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Objective: To compare the pharmacokinetic differences of the main components of Naoxintong capsule (NXTC) in normal and acute blood stasis rats. Materials and Methods: Rats were subcutaneously injected with adrenaline hydrochloride twice; during the two subcutaneous injections, the rats were placed in ice water for 4 min to reproduce the model rat of acute blood stasis. The normal and acute blood stasis rats were administrated a 5.04 g/kg dose of NXTC suspension. Then, blood samples were collected from the posterior retinal venous plexus at different time points. Plasma concentrations of four major bio-active components including caffeic acid, ferulic acid, formononetin, and tanshinone IIA in NXTC were measured using ultra-performance liquid chromatography coupled with triple-quadrupole mass spectrometry. Phoenix WinNonlin v6.2 software was used to calculate the pharmacokinetic parameters. Results: Compared with the normal rats, the acute blood stasis rats showed a significant decrease in Cmax of ferulic acid and formononetin, AUCall of caffeic acid and ferulic acid, and AUCINF_obs of ferulic acid. Conversely, an increase in the Vz_F_obs and MRTlast of ferulic acid and caffeic acid was observed. These findings demonstrate that the absorption of the four NXTC components was weakened in the acute blood stasis rats and that the elimination time was prolonged. Conclusions: The significant difference in some parameters of the four NXTC components between the normal and acute blood stasis rats might be caused by an increase in blood viscosity and the subsequent slowing down of blood flow in the acute blood stasis rats. The pharmacokinetic study conducted in pathological state can provide important information and scientific basis for further rational clinical application of NXTC.

Polygonum multiflorum (PM), a popular functional food, herbal and dietary supplement, is widely used as a tonic in China and East Asia. In recent years, it has attracted great concern for its ability to cause idiosyncratic drug-induced liver injury (IDILI). However, identifying individuals susceptible to IDILI remains challenging. This is a prospective study. For 6 patients whose serum alanine aminotransferase (ALT) after consuming PM was abnormally elevated (susceptible group), 15 patients with normal levels of liver injury markers were matched (tolerant group) based on similar baseline characteristics. ProcartaPlex Immunoassays were adopted to quantitatively detect 33 serum cytokines in the two groups of patients before consuming PM, to characterize the cytokine profile and screen differential cytokines. Subsequently, the susceptibility of potential biomarker to regulate PM-induced liver injury was validated in animal models. There were significant differences in the cytokine profile between susceptible and tolerant groups, wherein the susceptible patients showed immune perturbation characterized by high expression of multiple inflammatory cytokines, especially proinflammatory cytokine TNF-α level (P = 0.006). Among them, the cytokine TNF-α had the strongest correlation with ALT, the correlation coefficient was greater than 0.6, and the area under the receiver operating characteristic curve was more than 0.8. Animal experiments revealed that both PM water extract and its susceptibility component of liver injury, cis-stilbene glucoside, could cause liver injury in the mice pre-stimulated by TNF-α. Conversely, administration of the same dose of drugs on blank mice did not show any hepatotoxicity. In conclusion, immune perturbation mainly mediated by TNF-α may regulate the susceptibility to PM-induced liver injury. This provides a new perspective for the study of susceptibility to IDILI.

UPLC-TQ/MS was employed to determine the content of 8 main components(psoralen, isopsoralen, psoralenoside, isopsoralenoside, bavachin, psoralidin, corylin, and neobavaisoflavone) in tissues of normal and lipopolysaccharide(LPS)-induced model rats 0.5, 1, 2, 6, and 12 h after intragastric administration of 3.6 g·kg~(-1) ethanol extract of Psoraleae Fructus. The distribution characteristics of the 8 main components in the different tissues(liver, kidney, spleen, heart, and lung) were studied and compared. The results showed that the distribution behaviors of the components varied among different tissues. At different time points, the components presented wide and uneven distribution in the body. Liver and kidney had higher content of the components, followed by spleen, heart, and lung. In both normal and LPS-induced model rats, the content of the 8 main components was higher in liver and kidney and varied significantly among different tissues. The content of psoralen in the tissues of LPS-induced model rat was significantly higher than that of the normal group 12 h after administration. The reason may be that the modeling slowed down the absorption and distribution of psoralen. The LPS-induced model rats had higher content of psoralenoside and isopsoralenoside in the liver tissue than the normal rats, which indicated that the modeling increased the absorption and distribution of psoralenoside and isopsoralenoside in the liver tissue. Further, it is hypothesized that psoralenoside and isopsoralenoside may be toxic substances of Psoraleae Fructus-induced liver injury.

