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1.
Biomed Res Int ; 2022: 4336870, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35915792

RESUMO

Background: Danhong injection (DHI) is widely used in the treatment of cardiovascular and cerebrovascular diseases, and its safety and effectiveness have been widely recognized and applied in China. However, the potential molecular mechanism of action for the treatment of arrhythmia is not fully understood. Aim: In this study, through network pharmacology and in vitro cell experiments, we explored the active compounds of DHI for the treatment of arrhythmia and predicted the potential targets of the drug to investigate its mechanism of action. Materials and Methods: First, the potential therapeutic effect of DHI on arrhythmia was investigated in an in vitro arrhythmia model using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), in which calcium transients were recorded to evaluate the status of arrhythmia. Next, the active compounds and key targets in the treatment of arrhythmia were identified through network pharmacology and molecular docking, and the key signaling pathways related to the treatment of arrhythmia were analyzed. Furthermore, we used real-time quantitative reverse transcription PCR (qRT-PCR) to verify the expression levels of key genes. Results: Early afterdepolarizations (EADs) were observed during aconitine treatment in hiPSC-CMs, and the proarrhythmic effect of aconitine was partially rescued by DHI, indicating that the antiarrhythmic role of DHI was verified in an in vitro human cardiomyocyte model. To further dissect the underlying molecular basis of this observation, network pharmacology analysis was performed, and the results showed that there were 108 crosstargets between DHI and arrhythmia. Moreover, 30 of these targets, such as AKT1 and HMOX1, were key genes. In addition, the mRNA expression of AKT1 and HMOX1 could be regulated by DHI. Conclusion: DHI can alleviate aconitine-induced arrhythmia in an in vitro model, presumably because of its multitarget regulatory mechanism. Key genes, such as AKT1 and HMOX1, may contribute to the antiarrhythmic role of DHI in the heart.


Assuntos
Medicamentos de Ervas Chinesas , Células-Tronco Pluripotentes Induzidas , Aconitina/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Farmacologia em Rede
2.
Toxins (Basel) ; 14(7)2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35878224

RESUMO

Mesaconitine (MA), one of the main diterpenoid alkaloids in Aconitum, has a variety of pharmacological effects, such as analgesia, anti-inflammation and relaxation of rat aorta. However, MA is a highly toxic ingredient. At present, studies on its toxicity are mainly focused on the heart and central nervous system, and there are few reports on the hepatotoxic mechanism of MA. Therefore, we evaluated the effects of MA administration on liver. SD rats were randomly divided into a normal saline (NS) group, a low-dose MA group (0.8 mg/kg/day) and a high-dose MA group (1.2 mg/kg/day). After 6 days of administration, the toxicity of MA on the liver was observed. Metabolomic and network toxicology methods were combined to explore the effect of MA on the liver of SD rats and the mechanism of hepatotoxicity in this study. Through metabonomics study, the differential metabolites of MA, such as L-phenylalanine, retinyl ester, L-proline and 5-hydroxyindole acetaldehyde, were obtained, which involved amino acid metabolism, vitamin metabolism, glucose metabolism and lipid metabolism. Based on network toxicological analysis, MA can affect HIF-1 signal pathway, MAPK signal pathway, PI3K-Akt signal pathway and FoxO signal pathway by regulating ALB, AKT1, CASP3, IL2 and other targets. Western blot results showed that protein expression of HMOX1, IL2 and caspase-3 in liver significantly increased after MA administration (p < 0.05). Combined with the results of metabonomics and network toxicology, it is suggested that MA may induce hepatotoxicity by activating oxidative stress, initiating inflammatory reaction and inducing apoptosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Fosfatidilinositol 3-Quinases , Aconitina/análogos & derivados , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Interleucina-2 , Ratos , Ratos Sprague-Dawley , Ratos Wistar
3.
Molecules ; 27(13)2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35807297

