dissociate, which is a key step in conventional ultrafiltration method. In this paper, the filtrates after ultrafiltration were determined by HPLC-MS in substitution. The peaks with 20% reduction of MS response from the incubation vs control were considered to be ligand components to G-quadruplex. Two of the peaks with the relative abundance above 30% were identified as sanguinarine(SAN) and chelerine(CHE). Their circular dichroism conformations further proved that SAN and CHE are active ligands of HT4. In addition, another two gradients with high relative abundance were identified as protopine(PRO) and allpcryprotopine(ALL). The binding rate of SAN, CHE, PRO and ALL was calculated according to the HPLC-MS results, and the results showed a consistency with that of the molecular docking method. The proposed method can be used to screen active components from mixture.

[Advances in quality research of Cinnamomum cassia].

Cinnamomum cassis is one of the commonly used traditional Chinese medicines in China. Its genuine producing areas distribute in Guangdong and Guangxi provinces. As an important edible herb and export variety of China, the quality control and internationalization of quality standards of C. cassis is extremely significant. In the recent years, with the development of the cinnamon industry, relevant academic research and the upgrade of the international standards, it is necessary to summarize the quality-related progress of C. cassis. In the present review, the germplasm resources, specific quality marker(Q-marker) and quality standards of C. cassis were summarized on the basis of published research during the last 10 years.

[Label-free small molecule probe and target discovery of traditional Chinese medicine].

Target discovery is the core of elucidating the mechanism of traditional Chinese medicine( TCM),and it is also the key to correlate the chemical composition and pharmacological action of TCM. The traditional target screening methods such as the activitybased probe profiling,affinity chromatography,and protein microarray are commonly used in the past,however,which are limited in TCM due to the complexity of small molecules existed in the herbal medicine. The label-free small molecule probe is a recently well-applied technology in the target discovery of natural products,which is characterized by discovering the small molecule-protein ligation without any structural modification at the ligands,and is therefore suitable to the complex chemical constituents in TCM. Furthermore,this method is conducted on the basis of proteome,which is advanced in the discovery of new or multiple target proteins of TCM. Owing to the potential of label-free probe in the target discovery of TCM,its analytical principle,application status,and general protocol were reviewed in this paper. The label-free probe technology is anticipated to accelerate the mechanism-uncovering of TCM.

[Study on pharmacodynamic material basis of Naomaitong to protect neuronal cells based on PK-PD model].

The PK-PD correlation models by using pharmacodynamics and pharmacokinetics were applied to study the material basis of Naomaitong,a clinical empirical prescription for the treatment of cerebral apoplexy,in inhibiting the death of PC12 nerve cells induced by Na_2S_2O_4 and Glu. In this experiment,PC12 cell death models induced by Na_2S_2O_4 and Glu were established respectively.With LDH lateral leakage and NO content as pharmacodynamic indexes,PK-PD model was established by SVM algorithm to evaluate the effective components of Naomaitong in inhibiting neural cell death. The results showed that the positive correlation of emodin methyl ether-8-O-ß-D-glucopyranoside,aloe emodin,chrysophanol,rhein,emodin,ginsenoside Rg1,ginsenoside Rc,3'-methoxypuerarin and ligustilide was significant,obviously improving the LDH release and NO content. The results indicated that the contribution of Radix Puerariae Lobatae Radix and Rhei Radix et Rhizoma in Naomaitong could protect the nerve cell death induced by Na_2S_2O_4 and Glu respectively. PK-PD model was used to screen the neuroprotective components in Naomaitong,revealing the possible pharmacodynamic material basis of Naomaitong in the treatment of cerebral ischemia injury.