Angelicin: A leading culprit involved in fructus Psoraleae liver injury via inhibition of VKORC1.

ETHNOPHARMACOLOGICAL RELEVANCE: The adverse effects of Fructus Psoraleae (FP), especially liver injury, have attracted wide attention in recent years. AIM OF THE STUDY: To establish a system to explore potential hepatotoxic targets and the chief culprit of liver injury based on clinical experience, network pharmacological method, molecular docking, and in vitro and in vivo experiments. MATERIALS AND METHODS: Clinical applications and adverse reactions to FP were obtained from public literatures. Components absorbed in the blood were selected as candidates to search for potential active targets (PATs) of FP. Subsequently, potential pharmacological core targets (PPCTs) were screened through the "drug targets-disease targets" network. Non-drug active targets (NPATs) were obtained by subtracting the PPCTs from the PATs. The potential hepatotoxic targets (PHTs) of FP were the intersection targets obtained from Venn analysis using NPATs, hepatotoxic targets, and adverse drug reaction (ADR) targets provided by the databases. Then, potential hepatotoxic components and targets were obtained using the "NPATS-component" network relationship. Molecular docking and in vitro and in vivo hepatotoxicity experiments were performed to verify the targets and related components. RESULTS: Overall, 234 NPATs were acquired from our analysis, and 6 targets were identified as PHTs. Results from molecular docking and in vitro and in vivo experiments showed that angelicin is the leading cause of liver injury in FP, and VKORC1 plays an important role. CONCLUSION: The results indicate that six targets, especially VKORC1, are associated with the PHTs of FP, and angelicin is the leading culprit involved in FP liver injury via inhibition of VKORC1.

[A novel mouse allergy tested model and its application for traditional Chinese medicine injections's allergy evaluation].

When the drug induces the organism to produce a type Ⅰ allergic reaction, the combination of IgE and mast cells results in the degranulation of the mast cells. Release of vasoactive substances, increase in vascular permeability, and exudation of intravascular substances outside the blood vessels. Based on this pathophysiological mechanism, a mouse model that can objectively and quantitatively assess the allergic response to the injection has been established. ICR mice were sensitised by intraperitoneal injection of different doses of OVA once every two days for three times. 14 days after the last sensitization, a combination OVA solution of 4 times the sensitizing dose and Evans blue were injected intravenously into mice for the challenge. Compared with the normal group, OVA 0.625/2.5, 1.25/5, 2.5/10, 5/20 mg·kg~(-1) sensitized and challenged can induce allergic reactions mainly manifested by blue staining of the auricle in mice. Direct injection of OVA intravenously did not cause an auricular blue colouration reaction in mice. The passive cutaneous anaphylaxis reaction in mice was conducted with the aforementioned OVA-sensitized mouse serum, and there were obvious blue spots on the mouse's back. In addition, the content of anti-OVA-IgE in 5 mg·kg~(-1) OVA-sensitized mice was significantly increased. Ears and lungs of mice sensitized to OVA showed evident exudation inflammation. Significantly elevated inflammatory factors(VEGF and IL-10) were also detected in the serum of OVA-sensitized mice. The equivalent dose of OVA caused obvious allergic reactions in both guinea pigs and mice. Compared with nude mice, ICR and BALB/c mice are more sensitive to OVA sensitization. Injections of selected TCMI did not induce type Ⅰ allergic reactions in mice and guinea pigs, but there was a risk of inducing pseu-doallergic reactions in mice. The model is problematic and may well reflect the sensitization effect of allergens. It obtains the benefits of simple operation, accuracy, low cost, easy extension, and high repeatability. It is suitable for predicting and researching for IgE-dependent type Ⅰ allergic reactions.

[Risk assessment, safe medication and scientific supervision of traditional Chinese medicine containing aristolochic acids--toxicity is different among aristolochic acids, and detection and control of aristolochic acid â /â ¡ is critical].

