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1.
Fa Yi Xue Za Zhi ; 36(1): 115-119, 2020 Feb.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-32250090

RESUMO

Abstract: Aconitum is one of the most widely used Chinese herbal medicines, and aconitine is the major toxic component in it. Aconitine can induce a variety of arrhythmias, resulting in death. Acute ethanol consumption causes arrhythmia as well. Poisoning cases caused by aconitum medicinal liquor are frequently encountered in the practice of forensic medicine. The molecular mechanisms of myocardial toxicity of these two drugs have much in common, and both of them affect the sodium channel, calcium channel and potassium channel of myocardial cell membrane and so on. This paper analyzes and discusses the possible co-effects of ethanol-aconitine on cardiomyocyte channel proteins, by reviewing researches on the mechanism of cardiotoxicity of ethanol and aconitine in recent years, in order to provide ideas and references for the research on the molecular mechanism of arrhythmia caused by combined poisoning.


Assuntos
Arritmias Cardíacas , Aconitina , Aconitum , Medicamentos de Ervas Chinesas , Etanol , Humanos
2.
Phytomedicine ; 67: 153161, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31911401

RESUMO

BACKGROUND: Therapeutic applications of Fuzi (lateral root of Aconitum carmichaeli Debx) are seriously concerned with its toxic effects. Strategies and approaches to reducing toxicity are of great interest. PURPOSE: We aimed to characterize the diurnal rhythm of Fuzi toxicity, and to determine the role of metabolism and pharmacokinetics in generating toxicity rhythmicity. METHODS: Toxicity was determined based on assessment of heart injury and animal survival after dosing mice with Fuzi decoction at different circadian time points. Circadian clock control of pharmacokinetics and toxicity was investigated using Bmal1-deficient (Bmal1-/-) mice. RESULTS: Fuzi exhibited a diurnal rhythmicity in cardiotoxicity (reflected by plasma CK-MB and LDH levels). The highest level of toxicity was observed at ZT10 (5 PM), while the lowest level of toxicity occurred at ZT22 (5 AM). Also, a higher mortality rate was observed at ZT10 and lower mortality rates at other times of the day. ZT10 dosing of Fuzi generated higher systemic exposures of three toxic alkaloid ingredients aconitine (AC), hypaconitine (HA) and mesaconitine (MA) compared to ZT22. This was accompanied by reduced the formation of the metabolites (N-deethyl-AC, didemethyl-HA and 2­hydroxyl­MA) at ZT10. Bmal1 ablation resulted in an increased level of Fuzi toxicity at ZT22, while having no influences when drug was dosed at ZT10. As a consequence, circadian time-dependent toxicity of Fuzi was lost in Bmal1-deficient mice. In addition, Bmal1 ablation increased the plasma concentrations of AC, HA and MA in mice after oral gavage of Fuzi, and reduced formation of their metabolites (N-deethyl-AC, didemethyl-HA and 2­hydroxyl­MA). Moreover, Fuzi metabolism in wild-type liver microsomes was more extensive at ZT22 than at ZT10. Bmal1 ablation abrogated circadian time-dependency of hepatic Fuzi metabolism. CONCLUSIONS: Fuzi chronotoxicity in mice was attributed to time-varying hepatic metabolism and systemic exposure regulated by circadian clock. The findings may have implications in reducing Fuzi toxicity with a chronotherapeutic approach.


Assuntos
Aconitum/química , Relógios Circadianos/efeitos dos fármacos , Extratos Vegetais/farmacocinética , Extratos Vegetais/toxicidade , Fatores de Transcrição ARNTL/genética , Aconitina/análogos & derivados , Aconitina/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão/métodos , Relógios Circadianos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Microssomos Hepáticos/efeitos dos fármacos , Testes de Toxicidade/métodos
3.
Chem Biodivers ; 17(1): e1900600, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31793197

RESUMO

Four new hetisine-type C20 -diterpenoid alkaloids, named as coreanines A-D (1-4), were isolated from the roots of Aconitum coreanum, together with thirteen known alkaloids (5-17). Their structures were elucidated by extensive spectroscopic methods including IR, HR-ESI-MS and NMR techniques. All the isolated compounds were screened for the acetylcholinesterase (AChE) inhibitory effects, and none of them showed considerable inhibitory activity.


