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1.
IUBMB Life ; 72(8): 1765-1779, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32449271

RESUMO

Parkinson's disease (PD) induced by environmental toxins involves a multifactorial cascade of harmful factors, thus motivating the search for therapeutic agents able to act on the greatest number of molecular targets. This study evaluated the efficacy of 50 mg/kg purified anacardic acids (AAs), isolated from cashew nut shell liquid, on multiple steps of oxidative stress and inflammation induced by rotenone in the substantia nigra (SN) and striatum. Adult mice were divided into four groups: Control, rotenone, AAs + rotenone, and AAs alone. Lipoperoxidation, nitric oxide (NO) levels, and reduced glutathione (GSH)/oxidized gluthatione (GSSG) ratio were evaluated. NF-kB-p65, pro-IL-1ß, cleaved IL-1ß, metalloproteinase-9, Tissue Inhibitory Factor-1 (TIMP-1), tyrosine hydroxylase (TH), and glial fibrillary acidic protein (GFAP) levels were assessed by Western blot. In silico studies were also made using the SwissADME web tool. Rotenone increased lipoperoxidation and NO production and reduced TH levels and GSH/GSSG ratio in both SN and striatum. It also enhanced NF-kB-p65, pro, and cleaved IL-1ß, MMP-9, GFAP levels compared to control and AAs groups. The AAs alone reduced pro-IL-1ß in the striatum while they augmented TIMP1 and reduced MMP-9 amounts in both regions. AAs reversed rotenone-induced effects on lipoperoxidation, NO production, and GSH/GSSG ratio, as well as increased TH and attenuated pro-IL-1ß and MMP-9 levels in both regions, NF-kB-p65 in the SN and GFAP in the striatum. Altogether, the in vivo and in silico analysis reinforced multiple and defined molecular targets of AAs, identifying that they are promising neuroprotective drug candidates for PD, acting against oxidative and inflammatory conditions induced by rotenone.


Assuntos
Ácidos Anacárdicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Praguicidas/toxicidade , Ácidos Anacárdicos/química , Ácidos Anacárdicos/isolamento & purificação , Animais , Simulação por Computador , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Proteína Glial Fibrilar Ácida/genética , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Humanos , Interleucina-1beta/genética , Peroxidação de Lipídeos/efeitos dos fármacos , Metaloproteinase 9 da Matriz/genética , Camundongos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/etiologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/patologia , Inibidor Tecidual de Metaloproteinase-1/genética , Fator de Transcrição RelA/genética , Tirosina 3-Mono-Oxigenase/genética
2.
Nat Prod Commun ; 10(4): 581-4, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25973481

RESUMO

Bufotenine (1, 5-hydroxy-N,N-dimethyltryptamine) was isolated from seeds of Anadenanthera spp., a tree widespread in the Brazilian cerrado, using an efficient acid-base shakeout protocol. The conversion of bufotenine into N,N-dimethyltryptamine (4) and 5-methoxy-N,N-dimethyltryptamine (5) was accomplished through an innovative and short approach featuring the use of novel bufotenine-aminoborane complex (7). Furthermore, an easy methodology for conversion of bufotenine into 5-hydroxy-N,N,N-trimethyltryptamine (6) was well-established. This is the first study that highlights bufotenine as a resource for the production of N,N-dimethyltryptamines for either pharmacological and toxicological investigations or for synthetic purposes.


Assuntos
Bufotenina/química , Fabaceae/química , Metoxidimetiltriptaminas/síntese química , N,N-Dimetiltriptamina/síntese química , Brasil , Metoxidimetiltriptaminas/química , Modelos Moleculares , Estrutura Molecular , N,N-Dimetiltriptamina/química , Sementes/química
3.
Eur J Med Chem ; 45(8): 3480-9, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20537433

RESUMO

This work is part of a large program, which seeks to discover new antitumor isobenfuranones designed from anacardic acids. The synthetic strategy for the construction of the title compounds takes into consideration the use of inexpensive anacardic acids (2), the major natural cashew (Anacardium occidentale) nut-shell phenolic lipid, and features one-pot construction of fused-ring aromatic gamma-lactones, phthalides. The cytotoxicity screening in different human cancer cell lines (HL-60 leukemia, SF295 glioblastoma and MDA-MB435 melanoma) by the MTT assay showed that acyclic precursor (6), and isobenfuranones (1a and 1b) are active compounds. Interestingly, 1a exhibits significant antiproliferative effect against HL-60 cells and moderate activity against SF295 and MDA-MB435 cell lines. Analysis of mechanisms involved in the cytotoxic activity showed that active compounds were leading to DNA damage, triggering apoptosis or necrosis induction.


Assuntos
Ácidos Anacárdicos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzofuranos/química , Benzofuranos/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Benzofuranos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Oxigênio/química
4.
Toxicon ; 56(3): 339-48, 2010 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-20381513

RESUMO

Cutaneous secretions of toad species are an important source of bufadienolides, compounds that exhibit interesting structural features and biopharmacological properties. Here we describe the isolation of bufadienolides from the Brazilian toad Rhinella schneideri parotoid glands secretion, including: marinobufagin (1), bufalin (2), telocinobufagin (3), hellebrigenin (4), and the atypical 20S,21R-epoxymarinobufagin (5) besides the widespread beta-sitosterol (6). Starting from natural bufadienolides four derivatives were prepared: 3beta-acetoxy-marinobufagin (7), 3beta-acetoxy-bufalin (8), 3beta-acetoxy-telocinobufagin (9), and 3beta-acetoxy-20S,21R-epoxymarinobufagin (10). The cytotoxic evaluation showed that all natural bufadienolides and their derivatives exhibited moderate to strong activity against human HL-60, SF-295, MDA-MB-435, and HCT-8 cancer cell strains without hemolysis of mouse erythrocytes. The acetylated bufadienolides (7-9) and the epoxide 10 showed lesser peripheral blood lymphocytes (PBLs) inhibitory activity than their precursors, suggesting that chemical modifications on such compounds can play an important role on the modulation of their cytotoxic profile.


Assuntos
Bufanolídeos/farmacologia , Glândula Parótida/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Cromatografia Líquida de Alta Pressão , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier
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