The safety problem of traditional Chinese medicine containing aristolochic acid is of great concern in China and abraod, which poses a challenge in clinical application and supervision. There are many types of aristolochic acid analogues(AAAs) and 178 have been reported. According to the structure, they are classified into aristolochic acids(AAs) and aristololactams(ALs). The toxi-city is remarkably different among AAAs of different types. For example, AA-Ⅰ has strong nephrotoxicity and carcinogenicity, and the toxicity of AA-Ⅱ is lower than that of AA-Ⅰ. Besides, AA-Ⅳa and AA-Ⅰa are considered to have no obvious nephrotoxicity and carcinogenicity. The types and content of AAAs are significantly different among traditional Chinese medicines derived from different Aristolochiaceae species. For example, Asari Radix et Rhizoma and Aristolochiae Herba mainly consist of AAAs without obvious toxicity(such as AA-Ⅳa). The content of AAAs in compound preparations is related to the proportions of the medicinals and the processing method. The content of AA-Ⅰ in some compound preparations is very low or below the detection limit. Therefore, the author concludes that AAAs of different types have different toxicity, but not all AAAs has nephrotoxicity and carcinogenicity. Moreover, the toxicity of traditional Chinese medicines containing AAAs should not be generalized and AA-Ⅰ and AA-Ⅱ should be emphasized. In this paper, it is suggested that traditional Chinese medicine containing AAAs should be used rationally and research, analysis, and toxicological study of AAAs species and content should be strengthened. In addition, limit standards of AA-Ⅰ and AA-Ⅱ should be formulated and science-based supervision should be performed.

[Compatibility for toxicity attenuation of toxic traditional Chinese medicine: a review and strategies].

Toxicity-attenuating compatibility is an effective measure to ensure the safety of Chinese medicine. Involving the origin, processing method, compatibility mode, and dosage, it faces multiple challenges, such as the uncertainty of toxic substances, toxicity latency, indefinite safe dose, complex toxicity-efficacy relationship, and individual difference. As a result, research on clinical safety of Chinese medicine is limited by the consistency at "molecular-cellular-organ-overall" levels, unclear interaction of multiple medicinals and multiple substances, the "toxicity-efficacy-compatibility-syndrome" correlation, and the "dosage-time-toxicity-efficacy" conversion law. Therefore, following the principle of "starting from the clinical practice, verifying via the theoretical basis, and finally applying in clinical practice", we verified the toxicity at "molecular-cellular-organ-overall" levels, revealed the interaction of multiple medicinals and substances, collected evidence at multiple levels, clarified the "dosage-time-toxicity-efficacy" relationship, and tested the consistency between basic and clinical biomarkers. On this basis, we studied the toxicity-alleviating and efficacy-enhancing(preserving) compatibility characteristics, the fate of one medicinal and multiple medicinals in vivo, the molecular mechanism of toxicity, the "dosage-time-toxicity-efficacy" conversion law, and the clinical characteristics of toxic traditional Chinese medicine based on disease and syndrome. The three mechanisms of toxicity-attenuating compatibility reflect the seven-reaction theory in Chinese medicine compatibility. Finally, the strategies for safe use of Chinese medicine were proposed.

[Study on synergistic effect of Qingkailing Injection and Shengmai Injection on organ injury in endotoxemia rats].

As a dangerous disease with rapid progression, endotoxemia is easy to induce the damage to multiple organs. However, its specific and efficient treatment methods are still lacking at present. Both Qingkailing Injection(QKLI) and Shengmai Injection(SMI) have been proved effective in anti-inflammation, anti-endotoxin and organ protection. In this study, carrageenan and endotoxin were injected successively into rats to establish an endotoxemia model. Different doses of QKLI and SMI were administered to the endotoxemia rats by intraperitoneal injection separately or in combination. Then the count of white blood cells, the number of platelets, the content of cytokines, biochemical indexes, organ coefficient and pathological changes of main organs in the rats were detected. The results showed that the rats in the model group had obvious symptoms of endotoxemia, i.e., leucopenia, thrombocytopenia, increase in cytokines(IL-6 and TNF-α) and biochemical indexes of liver and kidney function as well as pathological damage to liver, kidney and lung. QKLI alone can alleviate the above symptoms of endotoxemia and the organ injury. SMI alone is less effective in improving disseminated intravascular coagulation(DIC) and cytokine secretion complicated with endotoxemia, but capable of reducing the inflammation degree of the lung, liver and kidney. The combination of QKLI and SMI remarkably increased the number of platelets in the peripheral blood, improved the liver and kidney function and reduced inflammatory factors, with lung, liver, kidney and other organ structures protected well. Moreover, the improvement effect of the combination of QKLI and SMI was stronger than those of the two injections alone at fixed doses, indicative of a synergistic effect.