Can Tu,1,2 Ming Niu,2 Ai-Wu Wei,3 Jin-Fa Tang,3 Le Zhang,2 Jing Jing,2 Xiao-He Xiao,2 Jia-Bo Wang2,4 1Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China; 3The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450000, People’s Republic of China; 4School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, People’s Republic of ChinaCorrespondence: Jia-Bo WangSchool of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, People’s Republic of ChinaEmail pharm_sci@126.comXiao-He XiaoChina Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of ChinaEmail pharmacy302xxh@126.comBackground: Drug-induced liver injury is a common adverse effect in clinical practice, with severe cases resulting in liver failure and even death. Identification and prediction of individuals susceptible to idiosyncratic DILI continues to remain a challenge.Methods: In this study, we report that cytokines in human serum can be used to identify and predict individuals susceptible to Polygonum multiflorum-induced DILI (PM-DILI) in retrospective and prospective cohort studies.Findings: In the retrospective pilot study, we compared serum cytokine expression profiles of the PM-DILI group (n=10) and the PM-Tolerant group (n=12) and found 10 cytokines with significant differences. In the replication cohort study, differences in the 10 cytokines between PM-DILI (n =11) and PM-Tolerant (n=13) groups were verified. Among them, 6 cytokines showed no significant differences at two time points, including liver injury and recovery stage of PM-DILI, suggesting that these 6 cytokines have no correlation with PM-DILI, however, they may be related to susceptibility. Furthermore, all the retrospective cohorts were combined, and a PM-DILI susceptibility prediction model was built by screening the 6 cytokines. The combination of (TNF-α and CCL-2) or VEGF showed the highest sensitivity and specificity. Finally, the efficacy of the above 3 cytokine combination models in predicting PM-DILI-susceptible individuals was verified before PM exposure in another independent prospective cohort (n=24), with sensitivity and specificity of 66.7% and 83.3%, respectively.Conclusion: This proof-of-concept study demonstrates that the serum cytokine combination reflecting dysimmunity could be used as a new method to predict PM-DILI, thus providing a new perspective for improving the clinical management of IDILI.Keywords: drug-induced liver injury, Polygonum multiflorum, cytokine, prediction, susceptible individual

The present study analyzed the potential biomarkers of chronic obstructive pulmonary disease(COPD) with lung-Qi deficiency syndrome by non-targeted metabolomics and explored the biological basis of this syndrome. Blood samples of 96 COPD patients with lung-Qi deficiency syndrome(COPD with lung-Qi deficiency syndrome group) and 106 healthy people(healthy control group) were collected, and the metabolic profiles of both groups were analyzed by ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS). Multivariate statistical analysis and differential metabolite screening were carried out by using Progenesis QI and Simca-P. Metabolic pathways were constructed through the MetaboAnalyst. Seven potential biomarkers, such as L-cystathionine, protoporphyrinogen Ⅸ, and citalopram aldehyde, were identified. Compared with the results in the healthy control group, the content of citalopram aldehyde, N1-methyl-2-pyridone-5-carboxamide, and 11β,17β-dihydroxy-4-androsten-3-one was significantly up-regulated, while that of the other four compounds such as L-cystathionine, dihydrotestosterone, protoporphyrinogen Ⅸ, and D-urobilinogen was down-regulated. These potential biomarkers involved six metabolic pathways, including cysteine and methionine metabolism, porphyrin and chlorophyll metabolism, drug metabolism of cytochrome P450, steroid hormone biosynthesis, glycine, serine, and threonine metabolism, and nicotinate and nicotinamide meta-bolism. This study is expected to provide a certain scientific basis for the research on traditional Chinese medicine syndrome of COPD with lung-Qi deficiency syndrome from the molecular biology level.

This study was designed to explore the alleviating effect and mechanism of Glycyrrhizae Radix et Rhizoma against Psora-leae Fructus-induced liver injury based on network pharmacology and cell experiments. The active components of Glycyrrhizae Radix et Rhizoma and Psoraleae Fructus were first retrieved from the Encyclopedia of Traditional Chinese Medicine(ETCM), Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), Comparative Toxicogenomics Database(CTD), and literature and further screened by SwissADME. The obtained 25 potential toxic components of Psoraleae Fructus and 29 flavonoids in Glycyrrhizae Radix et Rhizoma were input into the SwissTargetPrediction for target predication. A total of 818 targets related to liver injury were screened out based on GeneCards and MalaCards, and 91 common targets of Psoraleae Fructus, Glycyrrhizae Radix et Rhizoma, and liver injury were obtained from Venny. STRING was applied for constructing the PPI network, and Metascape for analyzing the biological processes and signaling pathways that common targets participated in. Cytoscape was used to construct the component-target-disease network and component-target-pathway network for Glycyrrhizae Radix et Rhizoma against Psoraleae Fructus-induced liver injury. The predicted core targets were proto-oncogene tyrosine-protein kinase(SRC), phosphatidylinositol 4,5-bisphosphate 3-kinase subunit alpha(PIK3 CA), RAC-alpha serine/threonine-protein kinase(AKT1), etc, with PI3 K-AKT signaling pathway, MAPK signaling pathway, apoptosis, Toll-like receptor signaling pathway, and NF-κB signaling pathway mainly involved. Following the scree-ning of the main toxic and pharmacodynamic components, the pharmacodynamic effects were investigated by cell experiments. The results showed that licochalcone A was mainly responsible for alleviating coryfolin-induced liver injury, licochalcone B for coryfolin-and psoralidin-induced liver injury, and echinatin for corylifolinin-and bakuchiol-induced liver injury. The preliminary revealing of the alleviating effect of Glycyrrhizae Radix et Rhizoma on Psoraleae Fructus-induced liver injury and the prediction of related mechanisms will provide reference for further mechanism research and reasonable clinical compatibility.