Assuntos
Acetilcolinesterase/metabolismo , Aconitum/química , Alcaloides/farmacologia , Inibidores da Colinesterase/farmacologia , Diterpenos/farmacologia , Raízes de Plantas/química , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Diterpenos/química , Diterpenos/isolamento & purificação , Electrophorus , Estrutura Molecular
4.
Fitoterapia ; 140: 104412, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31698060

RESUMO

Aconitum carmichaelii has been used in traditional Chinese medicine for treating various diseases for several thousand years. Based on the biosynthetic pathway of some alkaloids such as C19-diterpenoid alkaloids and obvious differences in alkaloid content between leaves of two A. carmichaelii varieties has been reported, we performed leaves transcriptome analysis of two A. carmichaelii varieties. Besides we characterized the biosynthetic pathway of salsolinol. A total of 56 million raw reads (8.28 G) and 55 million clean reads (8.24 G) were obtained from two varieties (Z175 and R184) leaves transcriptome, respectively, and 176,793 unigenes were annotated. 281 and 843 unigenes are involved in the salsolinol biosynthetic pathway and the formation of C19-diterpenoid alkaloids respectively. And including 34 and 24 unigenes are the differentially expressed genes (DEGs) in the biosynthesis pathway for C19-diterpenoid alkaloids and salsolinol between Z175 and R184 respectively, which were target genes to explore differences in C19-diterpenoid alkaloid and salsolinol biosynthesis in Z175 and R184. Thus genes involved in alkaloid biosynthesis and accumulation differ between varieties leaves. The mechanisms underlying the differences and their relevance require further exploration. The results expand our knowledge of alkaloids biosynthesis in A. carmichaelii leaves, and provide a theoretical basis for analysis differences in alkaloids biosynthesis patterns in different varieties.


Assuntos
Aconitum/química , Vias Biossintéticas , Isoquinolinas/química , Transcriptoma , Alcaloides/biossíntese , China , Diterpenos/química , Perfilação da Expressão Gênica , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química , Plantas Medicinais/química
5.
Artigo em Inglês | MEDLINE | ID: mdl-31877430

RESUMO

The aim of this study was to investigate the synergistic effect and underlying mechanism of compatibility of Aconiti Lateralis Radix Praeparata water-soluble alkaloids (FWA) and Ginseng Radix et Rhizoma total ginsenosides (RTG) on propafenone hydrochloride induced acute heart failure (AHF) rats. Firstly, hemodynamics and serum biochemical indexes were measured to observe the therapeutic effect of FWA, RTG and their compatibility on AHF rats. Non-target serum metabolomics and multicomponent pharmacokinetic experiments were then performed to reveal the mechanism from the two aspects of body reaction and drug behavior in vivo. Data showed the haemodynamics indexes (maximum change rate of left ventricular pressure, heart rate) and neuroendocrine cytokines (TNF-α and Nt-proBNP) levels in rats treated by compatibility of FWA and RTG were improved more significantly than that treated by single drug. Through metabolomics analysis, six metabolites, including L-pipecolic acid, L-arginine, uric acid, N-benzoylglycine, sphingosine-1-phosphate and phosphatidylinositol lyso 16:0, were selected and identified as the potential biomarkers of the synergistic effect. Furthermore, lysine degradation, arginine and proline metabolism, purine metabolism, sphingolipid metabolism, etc. were the differential pathways involved. The results of pharmacokinetics showed Cmax, AUClast and t1/2 of the four components (uracil, salsolinol, guanosine, higenamine) of FWA in compatibility group were obviously higher than that in single drug group, which indicated the absorption and bioavailability of these alkaloids were increased, and the residence time was prolonged after FWA combined with RTG. In conclusion, the therapeutic effect of FWA-RTG on AHF rats was enhanced and that might because the compatibility of FWA-RTG affected the process of some metabolites in AHF rats, and pharmacokinetic behavior of components in FWA was obviously influenced after co-administered with RTG.


Assuntos
Aconitum/química , Alcaloides , Ginsenosídeos , Insuficiência Cardíaca/metabolismo , Panax/química , Alcaloides/farmacocinética , Alcaloides/farmacologia , Animais , Sinergismo Farmacológico , Ginsenosídeos/farmacocinética , Ginsenosídeos/farmacologia , Coração/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Metabolômica , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley
6.
Zhongguo Zhong Yao Za Zhi ; 44(19): 4165-4170, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31872694

RESUMO

Aconiti Lateralis Radix Praeparata and Glycyrrhizae Radix et Rhizoma is a representative acid-alkali drug pair,commonly used in clinical application of traditional Chinese medicine( TCM). Its unique compatibility connotation fully embodied the wisdom of ancient people in drug use. In order to more comprehensively and deeply understand the scientific connotation of the compatibility of the two drugs,pharmacy workers have studied the mechanism of reducing toxicity and enhancing efficacy through their compatibility from the perspectives of chemistry,pharmacology and toxicology. On the basis of combing the previous research work,this paper interpreted the unique compatibility connotation from the three-level system of reducing the content of toxic components in vitro by hydrolysis,lipid exchange and formation of associations,the active constituents of Glycyrrhizae Radix et Rhizoma affecting the metabolism of toxic components and direct antagonism of the toxic effects of aconite in vivo. The existing problems and controversies of the modern mechanism of their compatibility were also proposed,providing a reference for further in-depth studies.


