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1.
Toxicon ; 191: 18-24, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33359390

RESUMO

Cylindrospermopsin (CYN) is a cyanotoxin of increasing worldwide environmental importance as it can harm human beings. Dexamethasone is a steroidal anti-inflammatory agent. Thus, we aimed at evaluating the pulmonary outcomes of acute CYN intoxication and their putative mitigation by dexamethasone. Male BALB/c mice received intratracheally a single dose of saline or CYN (140 µg/kg). Eighteen hours after exposure, mice instilled with either saline solution (Ctrl) or CYN were intramuscularly treated with saline (Tox) or 2 mg/kg dexamethasone (Tox + dexa) every 6 h for 48 h. Pulmonary mechanics was evaluated 66 h after instillation using the forced oscillation technique (flexiVent) to determine airway resistance (RN), tissue viscance (G) and elastance (H). After euthanasia, the lungs were removed and separated for quantification of CYN, myeloperoxidase activity and IL-6 and IL-17 levels plus histological analysis. CYN was also measured in the liver. CYN increased G and H, alveolar collapse, PMN cells infiltration, elastic and collagen fibers, activated macrophages, peroxidase activity in lung and hepatic tissues, as well as IL-6 and IL-17 levels in the lung. Tox + Dexa mice presented total or partial reversion of the aforementioned alterations. Briefly, CYN impaired pulmonary and hepatic characteristics that were mitigated by dexamethasone.


Assuntos
Alcaloides/toxicidade , Anti-Inflamatórios/uso terapêutico , Dexametasona/uso terapêutico , Animais , Fígado , Pulmão , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Função Respiratória
3.
Ecotoxicol Environ Saf ; 205: 111342, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32971455

RESUMO

Radix aconiti lateralis (Fuzi) is widely used in China as a traditional Chinese medicine for the treatment of asthenia, pain and inflammation. However, its toxic alkaloids often lead to adverse reactions. Currently, most of the toxicity studies on Fuzi are focused on the heart and nervous system, and more comprehensive toxicity studies are needed. In this study, based on the previous reports of Fuzi hepatotoxicity, serum pharmacochemistry and network toxicology were used to screen the potential toxic components of Heishunpian(HSP), a processed product of Fuzi, and to explore the possible mechanism of HSP-induced hepatotoxicity. The results obtained are expressed based on the toxicological evidence chain (TEC). It was found that 22 potential toxic components screened can affect Th17 cell differentiation, Jak-STAT signaling pathway, glutathione metabolism, and other related pathways by regulating AKT1, IL2, F2, GSR, EGFR and other related targets, which induces oxidative stress, metabolic disorders, cell apoptosis, immune response, and excessive release of inflammatory factors, eventually inducing liver damage in rats. This is the first study on HSP-induced hepatotoxicity based on the TEC concept, providing references for further studies on the toxicity mechanism of Fuzi.


Assuntos
Aconitum/química , Alcaloides/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Medicamentos de Ervas Chinesas/toxicidade , Modelos Biológicos , Alcaloides/sangue , Alcaloides/isolamento & purificação , Animais , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , China , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacocinética , Masculino , Medicina Tradicional Chinesa , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
4.
Toxicol Lett ; 331: 42-52, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32464236

RESUMO

Synthetic cathinones abuse remains a serious public health problem. Kidney injury has been reported in intoxications associated with synthetic cathinones, but the molecular mechanisms involved have not been explored yet. In this study, the potential in vitro nephrotoxic effects of four commonly abused cathinone derivatives, namely pentedrone, 3,4-dimethylmethcatinone (3,4-DMMC), methylone and 3,4-methylenedioxypyrovalerone (MDPV), were assessed in the human kidney HK-2 cell line. All four derivatives elicited cell death in a concentration- and time-dependent manner, in the following order of potency: 3,4-DMMC >> MDPV > methylone ≈ pentedrone. 3,4-DMMC and methylone were selected to further elucidate the mechanisms behind synthetic cathinones-induced cell death. Both drugs elicited apoptotic cell death and prompted the formation of acidic vesicular organelles and autophagosomes in HK-2 cells. Moreover, the autophagy inhibitor 3-methyladenine significantly potentiated cell death, indicating that autophagy may serve as a cell survival mechanism that protects renal cells against synthetic cathinones toxicity. Both drugs triggered a rise in reactive oxygen and nitrogen species formation, which was completely prevented by antioxidant treatment with N­acetyl­L­cysteine or ascorbic acid. Importantly, these antioxidant agents significantly aggravated renal cell death induced by cathinone derivatives, most likely due to their autophagy-blocking properties. Taken together, our results support an intricate control of cell survival/death modulated by oxidative stress, apoptosis and autophagy in synthetic cathinones-induced renal injury.


