ABSTRACT
OBJECTIVE@#The transformations that occur in diterpenoid alkaloids during the process of sand frying for Chinese herbal medicine preparation have yet to be clarified. This study investigated the structural changes that take place in 3-acetylaconitine during a simulation of heat-processing and evaluated the toxicity and biological activity of the pyrolysis products.@*METHODS@#The diterpenoid alkaloid 3-acetylaconitine was heated at 180 °C for 15 min to simulate the process of sand frying. The pyrolysis products were separated using column chromatography, and their structures were investigated using high-resolution electrospray ionization mass spectroscopy and nuclear magnetic resonance spectroscopy. Further, in vivo cardiotoxicity and acute toxicity of 3-acetylaconitine and its pyrolysis products were compared, and the aconitine-induced arrhythmia model was employed to evaluate the antiarrhythmic effect of the pyrolysis products.@*RESULTS@#Two new diterpenoid alkaloids, pyroacetylaconitine and 16-epi-pyroacetylaconitine, a pair of epimers at C-16, were isolated. After comparing the structures of these compounds, possible transformation pathways were proposed. Compared with the prototype compound, 3-acetylaconitine, the cardiotoxicity and acute toxicity of the heat-transformed products were significantly decreased. In the biological activity assay, the two pyrolysis products exhibited an effective increase in ventricular premature beat latency, a reduction in the occurrence of ventricular tachycardia, as well as an increase in the rate of arrhythmia inhibition, implying strong antiarrhythmic activity.@*CONCLUSION@#Compared with 3-acetylaconitine, its pyrolysis products displayed lower toxicity and good antiarrhythmic effects; thus, they have potential for being developed into antiarrhythmic medicines. Please cite this article as: Wang YJ, Wang Y, Tao P. Structural characterization, in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine. J Integr Med. 2023; 21(3): 302-314.
Subject(s)
Humans , Aconitine/chemistry , Cardiotoxicity , Sand , Alkaloids/toxicity , Arrhythmias, Cardiac/drug therapy , Diterpenes/toxicityABSTRACT
The tubers and roots of Aconitum (Ranunculaceae) are widely used as heart medicine or analgesic agents for the treatment of coronary heart disease, chronic heart failure, rheumatoid arthritis and neuropathic pain since ancient times. As a type of natural products mainly extracted from Aconitum plants, Aconitum alkaloids have complex chemical structures and exert remarkable biological activity, which are mainly responsible for significant effects of Aconitum plants. The present review is to summarize the progress of the pharmacological, toxicological, and pharmacokinetic studies of Aconitum alkaloids, so as to provide evidence for better clinical application. Research data concerning pharmacological, toxicological and pharmacokinetic studies of Aconitum alkaloids were collected from different scientific databases (PubMed, CNKI, Google Scholar, Baidu Scholar, and Web of Science) using the phrase Aconitum alkaloids, as well as generic synonyms. Aconitum alkaloids are both bioactive compounds and toxic ingredients in Aconitum plants. They produce a wide range of pharmacological activities, including protecting the cardiovascular system, nervous system, and immune system and anti-cancer effects. Notably, Aconitum alkaloids also exert strong cardiac toxicity, neurotoxicity and liver toxicity, which are supported by clinical studies. Finally, pharmacokinetic studies indicated that cytochrome P450 proteins (CYPs) and efflux transporters (ETs) are closely related to the low bioavailability of Aconitum alkaloids and play an important role in their metabolism and detoxification in vivo.
Subject(s)
Aconitum/chemistry , Alkaloids/toxicity , Biological Availability , Phytochemicals/toxicity , Plant Roots/chemistryABSTRACT
ABSTRACT Prosopis juliflora is a shrub that has been used to feed animals and humans. However, a synergistic action of piperidine alkaloids has been suggested to be responsible for neurotoxic damage observed in animals. We investigated the involvement of programmed cell death (PCD) and autophagy on the mechanism of cell death induced by a total extract (TAE) of alkaloids and fraction (F32) from P. juliflora leaves composed majoritary of juliprosopine in a model of neuron/glial cell co-culture. We saw that TAE (30 µg/mL) and F32 (7.5 µg/mL) induced reduction in ATP levels and changes in mitochondrial membrane potential at 12 h exposure. Moreover, TAE and F32 induced caspase-9 activation, nuclear condensation and neuronal death at 16 h exposure. After 4 h, they induced autophagy characterized by decreases of P62 protein level, increase of LC3II expression and increase in number of GFP-LC3 cells. Interestingly, we demonstrated that inhibition of autophagy by bafilomycin and vinblastine increased the cell death induced by TAE and autophagy induced by serum deprivation and rapamycin reduced cell death induced by F32 at 24 h. These results indicate that the mechanism neural cell death induced by these alkaloids involves PCD via caspase-9 activation and autophagy, which seems to be an important protective mechanism.
