Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 300
Filtrar
1.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502054

RESUMO

Equol (7-hydroxy-3-(4'-hydroxyphenyl)-chroman, EQ), one of the major intestinally derived metabolites of daidzein, the principal isoflavane found in soybeans and most soy foods, has recently attracted increased interest as a health-beneficial compound for estrogen-dependent diseases. However, based on its structure with two p-substituted phenols, this study aimed to examine whether EQ is a substrate for tyrosinase and whether it produces o-quinone metabolites that are highly cytotoxic to melanocyte. First, the tyrosinase-catalyzed oxidation of EQ was performed, which yielded three EQ-quinones. They were identified after being reduced to their corresponding catechols with NaBH4 or L-ascorbic acid. The binding of the EQ-quinones to N-acetyl-L-cysteine (NAC), glutathione (GSH), and bovine serum albumin via their cysteine residues was then examined. NAC and GSH afforded two mono-adducts and one di-adduct, which were identified by NMR and MS analysis. It was also found that EQ was oxidized to EQ-di-quinone in cells expressing human tyrosinase. Finally, it was confirmed that the EQ-oligomer, the EQ oxidation product, exerted potent pro-oxidant activity by oxidizing GSH to the oxidized GSSG and concomitantly producing H2O2. These results suggest that EQ-quinones could be cytotoxic to melanocytes due to their binding to cellular proteins.


Assuntos
Equol/metabolismo , Melanócitos/efeitos dos fármacos , Oxidantes/toxicidade , Quinonas/toxicidade , Cisteína/análogos & derivados , Cisteína/metabolismo , Glutationa/metabolismo , Células HEK293 , Humanos , Monofenol Mono-Oxigenase/metabolismo , Oxidantes/metabolismo , Ligação Proteica , Quinonas/metabolismo , Soroalbumina Bovina/metabolismo
2.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361004

RESUMO

This article reviews evidence suggesting that a common mechanism of initiation leads to the development of many prevalent types of cancer. Endogenous estrogens, in the form of catechol estrogen-3,4-quinones, play a central role in this pathway of cancer initiation. The catechol estrogen-3,4-quinones react with specific purine bases in DNA to form depurinating estrogen-DNA adducts that generate apurinic sites. The apurinic sites can then lead to cancer-causing mutations. The process of cancer initiation has been demonstrated using results from test tube reactions, cultured mammalian cells, and human subjects. Increased amounts of estrogen-DNA adducts are found not only in people with several different types of cancer but also in women at high risk for breast cancer, indicating that the formation of adducts is on the pathway to cancer initiation. Two compounds, resveratrol, and N-acetylcysteine, are particularly good at preventing the formation of estrogen-DNA adducts in humans and are, thus, potential cancer-prevention compounds.


Assuntos
Acetilcisteína/farmacologia , Carcinogênese/efeitos dos fármacos , Estradiol/farmacologia , Estrona/farmacologia , Quinonas/farmacologia , Resveratrol/farmacologia , Animais , Antioxidantes/farmacologia , Carcinogênese/genética , Adutos de DNA , Estradiol/toxicidade , Estrogênios/farmacologia , Estrogênios/toxicidade , Estrona/toxicidade , Humanos , Quinonas/toxicidade
3.
Chem Res Toxicol ; 32(12): 2509-2516, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31687807

RESUMO

Polybrominated diphenyl ethers (PBDEs) have been detected ubiquitously in biological and environmental samples. Growing epidemiological data suggested the obvious correlation of PBDEs exposure with adverse health outcomes toward human beings, but exact molecular mechanism(s) are limited. Especially, the toxicological information regarding PBDEs metabolites is missing. Thereafter, this study intends to explore unidentified cell death modalities caused by PBDEs reactive quinone-type metabolite, PBDEQ. We found that PBDEQ induces autophagy in an ROS-dependent manner. Interestingly, the results indicated that PBDEQ degraded ferritin and activated a selective autophagy (termed as ferritinophagy) by using NCOA4 as its cargo receptor. These processes may further promote the release of iron and ROS. These results suggested the incidence of ferritinophagy induced by PBDEQ, which may contribute to PBDE exposure-caused diseases and dysfunctions.