Traditional medicines have greatly contributed to people’s health worldwide. However, in recent years, the frequent occurrence of herb-induced liver injury (HILI) has raised public concerns regarding the safety of herbs. HILI not only severely impacts public health, thus increasing its medical burden, but also consumes medical resources. However, the pharmacoepidemiology and risk factors of HILI are still unclear due to the complexity of herbs (medication theory, drug composition, dual properties of drugs and food, etc.). China is the country with the most extensive use of herbs and cases of HILI worldwide. The safety profile of herbs (especially with respect to HILI) has also affected the use of herbs internationally. Therefore, this review focuses on the epidemic situation of HILI in mainland China to compile its characteristics, while focusing on the three main aspects of patients, drugs, and unreasonable prescriptions to explore the potential risk factors. Our objective was to provide a reference for HILI pharmacovigilance and risk prevention and control and contribute to Chinese knowledge of the realisation of the “Medication without Harm” global safe medication strategic goal of the World Health Organization.

As an effective antipyretic medicine,Indigo Naturalis has a long history of application in the field of Chinese medicine.The content of organics,mainly indigo and indirubin,is about 10%. However,the active ingredients and mechanism of its antipyretic effect have not yet been fully elucidated. In view of this,they were investigated in this study with the rectal temperature change as an indicator and 2,4-dinitrophenol-induced fever rats as subjects. The content of PGE2 and c AMP in the hypothalamus and the serum levels of TNF-α,IL-1β and IL-6 were determined by ELISA. Moreover,the plasma samples of fever rats were analyzed by metabonomics in combination with UPLC-Q-TOF-MS for the exploration of potential biomarkers and the discussion on the antipyretic mechanism of Indigo Naturalis and its active ingredients. The results showed that the rising trend of rectal temperature in rats was suppressed 0. 5 h after the treatment with Indigo Naturalis,organic matter,indigo or indirubin as compared with the rats of model group( Plt; 0. 05),among which Indigo Naturalis and organic matter had better antipyretic effect. ELISA results showed that organic matter and indigo can inhibit the expression of PGE2 and c AMP( Plt;0. 01),while Indigo Naturalis and organic matter were effective in curbing the increase in TNF-α( Plt;0. 05). A total of 21 endogenous metabolites were identified from the plasma samples of the Indigo Naturalis,organic matter,indigo and indirubin groups,which were mainly involved in glycerophospholipid metabolism.

The gene polymorphisms of ABCB1, EPHX1, and SCN1A were found to influence carbamazepine (CBZ) metabolism and resistance in epilepsy patients, but the relevance remains controversial. To reveal the relationships among the gene polymorphisms of ABCB1, EPHX1, SCN1A and the metabolism and resistance of CBZ, the databases of PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals, China Biology medicine disc and Wan Fang were retrieved for suitable studies up to April 2021. 18 studies containing 3293 epilepsy patients were included. The result revealed the gene polymorphism of ABCB1 c.3435C > T is significantly associated with altered concentration–dose ratios of CBZ (CDRCBZ) (CC vs. CT, OR = 0.25 (95% CI: 0.08–0.42), P = 0.004), and EPHX c.416A > G gene polymorphism may also significantly adjusted the concentration–dose ratios of carbamazepine-10, 11-trans dihydrodiol (CDRCBZD) (AA vs. GG, OR = 0.48 (95% CI: 0.01–0.96), P = 0.045; AG vs. GG, OR = 0.68 (95% CI: 0.16–1.20), P = 0.010, respectively) and the ratio of CBZD:carbamazepine-10,11-epoxide (CBZE) (CDRCBZD:CDRCBZE) (AG vs GG, OR = 0.83 (95% CI: 0.31–1.36), P = 0.002). Furthermore, ABCB1 c.3435C > T polymorphism was also observed to be significantly influenced CBZ resistance (CC vs TT, OR = 1.78 (95% CI: 1.17–2.72), P = 0.008; CT vs TT, OR = 1.60 (95% CI: 1.12–2.30), P = 0.01; CC + CT vs TT, OR = 1.61 (95% CI: 1.15–2.26), P = 0.006, respectively). Therefore, CBZ metabolism and resistance in patients with epilepsy may be adjusted by the gene polymorphisms of ABCB1 c.3435C > T and EPHX1 c.416A > G which provides the further scientific basis for clinical individualized therapy of epilepsy. However, larger sample size studies are still needed to provide further conclusive evidence.

Background Drug-induced liver injury is a common adverse effect in clinical practice, with severe cases resulting in liver failure and even death. Identification and prediction of individuals susceptible to idiosyncratic DILI continues to remain a challenge. Methods In this study, we report that cytokines in human serum can be used to identify and predict individuals susceptible to Polygonum multiflorum-induced DILI (PM-DILI) in retrospective and prospective cohort studies. Findings In the retrospective pilot study, we compared serum cytokine expression profiles of the PM-DILI group (n=10) and the PM-Tolerant group (n=12) and found 10 cytokines with significant differences. In the replication cohort study, differences in the 10 cytokines between PM-DILI (n =11) and PM-Tolerant (n=13) groups were verified. Among them, 6 cytokines showed no significant differences at two time points, including liver injury and recovery stage of PM-DILI, suggesting that these 6 cytokines have no correlation with PM-DILI, however, they may be related to susceptibility. Furthermore, all the retrospective cohorts were combined, and a PM-DILI susceptibility prediction model was built by screening the 6 cytokines. The combination of (TNF-α and CCL-2) or VEGF showed the highest sensitivity and specificity. Finally, the efficacy of the above 3 cytokine combination models in predicting PM-DILI-susceptible individuals was verified before PM exposure in another independent prospective cohort (n=24), with sensitivity and specificity of 66.7% and 83.3%, respectively. Conclusion This proof-of-concept study demonstrates that the serum cytokine combination reflecting dysimmunity could be used as a new method to predict PM-DILI, thus providing a new perspective for improving the clinical management of IDILI.

