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[PMID]:28777979
[Au] Autor:Hu XR; Chou GX; Zhang CG
[Ad] Endereço:The MOE Key Laboratory of Standardization of Chinese Medicines, and SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People's Republic of China; Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai 201203, People's Republic of China.
[Ti] Título:Flavonoids, alkaloids from the seeds of Crotalaria pallida and their cytotoxicity and anti-inflammatory activities.
[So] Source:Phytochemistry;143:64-71, 2017 Nov.
[Is] ISSN:1873-3700
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Three flavonoids, cropalliflavones A-C, including two homoisoflavonoids with rare skeletons; three previously undescribed alkaloids, usaramine-N-oxide and cropallins A-B; and sixteen known compounds, were isolated from the seeds of Crotalaria pallida Ait. The absolute configurations of cropalliflavone A and usaramine-N-oxide were established by an ECD calculation and X-ray crystallography, respectively. Additionally, cropalliflavone B showed anti-proliferative activity against the MCF-7 cell line with an IC value of 6.77 µM, and cropalliflavone C showed anti-inflammatory activity, with an IC value of 16.07 µM.
[Mh] Termos MeSH primário: Alcaloides/isolamento & purificação
Alcaloides/farmacologia
Anti-Inflamatórios/isolamento & purificação
Anti-Inflamatórios/farmacologia
Crotalaria/química
Flavonoides/isolamento & purificação
Flavonoides/farmacologia
Sementes/química
[Mh] Termos MeSH secundário: Alcaloides/química
Anti-Inflamatórios/química
Cristalografia por Raios X
Flavonoides/química
Seres Humanos
Concentração Inibidora 50
Células MCF-7
Conformação Molecular
Estrutura Molecular
Alcaloides de Pirrolizidina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alkaloids); 0 (Anti-Inflammatory Agents); 0 (Flavonoids); 0 (Pyrrolizidine Alkaloids); XJ86XWL8IY (retrorsine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170805
[St] Status:MEDLINE


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[PMID]:28763475
[Au] Autor:Kasarapu P; Porto-Neto LR; Fortes MRS; Lehnert SA; Mudadu MA; Coutinho L; Regitano L; George A; Reverter A
[Ad] Endereço:CSIRO Agriculture and Food, Queensland Bioscience Precinct, St. Lucia, Brisbane, Queensland, Australia.
[Ti] Título:The Bos taurus-Bos indicus balance in fertility and milk related genes.
[So] Source:PLoS One;12(8):e0181930, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Numerical approaches to high-density single nucleotide polymorphism (SNP) data are often employed independently to address individual questions. We linked independent approaches in a bioinformatics pipeline for further insight. The pipeline driven by heterozygosity and Hardy-Weinberg equilibrium (HWE) analyses was applied to characterize Bos taurus and Bos indicus ancestry. We infer a gene co-heterozygosity network that regulates bovine fertility, from data on 18,363 cattle with genotypes for 729,068 SNP. Hierarchical clustering separated populations according to Bos taurus and Bos indicus ancestry. The weights of the first principal component were subjected to Normal mixture modelling allowing the estimation of a gene's contribution to the Bos taurus-Bos indicus axis. We used deviation from HWE, contribution to Bos indicus content and association to fertility traits to select 1,284 genes. With this set, we developed a co-heterozygosity network where the group of genes annotated as fertility-related had significantly higher Bos indicus content compared to other functional classes of genes, while the group of genes associated with milk production had significantly higher Bos taurus content. The network analysis resulted in capturing novel gene associations of relevance to bovine domestication events. We report transcription factors that are likely to regulate genes associated with cattle domestication and tropical adaptation. Our pipeline can be generalized to any scenarios where population structure requires scrutiny at the molecular level, particularly in the presence of a priori set of genes known to impact a phenotype of evolutionary interest such as fertility.