Assuntos
Aconitum , Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Triterpenos , Humanos , Rizoma
7.
Zhongguo Zhong Yao Za Zhi ; 44(19): 4212-4218, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31872701

RESUMO

To study the effects of combination of Aconiti Lateralis Radix Praeparata( Fuzi) with Trichosanthis Fructus( Gualou) on cardiac function,electrocardiogram,inflammatory response and myocardial fibrosis in pressure overload( PO) rats,and further explore the mechanism based on ß2-AR/PKA signaling. PO rat model was established by constricting the abdominal aorta. Twelve weeks after the operation,these rats were randomly divided into model goup( PO),low dose Fuzi group( FL,5. 4 g·kg-1·d-1),Gualou group( GL,5. 4 g·kg-1·d-1),Fuzi and Gualou combination group( FG,5. 4 g·kg-1·d-1+5. 4 g·kg-1·d-1) and high dose Fuzi group( FH,10. 8 g·kg-1·d-1). At the same time,sham operation group was set. After intervention for 6 weeks,carotid blood pressure,cardiac function,electrocardiogram and heart mass index were measured. HE staining was used to observe the inflammatory response in the rat heart and kidney. Masson staining was used to determine the myocardial fibrosis. Western blot was used to detect the protein expression of ß2-AR and PKA. As compared with sham operation group,the blood pressure and heart mass index were obviously increased in PO model group,but there was no significant difference in various treatment groups in the above indexes. As compared with PO model group,FH treatment significantly increased the ejection fraction( EF) and GL treatment effectively enhanced the cardiac output( CO),but other treatment groups had no significant effect on these parameters. Moreover,FG treatment can synergistically attenuate QT and QTc internal prolongation,but it also aggravated inflammatory response in the heart and kidney tissues and promoted myocardial fibrosis as compared to FZ or GL alone treatment,with toxic effects equivalent to FH treatment group. Following FG and FH treatment,simultaneously,ß2-AR and PKA protein levels were significantly elevated,indicating that the increasing toxicity of FG could be associated with activation of ß2-AR/PKA signaling. These results suggested that combination of FZ and GL could synergistically enhance toxicity of FZ in special pathological states such as pressure overload,and caution should be taken in clinical application.


Assuntos
Aconitum , Medicamentos de Ervas Chinesas , Animais , Fibrose , Frutas , Ratos , Transdução de Sinais
8.
Int J Mol Sci ; 20(19)2019 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-31569464

RESUMO

Radix Aconiti Lateralis Preparata (fuzi) is the processed product of Aconitum carmichaelii Debeaux tuber, and has great potential anti-myocardial infarction effects, including improving myocardial damage and energy metabolism in rats. However, the effects of Radix Aconiti Lateralis Preparata extracts in a rat model of myocardial infarction have not yet been fully illustrated. Herein, Radix Aconiti Lateral Preparata was used to prepare Radix Aconiti Lateralis Preparata extract (RAE), fuzi polysaccharides (FPS), and fuzi total alkaloid (FTA). Then, we aimed to compare the effects of RAE, FPS, and FTA in MI rats and further explore their influence on small molecules in the heart. We reported that Radix Aconiti Lateralis Preparata extract (RAE) and fuzi total alkaloid (FTA) significantly improved left ventricular function and structure, and reduced myocardial damage and infarct size in rats with myocardial infarction by the left anterior descending artery ligation. In contrast, fuzi polysaccharides (FPS) was less effective than RAE and FTA, indicating that alkaloids might play a major role in the treatment of myocardial infarction. Moreover, via matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI), we further showed that RAE and FTA containing alkaloids as the main common components regulated myocardial energy metabolism-related molecules and phospholipids levels and distribution patterns against myocardial infarction. In particular, it was FTA, not RAE, that could also regulate potassium ions and glutamine to play a cardioprotective role in myocardial infarction, which revealed that an appropriate dose of alkaloids generated more obvious cardiotonic effects. These findings together suggested that Radix Aconiti Lateralis Preparata extracts containing an appropriate dose of alkaloids as its main pharmacological active components exerted protective effects against myocardial infarction by improving myocardial energy metabolism abnormalities and changing phospholipids levels and distribution patterns to stabilize the cardiomyocyte membrane structure. Thus, RAE and FTA extracted from Radix Aconiti Lateralis Preparata are potential candidates for the treatment of myocardial infarction.