Background: In view of a lack of consensus regarding the biomarkers of pre-diabetes and type 2 diabetes mellitus (T2DM), we sought to develop integrated biomarker profiling (IBP) of the metabolome. Methods: We studied 1,705 subjects including normal glucose tolerance, impaired fasting glucose (IFG), T2DM, and hyperlipidemia at five clinical centers in China. We aimed to construct the IBPs of IFG and T2DM, designed discovery, test, and validation phases. The discovery and test phases were employed to identify the potential serum biomarkers for IFG and T2DM. In the validation phase, the potential biomarkers were screened using Gini impurity to construct the IBP of IFG and T2DM based on the eXtreme Gradient Boosting (XGBoost) model, and individuals with hyperlipidemia were set as an interference group to evaluate the diagnostic accuracy of the IBP. Findings: Forty-one potential biomarkers were identified, in which 16 potential biomarkers were quantitatively analyzed. The IBP, which holistically reflected a mutually correlated bio-network, was constructed based on the XGBoost (AUC=0·823) model and Gini impurity (Top 10), and consisted of lysophosphatidylcholine (P-16:0), L-isoleucine, L-arginine, L-carnitine, L-phenylalanine, L-glutamic acid, L-lysine, L-methionine, L-leucine, and acetyl-L-carnitine. Besides, the service website ( http://pdm.lin-group.cn/) of the IBPs for IFG and T2DM was established to serve the public. Interpretation: IBP of the metabolome provides more consolidated evidence than isolated biomarkers, and might improve auxiliary diagnostic value in IFG and T2DM. Trial Registration: Chinese Clinical Trial Registry (ChiCTR1800014301). Funding Statement: This work was supported by the National Natural Science Foundation of China (grant number 81773891, 82073741), the National Great New Drugs Development Project of China (grant number 2017ZX09301-040), the National Key R&D Program of China (grant number 2020YFF01014606), and the Beijing Excellent Talent Project (grant number DFL20190702, 2018000021223TD09). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study protocols were approved by the Scientific Research Ethics Committee of Capital Medical University Affiliated Beijing Shijitan Hospital (2017-035) and registered on the Chinese Clinical Trial Registry (ChiCTR1800014301). All the participants provided their written informed consent.

Schisandrae Fructus (SF), the fruit of Schisandra chinensis (Turcz.) Baillon, has been used for the treatment of liver injury and metabolism-related disorders in China. The objective of this study was to investigate the effects of supplementation with ethanol extract of SF seed (EtSF-S) on serum/hepatic lipid and glucose levels as well as fecal total cholesterol (TC) contents in mice fed a normal diet (ND) or high-fat/fructose diet (HFFD) containing 15% lard oil and 15% fructose. Female ICR mice (18–20 g in body weight) were fed with ND or HFFD for 3 months, and then EtSF-S was added to both chow diets at increasing concentrations of 1, 5, and 10% (w/w). Thirty days later, serum and hepatic lipids, including TC, triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and glucose, were measured. Dietary supplementation with EtSF-S reduced hepatic TC (36 and 18%) and TG levels (38 and 28%) and increased serum HDL/LDL ratio (16 and 26%) in both ND- and HFFD-fed mice, respectively. Moreover, supplementation with EtSF-S elevated serum HDL (31%) in HFFD-fed mice and reduced serum LDL (27%) in ND-fed mice. EtSF-S treatment reduced fat mass (40%) in ND-fed mice and increased fecal TC contents (33%) in HFFD-fed mice. EtSF-S supplementation decreased hepatic glucose contents (29%) in both ND- and HFFD-fed mice. However, diet supplemented with EtSF-S elevated serum TG levels (up to 123%) and hepatic size (28%), but more importantly, suppressed the body weight gain (approximately 130%) in mice fed with HFFD. These findings suggested that dietary supplementation with EtSF-S as natural herbal function food may be a useful strategy for the treatment of patients with fatty liver disease or overweight without a high intake of sugar and fat.

Background: ABCB1, EPHX1 and SCN1A gene polymorphisms have been reported play important roles in individual variability carbamazepine (CBZ) metabolism and resistance, but the result of that association still remains controversial. Objective: To clarify the associations among ABCB1, EPHX1 and SCN1A gene polymorphisms and CBZ metabolism and resistance. Methods: The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology medicine disc and Wan Fang Database were searched for appropriate studies up to April 2020. Results: A total of 18 studies involving 3293 related epilepsy patients were included. ABCB1 c.3435C>T polymorphism was significantly associated with adjusted concentrations of CBZ (CC vs. CT, P=0.004), and EPHX c.416A>G polymorphism was significantly associated with carbamazepine-10, 11-trans dihydrodiol (CBZD) (AA vs. GG, P=0.045; AG vs. GG, P=0.010). Furthermore, ABCB1 c.3435C>T polymorphism was also observed to be significantly influenced CBZ resistance (CT vs TT, P=0.01; CC+CT vs TT, P=0.006). Conclusion: ABCB1 c.3435C>T polymorphism may affect the CBZ metabolism and resistance, EPHX1 c.416A>G polymorphism may only affect CBZ metabolism. These findings provided further evidence for individualized therapy of epilepsy patients in clinics. Nevertheless further large studies are still warranted to provide conclusive evidences.