[Mh] Termos MeSH primário: Bovinos/genética
Fertilidade/genética
Leite
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Algoritmos
Animais
Cruzamento
Biologia Computacional
Frequência do Gene
Variação Genética
Genótipo
Heterozigoto
Fenótipo
Filogenia
Análise de Componente Principal
Alcaloides de Pirrolizidina/química
Especificidade da Espécie
Taurina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Pyrrolizidine Alkaloids); 1EQV5MLY3D (Taurine); T82SFG1584 (indicine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170802
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181930


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[PMID]:28712707
[Au] Autor:Ke Z; Su Z; Zhang X; Cao Z; Ding Y; Cao L; Ding G; Wang Z; Liu H; Xiao W
[Ad] Endereço:State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Pharmaceutical Co., Ltd., Jiangsu, Lianyungang 222001, China.
[Ti] Título:Discovery of a potent angiotensin converting enzyme inhibitor via virtual screening.
[So] Source:Bioorg Med Chem Lett;27(16):3688-3692, 2017 08 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Prompted by the prominent role of angiotensin converting enzyme (ACE) in hypertension, heart failures, myocardial infarction and diabetic nephropathy, we have attempted to discover novel ACE inhibitors through ligand-based virtual screening. Molecular docking method and rigorously validated model was utilized to search a natural compounds database. Finally, 36 compounds were randomly selected and subjected to in vitro ACE kinase inhibitory assay using fluorescence assays method. The results showed that three compounds (Licochalcone A, Echinatin and EGCG) have strong potential to be developed as a new class of ACE inhibitors. Further chemical modification via fragment modifications guided by structure and ligand-based computational methodologies can lead to discover better agents as potential clinical candidates.
[Mh] Termos MeSH primário: Inibidores da Enzima Conversora de Angiotensina/química
Peptidil Dipeptidase A/metabolismo
[Mh] Termos MeSH secundário: Inibidores da Enzima Conversora de Angiotensina/metabolismo
Sítios de Ligação
Catequina/análogos & derivados
Catequina/química
Catequina/metabolismo
Chalconas/química
Chalconas/metabolismo
Avaliação Pré-Clínica de Medicamentos
Seres Humanos
Simulação de Acoplamento Molecular
Peptidil Dipeptidase A/química
Ligação Proteica
Estrutura Terciária de Proteína
Alcaloides de Pirrolizidina/química
Alcaloides de Pirrolizidina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Angiotensin-Converting Enzyme Inhibitors); 0 (Chalcones); 0 (Pyrrolizidine Alkaloids); 8R1V1STN48 (Catechin); BQM438CTEL (epigallocatechin gallate); EC 3.4.15.1 (Peptidyl-Dipeptidase A); JTV5467968 (licochalcone A); T82SFG1584 (indicine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE


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[PMID]:28650983
[Au] Autor:Liu W; Li X; Zhou B; Fang S; Ho W; Chen H; Liang H; Ye L; Tang J
[Ad] Endereço:Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, and Wuhan University School of Pharmaceutical Sciences, Wuhan, P. R. China.
[Ti] Título:Differential induction of apoptosis and autophagy by pyrrolizidine alkaloid clivorine in human hepatoma Huh-7.5 cells and its toxic implication.
