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1.
J Agric Food Chem ; 68(5): 1169-1185, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31922733

RESUMO

Epichloë endophytes in forage grasses have attracted widespread attention and interest of chemistry researchers as a result of the various unique chemical structures and interesting biological activities of their secondary metabolites. This review describes the diversity of unique chemical structures of taxa from Epichloë endophytes and grass infected with Epichloë endophytes and demonstrates their reported biological activities. Until now, nearly 160 secondary metabolites (alkaloids, peptides, indole derivatives, pyrimidines, sesquiterpenoids, flavonoids, phenol and phenolic acid derivatives, aliphatic metabolites, sterols, amines and amides, and others) have been reported from Epichloë endophytes and grass infected with Epichloë endophytes. Among these, non-alkaloids account for half of the population of total metabolites, indicating that they also play an important role in Epichloë endophytes and grass infected with Epichloë endophytes. Also, a diverse array of secondary metabolites isolated from Epichloë endophytes and symbionts is a rich source for developing new pesticides and drugs. Bioassays disclose that, in addition to toxic alkaloids, the other metabolites isolated from Epichloë endophytes and symbionts have notable biological activities, such as antifungal, anti-insect, and phytotoxic activities. Accordingly, the biological functions of non-alkaloids should not be neglected in the future investigation of Epichloë endophytes and symbionts.


Assuntos
Alcaloides/metabolismo , Endófitos/química , Epichloe/química , Poaceae/microbiologia , Simbiose , Alcaloides/química , Alcaloides/toxicidade , Animais , Endófitos/fisiologia , Epichloe/metabolismo , Insetos/efeitos dos fármacos , Gado/metabolismo , Poaceae/fisiologia
2.
J Chem Ecol ; 45(11-12): 914-925, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31802386

RESUMO

Frogs in the genus Phyllobates are known for the presence of batrachotoxin, a highly toxic alkaloid, in their skin. Nevertheless, Phyllobates frogs from Costa Rica and Panama (P. lugubris and P. vittatus) are considered non-toxic, as they have been reported to harbor low concentrations of this alkaloid. However, the potential toxicity of Central American Phyllobates has not been assessed experimentally. Our goal was to determine the toxicity of the whole skin of P. vittatus, an endemic species from the Southeastern Pacific region of Costa Rica. We performed median lethal dose (LD50) tests in mice to determine general toxicity, and an irritant assay based on the behavioral responses of mice to subcutaneous injection, to determine differences in irritability, as a measure of toxicity, among three study localities. Using UPLC-ESI-QTOF, we obtained chemical profiles of the methanolic extract of frog skins. Due to the absence of mortality at the studied doses, we were unable to estimate LD50. However, we recorded a list of toxicity symptoms in mice that are consistent with cardiotoxic effects, and found that mice presented more symptoms at higher concentrations of skin extracts during the first hour of the LD50 assays, recovering completely at all doses by the end of the assay. On the other hand, we did not detect differences in irritability among studied localities. Additionally, we putatively identified three toxic alkaloids (Batrachotoxinin A, DHQ 251A and Lehm 275A). This study provides the first experimental data on the toxicity and associated symptoms in mice, as well as the chemical profile of the skin of P. vittatus. We suggest that the skin alkaloids of P. vitattus may confer a chemical defense towards predators.


Assuntos
Alcaloides/análise , Alcaloides/toxicidade , Anuros/fisiologia , Misturas Complexas/análise , Misturas Complexas/toxicidade , Pele/química , Animais , Cromatografia Líquida de Alta Pressão/métodos , Simulação por Computador , Costa Rica , Bases de Dados de Compostos Químicos , Feminino , Dose Letal Mediana , Camundongos Endogâmicos ICR , Venenos/análise , Venenos/toxicidade , Espectrometria de Massas em Tandem/métodos
3.
PLoS Negl Trop Dis ; 13(10): e0007740, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31603908

RESUMO

Schistosomiasis is a serious worldwide parasitic disease. One of the best ways to control schistosomiasis is to control the population of Oncomelania hupensis snails. We sought to identify a high-efficiency biogenic molluscicide against Oncomelania with low toxicity, to avoid chemical molluscicide contamination and toxicity in aquatic organisms. We extracted quaternary benzo[c]phenanthridine alkaloids (QBAs) from Macleaya cordata fruits. Molluscicidal activity of the QBAs against Oncomelania was determined using bioassay. Our results showed that the extracted QBAs had a strong molluscicidal effect. In treatment of O. hupensis with QBAs for 48 h and 72 h, the lethal concentration (LC50) was 2.89 mg/L and 1.29 mg/L, respectively. The molluscicidal activity of QBAs was close to that of niclosamide (ethanolamine salt), indicating that QBAs have potential development value as novel biogenic molluscicides. We also analyzed physiological toxicity mechanisms by examining the activity of several important detoxification enzymes. We measured the effect of the extracted QBAs on the activities of glutathione S-transferase (GST), carboxylesterase (CarE), acid phosphatase (ACP), and alkaline phosphatase (AKP) in the liver of O. hupensis. We found that the effects of QBAs on detoxification metabolism in O. hupensis were time and concentration dependent. The activities of GST, CarE, AKP, and ACP in the liver of snails increased significantly in the early stage of treatment (24 h), but decreased sharply in later stages (120 h), compared with these activities in controls. GST, CarE, AKP, and ACP activity in the liver of snails treated with LC50 QBAs for 120 h decreased by 62.3%, 78.1%, 59.2%, and 68.6%, respectively. Our results indicate that these enzymes were seriously inhibited by the extracted QBAs and the detoxification and metabolic functions of the liver gradually weakened, leading to poisoning, which could be the main cause of death in O. hupensis snails.