Assuntos
Alcaloides/toxicidade , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Drogas Ilícitas/toxicidade , Rim/efeitos dos fármacos , Alcaloides/química , Benzodioxóis/química , Benzodioxóis/toxicidade , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Rim/metabolismo , Rim/patologia , Metanfetamina/análogos & derivados , Metanfetamina/química , Metanfetamina/toxicidade , Metilaminas/química , Metilaminas/toxicidade , Pentanonas/química , Pentanonas/toxicidade , Pirrolidinas/química , Pirrolidinas/toxicidade , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo
5.
Toxicon ; 176: 21-29, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31965970

RESUMO

Larkspurs, lupines, and death camas can be acutely toxic to livestock and are serious poisonous plant problems in western North America. The toxicity of these plants depends on the composition and concentrations of the toxic alkaloids in the plants. In this study, goats and cows were dosed sub-lethal doses of larkspur, lupine, and death camas. Rumen contents and ocular fluid samples were collected, and simple extraction, sample preparation, and analytical methods were developed for the detection of toxic alkaloids in the rumen contents and ocular fluid samples. Toxic alkaloids were detected in the rumen contents and ocular fluid samples from the goats and cows dosed larkspur, lupine, and death camas. In addition, results from a case report where rumen contents were analyzed from a steer that was suspected to have died due to larkspur are reported. This demonstrates the utility of the methods described for the diagnosis of acute plant poisonings.


Assuntos
Alcaloides/toxicidade , Delphinium , Lupinus , Plantas Tóxicas/toxicidade , Rúmen , Zigadenus , Animais , Bovinos , Olho/química , Cabras , Intoxicação por Plantas/veterinária
6.
Lett Appl Microbiol ; 70(4): 318-325, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31951031

RESUMO

Fermentation is a traditional processing method that can impact the abundance of relevant components in Chinese herbal medicines. Huafeng Dan Yaomu was processed by fermentation. In this study, we investigated changes in toxic alkaloids using high-performance liquid chromatography and analysed the changes in microbial communities during fermentation of Huafeng Dan Yaomu by Illumina MiSeq platform. The results indicated that highly toxic alkaloid compounds including aconitine, mesaconitine and hypaconitine were decreased, whereas benzoylmesaconine and benzoylhypaconitine were increased during fermentation. The dominant bacterial genera in the raw material (day 0) were Bacillus (58·38%), Enterobacter (16·05%), Enterococcus (4·10%) and others (11·48%). After 7 days of fermentation, Pediococcus predominated, increasing from 98·26 to 99·97%. The dominant fungal genera in the raw material (day 0) were Incertae_Sedis_incertae_sedis (45·36%), Eurotiales_unclassified (20·63%), Millerozyma (15·58%) and Saccharomycopsis (10·64%). After 7 days of fermentation, Saccharomycopsis was increased to 90·84%. After 14 days of fermentation, Pichia became the main fungal genera in the fermentation process. There were 16 bacterial genera and seven fungal genera that displayed significant correlation with toxic alkaloids. The dynamics of the microbiota and chemical compounds during fermentation of Huafeng Dan Yaomu were revealed, providing a foundation for further investigation of the effects of microbes on chemical compounds and insights into the manufacturing of Huafeng Dan Yaomu. SIGNIFICANCE AND IMPACT OF THE STUDY: Huafeng Dan Yaomu is a unique fermentation-based micro-organism product. This study reveals that the change in toxic alkaloids during fermentation was related to micro-organisms. The results of this study can be used to improve the Chinese herb medicine fermentation process, such as the selection of beneficial strains and their composition for modern fermentation. The results of this study may also provide new ideas for the processing of Traditional Chinese Medicine.