RESUMO

Aconiti Lateralis Radix Praeparata (Fu Zi) is the processed lateral root of Aconitum carmichaelii Debx, which is widely used in emergency clinics. Poisoning incidents and adverse reactions occur with the improper intake of Fu Zi. Metabolic characteristics of aconitum alkaloids of Fu Zi may vary, and the effects of Fu Zi in healthy and Long QT syndrome (LQTS) patients is unknown. In this experiment, 24 Sprague Dawley rats were randomly divided into three groups: 2.0, 1.0, and 0.5 g/kg dose groups, and blood samples were collected after the oral administration of Fu Zi extract. We used an ultra-high performance liquid chromatography-tandem mass spectrometry system to detect the concentrations of six aconitum alkaloids. Cell toxicity, calcium imaging, and patch-clamp recordings of human induced pluripotent stem cells-cardiomyocytes (hiPSC-CMs) of aconitine in healthy and LQTS were observed. We found that the AUC(0-48h), Cmax, and t1/2 of the six compounds increased with the multiplicative dosages; those in the high group were significantly higher than those in the low group. Aconitine concentration-dependently decreased the amplitude, which has no significant effect on the cell index of normal hiPSC-CMs. Aconitine at 5.0 µM decreased the cell index between 5-30 min for LQTS hiPSC-CMs. Meanwhile, aconitine significantly increased the frequency of calcium transients in LQTS at 5 µM. Aconitine significantly shortened the action potential duration of human cardiomyocytes in both normal and LQTS groups. These results show metabolic behaviors of aconitum alkaloids in different concentrations of Fu Zi and effects of aconitine in healthy and LQTS patients.


Assuntos
Aconitum , Alcaloides , Medicamentos de Ervas Chinesas , Células-Tronco Pluripotentes Induzidas , Síndrome do QT Longo , Aconitina/farmacologia , Aconitum/química , Alcaloides/análise , Alcaloides/farmacologia , Animais , Cálcio , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Humanos , Síndrome do QT Longo/induzido quimicamente , Miócitos Cardíacos , Ratos , Ratos Sprague-Dawley
4.
Neurotoxicology ; 91: 218-227, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35643327

RESUMO

The inhibition of the excessive release of glutamate in the brain has emerged as a promising new option for developing therapeutic strategies for neurodegenerative disorders. This study investigated the effect and mechanism of lappaconitine, a diterpenoid alkaloid found in species of Aconitum, on glutamate release in rat cerebral cortex nerve terminals (synaptosomes). Here, we report that in the rat cortical synaptosomal preparation, lappaconitine reduced the K+ channel blocker 4-aminopyridine (4-AP)-evoked Ca2+-dependent release of glutamate. The inhibitory effect of lappaconitine on the evoked glutamate release was blocked by the vesicular transporter inhibitor bafilomycin A1 and calcium-chelating agent ethylene glycol tetraacetic acid (EGTA), but was unaffected by exposure to the glutamate transporter inhibitor dl-threo-beta-benzyloxyaspartate (dl-TBOA). The depolarization-induced elevation of cytosolic calcium concentration ([Ca2+]c) was inhibited by lappaconitine, while the 4-AP-mediated depolarization of the synaptosomal membrane potential was not affected. The inhibition of glutamate release by lappaconitine was markedly decreased in synaptosomes pretreated with the Cav2.3 (R-type) channel blocker SNX-482 or the protein kinase A inhibitor H89. Nevertheless, the lappaconitine-mediated inhibition of glutamate release was not abolished by the intracellular Ca2+-release inhibitors dantrolene and CGP37157. Lappaconitine also significantly decreased the 4-AP-induced phosphorylation of PKA and SNAP-25, a presynaptic substrate for PKA. Our data suggest that lappaconitine reduces Ca2+ influx through R-type Ca2+ channels, subsequently reducing the protein kinase A cascade to inhibit the evoked glutamate release from rat cerebral cortex nerve terminals.


Assuntos
Aconitina , Cálcio , Proteínas Quinases Dependentes de AMP Cíclico , Ácido Glutâmico , 4-Aminopiridina/metabolismo , 4-Aminopiridina/farmacologia , Aconitina/análogos & derivados , Aconitina/farmacologia , Animais , Cálcio/metabolismo , Córtex Cerebral/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ácido Glutâmico/metabolismo , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Sprague-Dawley , Sinaptossomos
5.
Chin J Integr Med ; 28(8): 693-701, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35723815