Assuntos
Aconitum/química , Cardiotônicos/farmacologia , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Extratos Vegetais/farmacologia , Animais , Cardiotônicos/química , Metabolismo Energético/efeitos dos fármacos , Metabolômica/métodos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Extratos Vegetais/química , Ratos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Relação Estrutura-Atividade
9.
Zhongguo Zhong Yao Za Zhi ; 44(15): 3349-3357, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602894

RESUMO

Rat model of blood stasis syndrome was prepared by subcutaneous injecting of epinephrine hydrochlorid,then the model rats were administrated by Yunnan Baiyao for 15 days. Blood rheology,coagulation function and histopathology were chosen as indicators to evaluate the successful replication of blood stasis syndrome model and the treatment effect of Yunnan Baiyao. UPLC-Q-TOF-MS was used to rapidly analyze the serum samples of blood stasis syndrome rat after 15 days Yunnan Baiyao treatment,Progenesis QI software was employed to identify the alkaloids components. The results showed that Yunnan Baiyao reduced the plasma viscosity and whole blood viscosity of rats with blood stasis syndrome,prolonged thrombin and prothrombin time,reduced fibrinogen content,and effectively improved pathological state such as inflammatory cell infiltration,blood stasis,congestion and edema of various organs in rats with blood stasis syndrome. Seven alkaloids components from Aconitum kusnezoffii,including karacolidine,senbusine B,isotalatizidine,karakoline,denudatine,talatisamine and chasmanine were found in the rat serum after Yunnan Baiyao treatment. Based on the effectiveness of Yunnan Baiyao in the treatment of blood stasis syndrome induced by epinephrine hydrochloride in rats,alkaloids components from the root of A. kusnezoffii absorbed into blood after Yunnan Baiyao treatment were clarified rapidly and accurately with the help of UPLC-Q-TOF-MS. Karacolidine,senbusine B,isotalatizidine,karakoline,denudatine,talatisamine and chasmanine are the pharmacodynamic material basis of the root of A. kusnezoffii for activating blood circulation and removing blood stasis.


Assuntos
Aconitum/química , Circulação Sanguínea/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Animais , Viscosidade Sanguínea , Tempo de Protrombina , Ratos , Tempo de Trombina
10.
Zhongguo Zhong Yao Za Zhi ; 44(17): 3695-3704, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31602941

RESUMO

Aconitums,represented by Aconite Radix,Aconiti Lateralis Radix Praeparata and Aconiti Kusnezoffh Folium,is a kind of traditional Chinese medicine with a long medicinal history in China. They possess the significant toxicity and therapeutic effects simultaneously. Their potent effects of rescuing from dying,curing rheumatism,anti-inflammation,and analgesia make Aconitums highly regarded by physicians and pharmacists of various dynasties. However,countless poisoning cases caused by an irrational use of Aconitums were reported. In case of improper application and exceeding the therapeutic window,the acute cardiotoxicity and neurotoxicity would be caused,seriously threatening health and even life of the users. Therefore,the clinical application of Aconitums is limited to some extent. To avoid its toxicity and ensure the safety of medicinal use,Aconitums is usually used in a form of its processed products instead of the crude herbs,or combined with some other traditional Chinese medicines in a normal prescription. A proper processing and compatibility method can detoxicate its severe toxicity,reduce the adverse reactions,and also significantly broaden the indications and application range of Aconitums. This provides a guarantee for the secondary exploitation and utilization of Aconitums. In this paper,the traditional processing methods of Aconitums,along with the modern advancement were reviewed,and the mechanisms of detoxification by processing and compatibility were also illuminated. The physical detoxification mode and chemical detoxification mode were found as two main detoxification ways for Aconitums. In particular,the detoxification by hydrolysis,ion-pair,and saponification were three main means. The mechanisms illustrated in this paper can be a reference to the development of modern processing method and a guidance for appropriate use of Aconitums in clinical application.


Assuntos
Aconitum/química , Composição de Medicamentos/métodos , Medicamentos de Ervas Chinesas/química , Aconitum/toxicidade , China , Medicamentos de Ervas Chinesas/toxicidade , Medicina Tradicional Chinesa , Folhas de Planta/química , Raízes de Plantas/química
11.
Phytochemistry ; 167: 112111, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31491684

RESUMO

A C20-diterpenoid alkaloid with an unprecedented carbon skeleton, acoapetaludine A, together with ten undescribed aconitine-type C19-diterpenoid alkaloids, acoapetaludines B-K, were isolated from the whole plants of Aconitum apetalum (Huth) B. Fedtsch. (Ranunculaceae). The structures were elucidated based on a comprehensive spectroscopic data analysis. The absolute configuration of acoapetaludine A was determined by quantum ECD calculation. Acoapetaludines D and E exhibited weak anti-Helicobacter pylori activity at a minimum inhibitory concentration (MIC) of 100 and 50 µg/mL, respectively.