Assuntos
Alcaloides/toxicidade , Frutas/química , Gastrópodes/efeitos dos fármacos , Moluscocidas/toxicidade , Papaveraceae/química , Fenantridinas/toxicidade , Extratos Vegetais/toxicidade , Fosfatase Ácida/efeitos dos fármacos , Fosfatase Ácida/metabolismo , Fosfatase Alcalina/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Animais , Carboxilesterase/efeitos dos fármacos , Carboxilesterase/metabolismo , China , Glutationa Transferase/efeitos dos fármacos , Glutationa Transferase/metabolismo , Inativação Metabólica/efeitos dos fármacos , Fígado/metabolismo , Esquistossomose/prevenção & controle , Esquistossomose/transmissão
4.
Ecotoxicol Environ Saf ; 182: 109448, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31398781

RESUMO

The electrocoagulation (EC) technique is an alternative method of isolating natural products with the advantage of minimizing the amounts of organic solvents required for this process, which are often harmful to the environment. In this research, the EC and the conventional solvent extraction methods were used in the isolation of Stemona alkaloids from the aerial parts of Stemona aphylla. A comparison was made between the amounts of the isolated alkaloids and the solvents used. The isolated alkaloids were evaluated for their larvicidal, ovicidal and oviposition-deterrent activities against the dengue vector, Aedes aegypti. The morphology and histopatology of the alkaloid treated larvae were also investigated. Two Stemona alkaloids, (2'S)-hydroxystemofoline and stemofoline, were isolated from both the EC and the conventional method. The amounts of (2'S)-hydroxystemofoline from the EC method was about the same as that obtained from the conventional method. However, the amounts of stemofoline obtained from the EC method were about two times larger than those obtained from the conventional method. Importantly, the EC method required six times less total organic solvents. The larvicidal activity assays of (2'S)-hydroxystemofoline and stemofoline showed that these were highly effective against Aedes aegypti larvae with LC50 values of 3.91 µg/ml and 4.35 µg/ml, respectively. Whereas, the crude EC extract (LC50 = 11.86 µg/ml) showed greater larvicidal activity than the crude extract obtained from the conventional extraction method (LC50 = 53.40 µg/ml). The morphological observations of the (2'S)-hydroxystemofoline and the stemofoline treated larvae revealed that the anal gills were the sites of aberrations. A histopathological study showed that larvae treated with these alkaloids had cytopathological alterations to the epithelial cells of the midgut. At a concentration 40 µg/ml (2'S)-hydroxystemofoline showed 100% ovicidal activity on 24 h old eggs while stemofoline showed 97.2%. Furthermore, the oviposition-deterrent effects of (2'S)-hydroxystemofoline and stemofoline, at a concentration of 80 µg/ml were 99.5% and 97.2%, respectively.


Assuntos
Aedes/efeitos dos fármacos , Alcaloides/toxicidade , Controle de Mosquitos/métodos , Componentes Aéreos da Planta/química , Extratos Vegetais/toxicidade , Stemonaceae/química , Animais , Dengue/transmissão , Vetores de Doenças , Eletrocoagulação , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Mosquitos Vetores , Oviposição/efeitos dos fármacos
5.
PLoS One ; 14(7): e0218406, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291287

RESUMO

Linden (Tilia spp.), a profusely flowering temperate tree that provides bees with vital pollen and nectar, has been associated with bumble bee (Bombus spp.) mortality in Europe and North America. Bee deaths have been attributed, with inadequate evidence, to toxicity from mannose in nectar or starvation due to low nectar in late blooming linden. Here, we investigated both factors via untargeted metabolomic analyses of nectar from five T. cordata trees beneath which crawling/dead bumble bees (B. vosnesenskii) were observed, and of thoracic muscle of 28 healthy foraging and 29 crawling bees collected from linden trees on cool mornings (< 30°C). Nectar contained the pyridine alkaloid trigonelline, a weak acetylcholinesterase inhibitor, but no mannose. Principal component analysis of muscle metabolites produced distinct clustering of healthy and crawling bees, with significant differences (P<0.05) in 34 of 123 identified metabolites. Of these, TCA (Krebs) cycle intermediates were strongly represented (pathway analysis; P<0.01), suggesting that the central metabolism is affected in crawling bees. Hence, we propose the following explanation: when ambient temperature is low, bees with energy deficit are unable to maintain the thoracic temperature required for flight, and consequently fall, crawl, and ultimately, die. Energy deficit could occur when bees continue to forage on linden despite limited nectar availability either due to loyalty to a previously energy-rich source or trigonelline-triggered memory/learning impairment, documented earlier with other alkaloids. Thus, the combination of low temperature and nectar volume, resource fidelity, and alkaloids in nectar could explain the unique phenomenon of bumble bee mortality associated with linden.