[So] Source:PLoS One;12(6):e0179379, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Growing evidence suggests that the pyrrolizidine alkaloids (PAs)-induced hepatotoxicity is mediated by multiple cell death/defence modalities. However, the detailed mechanisms are still lacking. In this study, the hepatotoxic effects of four PAs including three retronecine-type ones (senecionine, seneciphylline and monocrotaline) and one otonecine-type (clivorine) on the proliferation of Huh-7.5 cells and the possible mechanisms were investigated. The results showed that all the PAs could inhibit cell proliferation and induce apoptosis in a concentration-dependent manner. Among them clivorine was the most significant one. In addition to its effect on apoptosis, clivorine treatment could promote autophagy in Huh-7.5 cells, as evidenced by the accumulation of autophagosomes, the enhancement of LC3B expression at the concentrations close to its IC0 value, and the increased conversion of LC3B-I to LC3B-II in the presence of lysosomal inhibitor (chloroquine) and decreased formation of green fluorescent protein (GFP)-LC3 positive puncta in the presence of autophagic sequestration inhibitor (3-methyladenine). Among the other tested PAs, senecionine and seneciphylline also activated autophagy at the same concentrations used for clivorine but monocrotaline did not. Furthermore, our study demonstrated that suppression or enhancement of autophagy resulted in the remarkable enhancement or suppression of senecionine, seneciphylline and clivorine-induced apoptosis at the concentration close to the IC10 for clivorine, respectively, indicating a protective role of autophagy against the PA-induced apoptosis at the low level of exposure. Collectively, our data suggest that PAs in different structures may exert different toxic disturbances on the liver cells. Apoptosis may be one of the most common models of the PA-induced cytotoxicity, while autophagy may be a structure-dependent defence model in the early stage of PA intoxication. Differential induction of apoptosis and autophagy probably depending on the concentration is essential for the cytotoxic potency of clivorine.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Autofagia/efeitos dos fármacos
Hepatócitos/efeitos dos fármacos
Alcaloides de Pirrolizidina/farmacologia
[Mh] Termos MeSH secundário: Carcinoma Hepatocelular/metabolismo
Linhagem Celular Tumoral
Hepatócitos/metabolismo
Seres Humanos
Neoplasias Hepáticas/metabolismo
Fagossomos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Pyrrolizidine Alkaloids); P180OM3SJM (clivorine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179379


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[PMID]:28558195
[Au] Autor:Rajarathinam B; Kumaravel K; Vasuki G
[Ad] Endereço:Department of Chemistry, Pondicherry University , Puducherry 605 014, India.
[Ti] Título:"In Water": Organocatalyzed Diastereoselective Multicomponent Reactions toward 2-Azapyrrolizidine Alkaloid Scaffolds.
[So] Source:ACS Comb Sci;19(7):455-463, 2017 Jul 10.
[Is] ISSN:2156-8944
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Synthesis of the 2-aza analogues of pyrrolizidine and spirooxindole-2-azapyrrolizidine hybrid, a spiro-tetracyclic scaffold possessing multiple contiguous stereocenters, by an exclusive regio-, chemo-, and diastereoselective multicomponent reaction in water is reported. This logical and didactical tactic has integrated the principles of an ideal organic synthesis, privileged substructure-based diversity-oriented synthesis, and biology-oriented synthesis to access hybrid heterocyclic scaffolds.
[Mh] Termos MeSH primário: Compostos Aza/síntese química
Alcaloides de Pirrolizidina/síntese química
Água/química
[Mh] Termos MeSH secundário: Catálise
Ciclização
Estrutura Molecular
Solubilidade
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aza Compounds); 0 (Pyrrolizidine Alkaloids); 059QF0KO0R (Water)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170531
[St] Status:MEDLINE
[do] DOI:10.1021/acscombsci.7b00038


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[PMID]:28551239
[Au] Autor:Martinello M; Borin A; Stella R; Bovo D; Biancotto G; Gallina A; Mutinelli F
[Ad] Endereço:National Reference Laboratory for Beekeeping, Istituto Zooprofilattico Sperimentale delle Venezie, Padova, Italy. Electronic address: mmartinello@izsvenezie.it.
[Ti] Título:Development and validation of a QuEChERS method coupled to liquid chromatography and high resolution mass spectrometry to determine pyrrolizidine and tropane alkaloids in honey.
[So] Source:Food Chem;234:295-302, 2017 Nov 01.
[Is] ISSN:0308-8146
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Awareness about pyrrolizidine alkaloids (PAs) and tropane alkaloids (TAs) in food was recently raised by the European Food Safety Authority stressing the lack of data and gaps of knowledge required to improve the risk assessment strategy. The present study aimed at the elaboration and validation of a method to determine PAs and TAs in honey. QuEChERS sample treatment and liquid chromatography coupled to hybrid high resolution mass spectrometry, were used. The method resulted in good linearity (R >0.99) and low limits of detection and quantification, ranging from 0.04 to 0.2µgkg and from 0.1 to 0.7µgkg respectively. Recoveries ranged from 92.3 to 114.8% with repeatability lying between 0.9 and 15.1% and reproducibility between 1.1 and 15.6%. These performances demonstrate the selectivity and sensitivity of the method for simultaneous trace detection and quantification of PAs and TAs in honey, verified through the analysis of forty commercial samples.