[Research progress on adverse reactions and pseudo-allergic reactions of traditional Chinese medicine injections].

Since the safety re-evaluation of traditional Chinese medicine(TCM) injections began in 2009, some TCM injection companies and research institutes have done a lot of work. And with the increase of drug development and drug production technology levels in China, the safety of some TCM injections has been greatly improved. There are safety risks in TCM injections, which are mainly reflected in unclear basis of medicinal materials, simple production process, poor controllability of quality standards, nonstan-dard drug instructions and irrational medication in the use process. This paper describes the research progress of the above-mentioned aspects of TCM injections. In addition, the author team found that adverse reactions of TCM injections are mainly pseudo-allergic reactions. Therefore, a lot of work has been done in detection of pseudo-allergic reactions, mechanism research and risk control. This part of the work is also described in this article.

The Involvement of the RhoA/ROCK Signaling Pathway in Hypersensitivity Reactions Induced by Paclitaxel Injection.

A high incidence of hypersensitivity reactions (HSRs) largely limits the use of paclitaxel injection. Currently, these reactions are considered to be mediated by histamine release and complement activation. However, the evidence is insufficient and the molecular mechanism involved in paclitaxel injection-induced HSRs is still incompletely understood. In this study, a mice model mimicking vascular hyperpermeability was applied. The vascular leakage induced merely by excipients (polyoxyl 35 castor oil) was equivalent to the reactions evoked by paclitaxel injection under the same conditions. Treatment with paclitaxel injection could cause rapid histamine release. The vascular exudation was dramatically inhibited by pretreatment with a histamine antagonist. No significant change in paclitaxel injection-induced HSRs was observed in complement-deficient and complement-depleted mice. The RhoA/ROCK signaling pathway was activated by paclitaxel injection. Moreover, the ROCK inhibitor showed a protective effect on vascular leakage in the ears and on inflammation in the lungs. In conclusion, this study provided a suitable mice model for investigating the HSRs characterized by vascular hyperpermeability and confirmed the main sensitization of excipients in paclitaxel injection. Histamine release and RhoA/ROCK pathway activation, rather than complement activation, played an important role in paclitaxel injection-induced HSRs. Furthermore, the ROCK inhibitor may provide a potential preventive approach for paclitaxel injection side effects.

[Safety of animal traditional Chinese medicine (TCM) injections].

Animal medicine injection is an important part of traditional Chinese medicine (TCM) injections. All or part of animals with a significant curative effect and little side reactions as raw materials as well as modern technology are used to produce traditional Chinese medicine injections with a reliable and rapid drug efficacy and high bioavailability. Due to the complex composition of traditional Chinese medicine injections, imperfect quality standards, and unreasonable clinical use, the incidence of adverse reactions of traditional Chinese medicine injections has been significantly higher than that of traditional Chinese medicine for oral use. Animal medicine injections contain rich protein and fat, and heteroproteins are the main sensitization source in animal medicine injections. At present, the adverse reactions of animal medicine injections are mainly manifested in the anaphylaxis-like reactions at skin, mucous membranes and organ systems. The adverse reactions that occur during the first medication are more common. Specific causes for allergic-like adverse reactions in animal injections and related substances in traditional Chinese medicine injections made of animals that induce allergies or anaphylactoid reactions are currently not specifically reported. This article reviews the current adverse reactions of animal TCM injections, allergies and pseudoallergic reactions of animal TCM injections, the pharmacokinetics of animal TCM injections, and the combined use of drugs, in order to improve the quality standards of Chinese medicine injections for animals and provide reference for further safety related research.