Although increasing reports from the literature on herbal-related hepatotoxicity, the identification of susceptibility-related factors and biomarkers remains challenging due to idiosyncratic drug-induced liver injury (IDILI). As a well-known Chinese medicine prescription, Xianling Gubao Capsule (XLGB) has attracted great attention due to reports of potential liver toxicity. But the mechanism behind it is difficult to determine. In this paper, we found that XLGB-induced liver injury belongs to IDILI through the analysis of clinical liver injury cases. In toxicological experiment assessment, co-exposure to XLGB and non-toxic dose of lipopolysaccharide (LPS) could cause evident liver injury as manifested by significantly increased plasma alanine aminotransferase activity and obvious liver histological damage. However, it failed to induce observable liver injury in normal rats, suggesting that mild immune stress may be a susceptibility factor for XLGB-induced idiosyncratic liver injury. Furthermore, plasma cytokines were determined and 15 cytokines (such as IL-1β, IFN-γ, and MIP-2α etc) were acquired by receiver operating characteristic (ROC) curves analysis. The expression of these 15 cytokines in LPS group was significantly up-regulated in contrast to the normal group. Meanwhile, the metabolomics profile showed that mild immune stress caused metabolic reprogramming, including sphingolipid metabolism, phenylalanine metabolism, and glycerophospholipid metabolism. 8 potential biomarkers (such as sphinganine, glycerophosphoethanolamine, and phenylalanine etc.) were identified by correlation analysis. Therefore, these results suggested that intracellular metabolism and immune changes induced by mild immune stress may be important susceptibility mechanisms for XLGB IDILI.

The main constituents of a typical medicinal herb, Polygonum multiflorum (Heshouwu in Chinese), that induces idiosyncratic liver injury remain unclear. Our previous work has shown that cotreatment with a nontoxic dose of lipopolysaccharide (LPS) and therapeutic dose of Heshouwu can induce liver injury in rats, whereas the solo treatment cannot induce observable injury. In the present work, using the constituent "knock-out" and "knock-in" strategy, we found that the ethyl acetate (EA) extract of Heshouwu displayed comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Results indicated a significant elevation of plasma alanine aminotransferase, aspartate aminotransferase, and liver histologic changes, whereas other separated fractions failed to induce liver injury. The mixture of EA extract with other separated fractions induced comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Chemical analysis further revealed that 2,3,5,4'-tetrahydroxy trans-stilbene-2-O-β-glucoside (trans-SG) and its cis-isomer were the two major compounds in EA extract. Furthermore, the isolated cis-, and not its trans-isomer, displayed comparable idiosyncratic hepatotoxicity to EA extract in LPS-treated rats. Higher contents of cis-SG were detected in Heshouwu liquor or preparations from actual liver intoxication patients associated with Heshouwu compared with general collected samples. In addition, plasma metabolomics analysis showed that cis-SG-disturbing enriched pathways remarkably differed from trans-SG ones in LPS-treated rats. All these results suggested that cis-SG was closely associated with the idiosyncratic hepatotoxicity of Heshouwu. Considering that the cis-trans isomerization of trans-SG was mediated by ultraviolet light or sunlight, our findings serve as reference for controlling photoisomerization in drug discovery and for the clinical use of Heshouwu and stilbene-related medications.

In the present study,non-targeted metabolomics technique was used to screen potentially susceptibility biomarkers in patients with mild liver function abnormalities during long-term use of Chinese herbal compound. According to the inclusion and exclusion criteria,we collected 7 cases of patients with abnormal liver function during the period of complete taking Chinese herbal medicine( 60 days),and 18 cases of patients with normal liver function in re-examination from the reproductive medicine center in our hospital. Ultra performance liquid chromatography coupled with time-of-flight mass spectrometry( UPLC-Q-TOF/MS~E) technique combined with Progenesis QI software was used to analyze the differential biomarkers in serum of patients with wild liver function abnormalities and normal liver function. 11 potential biomarkers such as bilirubin,pantothenic acid,hippuric acid,sphingomyelin,palmitic acid,and oleic acid were tentatively identified. Metabolic disorders in patients with herbal-induced mild liver abnormality were mainly related to two pathways: pantothenic acid and coenzyme A biosynthesis and linoleic acid metabolism. It could provide a reference for the early warning of mild liver function abnormalities of patients that may be caused by long-term use of Chinese medicine compound in clinical application,and will lay a foundation for further understanding the endogenous substance changes in different levels of liver injury.