[Mh] Termos MeSH primário: Contaminação de Alimentos/análise
Mel/análise
Alcaloides de Pirrolizidina/análise
Tropanos/análise
[Mh] Termos MeSH secundário: Cromatografia Líquida
Reprodutibilidade dos Testes
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Pyrrolizidine Alkaloids); 0 (Tropanes)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170529
[St] Status:MEDLINE


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[PMID]:28487121
[Au] Autor:van de Schans MGM; Blokland MH; Zoontjes PW; Mulder PPJ; Nielen MWF
[Ad] Endereço:RIKILT Wageningen University & Research, P.O. Box 230, 6700 AE, Wageningen, The Netherlands. Electronic address: milou.vandeschans@wur.nl.
[Ti] Título:Multiple heart-cutting two dimensional liquid chromatography quadrupole time-of-flight mass spectrometry of pyrrolizidine alkaloids.
[So] Source:J Chromatogr A;1503:38-48, 2017 Jun 23.
[Is] ISSN:1873-3778
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Pyrrolizidine alkaloids (PAs) and their and the corresponding N-oxides (PAs-ox) are genotoxic plant metabolites which can be present as unwanted contaminants in food products of herbal origin like tea and food supplements. PAs and PAs-ox come in a wide variety of molecular structures including many structural isomers. For toxicity assessment it is important to determine the composition of a sample and to resolve all isomeric PAs and PAs-ox, which is currently not possible in one liquid or gas chromatographic (LC or GC) run. In this study an online two dimensional liquid chromatography quadrupole time-of-flight mass spectrometry (2D-LC QToF-MS) method was developed to resolve isomeric PAs and PAs-ox. After comprehensive column and mobile phase selection a polar endcapped C column was used at pH 3 in the first dimension, and a cross-linked C column at pH 10 in the second dimension. Injection solvents, column IDs, flow rates and temperatures were carefully optimized. The method with column selection valve switching described in this study was able to resolve and visualize 20 individual PAs/PAs-ox (6 sets of isomers) in one 2D-LC QToF-MS run. Moreover, it was shown that all isomeric PAs/PAs-ox could be unambiguously annotated. The method was shown to be applicable for the determination and quantification of isomeric PAs/PAs-ox in plant extracts and could be easily extended to include other PAs and PAs-ox.
[Mh] Termos MeSH primário: Técnicas de Química Analítica/métodos
Cromatografia Líquida
Tecnologia de Alimentos/métodos
Espectrometria de Massas
Alcaloides de Pirrolizidina/química
[Mh] Termos MeSH secundário: Extratos Vegetais/química
Alcaloides de Pirrolizidina/análise
Alcaloides de Pirrolizidina/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Plant Extracts); 0 (Pyrrolizidine Alkaloids)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170511
[St] Status:MEDLINE


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[PMID]:28418776
[Au] Autor:He X; Xia Q; Fu PP
[Ad] Endereço:a National Center for Toxicological Research , US Food and Drug Administration , Jefferson , Arkansas , USA.
[Ti] Título:7-Glutathione-pyrrole and 7-cysteine-pyrrole are potential carcinogenic metabolites of pyrrolizidine alkaloids.
[So] Source:J Environ Sci Health C Environ Carcinog Ecotoxicol Rev;35(2):69-83, 2017 Apr 03.
[Is] ISSN:1532-4095
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Many pyrrolizidine alkaloids (PAs) are hepatotoxic, genotoxic, and carcinogenic phytochemicals. Metabolism of PAs in vivo generates four (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-DNA adducts that have been proposed to be responsible for PA-induced liver tumor formation in rats. In this present study, we determined that the same set of DHP-DNA adducts was formed upon the incubation of 7-glutathione-DHP and 7-cysteine-DHP with cultured human hepatocarcinoma HepG2 cells. These results suggest that 7-glutathione-DHP and 7-cysteine-DHP are reactive metabolites of PAs that can bind to cellular DNA to form DHP-DNA adducts in HepG2 cells, and can potentially initiate liver tumor formation.
