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OBJECTIVES@#To explore the possible mechanism of Yunaconitine poisoning by studying the changes of urine metabolic profile in rats chronically poisoned by Yunaconitine via non-targeted metabolomics.@*METHODS@#A rat model of Yunaconitine poisoning was established, and a metabolomics method based on UPLC-QTOF-MS technology was used to obtain the urine metabolic profile. Principal component analysis (PCA), orthogonal projections to latent structures-discriminant analysis (OPLS-DA), variable importance in projection (VIP) value greater than 1, fold change (FC) value greater than 3 or less than 0.33 and P value less than 0.05 were used to screen potential biomarkers related to the toxicity of Yunaconitine. The metabolic pathway analysis was performed through the MetaboAnalyst website and pathological changes of related tissues were observed.@*RESULTS@#Sixteen potential biomarkers including L-isoleucine were screened, which mainly involved six metabolic pathways including the biosynthesis and degradation of valine, leucine and isoleucine, pentose and glucuronate interconversions, and propanoate metabolism, alanine, aspartate and glutamate metabolism, tyrosine metabolism. Pathological studies showed that rat toxic change in nervous system, liver and cardiac caused by Yunaconitine.@*CONCLUSIONS@#Yunaconitine may cause neurotoxicity, hepatotoxicity and cardiotoxicity by affecting amino acid and glucose metabolism.
Subject(s)
Animals , Rats , Aconitine/analogs & derivatives , Biomarkers/metabolism , Chromatography, High Pressure Liquid , Metabolome , MetabolomicsABSTRACT
OBJECTIVE：To study the toxicity mechanism of yunacotine-induced arrhythmia in rats. METHODS ：Totally 32 rats were randomly divided by random number table method into normal control group ，yunacotine low-dose and high-dose groups （0.09，0.14 mg/kg），aconitine group （positive control ，0.88 mg/kg），with 8 rats in each group. Administration groups were given the corresponding drugs once a day ，and normal control group was given the constant volume of normal saline ，for consecutive 7 d. After last intragastric administration ，the changes of electrocardiogram （ECG） were observed. The contents of adenosine triphosphate（ATP）in myocardial tissue and Ca 2+ in myocardial cells ，the activities of Na +-K+-ATPase and Ca 2+-Mg2+-ATPase as well as the protein expression of ranolidine receptor 2（RyR2）and Ca 2+-ATPase（SERCA2）in myocardial tissue were determined. RESULTS：Compared with normal control group ，time limit of QRS wave and QTc intervals of rats were prolonged significantly in yunaconitine low-dose group （P＜0.01）. The content of Ca 2 + in myocardial cells ， the ATP contents ， the activities of Ca2+-Mg2+-ATPase and Na +-K+-ATPase as well as the protein expression of SERCA 2 in myocardial tissue were reduced significantly （P＜0.05 or P＜0.01）. The heart rate of rats in yunaconitine high-dose group and aconitine group were increased significantly （P＜ 0.05 or P＜0.01），and time limit of QRS wave and QTc intervals were significantly prolonged （P＜0.01）；the content of Ca 2+ in myocardial cells was increased significantly （P＜0.01）；ATP content ，the activities of Ca 2+-Mg2+-ATPase and Na +-K+-ATPase，and protein expression of RyR 2 and SERCA 2 in myocardial tissue were decreased significantly （P＜0.01）. CONCLUSIONS ： Yunaconitine can induce arrhythmia in rats ，the mechanism of which may be associated with Ca 2+ overload that resulted from reducing the activities of Na +-K+-ATPase and Ca 2+-Mg2+-ATPase and down-regulating the expression of related calcium transporter RyR2 and SERCA 2.