Assuntos
Alcaloides/metabolismo , Abelhas/fisiologia , Néctar de Plantas/metabolismo , Tilia/metabolismo , Alcaloides/toxicidade , Animais , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/toxicidade , Comportamento Alimentar , Metaboloma , Músculos/fisiologia , Néctar de Plantas/toxicidade , Tilia/toxicidade
6.
Molecules ; 24(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261913

RESUMO

A novel strategy was developed to identify hepatotoxic compounds in traditional Chinese medicines (TCMs). It is based on the exposure of HL-7702 cells to a TCM extract, followed by the identification and further determination of potential hepatotoxic compounds accumulated in the cells by liquid chromatography-tandem mass spectrometry (LC-MS/MS). As a case study, potential hepatotoxic components in Chelidonium majus L. were screened out. Five alkaloids (sanguinarine, coptisine, chelerythrine, protopine, and chelidonine) were identified by LC-MS/MS within 10 min, and their intracellular concentrations were first simultaneously measured by LC-MS/MS with a run time of 4 min. A cell viability assay was performed to assess the cytotoxicity of each alkaloid. With their higher intracellular concentrations, sanguinarine, coptisine, and chelerythrine were identified as the main hepatotoxic constituents in Ch. majus. The study provides a powerful tool for the fast prediction of cytotoxic components in complex natural mixtures on a high-throughput basis.


Assuntos
Alcaloides/análise , Alcaloides/toxicidade , Chelidonium/química , Fígado/citologia , Benzofenantridinas/análise , Benzofenantridinas/toxicidade , Berberina/análogos & derivados , Berberina/análise , Berberina/toxicidade , Alcaloides de Berberina/análise , Alcaloides de Berberina/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Avaliação Pré-Clínica de Medicamentos , Humanos , Isoquinolinas/análise , Isoquinolinas/toxicidade , Fígado/química , Fígado/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Espectrometria de Massas em Tandem , Testes de Toxicidade
7.
Mar Drugs ; 17(6)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151240

RESUMO

So far, the Futuna Islands located in the Central Indo-Pacific Ocean have not been inventoried for their diversity in marine sponges and associated chemical diversity. As part of the Tara Pacific expedition, the first chemical investigation of the sponge Narrabeena nigra collected around the Futuna Islands yielded 18 brominated alkaloids: seven new bromotryptamine derivatives 1-7 and one new bromotyramine derivative 8 together with 10 known metabolites of both families 9-18. Their structures were deduced from extensive analyses of nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) data. In silico metabolite anticipation using the online tool MetWork revealed the presence of a key and minor biosynthetic intermediates. These 18 compounds showed almost no cytotoxic effect up to 10 µM on human neuroblastoma SH-SY5Y and microglia BV2 cells, and some of them exhibited an interesting neuroprotective activity by reducing oxidative damage.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Poríferos/química , Alcaloides/isolamento & purificação , Alcaloides/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Humanos , Internet , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Oceano Pacífico , Clima Tropical
8.
Toxicol Lett ; 311: 91-97, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31054355

RESUMO

Phytomedicinal preparations containing extracts of the plant Chelidonium majus (Greater Celandine) have been used in the therapy of upper abdominal disorders. C. majus alkaloids (CAL) were suspected to be responsible for reported cases of liver symptoms including cases of acute liver failure in patients upon treatment with certain C. majus preparations. Based on these reports, a safe oral daily dose limit of not more than 2.5 mg CAL was established in the EU. However, C. majus extracts and individual CAL were not able to elicit similar adverse effects when given orally to pigs or rats. We found that CAL differ considerably in their cytotoxicity in rat hepatocytes in culture. The cationic congeners chelerythrine, coptisine and sanguinarine were the most toxic ones (EC20 values ≤2 µM) while the neutral congeners chelidonine, dihydrosanguinarine and protopine were less toxic, with a rank order of toxicity of coptisine > chelerythrine > sanguinarine > chelidonine > protopine > dihydrosanguinarine. Calculation of octanol-water partition coefficients revealed that the most cytotoxic CAL in hepatocytes were the cationic polar ones. At cytotoxic concentrations sanguinarine led to a marked decrease in reduced and oxidized intracellular glutathione while the much less cytotoxic dihydrosanguinarine did not. After glutathione depletion with menadione, CAL toxicity was only slightly enhanced. Comparison of the cytotoxic concentrations to reported liver levels in experimental animals suggests that the latter were too low to cause hepatotoxicity, probably due to an extremely low oral availability of certain CAL.