Subject(s)
Animals , Rats , Piperidines/toxicity , Autophagy/physiology , Neuroglia/drug effects , Prosopis/chemistry , Alkaloids/toxicity , Piperidines/isolation & purification , Autophagy/drug effects , Time Factors , Plant Extracts/toxicity , Cell Survival/drug effects , Cells, Cultured , Adenosine Triphosphate/analysis , Neuroglia/physiology , Cell Death/drug effects , Cell Death/physiology , Rats, Wistar , Alkaloids/isolation & purification , Membrane Potential, Mitochondrial/drug effects , Membrane Potential, Mitochondrial/physiologyABSTRACT
Cervical cancer is the fourth type of women neoplasia, with thousands of new cases annually. It is closely related to human papillomavirus (HPV) infection, which has more than 13 oncogenic types, among them HPV 16 and 18 are implicated in 70% of cervical carcinoma cases. Alkaloids are nitrogenated and naturally occurring compounds, showing several uses in medical treatment, including cytotoxic and antineoplastic activities. In this work we aim to evaluate the cytotoxic and chemotherapeutic potential of alkaloids against cervical cancer. In order to accomplish this purpose, we have made a survey of potentially effective alkaloids with cytotoxic activities over HPV-16+ and HPV-18+ cells (HeLa cells). Through a literature review between the years of 1980 and 2015, we described the major alkaloid sources, distribution in nature and also discussed the mechanisms of action for their cytotoxicity. We found that alkaloids showed efficacy as cytotoxic agents, inhibiting cell growth of the HPV-transformed cells in vitro and in vivo by means of activation of intrinsic and extrinsic pathways of apoptosis, which included the clivage of caspases and PARP-1 (Poli-Adenosyl- Ribose Protease 1), increase in p53 expression, release of cytochrome C and increase of cell death receptors expression like Fas, mainly observed in HeLa (HPV- 18+) cell lines. Moreover, these secondary metabolites helped in modulating the MDR (Multi-Drug Resistance) against the cell lines studied, which lead us to suggest their possible use as chemotherapeutic agents on the lesions caused by these viruses
O câncer cervical é a quarta neoplasia incidente em mulheres, com o surgimento de milhares de novos casos anualmente. Está altamente relacionado à infecção pelo papilomavírus humano (HPV), que apresenta mais de 13 tipos oncogênicos, dentre os quais os tipos 16 e 18 são encontrados em 70% dos casos de câncer do colo do útero (câncer cervical). Alcaloides são substâncias naturais nitrogenadas que apresentam diversos usos na terapia, incluindo atividades antineoplásica e citotóxica. Neste sentido, objetivamos neste trabalho avaliar o potencial citotóxico e quimioterápico de alcaloides sobre o câncer cervical. Para tanto, relacionamos os alcaloides com potencial citotóxico sobre HPV- 16+ e HPV-18+ (células HeLa), bem como mostramos suas principais fontes de obtenção, distribuição na natureza e discutimos os mecanismos de ação pelos quais realizam seu efeito citotóxico, através de uma revisão bibliográfica realizada entre o período de 1980 e 2015. Os alcaloides mostraram-se eficazes como drogas citotóxicas, inibindo o crescimento de células alteradas pelo HPV tanto in vitro quanto in vivo, com ativação de mecanismos intrínsecos e extrínsecos de apoptose, tais como ativação das caspases, clivagem de PARP-1 (Poli-ADP-Ribose Protease 1), aumento da expressão de p53, liberação de citocromo C e aumento da expressão de receptores de morte como o Fas, principalmente em células das linhagens HeLa (HPV-18+). Adicionalmente, esses metabólitos secundários auxiliaram na modulação da resistência a múltiplas drogas pelas linhagens de células estudadas, o que nos leva a sugerir o seu possível uso na quimioterapia das lesões provocadas por estes vírus.