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially fatal disease that is unpredictable and independent of the dose of the drug. Increasing evidence suggests that the majority of IDILI cases are immune-mediated, and the aberrant activation of inflammasome plays a vital role in progression. Psoraleae Fructus (PF), a tonic Chinese medicine, has been able to cause IDILI, but the precise mechanism of hepatotoxicity remains unclear. In this study, eight bioactive compounds involved in PF-induced inflammasome activation were investigated. The results demonstrated that psoralidin activated the inflammasomes followed by secreting caspase-1 and interleukin 1β (IL-1β) in a dose-dependent manner. Interestingly, MCC950, a potent inhibitor of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, could not entirely suppress the psoralidin-induced inflammasome activation. Moreover, psoralidin significantly induced IL-1β maturation and caspase-1 activation in NLRP3-knockout bone marrow-derived macrophages (BMDMs), suggesting that psoralidin not only activates the NLRP3 inflammasome but also activates other types of inflammasomes. The results also demonstrated that psoralidin activated the inflammasomes by promoting the C-terminal caspase recruitment domain (ASC) oligomerization, and the production of mitochondrial reactive oxygen species (mtROS) is a decisive factor in psoralidin-induced inflammasome activation. Importantly, in vivo data revealed that psoralidin induced hepatic inflammation, increased aminotransferase activity and increased the production of IL-1β and tumor necrosis factor(TNF-α) in a susceptible mouse model of lipopolysaccharide (LPS)-mediated IDILI. In summary, these results confirmed that psoralidin causes IDILI by inducing inflammasome activation. The study suggests that psoralidin is a possible risk factor and is responsible for PF-induced IDILI.

Xueshuantong Lyophilized Powder (XST), consisting of a series of saponins extracted from Panax notoginseng, is widely applied to treat acute cerebral infarction, stroke, and coronary heart disease in China. However, most adverse drug reactions (ADR) in clinic are caused by quality problems of XST. In this study, six batches of certainly abnormal, four batches of possibly abnormal XST, and eight batches of normal XST were obtained from the clinical practice. Their quality fluctuations were identified by ultra-performance liquid chromatography coupled with an electrospray ionization quadrupole time-of-flight mass spectrometry operating in MSE mode (UPLC-QTOF/MSE) and bioassays including antithrombin and proplasmin assay. Fourteen potential components responsible for clinical ADR were identified by UPLC-QTOF/MSE, especially ginsenoside Rg1, Rg3, Rb1 and notoginsenoside R1. In addition, 83.3% (5/6) and 50.0% (3/6) certainly abnormal samples could be identified by UPLC-QTOF/MSE and bioassay, respectively. Interestingly, further integration of the two methods could entirely identify all the certainly abnormal samples and inferred that all the possibly abnormal samples were closely related to their quality fluctuation. It indicates that it is advisable to combine UPLC-QTOF/MSE and bioassay for identifying quality fluctuation of XST, and thus reduce its ADR in clinic.

Danhong injection (DHI), one of the best-selling traditional Chinese medicine injections (TCMIs), is used extensively for treating myocardial infarction, atherosclerosis, coronary heart disease, and traumatic intracranial hematoma in clinics. It has attracted increasing attention as one of the most popular and valuable herbal medicines. However, the systematic analysis of the chemical constituents of DHI is difficult and thus has not been well established. In this paper, rapid, sensitive, and reliable ultra high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) was established to characterize the components of DHI. And the UNIFI software with the Traditional Medicine Library was applied to identify the chemical constituents of DHI for the first time, which is simpler and more effective. Under the optimized conditions, a total of 44 peaks including nucleotides, phenolic acids, and flavonoid glycosides were identified or tentatively characterized by comparing the retention time and MS data. The results may provide useful information for the further study of the pharmacology and mechanism of DHI. Furthermore, with the introduction of the UNIFI software into the analysis of TCM, this will provide a type of validated rapid and high-throughput methodology for the identification of constituents in Chinese herbal prescriptions; we expect that this approach would be useful for the screening and characterization of compounds in other famous TCM products.

To study the adverse reactions' factors to Danhong injection in the real world. A multi-center, large sample and prospective hospital centralized monitoring method was adopted, and 30 888 cases of Danhong injection from 37 national 3A hospitals were collected to carry out a nested case control design study. These cases were divided into adverse reaction group and non-adverse group. Single factor logistic regression and multiple factor logistic regression were used to analyze data, and investigate the correlation between adverse reaction and gender, allergy history, methods of administration, and combined drug use. One hundred and eight cases of adverse reactions in 30 888 patients were determined, with an incidence of 0.35%. The results showed that Danhong injection combined with other medication(potassium mendoxine magnesium, thymic peptide, celecoxib, fumarate bisoprolol) with history of adverse reactions including scephalosporin allergy and proprietary Chinese medicine allergies had more adverse reactions than the control group(

With the growth of number of Chinese patent medicines and clinical use, the rational use of Chinese medicine is becoming more and more serious. Due to the complexity of Chinese medicine theory and the uncertainty of clinical application, the prescription review of Chinese patent medicine always relied on experience in their respective, leading to the uncontrolled of clinical rational use. According to the traditional Chinese medicine (TCM) theory and characteristics of the unique clinical therapeutics, based on the practice experience and expertise comments, our paper formed the expert consensus on the prescription review of Chinese traditional patent medicine for promoting the rational use of drugs in Beijing. The objective, methods and key points of prescription review of Chinese patent medicine, were included in this expert consensus, in order to regulate the behavior of prescription and promote rational drug use.