Research Advances and Prospects on Mechanism of Sinomenin on Histamine Release and the Binding to Histamine Receptors.

Sinomenine (SIN) is widely used in China to treat a variety of rheumatic diseases (RA), and has various pharmacological effects such as anti-inflammatory, analgesic, and anti-tumor effects. However, due to the histamine release characteristics of SIN, its adverse reactions such as allergic reactions, gastrointestinal reactions, and circulatory systemic reactions have been drawing increasing attention. We present here a systematic review of the chemical structure, pharmacological effects, clinical application, and adverse reactions of SIN, a detailed discussion on the relationship between histamine/histamine receptor and mechanism of action of SIN. In addition, we simulated the binding of SIN to four histamine receptors by using a virtual molecular docking method and found that the bonding intensity between SIN and receptors varied in the order shown as follows: H1R > H2R ~ H3R > H4R. The docking results suggested that SIN might exhibit dual regulatory effects in many processes such as cyclooxygenase-2 (COX-2) expression, NF-κB pathway activation, and degranulation of mast cells to release histamine, thereby exhibiting pro-inflammatory (adverse reactions)/anti-inflammatory effects. This study provides a theoretical basis for the clinical treatment of inflammations seen such as in RA using SIN, and also suggests that SIN has great potential in the field of cancer treatment and will have very important social and economic significance.

A rational design to enhance the resistance of Escherichia coli phytase appA to trypsin.

Escherichia coli phytase appA, which hydrolyzes phytate, has been widely applied as an important feed supplement, but its resistance to trypsin needs to be improved. Six putative solvent-accessible amino acid residues (K74, K75, K180, R181, K183, and K363), which could be easily attacked by trypsin, were selected to improve trypsin tolerance of Escherichia coli phytase appA. Inspection of the three-dimensional structure and computational design via hydrogen bond analysis, six optimal mutation sites of K74D/K75Q/K180N/R181N/K183S/K363N, which strengthened the hydrogen bonding, were performed to generate three mutants. Results showed that the most beneficial mutant appA-M6 had a specific activity of 3262 U/mg with molecular weight of approximately 52-55 kDa. Similar to appA-WT, the optimal pH (4.5) and temperature (60 °C) of appA-M6 were unchanged. Compared with appA-WT, appA-M6 showed a significant enhancement (p < 0.05) in resistance to trypsin and a 3.8 °C increase in melting temperature (Tm). We concluded that introduction of hydrogen bonds and N-glycosylation modification resulted in decreased enzyme flexibility and increased the enzyme stability against proteolysis and thermal denaturation. The mutant appA-M6 generated in this study could be applied for the large-scale commercial production of phytase and thus could benefit the food and feed industry.

[Preclinical study on adverse reactions of Xingnaojing injection].

In this study, different batches of Xingnaojing injection products were first selected for pseudoallergic mice test, and the results showed that after injection of 6.6-fold clinical dose Xingnaojing injection, the mice showed a slight pseudoallergic reaction, while other mice injected with other batches of injections showed no obvious pseudoallergic reaction. Therefore, it is preliminarily believed that this mice model can effectively indicate the risk of pseudoallergic reactions in the clinical application of Xingnaojing injections. In addition, by changing some of the processes, a high concentration of Xingnaojing injection was prepared for mice pseudoallergic test and guinea pig systemic allergy test. The results showed no significant type Ⅰ allergic reaction in guinea pigs. Mild pseudoallergic reactions occurred in mice after a 6.6-fold clinical dose injection. Therefore, it is considered that for sensitive or idiosyncratic people, the concentration of certain chemical components in Xingnaojing injection will increase after entering the body, which may increase the risk of pseudoallergic reaction. However, due to the limitations of test models, the risk of Xingnaojing injection to induce allergic reactions cannot be ruled out. Finally, by increasing the content of borneol and Tween and (or) sodium chloride in Xingnnaojing Injection and testing its pseudoallergic reactions, the results showed that the combination of these three ingredients may produce new trace sensitization substance and induce pseudoallergic reactions.