Assuntos
Alcaloides/toxicidade , Chelidonium/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hepatócitos/efeitos dos fármacos , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Benzofenantridinas/toxicidade , Berberina/análogos & derivados , Berberina/toxicidade , Células Cultivadas , Chelidonium/química , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Hepatócitos/metabolismo , Hepatócitos/patologia , Isoquinolinas/toxicidade , Masculino , Estrutura Molecular , Cultura Primária de Células , Ratos Wistar , Relação Estrutura-Atividade
9.
Sci Justice ; 59(3): 234-247, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31054814

RESUMO

The emergence of new psychoactive substances (NPS) has raised many issues in the context of law enforcement and public drug policies. In this scenario, interdisciplinary studies are crucial to the decision-making process in the field of criminal science. Unfortunately, information about how NPS affect people's health is lacking even though knowledge about the toxic potential of these substances is essential: the more information about these drugs, the greater the possibility of avoiding damage within the scope of a harm reduction policy. Traditional analytical methods may be inaccessible in the field of forensic science because they are relatively expensive and time-consuming. In this sense, less costly and faster in silico methodologies can be useful strategies. In this work, we submitted computer-calculated toxicity values of various amphetamines and cathinones to an unsupervised multivariate analysis, namely Principal Component Analysis (PCA), and to the supervised techniques Soft Independent Modeling of Class Analogy and Partial Least Square-Discriminant Analysis (SIMCA and PLS-DA) to evaluate how these two NPS groups behave. We studied how theoretical and experimental values are correlated by PLS regression. Although experimental data was available for a small amount of molecules, correlation values reproduced literature values. The in silico method efficiently provided information about the drugs. On the basis of our findings, the technical information presented here can be used in decision-making regarding harm reduction policies and help to fulfill the objectives of criminal science.


Assuntos
Alcaloides/toxicidade , Anfetaminas/toxicidade , Simulação por Computador , Psicotrópicos/toxicidade , Testes de Toxicidade/métodos , Animais , Análise Discriminante , Toxicologia Forense , Redução do Dano , Humanos , Interações Hidrofóbicas e Hidrofílicas , Análise dos Mínimos Quadrados , Dose Letal Mediana , Camundongos , Estrutura Molecular , Análise Multivariada , Análise de Componente Principal , Ratos , Análise de Regressão
10.
Phytomedicine ; 60: 152832, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31031043

RESUMO

BACKGROUND: Successful cancer chemotherapy is hampered by resistance of cancer cells to established anticancer drugs. Numerous natural products reveal cytotoxicity towards tumor cells. PURPOSE: The present study was aimed to determine the cytotoxicity of a betaine-type alkaloid, ungeremine, towards 9 cancer cell lines including various sensitive and drug-resistant phenotypes. The mode of action of this compound was further investigated. METHODS: The cytotoxicity, ferroptotic and necroptotic cell death were determined by the resazurin reduction assay. Caspase activation was evaluated using the caspase-Glo assay. Flow cytometry was applied for the analysis of cell cycle analysis (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA). Apoptotic, necroptotic and autophagic markers were determined by Western blotting. CCRF-CEM leukemia cells were used for all mechanistic studies. RESULTS: Ungeremine displayed cytotoxic activity towards the 9 cancer cell lines tested, including drug-sensitive and MDR phenotypes. The IC50values obtained varied from 3.67 µM (in MDA-MB-231-BCRP breast carcinoma cells) to 75.24 µM (against in CEM/ADR5000 leukemia cells) for ungeremine and from 0.02 µM (against CCRF-CEM cells) to 122.96 µM (against CEM/ADR5000 cells) for doxorubicin (control drug). Ungeremine induced ferroptosis, necroptosis, autophagy as well as apoptosis mediated by caspase activation, MMP alteration and increase ROS production. CONCLUSION: The present investigation showed that ungeremine is a promising cytotoxic compoundthat could be further explored in the future to develop new anticancer drugs to fight sensitive and resistant phenotypes.