Assuntos
Autofagia/efeitos dos fármacos , Ferritinas/metabolismo , Éteres Difenil Halogenados/toxicidade , Coativadores de Receptor Nuclear/metabolismo , Quinonas/toxicidade , Animais , Ferroptose/efeitos dos fármacos , Ferro/metabolismo , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo
4.
Free Radic Biol Med ; 137: 169-180, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31026584

RESUMO

Quinones are a common motif in many biological compounds, and have been linked to tissue damage as they can undergo redox cycling to generate radicals, and/or act as Michael acceptors with nucleophiles, such as protein Cys residues, with consequent adduct formation. The kinetics and consequences of these Michael reactions are poorly characterized. In this study we hypothesized that adduction of protein Cys residues with quinones would be rapid, structure-dependent, quantitatively-significant, and result in altered protein structure and function. Multiple quinones were incubated with glyceraldehyde-3-phosphate dehydrogenase (GAPDH), creatine kinase (CK), papain, bovine (BSA) and human (HSA) serum albumins, with the kinetics of adduction and effects on protein structure and activity determined. Adduction rate constants at Cys residues, which were dependent on the quinone and protein structure, and thiol pKa, are in the range 102-105 M-1 s-1. p-Benzoquinone (BQ) induced dimerization of GAPDH and CK (but not BSA, HSA, or papain) in a dose- and time-dependent manner. Incubation of purified proteins, or cell lysates, with quinones resulted in a rapid loss of GAPDH and CK activity; this loss correlated well with the rate constant for Cys adduction. Glutathione (GSH) reacts competitively with quinones, and could reverse the loss of activity and dimerization of GAPDH and CK. Mass spectrometry peptide mass mapping provided evidence for BQ adduction to GAPDH to specific Cys residues (Cys149, Cys244), whereas all Cys residues in CK were modified. These data suggested that quinones can induce biological effects by rapid and selective formation of adducts with Cys residues in proteins.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Proteínas/química , Quinonas/química , Animais , Bovinos , Cisteína/química , Cisteína/metabolismo , Dimerização , Humanos , Cinética , Espectrometria de Massas , Oxirredução , Proteínas/metabolismo , Quinonas/toxicidade
5.
Appl Microbiol Biotechnol ; 103(8): 3317-3326, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30895364

RESUMO

A vast array of plant-based compounds has enriched red biotechnology to serve the human health and food. A peculiar medicinal plant which was an element of traditional Chinese medicine for centuries as a liver and kidney tonic, for life longevity and hair blackening, is Polygonum multiflorum Thunb. (PM) which is popularly known as "He shou wu" or "Fo-ti" and is rich in chemical components like stilbenes, quinones, and flavonoids which have been used as anti-aging, anti-alopecia, anti-cancer, anti-oxidative, anti-bacterial, anti-hyperlipidemia, anti-atherosclerosis, and immunomodulating and hepatoprotective agents in the modern medicine. The health benefits from PM are attained since long through commercial products such as PM root powder, extract, capsules, tincture, shampoo, and body sprays in the market. Currently, the production of these pharmaceuticals and functional foods possessing stilbenes, quinones, and flavonoids is through cell and organ cultures to meet the commercial demand. However, hepatotoxic effects of PM-based products are the stumbling blocks for its long-term usage. The current review encompasses a comprehensive account of bioactive compounds of PM roots, their biological activities as well as efficacy and toxicity issues of PM ingredients and future perspectives.


Assuntos
Biotecnologia , Medicamentos de Ervas Chinesas/farmacologia , Fallopia multiflora/química , Biotecnologia/tendências , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/toxicidade , Fallopia multiflora/metabolismo , Flavonoides/química , Flavonoides/metabolismo , Flavonoides/farmacologia , Flavonoides/toxicidade , Humanos , Medicina Tradicional Chinesa , Estrutura Molecular , Raízes de Plantas/química , Quinonas/química , Quinonas/metabolismo , Quinonas/farmacologia , Quinonas/toxicidade , Estilbenos/química , Estilbenos/metabolismo , Estilbenos/farmacologia , Estilbenos/toxicidade
6.
Toxicol Lett ; 306: 25-34, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30742880