[Mechanism of nephrotoxicity of rhubarb in rats].

The aim of this study was to investigate the renal toxicity of rhubarb and its mechanism. The SD rats were randomly divided into three groups: normal group and two rhubarb extract groups (16, 2 g·kg⁻¹). According to the dose conversion method between human and animal, rhubarb 16 g·kg⁻¹ and 2 g·kg⁻¹ were equivalent to 10 times and 1.25 times of human clinical dose respectively. Rhubarb extract was administered by a gastric gavage to rats once daily for 30 days. Serum urea nitrogen （BUN）, creatinine （CRE） and urine KIM-1, NGAL and renal morphology were analyzed. The expressions of OAT1, OAT3 and clusterin mRNA in kidney were measured. The results showed that the low dose of rhubarb had no obvious renal toxicity. The high dose group showed mild and moderate renal injury and a down-regulation of clusterin mRNA expression in the kidney tissue. The renal toxicity in male animals was heavier than that in female animals. There was no significant change in blood BUN and CRE in the high dose group. But urine NGAL level of the high dose group increased by 51.53% compared with normal group, of which male animals increased more significantly (P<0.05, compared with the normal group). The expressions of renal OAT1 and OAT3 mRNA in the low dose group were obviously higher than that in the normal group. The results indicated that the high dose of rhubarb could cause the renal toxicity. The dosage should be controlled reasonably in the clinical use. OAT1 and OAT3 mRNA related to anionic transport in kidney tissue played a compensatory protective role in rhubarb-induced renal injury. But the compensatory effect is relatively weak at the high dose level. In addition, routine renal function indicators BUN and CRE had limitation for monitoring the kidney toxicity of rhubarb. It is suggested that urine NGAL detection might be helpful for monitoring the renal toxicity of rhubarb.

[Pseudoallergic reaction characteristics of Qingkailing injection and preliminary screening of allergic substances].

This study aimed to explore the characteristics and the influencing factors of Qingkailing injection (QKLI) pseudoallergic reaction, and screen out the possible pseudoallergenic substances. The results showed that ICR and Kunming mice had stronger pseudoallergic reactions than BALB/c and C57 mice after being injected with the same dose of QKLI. The pseudoallergic reaction induced by QKLI that was prepared with 0.9% saline was stronger than that prepared with 5% glucose. When the dose was twice of the clinical dose, some batches of QKLI could cause significant or suspected pseudoallergic reactions; when the dose dropped to clinically equal times, all of the batches did not induce pseudoallergic reactions in mice. Different batches of QKLI induced different pseudoallergic reactions in mice. Therefore, QKLI's pseudoallergic reactions might have a certain relationship with different body constitutions. Different solvents might affect the safety of QKLI. QKIL-induced pseudoallergic reactions had the different characteristics between batches, and the dosage should be strictly controlled in clinical use. After the comparison of pseudoallergic reactions induced by different components and different intermediates of QKLI in mice, it was preliminary believed that pseudoallergenic substances might exist in intermediate Isatidis Radix extracts and Gardenia extracts, but specific pseudoallergens shall be furthered studied in subsequent experiences.

EOGD: the Euplotes octocarinatus genome database.

BACKGROUND: Euplotes, a ciliated protozoan, is a useful unicellular model organism. Studies on Euplotes have provided excellent insights into various basic biological principles. We have recently sequenced the macronuclear genome of the common freshwater species Euplotes octocarinatus to provide novel insights into Euplotes genetics and molecular biology. RESULTS: In this study, we present the E. octocarinatus Genome Database (EOGD), a functional annotation and analysis platform for the global study of the Euplotes genome. EOGD includes macronuclear genomic and transcriptomic data, predicted gene models, coding sequences, protein sequences, and functional annotations. The GBrowser and BLAST tools are embedded in EOGD to enable the search, visualization and analysis of E. octocarinatus genomic and transcriptomic data. CONCLUSIONS: EOGD is a useful resource for the research community, particularly for researchers who conduct genome-scale analysis and molecular biology studies of Euplotes or other ciliates. EOGD will be continuously updated to integrate more datasets and analytical tools. EOGD is freely available at http://ciliates.ihb.ac.cn/database/home/#eo .