RESUMO

OBJECTIVE: To explore the synergic mechanism of ginsenoside Rg1 (Rg1) and aconitine (AC) by acting on normal neonatal rat cardiomyocytes (NRCMs) and pentobarbital sodium (PS)-induced damaged NRCMs. METHODS: The toxic, non-toxic, and effective doses of AC and the most suitable compatibility concentration of Rg1 for both normal and damaged NRCMs exposed for 1 h were filtered out by 3- (4,5)-dimethylthiahiazo (-z-y1)-3,5-diphenytetrazoliumromide, respectively. Then, normal NRCMs or impaired NRCMs were treated with chosen concentrations of AC alone or in combination with Rg1 for 1 h, and the cellular activity, cellular ultrastructure, apoptosis, leakage of acid phosphatase (ACP) and lactate dehydrogenase (LDH), intracellular sodium ions [Na+], potassium ions [K+] and calcium ions [Ca2+] levels, and Nav1.5, Kv4.2, and RyR2 genes expressions in each group were examined. RESULTS: For normal NRCMs, 3000 µ mol/L AC significantly inhibited cell viability (P<0.01), promoted cell apoptosis, and damaged cell structures (P<0.05), while other doses of AC lower than 3000 µ mol/L and the combinations of AC and Rg1 had little toxicity on NRCMs. Compared with AC acting on NRCMs alone, the co-treatment of 3000 and 10 µ mol/L AC with 1 µ mol/L Rg1 significantly decreased the level of intracellular Ca2+ (P<0.01 or P<0.05), and the co-treatment of 3000 µ mol/L AC with 1 µ mol/L Rg1 significantly decreased the level of intracellular Ca2+ via regulating Nav1.5, RyR2 expression (P<0.01). For damaged NRCMs, 1500 µ mol/L AC aggravated cell damage (P<0.01), and 0.1 and 0.001 µ mol/L AC showed moderate protective effect. Compared with AC used alone, the co-treatment of Rg1 with AC reduced the cell damage, 0.1 µ mol/L AC with 1 µ mol/L Rg1 significantly inhibited the level of intracellular Na+ (P<0.05), 1500 µ mol/L AC with 1 µ mol/L Rg1 significantly inhibited the level of intracellular K+ (P<0.01) via regulating Nav1.5, Kv4.2, RyR2 expressions in impaired NRCMs. CONCLUSION: Rg1 inhibited the cardiotoxicity and enhanced the cardiotonic effect of AC via regulating the ion channels pathway of [Na+], [K+], and [Ca2+].


Assuntos
Ginsenosídeos , Aconitina/farmacologia , Animais , Apoptose , Cardiotônicos/farmacologia , Cardiotoxicidade/tratamento farmacológico , Sobrevivência Celular , Ginsenosídeos/farmacologia , Ratos
6.
PLoS One ; 17(6): e0270069, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35759460

RESUMO

Aconitum, as "the first drug of choice for invigorating Yang and saving lives", has been widely used for the treatment of heart failure. However, toxic components of Aconitum can easily lead to serious arrhythmia, even death (Y. CT., 2009; Zhang XM., 2018). In this study, a High Performance Liquid Chromatography (HPLC) method for the determination of aconitine (AC), mesaconitine (MA) and hypaconitine (HA) was established; The effect of Glycyrrhiza on CYP3A1 / 2 mRNA expression was detected by RT-PCR; SD rats were given Aconitum and compatibility of Glycyrrhizae and Aconitum by gavage respectively, the blood concentration of toxic components were determined by LC-MS / MS; The CHF rat model was established by intraperitoneal injection of adriamycin (2.5 mg / kg), and were randomly divided into model, Aconitum, the compatibility of Glycyrrhizae and Aconitum and Captopril group, 5 mice/group. After 4 weeks of gavage, the corresponding indexes were detected by ELISA and HPLC. The results showed that Ketoconazole significantly inhibited the metabolites of AC, MA and HA; Glycyrrhiza induced CYP3A gene expression; The level of ALD in the compatibility of Glycyrrhizae and Aconitum group was significantly lower than that in Aconitum group. After intervention with the compatibility of Glycyrrhizae and Aconitum, ATP increased, ADP decreased significantly. In conclusion, we found Glycyrrhiza promoted the metabolism of toxic components of Aconitum by up regulating the expression of CYP3A, and reduced the content of BNP, Ang II and ALD, improved the energy metabolism disorder of myocardium, alleviated the development of CHF.