Assuntos
Alcaloides/metabolismo , Bactérias/metabolismo , Medicamentos de Ervas Chinesas/metabolismo , Fungos/metabolismo , Plantas Medicinais/microbiologia , Alcaloides/análise , Alcaloides/toxicidade , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Medicamentos de Ervas Chinesas/análise , Fermentação , Fungos/classificação , Fungos/genética , Fungos/isolamento & purificação , Microbiota
7.
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
8.
Regul Toxicol Pharmacol ; 110: 104548, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31805361

RESUMO

Areca Nut (AN), the seed of tropical palm tree Areca catechu, is a widely chewed natural product with estimated 600 million users across the world. Various AN products, thriving in the market, portray 'Areca nut' or 'Supari' as mouth freshener and safe alternative to smokeless tobacco. Unfortunately, AN is identified as a Group 1 human carcinogen by International Agency for Research on Cancer (IARC). Wide variation in the level of alkaloids, broadly ranging from 2 to 10 mg/gm dry weight, is observed in diverse variety of AN sold worldwide. For the first time, various factors influencing the formation of carcinogenic alkaloids in AN at various stages, including during the growth, processing, and storage of the nut, are discussed. Current review illustrates the mechanism of cancer induction by areca alkaloids in humans and also compiles dose-dependent pharmacology and toxicology data of arecoline, the most potent carcinogenic alkaloid in AN. Careful monitoring of the arecoline content in AN can potentially be used as a tool in product surveillance studies to identify the variations in characteristics of various AN sample sold worldwide. The article will help to generate public awareness and sensitize the government bodies to initiate campaigns against AN use and addiction.


Assuntos
Alcaloides , Areca , Carcinógenos , Neoplasias/induzido quimicamente , Nozes , Alcaloides/farmacocinética , Alcaloides/farmacologia , Alcaloides/toxicidade , Animais , Areca/química , Carcinógenos/farmacocinética , Carcinógenos/farmacologia , Carcinógenos/toxicidade , Relação Dose-Resposta a Droga , Humanos , Neoplasias/metabolismo , Nozes/química
9.
Toxicol Mech Methods ; 30(2): 107-114, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31532267

RESUMO

In standard nonclinical drug safety evaluation studies, limitations exist in predicting the clinical risk of a drug based only on data from healthy animals. To obtain more comprehensive toxicological information on norisoboldine (NOR), we conducted an exploratory study using C57BL/6 mice in addition to healthy mice as models of dextran sodium sulfate (DSS) colitis to evaluate the safety of NOR. The healthy mice and DSS colitis mice were exposed to 30 or 90 mg NOR/kg body weight or water for 15 days. Compared with the model control group, 90 mg/kg of NOR aggravated the symptoms and colonic lesions of the DSS colitis mice and even caused death in two animals. No significant adverse effects were observed in the healthy mice. These different toxic reactions to NOR in the healthy and DSS colitis mice indicate that NOR toxicity varies by status among animals and suggests that the DSS colitis mouse model may be more susceptible, accurate and comprehensive in evaluating the safety of NOR. In conclusion, 90 mg/kg of NOR may be safe for healthy mice but not for DSS colitis mice. The DSS colitis mouse model, with many features similar to those of human colitis patients, may be a novel choice to counteract the deficiencies of using healthy mice to evaluate the safety of anti-inflammatory bowel disease (IBD) drugs, and further research is required.


Assuntos
Alcaloides/toxicidade , Colite/induzido quimicamente , Colo/efeitos dos fármacos , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Colite/sangue , Colite/patologia , Colo/imunologia , Colo/patologia , Relação Dose-Resposta a Droga , Marcação In Situ das Extremidades Cortadas , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Análise de Sobrevida
10.
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
11.
Genes (Basel) ; 10(11)2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31739571

RESUMO

Nicotine, the most abundant pyridine alkaloid in cultivated tobacco (Nicotiana tabacum L.), is a potent inhibitor of insect and animal herbivory and a neurostimulator of human brain function. Nicotine biosynthesis is controlled developmentally and can be induced by abiotic and biotic stressors via a jasmonic acid (JA)-mediated signal transduction mechanism involving members of the APETALA 2/ethylene-responsive factor (AP2/ERF) and basic helix-loop-helix (bHLH) transcription factor (TF) families. AP2/ERF and bHLH TFs work combinatorically to control nicotine biosynthesis and its subsequent accumulation in tobacco leaves. Here, we demonstrate that overexpression of the tobacco NtERF32, NtERF221/ORC1, and NtMYC2a TFs leads to significant increases in nicotine accumulation in T2 transgenic K326 tobacco plants before topping. Up to 9-fold higher nicotine production was achieved in transgenics overexpressing NtERF221/ORC1 under the control of a constitutive GmUBI3 gene promoter compared to wild-type plants. The constitutive 2XCaMV35S promoter and a novel JA-inducible 4XGAG promoter were less effective in driving high-level nicotine formation. Methyljasmonic acid (MeJA) treatment further elevated nicotine production in all transgenic lines. Our results show that targeted manipulation of NtERF221/ORC1 is an effective strategy for elevating leaf nicotine levels in commercial tobacco for use in the preparation of reduced risk tobacco products for smoking replacement therapeutics.