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Objective To investigate the content changes of two alkaloid before and after the processing of Aconitumvilmorinianum and its effect on cardiotoxicity. MethodsThe UPLC method was used to determine the content of yunaconitine and 8-acetylacetonarine before and after the processing of A.vilmorinianum. The half lethal dose (LD50) of A.vilmorinianum to rats was determined by Bliss method. Rats wereig administrated A.vilmoriniauum and its processed products for 14 d. The chages of II lead electrocardiogram of anesthetized rats and myocardial morphology were observed,and the serum levels of lactate kinase (CK) and lactate dehydrogenase (LDH)were detected. Results The content of yunaconitine before and after the preparation of A.vilmorinianum was 263.96 μg/g and not detected respectively. The content of 8-acetylacetonarine was not detected and 568.47 μg/g respectively. The LD50 of the raw product was crude drug4.2 g/kg, and the maximum dose of the processed product was crude drug18.0 g/kg; In the anesthetized rats of the raw group, ventricular premature beats, ventricular bipolar law, and ventricular fibrillation occurred successively. The processed product group showed bradycardia in the early stage and returned to normal in 60 min; Compared with the blank group, the LDH and CK levels in the raw group were significantly increased (P< 0.05), and only the LDH level was significantly increased in the processed product group (P< 0.05); The gap between myocardial fibers in the raw group was significantly enlarged, and the infiltration of inflammatory cells was obvious. The myocardial fibers of the product group are arranged neatly, and individual inflammatory cells infiltrated in the interstitial. Conclusion At the given dose, A.vilmorinianum has greater cardiotoxicity, and the toxicity of A.vilmorinianum is obviously reduced after processing.
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Objective To establish an acute yunaconitine poisoning rat model with a single oral administration and to determine the contents of yunaconitine in rat tissues by UPLC-MS/MS method, then investigate the distribution of yunaconitine in rats. Method The rats were randomly divided into three groups and were intragastrically administered a single dose of 2.2mg/kg,1.1mg/kg,0.7mg/kg yunaconitine, respectively.. The rats were killed 2h later, the stomach tissue, intestine tissue, liver tissue, pancreas tissue, kidney tissue, lung tissue, spleen tissue, heart tissue, bladder tissue, testis tissue, brain tissue and heart blood samples were collected. The contents of yunaconitine in the biological materials were determined by UPLC-MS/MS method after the biological samples extracted by liquid-liquid extraction. Result A rat model of the yunaconitine poisoning was made with a single dose of 1.1mg/kg, the concentrations of yunaconitine displayed in the organs with the following order:stomach, small intestine, liver, pancreas, kidney, lung, spleen, heart, bladder, testis, heart blood and brain. Conclusion Yunaconitine was widely distributed in rats, especially the levels in the stomach, small intestine and liver were the highest. The conclusion provides a basis for the selection of test materials for the poisoning of Aconitum vilmorinianum Kom.
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Objective To study the chemical constituents in the roots of Aconitum hemsleyanum var. circinatum. Methods The constituents were isolated and purified by silica gel chromatography from the roots of Aconitum hemsleyanum var. circinatum, and the structures were identified by spectral analysis (1H-NMR, 13C-NMR, and MS). Results Seventeen compounds were isolated from Aconitum hemsleyanum var. circinatum and characterized as sachaconitine (1), 8-O-methylsachaconitine (2), liljestrandisine (3), talatisamine (4), chasmannine (5), 8-O-methyltalatisamine (6), 14-O-acetyltalatisamine (7), 8-deacetyl-yunaconitine (8), crassicautine (9), crassicaudine (10), crassicauline A (11), vilmorianine C (12), vilmorianine A (13), yunaconitine (14), transconitine B (15), kongboendine (16), and franchetine (17). Conclusion Seventeen compounds are isolated from Aconitum hemsleyanum var. circinatu. Compounds 2-3, 6-7, 9, and 12-16 are isolated from Aconitum hemsleyanum var. circinatum for the first time.
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Objective To conduct comparative study on the analgesic and anti-inflammatory effects as well as the acute toxicity of yunaconitine and 8-deacetyl-yunaconitine isolated from the processed products of Aconiti Knsnezoffii Radix.Methods The methods of hot plate test and writhing test were used to evaluate the analgesic effect. Anti-inflammation action was observed by the models of auricle swelling caused by dimethylbenzene. LD50 was determined by the method of Bliss.Results Yunaconitine and 8-deacetyl-yunaconitine have analgesia effect on the pain caused by hot-plate, but there were no statistically significant difference. The pain caused by acetic acid had obvious analgesic action. High and low dose of yunaconitine could significantly reduce the number of mice body torsion and extend the incubation period of pain in mice. The effect of 8-deacetyl-yunaconitine was remarkable only in the high dose. Compared with solvent group, there were little differences in inhibiting effect of auricle swelling caused by dimethylbenzene, and anti-inflammatory action was not exact. The poisonousness of yunaconitine was nearly 20 times of 8-deacetyl-yunaconitine.Conclusion Yunaconitine and 8-deacetyl-yunaconitine may be the analgesic medicine for peripheral analgesic effect. The poisonousness of 8-deacetyl-yunaconitine is less than yunaconitine, the effect is remarkable to the pain caused by acetic acid, and the security is high.