Assuntos
Aconitum , Medicamentos de Ervas Chinesas , Glycyrrhiza uralensis , Insuficiência Cardíaca , Aconitina/farmacologia , Aconitum/metabolismo , Aconitum/toxicidade , Animais , Cromatografia Líquida de Alta Pressão/métodos , Citocromo P-450 CYP3A/genética , Medicamentos de Ervas Chinesas/farmacologia , Glycyrrhiza uralensis/metabolismo , Insuficiência Cardíaca/prevenção & controle , Camundongos , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley
7.
Pak J Pharm Sci ; 35(2): 519-528, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35642408

RESUMO

This study aimed to illustrate the curative effect of Fuzi Lizhong Decoction, which is composed of Aconitum carmichaeli Debeaux, Zingiber officinale Roscoe, Codonopsis pilosula (Franch.), Atractylodes macrocephala Koidz and Glycyrrhiza uralensis Fisch. and contained components such as benzoyl aconitine, benzoyl aconitine, atractyl lactone I, atractylenolide II, ginsenoside, emodin, glycyrrhizin, glycyrrhizin, 8-gingerol and 10-gingerol, on stomach ulcer based on ultra-performance liquid chromatography/mass spectrometry metabolomics analysis. Rats urine samples of three groups were detected by ultra-performance liquid chromatography/mass spectrometry. Then, stomach ulcer biomarkers were filtered out by EZinfo 2.0 software. After that, analysis of variance was used for picking up significantly retroved biomarkers in treated group. Compounds were identified based on MS/MS spectrum, accurate mass weight and retention time. Twelve metabolites including 2-Methylhippuic acid, Kynurenic acid, 2-Indolecarboxylic acid, Pyrocatechol, Caproic acid, 2,3-Dihydrobenzofuran, 4-Ethylphenol, Lanthionine ketimine, Traumatic acid, Indole-3-carboxilic acid-O-sulphate, Vanillic acid 4-sulfate, 6-Mecaptopurine ribonudeoside 5'-diphosphate were identified as stomach ulcer biomarkers. Among them, ten ones except for 2-Methylhippuic acid and 2-Indolecarboxylic acid retrieved. Pathways involved tryptophan metabolism, benzoate degradation, bisphenol degradation and α-linolenic acid metabolism. In conclusion, Fuzi Lizhong Decoction may cure stomach ulcer by improving tryptophan metabolism, benzoate degradation, bisphenol degradation and α-linolenic acid metabolism.


Assuntos
Medicina Tradicional Chinesa , Úlcera Gástrica , Aconitina , Animais , Benzoatos , Biomarcadores , Cromatografia Líquida de Alta Pressão/métodos , Diterpenos , Medicamentos de Ervas Chinesas , Ácido Glicirrízico , Ratos , Espectrometria de Massas em Tandem/métodos , Triptofano , Ácido alfa-Linolênico
8.
Bull Exp Biol Med ; 173(2): 219-223, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35739330

RESUMO

In in vitro experiments on isolated rat hippocampal neurons, we studied the electrophysiological mechanisms of the antiarrhythmic effects of N-deacetyllappaconitine monochlorhydrate (DALCh), active metabolite of lappaconitine hydrobromide (allapinin). Electrical activity of neurons was recorded by the patch-clamp method in the whole cell configuration. It was shown that DALCh increased the duration of both slow and fast depolarization phases and decreased the amplitude of the action potential. DALCh effectively inhibited transmembrane currents of Na+ ions and partially K+ ions through the corresponding transmembrane voltage-gated ion channels. Thus, DALCh, in contrast to lappaconitine hydrobromide, belongs not to 1C, but to the 1A class of antiarrhythmics according to the Vaughan-Williams classification.


Assuntos
Neurônios , Canais de Potássio , Aconitina/análogos & derivados , Potenciais de Ação , Animais , Antiarrítmicos/farmacologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Canais de Potássio/metabolismo , Ratos
9.
BMC Complement Med Ther ; 22(1): 160, 2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35710396

RESUMO

BACKGROUND: The present study aimed to determine the protective effects of hypaconitine (HA) and glycyrrhetinic acid (GA) against chronic heart failure (CHF) in the rats and to explore the underlying molecular mechanisms. METHODS: The CHF rat model was established by transverse-aortic constriction (TAC) operation. Transthoracic echocardiography and hematoxylin eosin (HE) staining were used to evaluate the pathophysiological and histopathological changes of CHF model. The total cholesterol (TCHO) and triglyceride (TG) levels were determined by ELISA assay. The protein expression of fibroblast growth factor 2 (FGF2), vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) in the rat ventricular tissues was determined by immunohistochemistry. The serum metabolites were determined by LC-MS/MS assay. RESULTS: After applied the HA + GA, the cardiac tissue and structure were obviously improved, and the HA + GA treatment also significantly reduced the plasma levels of TCHO and TG in the CHF rats. The expression of FGF2 and VEGFA protein was up-regulated and the expression of eNOS protein was down-regulated in the ventricular tissues of CHF rats, which was significantly restored after HA + GA treatment. HA + GA treatment down-regulated serum isonicotinic acid, phosphatidylcholine, cardiolipin, estrogen glucuronide, and glycocholic acid, up-regulated serum sphingosine and deoxycholic acid in the CHF rats. CONCLUSIONS: In conclusion, HA + GA showed protective effects on CHF in the rats, and the HA + GA may exert protective effects by reducing lipid levels, up-regulating the expression of FGF2 and VEGFA proteins, attenuating eNOS protein expression, and modulating metabolic pathways. However, the molecular mechanisms underlying HA + GA-mediated effects still require further examination.