Assuntos
Aconitum/química , Alcaloides/química , Alcaloides/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Diterpenos/química , Helicobacter pylori/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular
12.
BMC Res Notes ; 12(1): 408, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307543

RESUMO

OBJECTIVE: Aconitum plants (Ranunculaceae) exhibit toxicity, and accidental ingestion of the plants has been reported in Japan. Identifying the cause of poisoning is important for emergency medical treatment, and a rapid and simple detection technique is required for the identification of poisoning cause. In the present study, we developed a rapid and simple method for detecting Aconitum plant DNA using a loop-mediated isothermal amplification (LAMP) assay. RESULTS: Specific LAMP primers for Aconitum plants were designed based on the trnL-trnF intergenic spacer region. Using the LAMP primers, the LAMP assay included an initiation reaction of 10 min followed by amplification for 20 min at the isothermal reaction temperature of 65 °C. The LAMP reaction was demonstrated to be specific and highly sensitive to Aconitum plants, given that the assay can be used for 1 pg of purified DNA. Using raw extracted DNA as template, the entire detection procedure from DNA extraction to final detection required only 30 min. Moreover, the protocol identified samples containing approximately 5 mg of Aconitum plants cooked and digested with artificial gastric juice. The currently proposed protocol exhibits good potential as a screening method of Aconitum plant poisoning for emergency medical care.


Assuntos
Aconitum/genética , Aconitum/envenenamento , DNA de Plantas/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Intoxicação por Plantas/diagnóstico , Animais , Humanos , Extratos Vegetais/genética , Extratos Vegetais/envenenamento , Coelhos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
13.
J Appl Microbiol ; 127(5): 1532-1545, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31304623

RESUMO

AIMS: The aims of this study were to investigate the biocontrol effects of Penicillium griseofulvum strain CF3 and its mechanisms against soil-borne root pathogens (Fusarium oxysporum and Sclerotium rolfsii) of the medical plant Aconitum carmichaelii Debx. METHODS AND RESULTS: The effects of P. griseofulvum strain CF3 were evaluated with regard to the hyphal growth of S. rolfsii and F. oxysporum, the sclerotial formation and germination of S. rolfsii and its expression of sclerotia-formation-related genes. A field experiment was conducted to explore how strain CF3 controls the severity of soil-borne diseases, promotes the growth of A. carmichaelii plants and mediates shifts in the culturable rhizosphere microbial populations. The results showed that treatment with a cell-free culture filtrate of strain CF3 considerably inhibited the hyphal growth of both S. rolfsii and F. oxysporum, in addition to limiting the sclerotial formation and germination of S. rolfsii. Three genes related to sclerotial formation (ArsclR, ArnsdD1 and ArnsdD2) were predicted in S. rolfsii and their expression was found suppressed by the CF3 treatment. Field application of the CF3 biocontrol agent in a powder form (1·9 × 1010 conidia per gram of substrate) reduced soil-borne disease severity by 15·0%. The shoot and root growth of A. carmichaelii plants was promoted by 61·6 and 83·1% respectively, as the biocontrol strain massively colonized the rhizosphere soil. The CF3 treatment also markedly reduced the density of some known species harmful to plants while increasing the density of some beneficial species in the rhizosphere soil. SIGNIFICANCE AND IMPACT OF THE STUDY: Genes related to sclerotia formation of S. rolfsii are predicted for the first time and their expression patterns in the presence of P. griseofulvum strain CF3 are evaluated. This comprehensive study provides a candidate fungal biocontrol strain and reveals its potential mechanisms against S. rolfsii and F. oxysporum in A. carmichaelii plants.


Assuntos
Aconitum/microbiologia , Basidiomycota/crescimento & desenvolvimento , Fusarium/crescimento & desenvolvimento , Penicillium/fisiologia , Doenças das Plantas/microbiologia , Aconitum/crescimento & desenvolvimento , Antibiose , Basidiomycota/fisiologia , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Fusarium/fisiologia , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/microbiologia , Rizosfera , Microbiologia do Solo , Esporos Fúngicos/crescimento & desenvolvimento
14.
Zhongguo Zhong Yao Za Zhi ; 44(12): 2433-2443, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359708

RESUMO

Aconiti Radix is a commonly used traditional Chinese medicine( TCM) herb in clinic,with the effects in expelling wind and removing damness,warming menstruation and relieving pain. With a long medicinal history and high medicinal value,it was used for anemofrigid-damp arthralgia,arthralgia,cold hernia and anesthesia analgesia. Modern pharmacological studies have shown that Aconiti Radix has a good therapeutic effect on rheumatoid arthritis,neuropathic pain and hypertension. As a well-known toxic TCM herb,its main pharmacodynamic and toxic components are alkaloids,which can lead to neurotoxicity and cardiotoxicity while exerting anti-inflammatory,analgesic,anti-tumor and other pharmacodynamic effects. Therefore,it is often processed to reduce its toxicity or combined with Paeoniae Radix Alba and Stephaniae Tetrandrae Radix to achieve the purpose of reducing toxicity and increasing efficacy in clinic.In recent years,with the deepening of the study on the incompatibility of TCM represented by " eighteen incompatible herbs",there have been new findings about TCM incompatibility. It has been found complementary effect,rather than no obvious toxic and side effects after the combination with incompatible herbs of Aconiti Radix. To provide the basis for further study and clinical application of Aconiti Radix,this paper reviewed chemical components,pharmacological action,toxicity and compatibility of Aconiti Radix by consulting relevant literatures published in recent years at home and abroad. Meanwhile,this paper also described the relationship between chemical constituents,as well as anti-inflammatory,analgesic,anti-tumor and other pharmacological effects and toxicity.