Assuntos
Alcaloides/toxicidade , Alcaloides de Amaryllidaceae/toxicidade , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Indolizinas/toxicidade , Extratos Vegetais/toxicidade , Alcaloides de Amaryllidaceae/química , Antineoplásicos Fitogênicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Indolizinas/química , Extratos Vegetais/química , Espécies Reativas de Oxigênio/metabolismo
11.
J Ethnopharmacol ; 238: 111866, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30970283

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The seeds of Peganum harmala Linn, in which the most abundant active compounds are harmaline and harmine, have been widely used as a traditional medicine in various countries to treat a broad spectrum of diseases including asthma, cough, depression, Parkinson's and Alzheimer's diseases. However, few studies on long-term or subchronic toxicity of seeds of P. harmala were reported after overdose. AIM OF THE STUDY: To investigate the subchronic toxicity and concomitant toxicokinetics of total alkaloid extracts from seeds of P. harmala (TAEP) after oral administration for four weeks in rats. MATERIALS AND METHODS: The subchronic toxicity and concomitant toxicokinetics of TAEP were evaluated after 28-day oral administration in rats at daily dose levels of 15, 45, and 150 mg/kg. The signs of toxicity and mortality were monitored and recorded daily. The body weight and average food consumption were measured weekly. The analyses of hematology, biochemistry, urine, relative organ weights and histopathology were conducted at the termination of treatment and recovery phase. For concomitant toxicokinetics study, the plasma toxicokinetic parameters, tissue distribution, and excretion of predominant ingredients harmaline and harmine in TAEP and metabolites harmalol and harmol were tested. RESULTS: Following initial repeated exposure to high-dose (150 mg/kg/day) of TAEP excitotoxic reaction, such as tremor, was observed, but tolerated on the fourth day after multiple dosing. The significant alterations in blood glucose and lipid metabolism in liver were observed, but recovered after four weeks of drug withdrawal. The no-observed-adverse-effect level (NOAEL) of TAEP was considered to be 45 mg/kg/day under the present study conditions. There were no significant gender differences in most indexes of subchronic toxicity throughout the experimental period with the exception of food consumption and body weight. In concomitant toxicokinetics study, the alterations of dynamic characteristic for harmaline, harmine and metabolite harmol after multiple oral administration at three doses had been observed. Harmaline, harmine and metabolites harmalol and harmol were widely distributed in organs and there was no accumulation in the tissues examined. The reduction of harmaline and metabolite harmalol in brain after multiple dosing at dose of 150 mg/kg might be closely related to the tremor tolerance. The main excretory pathway for metabolites harmalol and harmol was urinary excretion via kidney. CONCLUSIONS: The results revealed that TAEP at doses of 15 and 45 mg/kg/day in rats might be safe. Excitotoxic reaction such as tremor occurred initially at dose of 150 mg/kg/day, however, the toxicity was tolerant and reversible. In addition, harmaline and harmine in TAEP had a quick absorption into blood and metabolized to harmalol and harmol, and there was no drug accumulation in the detected tissues. Further studies should be investigated to clarify the mechanisms of tremor tolerance and neurotoxicity of TAEP.


Assuntos
Alcaloides/farmacocinética , Alcaloides/toxicidade , Peganum , Extratos Vegetais/farmacocinética , Extratos Vegetais/toxicidade , Administração Oral , Animais , Feminino , Alcaloides de Harmala/sangue , Masculino , Ratos Wistar , Sementes , Testes de Toxicidade Subcrônica , Toxicocinética , Tremor/induzido quimicamente
12.
Forensic Sci Int ; 298: 1-9, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30870699

RESUMO

Current trend of novel psychoactive substances (NPS) among teenagers is posing new clinical, scientific and forensic societal questions. Synthetic cathinones are among the most consumed groups of NPS appearing on the street market and internet on a regular basis. The properties of these substances change regularly, due to structural modification to circumvent legislation. This practice makes almost impossible to characterize its toxicological profiles on an acceptable time scale, mostly due to the time-consuming experiments that must be held in animal models or human cells by standard methods. Such an issue demands the development of a rapid and inexpensive methodology to be used as a high-throughput screening of cathinones' toxicity. The yeast Saccharomyces cerevisiae shares highly conserved molecular and cellular mechanisms with human cells and has been used before for pharmacological drugs. In the present work it is proposed to use S. cerevisiae growth curves as a high throughput screening method to profile synthetic cathinones toxicity in a short time scale. The results obtained by S. cerevisiae growth curves analysis were compared to differentiated SH-SY5Y human neuronal cells and similar responses were found. The screening tool methodology has shown able to prioritize the most toxics NPS and can be useful for early warning programs on NPS.


Assuntos
Alcaloides/toxicidade , Drogas Desenhadas/toxicidade , Ensaios de Triagem em Larga Escala/métodos , Testes de Toxicidade , Diferenciação Celular , Linhagem Celular , Sobrevivência Celular , Humanos , Modelos Biológicos , Neurônios/efeitos dos fármacos , Saccharomyces cerevisiae
13.
Toxicon ; 161: 33-39, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30826472