Assuntos
Ácido Glicirretínico , Insuficiência Cardíaca , Aconitina/análogos & derivados , Animais , Cromatografia Líquida , Fator 2 de Crescimento de Fibroblastos , Ácido Glicirretínico/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Ratos , Espectrometria de Massas em Tandem , Fator A de Crescimento do Endotélio Vascular
10.
Biomed Pharmacother ; 151: 113115, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35605296

RESUMO

Aconitine is a diterpenoid alkaloid, which mainly exists in the plants of Aconitum. In the last decade, a plethora of studies on the pharmacological activities of aconitine has been conducted and demonstrated that aconitine possessed an extensive range of pharmacological activities such as anti-tumor, anti-inflammatory, analgesic, local anesthesia, and immunomodulatory effects. Pharmacokinetic studies indicated that aconitine may have the characteristics of poor bioavailability, wide distribution, and slow elimination. However, studies have also found that aconitine has toxic effects on the heart, nerves, embryos, etc. Therefore, we believe that aconitine may not be suitable for heart patients and pregnant women to treat related diseases. It is important to note that all of these pharmacological effects require further high-quality studies to determine the clinical efficacy of aconitine. This review aims to summarize the advances in pharmacological, pharmacokinetics, toxicity, and detoxification of aconitine in the last decade with an emphasis on its anti-tumor and anti-inflammatory activities, to provide researchers with the latest information and point out the limitations of relevant research at the current stage and the aspects that should be strengthened in future research.


Assuntos
Aconitum , Alcaloides , Medicamentos de Ervas Chinesas , Aconitina/farmacocinética , Aconitina/toxicidade , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Humanos , Gravidez
11.
Food Chem ; 391: 133234, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-35605540

RESUMO

The dual functions of phytotoxin, such as aconitine, with biological activity and toxicity ignited the related food poisoning intentionally or accidentally from time to time. The fast and accurate qualitative analysis is a prerequisite for tracking the source of poisoning and taking correct treatments. Taking the single molecule level sensitivity and molecular fingerprinting of Surface-enhanced Raman spectroscopy (SERS), we developed a highly sensitive and accurate strategy for the trace detection of three structurally similar aconitines (ATs) (aconitine, mesaconitine and hypoaconitine) by employing the 100 nm Ag NPs colloid as the SERS substrate. It was figured out that the lowest detectable concentration is in the level of 5.0 µg/L for these three ATs with the linear range of 5.0-100.0 µg/L. The qualitative and quantitative analysis of trace ATs spiked in various food samples was realized in 3 mins, which demonstrated the SERS based strategy is very promising towards the fast and on-site detection of ATs in the field of food safety or criminal identification.


Assuntos
Aconitum , Nanopartículas Metálicas , Aconitina , Nanopartículas Metálicas/química , Análise Espectral Raman/métodos
13.
Toxicol Appl Pharmacol ; 445: 116024, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35439480

RESUMO

Bulleyaconitine A (BLA), a toxic Aconitum alkaloid, is a potent analgesic that is clinically applied to treat rheumatoid arthritis, osteoarthritis and lumbosacral pain. BLA-related adverse reactions occur frequently, but whether the underlying mechanism is related to its metabolic interplay with drug-metabolizing enzymes remains unclear. This study aimed to elucidate the metabolic characteristics of BLA and its affinity action and mechanism to drug-metabolizing enzymes to reveal whether BLA-related adverse reactions are modulated by enzymes. After incubation with human liver microsomes and recombinant human cytochrome P450 enzymes, we found that BLA was predominantly metabolized by CYP3A, in which CYP3A4 had an almost absolute advantage. In vitro, the CYP3A4 inhibitor ketoconazole noticeably suppressed the metabolism of BLA. In vivo, the AUC0-∞ values, cardiotoxicity and neurotoxicity of BLA in Cyp3a-inhibited mice were all obviously enhanced (P < 0.05) compared to those in normal mice. In the enzyme kinetics study, BLA was found to be a sensitive substrate of CYP3A4, and its characteristics were consistent with substrate inhibition (Km = 39.36 ± 10.47 µmol/L, Ks = 83.42 ± 19.65 µmol/L). BLA was further identified to be a competitive inhibitor of CYP3A4 with Ki = 53.64 µmol/L, since the intrinsic clearance (CLint) of midazolam, a selective CYP3A4 substrate, decreased significantly (P < 0.05) when incubated with BLA together in mouse liver microsomes. Overall, BLA is a sensitive substrate and competitive inhibitor of CYP3A4, and clinical adverse reactions of BLA may mechanistically related to the CYP3A4-mediated drug-drug interactions.