Assuntos
Nicotina/biossíntese , Reguladores de Crescimento de Planta/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Tabaco/metabolismo , Fatores de Transcrição/genética , Acetatos/metabolismo , Alcaloides/biossíntese , Alcaloides/toxicidade , Anabasina/biossíntese , Anabasina/toxicidade , Ciclopentanos/metabolismo , Etilenos/metabolismo , Regulação da Expressão Gênica de Plantas , Sequências Hélice-Alça-Hélice/genética , Nicotina/análogos & derivados , Nicotina/economia , Nicotina/toxicidade , Oxilipinas/metabolismo , Folhas de Planta/genética , Folhas de Planta/metabolismo , Plantas Geneticamente Modificadas/genética , Regiões Promotoras Genéticas/genética , Piridinas/toxicidade , Tabaco/genética , Produtos do Tabaco/economia , Produtos do Tabaco/toxicidade , Fatores de Transcrição/metabolismo
12.
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
13.
Toxins (Basel) ; 11(10)2019 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581717

RESUMO

Alkaloids have protective functions for plants and can play an important role in living organisms. Alkaloids may have a wide range of pharmacological activities. Many of them have cytotoxic activity. Nowadays, cancer has become a serious public health problem. Searching for effective drugs with anticancer activity is one of the most significant challenges of modern scientific research. The aim of this study was the investigation of cytotoxic activity of extracts obtained from Corydalis lutea root and herb, Dicentra spectabilis root and herb, Fumaria officinalis, Macleaya cordata leaves and herb, Mahonia aquifolia leaves and cortex, Meconopsis cambrica root and herb on FaDu, SCC-25, MCF-7, and MDA-MB-231 cancer cell lines. The cytotoxic activity of these extracts has not been previously tested for these cell lines. The aim was also to quantify selected alkaloids in the investigated extracts by High Performance Liquid Chromatography (HPLC). The analyses of alkaloid content were performed using HPLC in reversed phase (RP) mode using Polar RP column and mobile phase containing acetonitrile, water and ionic liquid (IL). Cytotoxic effect of the tested plant extracts and respective alkaloid standards were examined using human pharyngeal squamous carcinoma cells (FaDu), human tongue squamous carcinoma cells (SCC-25), human breast adenocarcinoma cell line (MCF-7), human triple-negative breast adenocarcinoma cell line (MDA-MB-231). All investigated plant extracts possess cytotoxic activity against tested cancer cell lines: FaDu, SCC-25, MCF-7, and MDA-MB-231. The highest cytotoxic activity against FaDu, SCC-25, and MCF-7 cell lines was estimated for Macleaya cordata leaf extract, while the highest cytotoxic activity against MDA-MB-231 cell line was obtained for Macleaya cordata herb extract. Differences in cytotoxic activity were observed for extracts obtained from various parts of investigated plants. In almost all cases the cytotoxic activity of investigated plant extracts, especially at the highest concentration against tested cell lines was significantly higher than the activity of anticancer drug etoposide. Our investigations exhibit that these plant extracts can be recommended for further in vivo experiments to confirm their anticancer activity.


Assuntos
Alcaloides , Antineoplásicos , Isoquinolinas , Magnoliopsida , Extratos Vegetais , Alcaloides/análise , Alcaloides/toxicidade , Antineoplásicos/análise , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Humanos , Isoquinolinas/análise , Isoquinolinas/toxicidade , Extratos Vegetais/análise , Extratos Vegetais/toxicidade , Espectrometria de Massas em Tandem
14.
Neurotoxicology ; 75: 158-173, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31473217