Subject(s)
Alkaloids/therapeutic use , Alkaloids/toxicity , Uterine Cervical Dysplasia/drug therapy , PapillomaviridaeABSTRACT
Piplartine {5,6-dihydro-1-[1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl]-2(1H)pyridinone} and piperine {1-5-(1,3)-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]piperidine} are alkaloid amides isolated from Piper. Both have been reported to show cytotoxic activity towards several tumor cell lines. In the present study, the in vivo antitumor activity of these compounds was evaluated in 60 female Swiss mice (N = 10 per group) transplanted with Sarcoma 180. Histopathological and morphological analyses of the tumor and the organs, including liver, spleen, and kidney, were performed in order to evaluate the toxicological aspects of the treatment with these amides. Administration of piplartine or piperine (50 or 100 mg kg-1 day-1 intraperitoneally for 7 days starting 1 day after inoculation) inhibited solid tumor development in mice transplanted with Sarcoma 180 cells. The inhibition rates were 28.7 and 52.3 percent for piplartine and 55.1 and 56.8 percent for piperine, after 7 days of treatment, at the lower and higher doses, respectively. The antitumor activity of piplartine was related to inhibition of the tumor proliferation rate, as observed by reduction of Ki67 staining, a nuclear antigen associated with G1, S, G2, and M cell cycle phases, in tumors from treated animals. However, piperine did not inhibit cell proliferation as observed in Ki67 immunohistochemical analysis. Histopathological analysis of liver and kidney showed that both organs were reversibly affected by piplartine and piperine treatment, but in a different way. Piperine was more toxic to the liver, leading to ballooning degeneration of hepatocytes, accompanied by microvesicular steatosis in some areas, than piplartine which, in turn, was more toxic to the kidney, leading to discrete hydropic changes of the proximal tubular and glomerular epithelium and tubular hemorrhage in treated animals.
Subject(s)
Animals , Female , Mice , Alkaloids/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , Benzodioxoles/therapeutic use , Piper/chemistry , Piperidines/therapeutic use , Piperidones/therapeutic use , Polyunsaturated Alkamides/therapeutic use , /drug therapy , Alkaloids/isolation & purification , Alkaloids/toxicity , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/toxicity , Benzodioxoles/isolation & purification , Benzodioxoles/toxicity , Cell Proliferation/drug effects , Disease Models, Animal , Kidney/drug effects , Kidney/pathology , Liver/drug effects , Liver/pathology , Neoplasm Transplantation , Piperidines/isolation & purification , Piperidines/toxicity , Piperidones/isolation & purification , Piperidones/toxicity , Plant Extracts/isolation & purification , Plant Extracts/therapeutic use , Plant Extracts/toxicity , Plant Roots/chemistry , Polyunsaturated Alkamides/isolation & purification , Polyunsaturated Alkamides/toxicity , /pathology , Spleen/drug effects , Spleen/pathologyABSTRACT
La información del presente escrito es con el fin de dar a conocer la identificación de alcaloides del hongo Claviceps spp en sorgo proveniente del estado de Morelos, México. Se describe el ciclo de vida de Claviceps purpurea (ergot o cornezuelo), sus caracterísicas macroscópicas, toxicidad, número de esclerosis necesarias para inducir la intoxicación, efectos farmacológicos de los alcaloides (ergonovina y engotamina), signos clínicos y hallazgos de necropsia de la intoxicación por alcaloides del Claviceps purpurea. Y finalmente se describe la identificación de tres compuestos (alcaloides) por cromatografía de capa fina en el sorgo del estado de Morelos; con comportamiento igual al de derivados del maleato de ergonovina, pero sin reaccionar al colorante de van Urk
Subject(s)
Animals , Edible Grain/parasitology , Alkaloids/toxicity , Fungi/growth & development , Fungi/pathogenicity , Animal Feed/toxicity , Chromatography, Thin Layer , Plants, ToxicABSTRACT
Los géneros de la familia leguminosae se caracterizan por contener alcaloides con esqueleto quinolizidínico. Entre ellos se encuentra el género Lupinos, el cual está representado en Venezuela por varias especies, poco estudiadas botánicamente. En este trabajo se presentan los resultados obtenidos del estudiante de los alcaloides de Lupinos eremonomos S. y L. meridanus Mortiz
Subject(s)
Alkaloids/chemistry , Alkaloids/classification , Alkaloids/toxicity , Botany/methods , Sparteine/adverse effects , TherapeuticsABSTRACT
The subacute and chronic toxicity of taxine, was investigated in mice. The drug was administered as sulphate salt at dosages of 4.5, 6, 8 mg/kg body weight by daily single subcutaneous injection. The treatment lasted 3 weeks for subacute and 3 months for chronic tests. The evaluated biochemical and hematological parameters as well as the pathological examinations and behavioural observations on the animals showed no harmful effect attributable to the drug. It was concluded that long-term application of taxine was well tolerated by mice
Subject(s)
Animals, Laboratory , Alkaloids/toxicity , MiceABSTRACT
Os alcalóides furoquinoleínico esquimianina e benzofenantridínico celeritrina, extraídos de uma espécie da família Rutaceae foram testados quanto ao aspecto tóxico-genético através do cromoteste-SOS. Nos testes realizados na ausência de metabolizaçäo, ambos alcalóides näo mostraram atividade genotóxica, sendo que a esquimianina apresentou um efeito citotóxico nas concentraçöes mais elevadas. Na presença de mistura de ativaçäo metabólica, a esquimianina mostrou-se genotóxica sendo que este efeito foi mais acentuado quando se empregou fraçäo microssomal induzida com Aroclor 1254 em relaçäo aquela induzida com 3-metilcolantreno