RESUMO

Larkspurs (Delphinium spp.) are native perennial plants that have a serious toxic potential to cattle on foothill and mountain rangelands in the western United States. Livestock death due to larkspur toxicity is attributed to norditerpenoid alkaloids. Diagnosing plant poisonings in livestock is often challenging. The objective of this study was to evaluate the use of three matrices; earwax, oral fluid, and nasal mucus, as noninvasive specimens to determine livestock exposure to larkspurs. Reversed phase high performance liquid chromatography - high resolution mass spectrometry was used to analyze for norditerpene alkaloids, in all three matrices, in cattle administered a single dose of larkspur. Earwax, oral fluid, and nasal mucus were collected over 6 days post-dosing. Methyllycaconitine (MLA) and deltaline concentrations in earwax ranged from 0.4 ±â€¯0.1 to 0.2 ±â€¯0.06 and 0.6 ±â€¯0.5 to 0.11 ±â€¯0.08 ng/mg, respectively. MLA and deltaline concentrations in oral fluid ranged from 0.08 ±â€¯0.03 to 0.01 ±â€¯0.002 ng/mg and 0.07 ±â€¯0.03 ng/mg to not detected (ND), respectively. MLA and deltaline concentrations in nasal mucus ranged from 0.2 ±â€¯0.13 to 0.03 ±â€¯0.01 ng/mg and 0.2 ±â€¯0.12 ng/mg to ND, respectively. The ability to detect differing norditerpene alkaloid chemotypes from two different Delphinium spp. was also possible in the three matrices. This study demonstrates the potential of earwax, oral fluid, and nasal mucus as noninvasive specimens for chemical analyses to aid in the diagnosis of livestock that may have been exposed to and poisoned by larkspur plants.


Assuntos
Aconitina/análogos & derivados , Doenças dos Bovinos/diagnóstico , Doenças dos Bovinos/etiologia , Delphinium/envenenamento , Diterpenos/toxicidade , Intoxicação por Plantas/veterinária , Aconitina/análise , Aconitina/química , Aconitina/toxicidade , Alcaloides/análise , Alcaloides/química , Alcaloides/toxicidade , Animais , Bovinos , Cromatografia Líquida de Alta Pressão , Diterpenos/análise , Diterpenos/química , Gado , Masculino , Intoxicação por Plantas/diagnóstico , Plantas Tóxicas , Manejo de Espécimes/veterinária , Estados Unidos
14.
J Agric Food Chem ; 67(13): 3670-3678, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30860836

RESUMO

Imidazole alkaloids represent a rather small group of alkaloids and are assumed not to be of significance to the human food chain so far. In this study, novel imidazole alkaloids occurring in tomato products were synthesized and structurally characterized by nuclear-magnetic-resonance spectroscopy and high-resolution mass spectrometry. These alkaloids are amides of either histidinol or histamine and short-chain fatty acids and could be quantitated in all of the 28 analyzed tomato products using a newly developed and validated LC-MS/MS-based method. Levels ranged from approximately 5 µg/kg to almost 3 mg/kg in the analyzed tomato products, and N-caprylhistidinol and its putative isomer were shown to occur in the highest amounts. These imidazole alkaloids are thus regularly ingested in considerable amounts as part of the human diet. In the course of evaluating their effects on the viability of HT-29 cells, all compounds were shown to significantly reduce cell viability starting at concentrations of 100 µM.


Assuntos
Alcaloides/química , Alcaloides/toxicidade , Imidazóis/química , Imidazóis/toxicidade , Lycopersicon esculentum/química , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida/métodos , Frutas/química , Células HT29 , Humanos , Espectrometria de Massas em Tandem/métodos
15.
J Anim Sci ; 97(3): 1415-1423, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30772897

RESUMO

Cattle losses from larkspur (Delphinium spp.) toxicity are a long-term challenge on the rangelands of western North America. In addition to animal factors that affect livestock poisonings, plant alkaloid composition (chemotype) affects the intoxication of cattle because some chemotypes are significantly more toxic. Differences in larkspur chemotype toxicity are due to the ratios of N-(methylsuccinimido) anthranoyllycoctonine (MSAL)-type alkaloids to non-MSAL-type alkaloids and the concentrations of those alkaloids in the plant material. The objective of this study was to compare the responses of 6 Angus heifers to 6 chemotypes of larkspur using a Latin square study design. These Angus heifers from the USDA-ARS, Meat Animal Research Center in Clay Center, NE, were chosen for this research because they are the most larkspur-susceptible cattle observed to date. The 6 heifers were given an oral dose of dried ground larkspur and tested for muscle weakness with an exercise test (i.e., walk time). The 6 chemotypes of larkspur had non-MSAL to MSAL-type alkaloid ratios ranging from 1.4:1 to 6:1 and were administered at an oral dose of 7.5 mg/kg MSAL-type alkaloids BW. There was a treatment effect due to larkspur chemotype (P < 0.0001), and period effects were not significant (P = 0.6). There were also significant correlations between the length of time walking on a dirt track at 5 to 6 km/h, and total alkaloid dose (r = -0.92, P = 0.0045) and alkaloid ratio (r = -0.81, P = 0.0258). Serum alkaloid concentrations at 24 h after dosing were representative of the relative abundance of the alkaloid in the plant material. Results from this work suggest that total alkaloid concentrations in combination with alkaloid ratios can be used together to accurately predict the plant risk component of larkspur poisoning to grazing cattle. Animal factors such as cattle age, breed, and sex must also be considered to comprehensively manage larkspur risk.