RESUMO

Synthetic cathinones also known as ß-keto amphetamines are a new group of recreational designer drugs. We aimed to evaluate the cytotoxic potential of thirteen cathinones lacking the methylenedioxy ring and establish a putative structure-toxicity profile using differentiated SH-SY5Y cells, as well as to compare their toxicity to that of amphetamine (AMPH) and methamphetamine (METH). Cytotoxicity assays [mitochondrial 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) reduction and lysosomal neutral red (NR) uptake] performed after a 24-h or a 48-h exposure revealed for all tested drugs a concentration-dependent toxicity. The rank order regarding the concentration that promoted 50 % of toxicity, at 24 h exposure, by the MTT assay was: 3,4-dimethylmethcathinone (3,4-DMMC) > METH > mephedrone ≈ α-pyrrolidinopentiophenone > AMPH ≈ methedrone > pentedrone > buphedrone ≈ flephedrone >α-pyrrolidinobutiophenone > methcathinone ≈ N-ethylcathinone >α-pyrrolidinopropiophenone >N,N-dimethylcathinone ≈ amfepramone. Apoptotic cell death signs were seen for all studied cathinones. 3,4-DMMC, methcathinone and pentedrone triggered autophagy activation, as well as increased reactive oxygen species production, and N-acetyl-L-cysteine (NAC) totally prevented that rise. Importantly, NAC was also able to prevent the cytotoxicity promoted by 6 tested drugs, ruling for an involvement of oxidative stress in the toxic events observed. The increased lipophilic chain on the alpha carbon, the presence and the high steric volume occupied by the substituents on the aromatic ring, and the substitution of the pyrrolidine ring by its secondary amine analogue have proved to be key points for the cytotoxicity profile of these cathinones. The structure-toxicity relationship established herein may enlighten future human relevant mechanistic studies, and future clinical approaches on intoxications.


Assuntos
Alcaloides/toxicidade , Anfetaminas/toxicidade , Neurônios/efeitos dos fármacos , Alcaloides/química , Anfetaminas/química , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Microscopia de Contraste de Fase , Neurônios/ultraestrutura , Propiofenonas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
15.
J Mol Cell Cardiol ; 136: 102-112, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31526813

RESUMO

The use of recreational drugs, including new psychoactive substances (NPS), is paralleled by emergency department visits of drug users with severe cardiotoxicity. Drug-induced cardiotoxicity can be the (secondary) result of increased norepinephrine blood concentrations, but data on potential drug-induced direct effects on cardiomyocyte function are scarce. The presence of hundreds of NPS therefore calls for efficient screening models to assess direct cardiotoxicity. We investigated effects of four reference compounds (3-30 nM dofetilide, nifedipine and isoproterenol, and 1-10 µM mexiletine) and six recreational drugs (0.01-100 µM cocaine, 0.01-1000 µM amphetamine, MDMA, 4-fluoroamphetamine, α-PVP and MDPV) on cardiomyocyte function (beat rate, spike amplitude and field potential duration (FPD ≈ QT interval in ECGs)), using Pluricyte® human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes cultured on ready-to-use CardioPlate™ multi-well microelectrode arrays (mwMEAs). Moreover, the effects of exposure to recreational drugs on cell viability were assessed. Effects of reference compounds were in accordance with the literature, indicating the presence of hERG potassium (dofetilide), sodium (mexiletine) and calcium (nifedipine) channels and α-adrenergic receptors (isoproterenol). All recreational drugs decreased the spike amplitude at 10-100 µM. All amphetamine-type stimulants and α-PVP decreased the beat rate at 300 µM, while cocaine and MDPV did so at 10 µM and 30 µM, respectively. All drugs increased the FPD, however at varying concentrations. MDMA, MDPV and amphetamine affected cardiomyocyte function at concentrations relevant for human exposure, while other drugs affected cardiomyocyte function only at higher concentrations (≥ 10 µM). Cell viability was only mildly affected at concentrations well above the lowest concentrations affecting cardiomyocyte function. We demonstrate that MEA recordings of hiPSC-derived cardiomyocytes enable screening for acute, direct effects on cardiomyocyte function. Our data further indicate that tachycardia in patients exposed to recreational drugs is likely due to indirect drug effects, while prolonged repolarization periods (prolonged QTc interval) could (partly) result from direct drug effects on cardiomyocyte function.


Assuntos
Cardiotoxicidade/etiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Drogas Ilícitas/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Psicotrópicos/toxicidade , Alcaloides/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cocaína/toxicidade , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/instrumentação , Humanos , Indóis/toxicidade , Células-Tronco Pluripotentes Induzidas , Síndrome do QT Longo/induzido quimicamente , Microeletrodos , Miócitos Cardíacos/metabolismo , Testes de Toxicidade/instrumentação , Testes de Toxicidade/métodos
16.
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
17.
Toxins (Basel) ; 11(8)2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430938