Assuntos
Aconitum/química , Alcaloides , Medicamentos de Ervas Chinesas/farmacologia , Raízes de Plantas/química , Humanos , Medicina Tradicional Chinesa
15.
J Ethnopharmacol ; 242: 112053, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31271819

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: CaoWu (Aconiti Kusnezoffii Radix), well known for its high toxicity leading to fatal ventricular arrhythmias, is detoxified by HeZi (Terminalia Chebula Retz) decoction to prepare ZhiCaoWu (Aconiti Kusnezoffii Radix Preparata) as one part of ingredients of NaRu-3 pill which is used for the treatment of rheumatoid arthritis (RA). Aconitine (AC) is a highly toxic alkaloid of CaoWu and it is used as toxic target marker for the quality control (QC) of ZhiCaoWu. In the traditional processing method, the vanish of astringent or spicy feeling in tongue is the important detoxification indicator of ZhiCaoWu. However, how CaoWu is detoxified to ZhiCaoWu and whether the appropriate content of AC in ZhiCaoWu can be efficiently perceived after the empirical detoxification still lack factual basis. AIM OF THE STUDY: The present study aimed to optimize the traditional processing method for precision detoxification of CaoWu through biomimetic linking kinetics and human toxicokinetics (TK) of AC, with a view of providing insights into the changes of toxic target marker. MATERIALS AND METHODS: CaoWu medicinal slices (Mes) and coarse powder (Cop) were processed by blank HeZi decoction through the soaking method for 7 days. High-performance liquid chromatography (HPLC) was used for the analysis of the samples. The acidity of blank HeZi decoction and HeZi processing decoction was directly determined by pH meter. The non-compartment analysis (NCA) was used to have an intuitive appreciation for AC and pH changes in HeZi processing decoction while the compartment model method was used to build the biomimetic linking kinetics model with the covariate. The inter-species scaling of animal TK parameters was conducted to predict human AC TK profiles. The possible uptake ways of AC (rapid-release or extended-release) for humans were attempted to assess the poisoning risk of AC in NaRu-3 pill. Based on the target content of AC in ZhiCaoWu, the biomimetic linking kinetics model was explored to optimize the traditional processing detoxification method of CaoWu. The assays of determining inflammatory cytokines in lipopolysaccharides (LPS)-induced RAW264.7 cells were performed to investigate the inflammatory modulation effects of AC in vitro. RESULTS: ZhiCaoWu was prepared by eliminating redundant AC in CaoWu through the repeatable replacement of HeZi processing decoction in which its acidity (pH) was affected. AC-pH changes in HeZi processing decoction were adequately depicted by a biomimetic linking kinetics model whose predictive power was determined by comparing the predictions of AC in ZhiCaoWu with the reported data. Rapid-release AC at the converted dose of 111.1 and 417.6 µg (0.011 and 0.042% of AC in NaRu-3 pill) reached maximum blood concentrations of 26.1 and 98.1 ng/mL at 0.3 h, in comparison with minimum human lethal concentration (100 ng/mL). Achieving the target content of AC (0.04%) in ZhiCaoWu or AC (0.011%) in NaRu-3 pill to precisely control the poisoning risk, the potential optimized protocols were that the processing time at 0.2-0.8% of AC in CaoWu was 2.0-4.4 days for Cop and 2.7-6.2 days for Mes. Correspondingly, pH values in HeZi processing decoction were 3.95 and 3.77 for Cop and Mes, respectively. Meanwhile, Lipopolysaccharides (LPS)-induced RAW264.7 cells were exposed to 0, 20, and 200 µM of AC for 12 h and AC at 20 µM enhanced the levels of IL-6, IL-10 and TNF-α. CONCLUSIONS: Thus, for the first time, a biomimetic linking kinetics model was built to optimize the traditional detoxification method. Moreover, pH changes could be developed as surrogate endpoint for guiding the processing detoxification of CaoWu. Notably, setting the content limit of AC (0.011%) was very rational to control the poisoning risk of NaRu-3 pill. In addition, it was possible that there existed the more complex mechanisms of AC for inflammatory modulation in vitro.