Assuntos
Aconitina , Citocromo P-450 CYP3A , Proteínas de Membrana , Microssomos Hepáticos , Proteínas de Saccharomyces cerevisiae , Aconitina/análogos & derivados , Aconitina/farmacologia , Animais , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Cetoconazol/farmacologia , Proteínas de Membrana/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Proteínas de Saccharomyces cerevisiae/farmacologia
14.
J Ethnopharmacol ; 293: 115270, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35405250

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Aconitine, a C19-norditerpenoid alkaloid, derives from many medicinal plants such as Aconitum carmichaelii Debx. (Chinese:), Aconitum kusnezoffii Reichb (Chinese:), which were used to rheumatic fever, painful joints and some endocrinal disorders. AIMS OF THE REVIEW: The present paper reviews research progress relating to the pharmacokinetics, physiological and pathological processes of aconitine, while some promising research direction and the detoxification of aconitine are also discussed. MATERIALS AND METHODS: The accessible literature on aconitine, from 1990 to 2020, obtained from published materials of electronic databases, such as SCI finder, PubMed, Web of Science, Science Direct, Springer and Google Scholar was systematically analyzed. RESULTS: In this review, we address the pharmacokinetics of aconitine, as well as its pharmacological effects including anti-cancer, anti-inflammatory, anti-virus, immunoregulation, analgesic, insecticide and inhibition of androgen synthesis. Further, we summarize the toxicity of aconitine such as cardiotoxicity and neurotoxicity, on which we strikingly focus on the ways to reduce the toxicity of aconitine based. CONCLUSIONS: Aconitine plays an vital role in a wide range of physiological and pathological processes and we can reduce the toxicity of aconitine by compatibility and hydrolysis. Although some issues still exist, such as the correlative relationship between the dose and toxicity of aconitine not being clear, our review may provide new ideas for the application of aconitine in the treatment of related diseases.


Assuntos
Aconitum , Alcaloides , Medicamentos de Ervas Chinesas , Plantas Medicinais , Aconitina/farmacocinética , Aconitina/toxicidade , Anti-Inflamatórios , Medicamentos de Ervas Chinesas/farmacologia
15.
Mar Drugs ; 20(3)2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35323499

RESUMO

The α7 nicotinic acetylcholine receptor (nAChR) is widely distributed in the central and peripheral nervous systems and is closely related to a variety of nervous system diseases and inflammatory responses. The α7 nAChR subtype plays a vital role in the cholinergic anti-inflammatory pathway. In vivo, ACh released from nerve endings stimulates α7 nAChR on macrophages to regulate the NF-κB and JAK2/STAT3 signaling pathways, thereby inhibiting the production and release of downstream proinflammatory cytokines and chemokines. Despite a considerable level of recent research on α7 nAChR-mediated immune responses, much is still unknown. In this study, we used an agonist (PNU282987) and antagonists (MLA and α-conotoxin [A10L]PnIA) of α7 nAChR as pharmacological tools to identify the molecular mechanism of the α7 nAChR-mediated cholinergic anti-inflammatory pathway in RAW264.7 mouse macrophages. The results of quantitative PCR, ELISAs, and transcriptome analysis were combined to clarify the function of α7 nAChR regulation in the inflammatory response. Our findings indicate that the agonist PNU282987 significantly reduced the expression of the IL-6 gene and protein in inflammatory macrophages to attenuate the inflammatory response, but the antagonists MLA and α-conotoxin [A10L]PnIA had the opposite effects. Neither the agonist nor antagonists of α7 nAChR changed the expression level of the α7 nAChR subunit gene; they only regulated receptor function. This study provides a reference and scientific basis for the discovery of novel α7 nAChR agonists and their anti-inflammatory applications in the future.