Naoxintong capsule (NXTC) is an oral Chinese preparation produced by modern technology, derived from the classic preparation of Buyang Huanwu decoction which was recorded by WANG Qing-ren (Qing dynasty) in Yilingaicuo Juanxia Tanweilun. NXTC is composed of 16 herbs including insect herbs and some blood circulation herbs, with the effects of supplementing Qi and activating blood circulation, dispersing blood stasis and dredging collaterals. In clinical application, it is mainly used for stroke, cerebral infarction, vascular dementia, ischemic cerebrovascular disease, transient ischemic attack, coronary heart disease, angina pectoris, ischemic cardiomyopathy, diabetic cardiomyopathy, myocardial infarction, chronic heart failure, chronic complications of diabetes, essential hypertension, hyperlipidemia and other cardiovascular and cerebrovascular diseases, and has achieved good therapeutic effect on above diseases or their concurrent diseases. Its clinical efficacy is mainly achieved through the improvement in related links of brain protection, neuroprotection, cardioprotection, hemorheology, et al. Nearly 200 chemical constituents identified in NXTC are important pharmacological basis for its functions. At present, however, most of its pharmacological basic researches are focused on plant herbs, and the three kinds of insect herbs remain to be further studied. The researches on clinical effectiveness are more comprehensive; the safety study of long-term application in real world is ongoing by our team, and its results are yet to be published after finishing the study. Through the systematic and comprehensive combing and elaboration of the research progresses on the chemical compositions, pharmacological action and clinical application of NXTC, it can provide a reference for the in-depth study of this preparation, with a great significance for the quality control, secondary development and internationalization promotion of NXTC.

To establish HPLC-MS/MS method for simultaneous determination of 14 toxic or active components in Fuzi formula granules, and further analyze the quality consistency of 29 batches of formula granules by considering the cluster analysis (CA), principal component analysis (PCA), and partial least squares discriminant analysis (PLS-DA) and other chemometrics methods. Phenomenonex Gemini C18 column (4.6 mm×150 mm, 5 μm) was used with 0.1% formic acid solution (A) -acetonitrile (B) as the mobile phase. The mass spectrum was scanned by ESI⁺ multiple reaction monitoring (MRM) mode. The contents of aconitine, mesaconitine, hypaconitine, Indaconitine, benzoylaconine, benzoylmesaconine, benzoylhypaconitine, aconine, fuziline, neoline, talatisamine, songorine, higenamine and salsoline were determined. The results showed that 14 compounds had a good linear relationship within their respective concentration range (R²0.990 0). The limit of quantification was 2.07-7.71 mg·L⁻¹, and the average recovery was 96.07%-102.2%. The content determination results demonstrated that all batches of Fuzi formula granules had very low hypertoxic ingredients and high safety, while the content of active ingredients was greatly different. CA and PCA results showed that there were significant differences in the formula granules between two manufacturers; even though the different batches of samples from the same manufacturer had certain differences, but the difference in manufacturer A was less than that of B. Further PLS-DA showed that the content of cardiotonic substance salsola in the formula granules from manufacturer A was generally higher, while the contents of analgesic and anti-inflammatory substances benzoylmesaconitine and fuziline were generally lower than those in the products from manufacturer B. In conclusion, the safety of Fuzi formula granules was assured well, but the consistency needed to be improved. We recommend that all manufacturers establish strict standard for decoctions in the production process, and form a unified standard method to produce better Fuzi formula granules.

To analyze the clinical application characteristics of Danggui-Chuanxiong(DG-CX) herb pair in Chinese medicines on basis of real-world, and provide reference for explaining the inherent compatibility regularity and the relationship between clinical applications and disease species. From April 1, 2014 to June 30, 2014, a total of 8 792 prescriptions with both "DG"and "CX" in a large third-grade class-A traditional Chinese medicine(TCM) hospital were selected to establish the database for analyzing the ratio, dosage, and corresponding disease species of DG-CX herb pair. The results showed that, "DG-CX" with ratio "1∶1" had the highest frequency in clinical application(42.4%); the dosage was mainly of 15 g for both DG and CX; the disease species were mainly of encephalopathy and pulmonary diseases. "DG-CX" herb pairs with a ratio greater than "1∶1" accounted for 33.3% of all the prescriptions, and the ratio "3∶2" appeared to be most frequent among them; the dosage was mainly of 15 g for DG and and 10 g for CX; the disease species were mainly of encephalopathy diseases. "DG-CX" herb pairs with a ratio less than "1∶1" accounted for 24.3% of all the prescriptions, and the ratio "2∶3" appeared to be most frequent among them; the dosage was mainly of 10 g for DG and 15 g for CX; the disease species were mainly of encephalopathy diseases. Statistical method was applied to study the compatibility and application characteristics of Chinese herb pairs in clinical prescriptions, effectively discover the medication regularity, provide theoretical basis for clinical herbal prescriptions and provide scientific guidance and reliable data for modern research of Chinese herb pairs.