Assuntos
Alcaloides/química , Doenças dos Bovinos/etiologia , Delphinium/química , Intoxicação por Plantas/veterinária , Alcaloides/toxicidade , Animais , Bovinos , Delphinium/toxicidade , Feminino , América do Norte , Plantas Tóxicas
16.
Anal Biochem ; 569: 10-15, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30639284

RESUMO

A novel method for non-target screening of toxicants in poisonous honey was established in this study. Poisonous honey and nontoxic honey were contrastive detected using liquid chromatography quadrupole-time-of-flight mass spectrometry and analyzed by Mass Profiler Professional Software. 4 poisonous alkaloids were screened out and confirmed by comparison with reference compounds. In order to investigate the source of these poisonous alkaloids, 6 poisonous alkaloids, ubiquitous in Gelsemium elegan, from honey, honeybees, pollen in honeycomb and different organs of Gelsemium elegan, were quantified by liquid chromatography triple-quadrupole tandem mass spectrometry. The results showed that alkaloids composition characteristics in honey, honeybees, and pollen were similar to those in the flower and bud of Gelsemium elegan and significant different from those in leave, stem and root. This result demonstrated that poisonous alkaloids in honey were come from the gathering honey process. This strategy provided an efficient and rapid method for non-target screening of toxicants in food.


Assuntos
Mel/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Alcaloides/análise , Alcaloides/toxicidade , Cromatografia Líquida de Alta Pressão , Gelsemium/química , Gelsemium/metabolismo , Pólen/química , Testes de Toxicidade
17.
Toxicol Lett ; 305: 10-18, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30639578

RESUMO

Aconitine (AC) and mesaconitine (MA) are major bioactive diterpenoid alkaloids derived from herbal aconitum plants. Emerging evidence indicates that AC plays a pivotal role in the cardiotoxicity for aconite poisoning. However, the cardiotoxicity data of MA, especially those on the difference between AC and MA are quite limited. Zebrafish embryos were used in this study for toxicological screening, and the cardiac morphology and function were observed. Embryos were analyzed by means of high-performance liquid chromatography (HPLC) after exposure and pharmacokinetic behaviors were also investigated. Results showed that 1.5% of the aconitum alkaloids penetrated into the zebrafish embryos. 2.5 µg/L AC and 20 µg/L MA caused a deficient cardiovascular system with yolk sac hemorrhage and early cardiac dysfunctions were observed in 96 h post-fertilization. AC showed greater cardiotoxicity than MA by comparing the EC50 of pericardium edema. Aconitum alkaloids exposure also resulted in a significant decrease in the expression of cardiac genes (Tbx5, Gata4, and Nkx2.5) from an early stage (12-24 hpf), which may partly explained that the death caused by aconitum is most likely to occur within the first 24 h. In addition, a high percentage of apoptotic cells was observed in the brain region, which identified another potential target of the DDA action in zebrafish embryos.


Assuntos
Aconitum/química , Alcaloides/toxicidade , Apoptose/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Coração/efeitos dos fármacos , Aconitina/análogos & derivados , Aconitina/toxicidade , Aconitum/envenenamento , Alcaloides/química , Animais , Coração/embriologia , Estrutura Molecular , Peixe-Zebra/embriologia
18.
Psychopharmacology (Berl) ; 236(3): 1107-1117, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30276421

RESUMO

RATIONALE: Synthetic cathinones ("bath salts") are ß-ketone analogs of amphetamines, yet few studies have examined their potential neurotoxic effects. OBJECTIVE: In the current study, we assessed the persistent behavioral and neurochemical effects of exposure to the second-generation synthetic cathinone α-pyrrolidinopropiophenone (α-PPP). METHODS: Male, Swiss-Webster mice were exposed to α-PPP (80 mg/kg) using a binge-like dosing regimen (QID, q2h). Behavior was assessed 4-5 days after the dosing regimen, and neurochemistry was assessed the following day. Behavior was studied using the elevated plus maze, Y-maze, and novel object recognition tests. Regional levels of dopamine, serotonin, norepinephrine, and the major dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the prefrontal cortex and striatum using high-pressure liquid chromatography. Additional experiments assessed the time courses of the effects of α-PPP on locomotor activity and core temperature using telemetry. RESULTS: Exposure to α-PPP significantly impaired performance in the Y-maze, decreased overall exploratory activity in the novel object recognition test, and resulted in regionally specific depletions in monoamine neurochemistry. In contrast, it had no significant effect on elevated plus maze performance or object discrimination in the novel object recognition test. The locomotor-stimulant effects of α-PPP were comparable to cocaine (30 mg/kg), and α-PPP (80 mg/kg) did not induce hyperthermia. CONCLUSIONS: α-PPP exposure results in persistent changes in exploratory behavior, spatial working memory, and monoamine neurochemistry. This research highlights potential dangers of α-PPP, including potential neurotoxicity, and suggests that the mechanisms underlying the persistent untoward effects of the cathinones may be distinct from those of the amphetamines.