Assuntos
Aconitina/análogos & derivados , Anti-Inflamatórios/farmacologia , Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Conotoxinas/farmacologia , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Aconitina/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Células RAW 264.7 , Receptor Nicotínico de Acetilcolina alfa7/genética
16.
Fundam Clin Pharmacol ; 36(4): 601-611, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35060168

RESUMO

Aconitum alkaloids are considered to be the characteristic bioactive ingredients of Aconitum species, which are widely applied to the treatment of diverse diseases, and aconitine (AC) is found in most Aconitum plants. Research evidence shows that low-dose AC has a good therapeutic potential in heart failure, myocardial infarction, neuroinflammatory diseases, rheumatic diseases, and tumors, which has become one of the hotspots in global research in recent years. However, the cardiotoxicity and neurotoxicity of AC have also attracted extensive attention. Excessive use of AC always induces ventricular tachyarrhythmia and heart arrest, even can be potentially lethal. Therefore, AC cannot simply be regarded as a good medicine or a toxicant, but its underlying curative and toxic properties remained chaos. In order to dig the unique pharmacological value of AC while preventing its toxicity, the pharmacological activities and toxic effects of AC were summarized in this paper, providing new insight into the safe and effective use of AC in clinical practice.


Assuntos
Aconitum , Alcaloides , Aconitina/toxicidade , Cardiotoxicidade/etiologia
17.
Res Vet Sci ; 143: 124-133, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35026629

RESUMO

Aconitine is a plant toxin derived from aconitum genus and well known for its neurological and vascular toxicity. However, the mechanism of toxicity on the growth and apoptosis of the neurological cells has not been well investigated. In this study, we used HT22 cell lines derived from hippocampus to explore the mechanism. We began with examination of the viability and DA (dopamine) contents of cells treated with different dose of aconitine. In this study, we investigated the role of apoptosis in AC-induced HT22 cells. Our results showed that aconitine inhibited HT22 cells growth and increased DA contents in a dose dependent manner. Aconitine treatment induced apoptosis in HT22 cells and we found aconitine induced apoptosis by upregulating the expression of Bax, Cyto c, Apaf-1, Caspase9, Fas, Fas-L, Fadd, Caspase8, Caspase3 with concomitant decreasing of Bcl-2 and Bid expression. Collectively, results suggest that aconitine induce apoptosis through mitochondrial-mediated and death receptor signaling pathways in HT22 cells.


Assuntos
Aconitina , Apoptose , Aconitina/toxicidade , Animais , Linhagem Celular , Hipocampo/metabolismo , Mitocôndrias/metabolismo , Receptores de Morte Celular/metabolismo , Transdução de Sinais , Receptor fas/metabolismo
18.
Sci Rep ; 12(1): 54, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34997096

RESUMO

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Several studies have demonstrated that α7 nicotinic acetylcholine receptors (α7nAChRs) exert anti-inflammatory effects on immune cells and nicotine suppress UC onset and relapse. Plasmacytoid dendritic cells (pDCs) reportedly accumulate in the colon of UC patients. Therefore, we investigated the pathophysiological roles of α7nAChRs on pDCs in the pathology of UC using oxazolone (OXZ)-induced Th2-type colitis with BALB/c mice. 2-deoxy-D-glucose, a central vagal stimulant suppressed OXZ colitis, and nicotine also ameliorated OXZ colitis with suppressing Th2 cytokines, which was reversed by α7nAChR antagonist methyllycaconitine. Additionally, α7nAChRs were expressed on pDCs, which were located very close to cholinergic nerve fibers in the colon of OXZ mice. Furthermore, nicotine suppressed CCL21-induced bone marrow-derived pDC migration due to Rac 1 inactivation, which was reversed by methyllycaconitine, a JAK2 inhibitor AG490 or caspase-3 inhibitor AZ-10417808. CCL21 was mainly expressed in the isolated lymphoid follicles (ILFs) of the colon during OXZ colitis. The therapeutic effect of cholinergic pathway on OXZ colitis probably through α7nAChRs on pDCs were attributed to the suppression of pDC migration toward the ILFs. Therefore, the activation of α7nAChRs has innovative therapeutic potential for the treatment of UC.