[Mh] Termos MeSH primário: Carcinógenos/toxicidade
Cisteína/análogos & derivados
Glutationa/análogos & derivados
Pirróis/toxicidade
Alcaloides de Pirrolizidina/toxicidade
[Mh] Termos MeSH secundário: Animais
Cisteína/metabolismo
Cisteína/toxicidade
Adutos de DNA
Glutationa/metabolismo
Glutationa/toxicidade
Alcaloides de Pirrolizidina/metabolismo
Ratos
Ratos Endogâmicos F344
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (7-cysteine-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine); 0 (7-glutathione-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine); 0 (Carcinogens); 0 (DNA Adducts); 0 (Pyrroles); 0 (Pyrrolizidine Alkaloids); GAN16C9B8O (Glutathione); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.1080/10590501.2017.1298358


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[PMID]:28406050
[Au] Autor:Chung SWC; Lam ACH
[Ad] Endereço:a Food and Environmental Hygiene Department , Food Research Laboratory , Hong Kong (SAR), China.
[Ti] Título:Investigation of pyrrolizidine alkaloids including their respective N-oxides in selected food products available in Hong Kong by liquid chromatography electrospray ionisation mass spectrometry.
[So] Source:Food Addit Contam Part A Chem Anal Control Expo Risk Assess;34(7):1184-1192, 2017 Jul.
[Is] ISSN:1944-0057
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:This study determined the levels of pyrrolizidine alkaloids (PAs), including their respective N-oxides, in foodstuffs available in Hong Kong by liquid chromatography-electrospray ionisation tandem mass spectrometry. A total of 234 samples (48 food items) were collected randomly from a local market and analysed. About 50% of samples were found to contain detectable amount of PAs. Amongst the 48 food items, PAs were not detected in 11 food items, including barley flour, beef, cattle liver, pork, pig liver, chicken meat, chicken liver, milk, non-fermented tea, Melissa tea and linden tea. For those found to contain detectable PAs, the summed PA content ranged up to 11,000 µg kg . The highest sum of PA content among the 37 food items calculated with lower bound was cumin seed, then followed by oregano, tarragon and herbs de Provence with ranges of 2.5-11,000, 1.5-5100, 8.0-3300 and 18-1300 µg kg respectively. Among the samples, the highest sum of PA content was detected in a cumin seed sample (11,000 µg kg ), followed by an oregano (5100 µg kg ), a tarragon (3300 µg kg ) and a herbs de Provence (1300 µg kg ). In general, the results of this study agreed well with other published results in peer-reviewed journals, except that the total PAs in honey and specific tea infusion in this study were comparatively lower.
[Mh] Termos MeSH primário: Contaminação de Alimentos/análise
Óxidos/análise
Alcaloides de Pirrolizidina/análise
Alcaloides de Pirrolizidina/química
[Mh] Termos MeSH secundário: Cromatografia Líquida
Hong Kong
Espectrometria de Massas por Ionização por Electrospray
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Oxides); 0 (Pyrrolizidine Alkaloids)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170414
[St] Status:MEDLINE
[do] DOI:10.1080/19440049.2017.1319579


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[PMID]:28379594
[Au] Autor:Neuman MG; Cohen LB; Steenkamp V
[Ad] Endereço:In Vitro Drug Safety & Biotechnology, Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. manuela.neuman@utoronto.ca.
[Ti] Título:Pyrrolizidine alkaloids enhance alcohol-induced hepatocytotoxicity in vitro in normal human hepatocytes.
[So] Source:Eur Rev Med Pharmacol Sci;21(1 Suppl):53-68, 2017 Mar.