RESUMO

A study was undertaken to determine the effects of feeding two levels of perennial ryegrass alkaloids (nil vs. moderate) under two climatic conditions. Alkaloids were fed via endophyte-infected perennial ryegrass seed and hay. Twenty-four Merino ewe weaners (six months, initial BW 32 ± 1.7 kg) were used in a study that lasted for 21 days after 14 days of adaptation. Sheep were fed either a control or alkaloid (Alk, 110 µg/kg LW ergovaline and 75 µg/kg LW lolitrem B) supplemented diet. Sheep were exposed to either constant thermoneutral (TN, 21-22 °C, 49% RH) or mildly heated (HS, 33 °C 1000-1500 h, 28% relative humidity) conditions. Dietary Alk and HS reduced dry matter intake (DMI) (p < 0.001, p = 0.02, respectively) with the combination of both reducing DMI by 42%. Reductions in DMI resulted in a lower daily gain in the Alk treatment (p < 0.001). Feed digestibility was reduced in the combined treatment (p = 0.03). Rectal temperature, respiration rate, and skin temperature increased in the Alk treatment. Plasma prolactin concentrations were decreased by Alk and increased by mild HS. The data indicate that production is compromised in the presence of Alk and mild HS, with this effect being exacerbated by a combination of both.


Assuntos
Alcaloides/toxicidade , Temperatura Alta , Lolium/química , Prolactina/sangue , Taxa Respiratória/efeitos dos fármacos , Ração Animal/análise , Animais , Humanos , Ovinos
18.
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
19.
Mar Drugs ; 17(7)2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31330850

RESUMO

Pinnatoxins (PnTXs) are emerging neurotoxins that were discovered about 30 years ago. They are solely produced by the marine dinoflagellate Vulcanodinium rugosum, and may be transferred into the food chain, as they have been found in various marine invertebrates, including bivalves. No human intoxication has been reported to date although acute toxicity was induced by PnTxs in rodents. LD50 values have been estimated for the different PnTXs through the oral route. At sublethal doses, all symptoms are reversible, and no neurological sequelae are visible. These symptoms are consistent with impairment of central and peripheral cholinergic network functions. In fact, PnTXs are high-affinity competitive antagonists of nicotinic acetylcholine receptors (nAChRs). Moreover, their lethal effects are consistent with the inhibition of muscle nAChRs, inducing respiratory distress and paralysis. Human intoxication by ingestion of PnTXs could result in various symptoms observed in episodes of poisoning with natural nAChR antagonists. This review updates the available data on PnTX toxicity with a focus on their mode of action on cholinergic networks and suggests the effects that could be extrapolated on human physiology.


Assuntos
Dinoflagelados/química , Toxinas Marinhas/toxicidade , Antagonistas Nicotínicos/toxicidade , Paralisia/induzido quimicamente , Envenenamento/etiologia , Acetilcolina/metabolismo , Alcaloides/química , Alcaloides/toxicidade , Animais , Modelos Animais de Doenças , Humanos , Dose Letal Mediana , Toxinas Marinhas/química , Músculos/efeitos dos fármacos , Músculos/inervação , Músculos/metabolismo , Antagonistas Nicotínicos/química , Receptores Nicotínicos/metabolismo , Compostos de Espiro/química , Compostos de Espiro/toxicidade , Transmissão Sináptica/efeitos dos fármacos , Testes de Toxicidade Aguda
20.
Toxins (Basel) ; 11(8)2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357471

RESUMO

The increasing application of toxic plant substances to deter and fight ticks proves the need for investigations focused on the elucidation of their impact on the developmental stages and populations of these arthropods. We examined the course of embryogenesis and egg hatch in Hyalomma marginatum ticks under the effect of cytotoxic plant substances. The investigations demonstrated that the length of embryonic development of egg batches treated with 20 µL of a 0.1875% colchicine solution did not differ significantly from that in the control group. Colchicine caused the high mortality of eggs (16.3%) and embryos (9.7%), disturbances in larval hatch (8.1%), and lower numbers of normal larval hatches (65.6%). In 0.2% of the larvae, colchicine induced anomalies in the idiosoma (67.6%) and gnathosoma (22.5%) as well as composite anomalies (8.5%). The study demonstrates that cytotoxic compounds with an effect similar to that of colchicine can reduce tick populations and cause teratological changes, which were observed in the specimens found during field studies. Since there are no data on the toxic effects of active plant substances on other organisms and the risk of development of tick resistance, a strategy for the use of such compounds in tick control and the management of plant products should be developed.


Assuntos
Alcaloides/toxicidade , Colchicina/toxicidade , Citotoxinas/toxicidade , Ixodidae/efeitos dos fármacos , Animais , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Extremidades , Feminino , Ixodidae/embriologia , Ixodidae/crescimento & desenvolvimento , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Deformidades Congênitas dos Membros/induzido quimicamente , Masculino
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