[Pharmacokinetic characteristics of fourteen main components of Gegen Qinlian Decoction in rats].

Animal traditional Chinese medicine has a long history of application in China, and its clinical application is very extensive. Due to the complex chemical composition in animal traditional Chinese medicine, the basis of chemical research is relatively weak, which leads to the unclear composition and toxic components of many animal Chinese medicines. The relationship between the medicinal and toxic components of animal Chinese medicine has not yet been elucidated. The non-clinical safety evaluation of animal traditional Chinese medicine mainly includes acute toxicity, long-term toxicity, safety pharmacology, reproductive toxicity, genotoxicity experiments, and experimental studies such as carcinogenicity are needed when necessary. The current preclinical safety research on animal traditional Chinese medicine is mainly based on the study for toxic animal traditional Chinese medicines. Most animal Chinese medicines have not carried out systematic preclinical and clinical safety studies. The research method is mainly focused on acute toxicity test. It is necessary to carry out systematic preclinical safety studies on animal traditional Chinese medicines, to clarify the possible side effects and its characteristics, its toxic target organs, toxic doses and poisoning mechanisms induced by different animal traditional Chinese medicines. Finally, this paper suggests that in the preclinical safety study of animal traditional Chinese medicine, in-depth research and comparison should be carried out in combination with chemical substance foundation, origin, and collection season, and the safety of "non-toxic" animal traditional Chinese medicine should be carried out when necessary. In addition, it is necessary to rationally use the cutting-edge technologies and methods of toxicology research to fully clarify the preclinical safety information of animal Chinese medicines.

[Study and opinion on toxicity of aristolochic acid].

On October 18th, 2017, a research article named "Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia" was published on Science Translational Medicine. This article pointed out that herbs containing aristolochic acids could cause liver cancer by inducing the specific "aristolochic acids mutational signature". The public was also suggested to avoid the intake of herbs containing aristolochic acids. Since 2000, CFDA has gradually abolished the medicinal standards for herbs containing aristolochic acids such as caulis aristolochiae manshuriensis, aristolochia heterophylla and radix aristolochiae. Related drugs have been strengthened supervision since then. Chinese Pharmacopoeia has also removed the records of a series of related herbs. State Administration of Traditional Chinese Medicine held a conference on the "toxicity" of aristolochic acids as soon as the article was published. After a discussion of the studies on the toxicity of aristolochic acids, experts attending the meeting discovered several problems, including the unclearness of exposure history, tumor-producing dose and latent period, the absence of some key factors such as hepatitis B, the small sample size, miscellaneous factors, incomplete evidence chains, the missing of analyses between data with huge differences, the insufficiency of fundamental research arguments, etc. In order to understand the toxicity of aristolochic acids and the carcinogenic risks, as well as guide clinical safe medication, the experts suggested that：①Complete the systematical evaluation of aristolochic acids carcinogenicity as soon as possible. Scientifically elucidate the relationship between aristolochic acids and the genesis of liver cancer. ②Establish medication risk warnings of aristolochic acids and strengthen the supervision. ③Make an in-depth study of the toxicity of traditional Chinese medicine. Find out the adverse effects of all traditional Chinese medicine step by step.

[Adverse reaction and screening of sensitizing substance of Shuxuening injection].