Assuntos
Alcaloides/toxicidade , Corpo Estriado/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Propiofenonas/toxicidade , Pirrolidinas/toxicidade , /efeitos dos fármacos , Animais , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Norepinefrina/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Serotonina/metabolismo
19.
J Pharm Pharmacol ; 71(2): 260-269, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30303245

RESUMO

OBJECTIVES: To assess the antiplasmodial activity of the ethanol extract of Xylopia sericea leaves, Annonaceae, often associated with antimalarial use and to perform a bioguided isolation of active compounds. METHODS: Dereplication of ethanol extract by the UPLC-DAD-ESI-MS/MS technique allowed the identification of the major constituents, isolation and identification of alkaloids. The antiplasmodial and cytotoxic activity of the extract, fractions and isolated compounds was evaluated against the chloroquine-resistant W2 strain Plasmodium falciparum and HepG2 cells, respectively. KEY FINDINGS: Ethanol extract showed high reduction of parasitemia as well as moderate cytotoxicity (86.5 ± 3.0% growth inhibition at 50 µg/ml and CC50 72.1 ± 5.1 µg/ml, respectively). A total of eight flavonoids were identified, and two aporphine alkaloids, anonaine and O-methylmoschatoline, were isolated. Anonaine disclosed significant antiplasmodial effect and moderate cytotoxicity (IC50 23.2 ± 2.7 µg/ml, CC50 38.3 ± 2.3 µg/ml, SI 1.6) while O-methylmoschatoline was not active against P. falciparum and showed a low cytotoxicity (33.5 ± 1.9% growth inhibition at 50 µg/ml, CC50 274.4 ± 0.5 µg/ml). CONCLUSIONS: Characterization of Xylopia sericea leaves ethanol extract by UPLC-DAD-ESI-MS/MS as well as its antiplasmodial activity and the occurrence of anonaine and O-methylmoschatoline in this Xylopia species are reported by the first time.


Assuntos
Alcaloides/farmacologia , Antimaláricos/farmacologia , Extratos Vegetais/farmacologia , Xylopia/química , Alcaloides/isolamento & purificação , Alcaloides/toxicidade , Antimaláricos/isolamento & purificação , Antimaláricos/toxicidade , Aporfinas/isolamento & purificação , Aporfinas/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Dioxóis/isolamento & purificação , Dioxóis/farmacologia , Etanol/química , Células Hep G2 , Humanos , Concentração Inibidora 50 , Extratos Vegetais/administração & dosagem , Extratos Vegetais/toxicidade , Folhas de Planta , Plasmodium falciparum/efeitos dos fármacos , Espectrometria de Massas em Tandem/métodos
20.
Toxicol Lett ; 301: 79-89, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30465810

RESUMO

New psychoactive substances (NPS) are still an emerging issue in clinical and forensic toxicology. Information about their cytotoxic potential is limited or even unavailable before distribution and thus their intake can be of high risk for consumers. The aim of the presented study was to develop a strategy to identify cytotoxic potential of NPS based on a high content screening assay (HCSA) using HepG2 cell line and four fluorescent dyes, namely Hoechst33342, TMRM, CAL-520, and TOTO-3. The HCSA was optimized to work without an automated analyzer by using the model compounds fluvastatin, paracetamol, propranolol, and simvastatin. The following parameters were monitored: stained nuclei as a measure for cell count as well as nuclear size and nuclear intensity (all Hoechst33342), mitochondrial membrane potential (TMRM), cytosolic calcium level (CAL-520), and plasma membrane integrity (TOTO-3). The present study showed strong cytotoxic potential for the NPS 5F-PB-22 and MDAI, moderate effects for MDMA, MDPV, methylone, cathinone, 4-MEC, and mephedrone, and no toxic effects for methamphetamine. To assess the metabolic suitability of HepG2 cells under the chosen conditions, cell culture supernatants were analyzed by liquid chromatography-high resolution-tandem mass spectrometry. Metabolites were merely detected for lipophilic drugs such as 5F-PB-22 and MDPV and in addition with a much lower abundance in comparison to the parent compound but the study only allowed a qualitative look for metabolites and the used liver cell line might not ideal when considering metabolism.


Assuntos
Bioensaio , Testes de Toxicidade , Acetaminofen/análise , Alcaloides/toxicidade , Cromatografia Líquida , Corantes Fluorescentes/análise , Fluvastatina/análise , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Indanos/toxicidade , Indóis/toxicidade , Potencial da Membrana Mitocondrial , Metanfetamina/análogos & derivados , Metanfetamina/toxicidade , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Propranolol/análise , Quinolinas/toxicidade , Sinvastatina/análise , Espectrometria de Massas em Tandem
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