Assuntos
Aconitina , Aconitum , Modelos Teóricos , Terminalia , Aconitina/análise , Aconitina/farmacocinética , Aconitina/toxicidade , Animais , Biomimética , Citocinas/metabolismo , Composição de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Cinética , Camundongos , Células RAW 264.7 , Coelhos , Ratos , Toxicocinética
16.
J Nat Med ; 73(4): 789-799, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31222559

RESUMO

Diterpenoid alkaloids with remarkable chemical properties and biological activities are frequently found in plants of the genera Aconitum, Delphinium, and Garrya. However, little information has been reported on the antiproliferative effects of the diterpenoid alkaloid constituents of Aconitum and Delphinium plants. C-1 and 14 esterifications of delcosine (1) were carried out to provide 39 new diterpenoid alkaloid derivatives (3-14, 16-29, 3a-7a, 9a, 13a, 13b, 14a, 14b, 16a, 17a, 24a, 35a). Selected compounds (3-14, 16-29, 3a-7a, 9a, 13a, 13b, 14a, 14b, 16a, 17a, 24a, 35a) were evaluated for antiproliferative activity against three to five human tumor cell lines including triple-negative breast cancer (TNBC) and P-glycoprotein (P-gp) overexpressing multidrug-resistant (MDR) subline. Several newly synthesized delcosine derivatives (6, 7, 13, 13a, 13b) showed substantial suppressive effects against all human tumor cell lines tested. In contrast, the natural alkaloids (1, 31, 33) showed no effect. Most of the active compounds were delcosine derivatives with two specific substitution patterns-C-1 and C-1,14. In particular, 1-acyldelcosine derivative (5-7) displayed more potency than 1,14-diacyldelcosine derivatives (5a-7a). These acylated alkaloid derivatives caused accumulation of TNBC cells at sub-G1 within 24 h. 1-Acylation of 1 appears to be critical for producing antiproliferative activity in this alkaloid class and a means to provide promising new leads for further development into antitumor agents.


Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , Extratos Vegetais/farmacologia , Aconitum/química , Alcaloides/química , Linhagem Celular Tumoral , Delphinium/química , Diterpenos/química , Humanos , Magnoliopsida/química , Relação Estrutura-Atividade
17.
Molecules ; 24(10)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137469

RESUMO

Aconitum carmichaeli with Ampelopsis japonica (AA) is a classical traditional Chinese medicine (TCM) formula. There are a lot of examples showing that AA can be used to treat rheumatoid arthritis, but its mechanism of action is still not completely clear. In this research, collagen-induced arthritis (CIA) was chosen as a rheumatoid arthritis (RA) model. Rats of treated groups were continuously administered Aconitum carmichaeli (AC), Ampelopsis japonica (AJ) and Aconitum carmichaeli + Ampelopsis japonica (AA) orally once a day from the day after the onset of arthritis (day 7) until day 42. The results showed that AA not only significantly reduced paw swelling, but also improved the levels of TNF-α and IL-6 in serum. GC-MS-based urine metabonomics was established to analysis metabolic profiles and 21 biomarkers of RA rats were identified by the Partial Least Squares Discriminant Analysis (PLS-DA) and Support Vector Machine (SVM) methods. The prediction rate of the SVM method for the 21 biomarkers was 100%. Twenty of 21 biomarkers, including D-galactose, inositol and glycerol, gradually returned to normal levels after administration of AA. Metabolomic Pathway Analysis (MetPA) generated three related metabolic pathways-galactose metabolism, glycerolipid metabolism and inositol phosphate metabolism-which explain the mechanism of AA treatment of rheumatoid arthritis. This research provides a better understanding of the therapeutic effects and possible therapeutic mechanism of action of a complex TCM (AA) on rheumatoid arthritis.


Assuntos
Aconitum/química , Ampelopsis/química , Artrite Experimental/tratamento farmacológico , Cromatografia Gasosa-Espectrometria de Massas/métodos , Metabolômica , Extratos Vegetais/uso terapêutico , Animais , Artrite Experimental/urina , Biomarcadores/metabolismo , Análise Discriminante , Feminino , Análise dos Mínimos Quadrados , Metaboloma , Ratos Sprague-Dawley , Máquina de Vetores de Suporte
18.
Zhongguo Zhong Yao Za Zhi ; 44(5): 1010-1018, 2019 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-30989863