In this study, by the means of the active systemic allergy test in guinea pigs, passive skin allergy test in rats and pseudoallergic test in mice, it was determined that the "allergic reaction" of Shuxuening injection(SXNI) may not be a true IgE-mediated allergic reactions, but mainly of pseudoallergic reaction. Further pseudoallergic test proved that the pseudoallergic reactions of SXNI had difference between batches and showed dose dependence, so it was recommended to establish SXNI pseudoallergic reaction detection method for timely detecting and controlling the product risk of each batch products. In addition, as the pseudoallergic reactions of SXNI were dose-dependent, the dose and concentration of SXNI should be strictly controlled in clinical use. Then the main pseudoallergenic reaction test was conducted for the main monomer components in SXNI and the different fractions of Ginkgo biloba extract in mice, and the results showed that the sensitizing substances may mainly exist in YXY-3 fractions containing flavonol glycosides. By further chemically separating YXY-3, we got four chemical components. Among these four components, YXY-3-1 and YXY-3-2 were testified as the main allergenic components in SXNI through pseudoallergic test in mice. To make sure the specific chemical constituent that is responsible for the pseudoallergic reaction, in-depth study in follow-up experiments should be needed.

[Risk control of traditional Chinese medicines containing aristolochis acids (AAs) based on influencing factors of content of AAs].

Aristolochic acids (AAs) widely exist in such plants as Aristolochia and Asarum. The renal toxicity of AAs as well as its carcinogenicity to urinary system have been widely known. In 2003 and 2004, China prohibited the use of Aristolochiae Radix, Aristolochiae Manshuriensis Caulis and Aristolochiae Fangchi Radix, and required administering other AAs-containing medicines in accordance with the regulations for prescription drugs. In this paper, we retrieved literatures on the content determination of AAs in recent 10 years in China. It suggested that the AAs content is lower in Asarum herb, especially in its roots and rhizomes, and most of which do not show detectable amount of AA-I. Some of traditional Chinese medicines show fairly small amount of detectable AA-I. The AAs content in Aristolochia herb (including Fructus Aristolochiae, kaempfer dutchmanspipe root) is relatively high; however, there are fewer literatures for studying the content determination of AAs in Chinese patent medicines. There were many factors affecting AAs content, including the parts used, origins, processing methods, extraction process. It suggested that we should pay attention to the toxicity of Chinese medicines containing AAs and use these decoction pieces and traditional Chinese medicines cautiously. In addition, basic studies for the origins, processing methods and extraction process of Chinese patent medicines containing AAs, as well as supervision and detection of AAs content in traditional Chinese medicinal materials, decoction pieces and Chinese patent medicines shall be strengthened for reducing medication risk and guaranteeing clinical medication safety.

[Research progress of Rho/ROCK signal pathway].

Rho GTPases belong to Ras superfamily, which is reported to involve in cell migration, phagocytosis, contraction and adhesion. ROCK (also known as Rho-associated kinase) is considered to be one of the most important downstream targets of Rho that is widely investigated. Rho/ROCK signal pathway induces cytoskeletal reorganization, cell migration and stress fiber formation, affects endothelial permeability, tissue constriction and growth, involves in diabetic nephropathy, eye disease, cancer, heart disease, nerve injury disease, hypertension, radiation injury and leukemia. As a novel drug research target, Rho/ROCK signal pathway has received more and more attention. This review provides the basic characteristics and physiological effects of Rho/ROCK signal pathway, the relationships between Rho/ROCK signal pathway and diseases, and the therapeutic methods based on the Rho/ROCK signal pathway.

[Review on requirements of drug allergy or pseudoallergic reactions in pre-clinical evaluation].

Drug allergy and pseudoallergic reactions are main adverse drug reactions. Allergy is mainly induced by the immunogenicity of drug, drug metabolic products or drug additive. Pseudoallergic reactions may result from the irritation or activation of inflammatory material release. Pre-clinical evaluation of drug allergy and pseudoallergic reactions is included in immunotoxicity evaluation. Now there is no in vivo or in vitro method that could predict all kinds of allergy or pseudoallergic reactions due to the different mechanisms. In the past few years, FDA, SFDA OECD, ICH and WHO have published several guidelines on per-clinical immunotoxicity evaluation, however, no agreement has been reached on allergy and pseudoallergic reactions evaluation. This article reviews the requirements of allergy and pseudoallergic reactions in pre-clinical evaluation.