Traditional Chinese medicine injections (TCMIs) have played an irreplaceable role for treating some clinical emergency, severe illness, and infectious diseases in China. In recent years, the incidence rates of adverse drug reactions (ADRs) of TCMIs have increased year by year. Danhong injection (DHI) is one representative TCMI comprised of Danshen and Honghua for treating cardiovascular and cerebrovascular diseases in clinic. In present study, the postmarketing safety surveillance and reevaluation of DHI were reported. Total 30888 patients in 37 hospitals from 6 provinces participated in the study. The results showed that the ADR incidence rate of DHI was 3.50‰. Seventeen kinds of new adverse reactions of DHI were found. The main type of ADRs of DHI was type A (including sweating, dizziness, headache, flushing, vasodilation, eye hemorrhage, faintness, chest pain, palpitations, breathlessness, anxious, nausea, flatulence, vomiting, hypotension, hypertension, local numbness, dyspnea, joint disease, and tinnitus) accounting for 57.75%. The severities of most ADRs of DHI were mild and moderate reactions accounting for 25.93% and 66.67%, respectively. The main disposition of ADRs of DHI was drug withdrawal and without any treatments. The results can provide basis for amendment and improvement of the instructions of DHI, as well as demonstration and reference for the postmarketing safety surveillance and reevaluation of other TCMIs. And the rationality, scientificity, and safety of clinical applications of TCMIs could be improved.

OBJECTIVE To explore security revaluation of Danhong injection and study correlative influencing factor of ADR/ADE. METHOD The retrospective nested case-control study was carried out in hospitalized patients of the first affiliated hospital of Henan university of traditional Chinese medicine (TCM). The 8 452 cases of participation Danhong injection adverse reaction scentralized monitoring were defined as the study cohort. Adverse reactions occurred in patients with data as the case group, according to choose control group by methods of group design and individual matching in accordance with the ratio of 1:4 (The case group 52 cases and 208 patients in control group), to estimate the correlative fluencing factor of ADR/ADE. RESULT The univariate analysis indicated that factors which OR value of group design reaching significance level were gender, personal allergichistory and medication days (P

OBJECTIVE To study Danhong injection adverse reactions (ADR) incidence, nature and clinical performance, provide the basis for the clinical safety of drugs. METHOD Multi-center, a large sample of hospitals focused on monitoring method. RESULT Danhong injection ADR for the rapid onset and ease the quick recovery, the rate was 0. 682% , the newly discovered ADR constipation, sweating, tinnitus, irritability, joint disease, erythema, venous pain, phlebitis, local numbness, pain, weakness, gastrointestinal ulcer bleeding, vasospasm, cyanosis. CONCLUSION Danhong injection adverse reactions are type A adverse reactions occasionally, centralized monitoring of hospital medicine injection method is to carry out post-marketing safety re-evaluation of appropriate methods.

OBJECTIVE To study the adverse reaction of Danhong injection with four kinds of methods, central monitoring method, chart review method, literature study method and spontaneous reporting method, and to compare the differences between them, explore an appropriate method to carry out post-marketing safety evaluation of traditional Chinese medicine injection. METHOD Set down the adverse reactions' questionnaire of four kinds of methods, central monitoring method, chart review method, literature study method and collect the information on adverse reactions in a certain period. Danhong injection adverse reaction information from Henan Province spontaneous reporting system was collected with spontaneous reporting method. Carry on data summary and descriptive analysis. RESULT Study the adverse reaction of Danhong injection with four methods of central monitoring method, chart review method, literature study method and spontaneous reporting method, the rates of adverse events were 0.993%, 0.336%, 0.515%, 0.067%, respectively. Cyanosis, arrhythmia, hypotension, sweating, erythema, hemorrhage dermatitis, rash, irritability, bleeding gums, toothache, tinnitus, asthma, elevated aminotransferases, constipation, pain are new discovered adverse reactions. CONCLUSION The central monitoring method is the appropriate method to carry out post-marketing safety evaluation of traditional Chinese medicine injection, which could objectively reflect the real world of clinical usage.

The progress of information technology promotes the development of new light emissive display devices. As one of great potential display techniques, organic electroluminescent (EL) thin film devices has characterized by the low driven voltage, high fluorescence quantum efficiencies, wide emitting spectrum and physical flexibility, attract much more attentions around the world in the last few years[1] [2]. Different from inorganic electroluminescent thin film device, organic EL thin film device are based on the injection effect for luminescence, that is due to the recombination of electron and holes in the diode junction region, therefore organic EL thin film device is one kind of LED device. It is important to construct an organic thin film diode structure. The currency problem is how to produce an organic LED diode of high lighting efficiency and of long working time. There are two ways to improve the device performance, one is from the material point of view, that is to say by finding out new EL materials, by the different doping methods or by the combination or a new design organic-inorganic compound to arrive the goal; the second way to realize the performance is by improving coating process, or optimization thin film diode structure. In this paper, we present our primary research works in organic EL thin film devices.

In order to develop optical coating devices for high power laser systems, it is necessary to have coatings with ultra low absorption loss, high laser damage threshold and good mechanical adhersion properties. Ion assisted deposition (IAD) is known to produce thin films with characteristics that the conventional thermal evaporation techniques can not realise[1], and meets the needs of this.

The most successful optical components for high power laser are those which most constructively deal with the problem of absorption of laser radiation and removed of waste heat to protect them from distortion and even damage.