RESUMO

The aim of this paper was to provide reference for the clinical safety use of aconite through the retrieval of literature about adverse reactions,predict its mechanism of cardiac toxicity by using network pharmacology,and provide ideas for the studies on toxicity mechanism of toxic Chinese medicines. The papers on adverse reactions of aconite were searched to established a database and summarize the adverse reactions of aconite. The results of literature review showed that the main causes for adverse reactions in clinical use of aconite included overdose use,short cooking time,consumption of medicinal liquor/medicinal diet,external use and misuse and so on. Therefore,the dosage of aconite should be strictly followed in clinical application,and the decoction method should be notified to the patients in detail to avoid taking the medicinal liquor and diet containing aconite,so as to prevent the occurrence of adverse reactions as much as possible,and make the best use of aconite in clinical application in avoid its toxicity. At the same time,based on the results of literature review,the network construction and visual analysis of cardio toxicity produced by aconite were carried out by using the network pharmacology technologies. RESULTS: showed that aconite can be applied to eight biological processes such as action potential of cardiac myocytes,cardiac conduction-related cell signal transduction,cardiac myocytes contraction,action potential involved in cardiac myocytes contraction,and signal transduction from atrial myocardial cells to atrioventricular node cells,and three target genes(SCN5 A,GJA1,GJA5). It was predicted that Aconiti Lateralis Radix Praeparata may influence cardiomyocyte depolarization,intercellular information transmission and material exchange by acting on three target genes(SCN5 A,GJA1,GJA5) and regulating the sodium channel protein and the expression of gap junction protein,thus affecting the heart rhythm as well as its structure and function and causing cardiac toxicity.


Assuntos
Aconitum/química , Cardiotoxicidade , Medicamentos de Ervas Chinesas/toxicidade , Aconitum/toxicidade , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Raízes de Plantas/química , Raízes de Plantas/toxicidade
19.
Zhongguo Zhong Yao Za Zhi ; 44(4): 717-722, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30989884

RESUMO

Eight C_(19)-diterpenoid alkaloids( 1-8) were isolated from the ethyl acetate soluble fraction of 95% ethanol extract of the ground roots of Aconitum austroyunnanense through various column chromatographies on silica gel,ODS,Sephadex LH-20 and MCI gel.Their structures were elucidated as 14α-benzoyloxy-13ß,15α-dihydroxy-1α,6α,8ß,16ß,18-pentamethoxy-19-oxoaconitan( 1),N-deethylaconitine( 2),spicatine B( 3),leucanthumsine A( 4),acofamine B( 5),macrorhynine B( 6),aconitilearine( 7),and ambiguine( 8) based on their chemical and physicochemical properties and spectroscopic data. Compound 1 was a new compound and alkaloids 2-8 were isolated from this plant for the first time. Some isolated alkaloids were tested in vitro for cytotoxic potential by employing the MTT method. As a result,alkaloid 1 exhibited weak cytotoxic activity against three tested tumor cell lines( A-549,He La,and Hep G2) with IC_(50) values less than 20 µmol·L~(-1).


Assuntos
Aconitum , Alcaloides , Diterpenos , Estrutura Molecular , Raízes de Plantas
20.
Zhongguo Zhong Yao Za Zhi ; 44(3): 482-488, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30989912

RESUMO

The powder X-ray diffraction(PXRD) technique was used to investigate fourteen kinds of Ranunculaceae herbal decoction pieces(RHDP) recorded in Chinese Pharmacopoeia and to explore a novel PXRD quality control method for RHDP. The results indicated that only three RHDP-Paeoniae Radix Alba, Paeoniae Radix Rubra, and Moutan Cortex, contained calcium oxalate monodydrate(COM), whereas no COM existed in other eleven kinds of RHDP. The difference in PXRD for Paeoniae Radix Alba and Paeoniae Radix Rubra from different growing areas were investigated. The quantitative analysis method for COM was discussed by considering the water-boiling manufacturing process of herbal decoction pieces. The water-boiling experiments revealed that the PXRD peaks from COM crystals in RHDP were enhanced significantly after boiling. Paeoniae Radix Alba, Paeoniae Radix Rubra, Moutan Cortex, Aconiti Lateralis Radix Praeparata, Aconiti Radix, Aconiti Kusnezoffii Radix, and Anemone Raddeanae Rhizoma exhibited a similar series of broader peaks in the 2θ region of 15° to 35°, whose origins were discussed on the basis of chemical constituents RHDP reported by other researchers. These diffraction broader peaks most likely originated from periodic orientation of benzene ring in organic molecular crystals of aconitine-and paeonolum-based alkaloids and glycosides chemical constituents, subsequently, possibly from some other organic constituents. The PXRD technique can be used to rapidly identify Cimicifuga heracleifolia with an amorphous dispersion peak and C. dahurica with a sharp-peak feature. Climatidis Radix et Rhizoma exhibited a series of sharp PXRD peaks. The PXRD method can provide a valuable quality control method for RHDP.


Assuntos
Medicamentos de Ervas Chinesas/química , Compostos Fitoquímicos/análise , Ranunculaceae/química , Aconitum/química , Paeonia/química , Rizoma/química , Difração de Raios X
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