[Is] ISSN:2284-0729
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Herbal remedies containing pyrrilidozine alkaloids (PA)s can induce liver damage, including hepato-sinusoidal obstruction syndrome (HSOS) or veno-occlusive liver disease (VOD). Some individuals misusing alcohol consume also teas and/or herbal remedies containing PA. The interaction or additive toxicity of alcohol to PA toxicity needs to be addressed. The objectives of this study are 1) to review the scientific literature on the PA-induced liver toxicity; 2) identify possible mechanism(s) involved in PA-induced hepatocytotoxicity in the presence or absence of ethanol (EtOH) in vitro in normal human hepatocytes (NHH) in primary culture. To respond to the first objective, we systematically search all the literature engines (PubMed, Google Scholar) for liver induced damage due to PAs and summarize the results in an introductory systematic review. ORIGINAL ARTICLE EXPERIMENTAL DESIGN AND METHODS: Cells were exposed to one dose of 100 mmol/L EtOH for 24 hrs and to 2 doses of 100 mmol/L EtOH for consecutive 24 hrs periods, in the presence or absence of PAs (10 mg/mL), or the caspase-3 inhibitor IDN-1965 (50 µmol/L). Cells were analyzed for apoptosis by light microscopy, immuno-histochemistry, measuring cytokeratin-18 fragmentation, and transmission electron microscopy (TEM) (6000 cells/treatment). Cytotoxicity was determined using succinate dehydrogenase (SDH) activity, an enzyme specific to the mitochondria. RESULTS: In NHH cells, a 100 mmol/L dose of Et-OH resulted in 22±2.5 apoptosis (p<0.001 vs. control). Two consecutive doses of 100 mmol/L Et-OH for 24 hrs each caused 36±3.0% apoptosis (p<0.001 vs. control and p<0.05 vs. one dose Et-OH). Pre-treatment with 50 µmol/L caspase inhibitor significantly reduced Et-OH-induced apoptosis [12±1.5% in 100 mmol/L (p<0.05) and 20±4.0% in 2×100 mmol/L (p<0.001)]. In addition, pre-treatment with 50 µmol caspase inhibitor in cells treated with PA + EtOH reduced apoptosis significantly (vs. non-exposed to caspase-inhibitor): Δ -22±3.0 % (p<0.05). HPC significantly decreased apoptosis compared to conditions lacking this supplementation in cells treated with EtOH-exposed cells present ballooning, Mallory bodies, changes in mitochondrial cristae and apoptosis by TEM. Pre-treatment with 50 µmol caspase inhibitor significantly reduced 100 mmol/L EtOH-induced (one dose) in NHH by 14±0.5% (p<0.05) compared to cells not exposed to the caspase-inhibitor. In cells treated concomitantly with PA and EtOH 100 mM Mallory-bodies and apo-necrotic cells have been observed. Pre-treatment with 50 µmol caspase inhibitor reduced the mitochondrial damage. A significant depletion in glutathione (GSH) was observed in Et-OH treated cells after 1 and 2 treatments (p<0.001 vs. control). Treatment with Et-OH enhanced PA-induced GSH-depletion and resulted in a significant increase in PA-induced cytotoxicity (p<0.001 vs. Et-untreated cells). Exposure to EtOH increased the cell culture media levels of the pro-inflammatory cytokine TNF. PA + EtOH-treated cells increased TNF-α levels in media compared to EtOH alone [86±8 vs. 53±5 pg/mL in cells exposed to 100 mmol/L EtOH (p<0.05) and 218±14 vs. 179±8 pg/mL in cells exposed to 2×100 mmol/L EtOH (p<0.05)]. CONCLUSIONS: PA up-regulates EtOH-induced hepatocytotoxicity by inducing the inflammatory cytokines and enhancing the apoptotic effects of ethanol. There is a need for monitoring herbal medicine in order to optimize traditional medicine use and maximize the clinical benefits. Additionally, there is necessary to communicate to physicians the possible negative results of herbal remedies use. Also, the interactions between herbal remedies and drugs of misuse should be communicated to consumers.
[Mh] Termos MeSH primário: Etanol/toxicidade
Hepatócitos/efeitos dos fármacos
Alcaloides de Pirrolizidina
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Doença Hepática Induzida por Substâncias e Drogas
Seres Humanos
Indóis/farmacologia
Oligopeptídeos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Indoles); 0 (N-((1,3-dimethylindole-2-carbonyl)-valinyl)-3-amino-4-oxo-5-fluoropentanoic acid); 0 (Oligopeptides); 0 (Pyrrolizidine Alkaloids); 3K9958V90M (Ethanol)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170406
[St] Status:MEDLINE



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