Assuntos
Neurônios Colinérgicos/efeitos dos fármacos , Colite Ulcerativa/tratamento farmacológico , Células Dendríticas/efeitos dos fármacos , Neuroimunomodulação , Células Th2/metabolismo , Aconitina/análogos & derivados , Aconitina/farmacologia , Aconitina/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Caspase 3/metabolismo , Inibidores de Caspase/farmacologia , Inibidores de Caspase/uso terapêutico , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colo/metabolismo , Células Dendríticas/metabolismo , Desoxiglucose/farmacologia , Desoxiglucose/uso terapêutico , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Janus Quinase 2/metabolismo , Camundongos Endogâmicos BALB C , Neuropeptídeos/metabolismo , Nicotina/farmacologia , Nicotina/uso terapêutico , Oxazolona/toxicidade , Fator de Transcrição STAT3/metabolismo , Células Th2/efeitos dos fármacos , Tirfostinas/farmacologia , Tirfostinas/uso terapêutico , Nervo Vago/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Receptor Nicotínico de Acetilcolina alfa7/genética , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo
19.
AAPS PharmSciTech ; 23(1): 61, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35059926

RESUMO

The objective of this study was to develop a lappaconitine (LA) transdermal patch with counter-ion to increase the transdermal permeability of the drug, and a theory of counter-ion altering the conformation of the skin keratin was put forward based on the in vitro skin permeation study and physicochemical properties of ion-pairs. Formulation factors including pressure sensitive adhesives (PSAs), drug-loading, counter-ions and molar ratios of counter-ion were screened by in vitro skin permeation study. The optimized formulation was composed of 7% LA, 1.5 mole cinnamic acid and AAOH (PSA containing hydroxyl group synthesized by our laboratory) as an adhesive matrix. The optimized patch was evaluated by the pharmacokinetic and analgesic pharmacodynamic studies. AUC0-t and pain inhibition ratio of the optimized patch were 2450.40 ± 848.52 h ng/mL and 81.18%, which showed good absorption into the skin and excellent analgesic effect. The mechanism of facilitated transdermal drug permeation by counter-ion was investigated by ATR-FTIR, thermal analysis, FTIR, XPS and molecular docking. The results indicated that after the formation of ion-pairs, the excess counter-ions would alter the conformation of the skin keratin, thus increasing the transdermal penetration of LA. In conclusion, the LA patch was successfully optimized, and the effect of counter-ions on the skin was clarified at the molecular level. These findings provided additional references for the application of counter-ion in the transdermal drug delivery system.


Assuntos
Queratinas , Absorção Cutânea , Aconitina/análogos & derivados , Íons , Simulação de Acoplamento Molecular
20.
Naunyn Schmiedebergs Arch Pharmacol ; 395(1): 65-76, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34727218

RESUMO

Aconitine linoleate (1) is a lipo-diterpenoid alkaloid, isolated from Aconitum sinchiangense W. T. Wang. The study aimed at investigating the anti-proliferative efficacy and the underlying mechanisms of 1 against MCF-7 and MCF-7/ADR cells, as well as obvious the safety evaluation in vivo. The cytotoxic activities of 1 were measured in vitro. Also, we investigated the latent mechanism of 1 by cell cycle analysis in MCF-7/ADR cells and topo I and topo IIα inhibition assay. Molecular docking is done by Discovery Studio 3.5 and Autodock vina 1.1.2. Finally, the acute toxicity of 1 was detected on mice. 1 exhibited significant antitumor activity against both MCF-7 and MCF-7/ADR cells, with IC50 values of 7.58 and 7.02 µM, which is 2.38 times and 5.05 times more active, respectively than etoposide in both cell lines, and being 9.63 times more active than Adriamycin in MCF-7/ADR cell lines. The molecular docking and the topo inhibition test found that it is a selective inhibitor of topoisomerase IIα. Moreover, activation of the damage response pathway of the DNA leads to cell cycle arrest at the G0G1 phase. Furthermore, the in vivo acute toxicity of 1 in mice displayed lower toxicity than aconitine, with LD50 of 2.2 × 105 nmol/kg and only slight pathological changes in liver and lung tissue, 489 times safer than aconitine. In conclusion, compared with aconitine, 1 has more significant anti-proliferative activity against MCF-7 and MCF-7/ADR cells and greatly reduces in vivo toxicity, which suggests this kind of lipo-alkaloids is powerful and promising antitumor compounds for breast cancer.


Assuntos
Aconitina/farmacologia , Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Aconitina/administração & dosagem , Aconitina/toxicidade , Aconitum/química , Animais , Animais não Endogâmicos , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Ácido Linoleico/química , Células MCF-7 , Masculino , Camundongos , Simulação de Acoplamento Molecular , Células NIH 3T3 , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores
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