Genotoxicity research takes an important place in traditional Chinese medicine safety evaluation. Genotoxicity test on traditional Chinese medicine has been paid great attention since 1970s. Currently, the most developed genotoxicity test methods included: bacterial reverse mutation test and mouse lymphoma assay which are used to detect relevant genetic changes, micronucleus test and chromosomal analysis which are used to measure chromosomal aberration, and single cell electrophoresis assay which is used to test DNA damage. This article reviews research progress on genotoxicity of traditional Chinese medicine, evaluation methods of genotoxicity, the problems and solutions on genotoxicity evaluation of traditional Chinese medicine, and new technique used in genotoxicity test.
The goal of this article is to establish the conditions of excitation where one has to deal with ultrasound contrast agent (UCA) microbubbles pulsating near biological tissues with spherical boundary in ultrasound field for targeted drug delivery and cavitation-enhanced thrombolysis, etc., and contributes to understanding of mechanisms at play in such an interaction. A modified model is presented for describing microbubble dynamics near a spherical boundary (including convex boundary and concave boundary) with an arbitrary-sized aperture angle. The novelty of the model is such that an oscillating microbubble is influenced by an additional pressure produced by the sound reflection from the boundary wall. It is found that the amplitude of microbubble oscillation is positively correlated to the curve radius of the wall and negatively correlated to the aperture angle of the wall and the sound reflection coefficient. Moreover, the natural frequency of the microbubble oscillation for such a compliable wall increases with the wall compliance, but decreases with the reduction of the wall size, indicating distinct increase of the natural frequency compared to a common rigid wall. The proposed model may allow obtaining accurate information on the radiation force and signals that may be used to advantage in related as drug delivery and contrast agent imaging.
Myocardial infarction (MI) is a major disease burden. Wild-type p53-induced phosphatase 1 (Wip1) has been studied extensively in the context of cancer and the regulation of different types of stem cells, but the role of Wip1 in cardiac adaptation to MI is unknown. We investigated the significance of Wip1 in a mouse model of MI.The study began in June 2014 and was completed in July 2016. We compared Wip1-knockout (Wip1-KO) mice and wild-type (WT) mice to determine changes in cardiac function and survival in response to MI. The heart weight/body weight (HW/BW) ratio and cardiac function were measured before MI. Mouse MI was established by ligating the left anterior descending (LAD) coronary artery under 1.5% isoflurane anesthesia. After MI, survival of the mice was observed for 4 weeks. Cardiac function was examined by echocardiography. The HW/BW ratio was analyzed, and cardiac hypertrophy was measured by wheat germ agglutinin staining. Hematoxylin and eosin (H&E) staining was used to determine the infarct size. Gene expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) was assessed by quantitative real-time polymerase chain reaction (qPCR), and the levels of signal transducers and activators of transcription 3 (stat3) and phosphor-stat3 (p-stat3) were also analyzed by Western blotting. Kaplan-Meier survival analysis, log-rank test, unpaired t-test, and one-way analysis of variance (ANOVA) were used for statistical analyses.Wip1-KO mice had a marginally increased HW/BW ratio and slightly impaired cardiac function before LAD ligation. After MI, Wip1-deficient mice exhibited increased mortality (57.14% vs. 29.17%; n = 24 [WT], n = 35 [Wip1-KO], P< 0.05), increased cardiac hypertrophy (HW/BW ratio: 7 days: 7.25 ± 0.36 vs. 5.84 ± 0.18, n = 10, P< 0.01, and 4 weeks: 6.05 ± 0.17 vs. 5.87 ± 0.24, n = 10, P > 0.05; cross-sectional area: 7 days: 311.80 ± 8.29 vs. 268.90 ± 11.15, n = 6, P< 0.05, and 4 weeks: 308.80 ± 11.26 vs. 317.00 ± 13.55, n = 6, P > 0.05), and reduced cardiac function (ejection fraction: 7 days: 29.37 ± 1.38 vs. 34.72 ± 1.81, P< 0.05, and 4 weeks: 19.06 ± 2.07 vs. 26.37 ± 2.95, P< 0.05; fractional shortening: 7 days: 13.72 ± 0.71 vs. 16.50 ± 0.94, P< 0.05, and 4 weeks: 8.79 ± 1.00 vs. 12.48 ± 1.48, P< 0.05; n = 10 [WT], n = 15 [Wip1-KO]). H&E staining revealed a larger infarct size in Wip1-KO mice than in WT mice (34.79% ± 2.44% vs. 19.55% ± 1.48%, n = 6, P< 0.01). The expression of IL-6 and p-stat3 was downregulated in Wip1-KO mice (IL-6: 1.71 ± 0.27 vs. 4.46 ± 0.79, n = 6, P< 0.01; and p-stat3/stat3: 1.15 ± 0.15 vs. 1.97 ± 0.23, n = 6, P< 0.05).The results suggest that Wip1 could protect the heart from MI-induced ischemic injury.
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.
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.
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.
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.
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.
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.
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.
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