RESUMO

Autophagy, which works to remove stress and maintain cellular homeostasis, is usually considered a "pro-survival" signal. Contrarily, apoptosis is programmed "pro-death" machinery. Polychlorinated biphenyls (PCBs) are a group of ubiquitous industrial pollutants. Our previous studies illustrated that a PCB quinone metabolite, PCB29-pQ, elicited both autophagy and apoptosis. However, the signaling underlying the autophagy and apoptosis cross-talk has not been characterized. Here, we found that PCB29-pQ-induced autophagy mainly occurred at a lower concentration (5 µM), while apoptosis mostly arose at a higher concentration (15 µM) in HepG2 cells. Next, we demonstrated the elevation of intracellular calcium levels and calpain activity with PCB29-pQ treatment; however, the unaffected subcellular location of truncated ATG5 and Beclin1 suggested the irrelevance of calpain towards the autophagy-to-apoptosis signaling shift. HMGB1 and p53 both serve as transcription factors that play crucial roles in the regulation of PCB29-pQ-induced autophagy and apoptosis. PCB29-pQ not only enhanced the expression of HMGB1 and p53 but also promoted their binding and cytosolic translocation. Interestingly, HMGB1 rather than p53 plays a primary role in 5 µM of PCB29-pQ-induced autophagy in the nucleus; however, p53 promoted apoptosis to a great extent in the cytosol at the dose of 15 µM PCB29-pQ. Together, HMGB1 and p53 provided a subtle balance between autophagy and apoptosis, thus determining the fate of PCB29-pQ-treated cells.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Proteína HMGB1/metabolismo , Bifenilos Policlorados/toxicidade , Quinonas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Cálcio/metabolismo , Calpaína/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Transporte Proteico/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia
7.
Bioorg Chem ; 85: 240-252, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30640072

RESUMO

A small library of antiplasmodial methoxy-thiazinoquinones, rationally designed on the model of the previously identified hit 1, has been prepared by a simple and inexpensive procedure. The synthetic derivatives have been subjected to in vitro pharmacological screening, including antiplasmodial and toxicity assays. These studies afforded a new lead candidate, compound 9, endowed with higher antiplasmodial potency compared to 1, a good selectivity index when tested against a panel of mammalian cells, no toxicity against RBCs, a synergistic antiplasmodial action in combination with dihydroartemisinin, and a promising inhibitory activity on stage V gametocyte growth. Computational studies provided useful insights into the structural requirements needed for the antiplasmodial activity of thiazinoquinone compounds and on their putative mechanism of action.


Assuntos
Antimaláricos/farmacologia , Quinonas/farmacologia , Tiazinas/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/toxicidade , Artemisininas/farmacologia , Linhagem Celular Tumoral , Células Cultivadas , Teoria da Densidade Funcional , Sinergismo Farmacológico , Eritrócitos/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Modelos Químicos , Simulação de Dinâmica Molecular , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Quinonas/síntese química , Quinonas/toxicidade , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/toxicidade
8.
Eur J Pharm Sci ; 116: 26-36, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29055734

RESUMO

In the present work, we have developed a photosensitizer hypocrellin B (HB) and nano silver loaded PLGA-TPGS nanoparticles with improved singlet oxygen production for enhanced photodynamic effect for the efficient treatment of age related macular degeneration. Random copolymer (PLGA-TPGS) synthesized by ring opening and bulk polymerization was characterized by IR, 1H NMR and TGA analysis. HBS-CP-NPs prepared by nanoprecipitation techniques were spherical shaped 89.6-753.6nm size particles with negative zeta potential. The average encapsulation efficiency was 84.06±11.43% and HB release from the HBS-CP-NPs was found to be biphasic with a slow release of 1.41% in the first 8h and 48.91% during 3days as measured by RP-HPLC. DSC thermograms indicate that HB was dispersed as amorphous form in HBS-CP-NPs. The ROS generation level of HBS-CP-NPs was significantly higher than that of HB/HB-CP-NPs. The production of 1O2 of HBS-CP-NPs has been assessed using EPR spectrometer. The 1O2 generating efficiency follows the order of nano silver>HB-CP-NPs>HBS-CP-NPs>pure HB drug solution. The superior phototoxic effect of HBS-CP-NPs (85.5% at 50µM) was attained at 2h irradiation in A549 cells. Significant anti angiogenic effect of HBS-CP-NPs was observed in treated CAM embryos. Following intravenous injection of HBS-CP-NPs to rabbits, the maximum amount of HB was found in retina (3h), iris (9h), aqueous humour (9h) and vitreous humour (9h).


Assuntos
Olho/efeitos dos fármacos , Nanopartículas/química , Perileno/análogos & derivados , Fármacos Fotossensibilizantes/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Quinonas/química , Células A549 , Animais , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos , Liberação Controlada de Fármacos , Olho/metabolismo , Humanos , Luz , Degeneração Macular/tratamento farmacológico , Masculino , Tamanho da Partícula , Perileno/química , Perileno/farmacocinética , Perileno/toxicidade , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/toxicidade , Quinonas/farmacocinética , Quinonas/toxicidade , Coelhos , Prata/química , Oxigênio Singlete/química , Propriedades de Superfície , Distribuição Tecidual
9.
Curr Med Chem ; 24(34): 3681-3697, 2017 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-28714385

RESUMO

BACKGROUND: Natural medicine monomers (NMMs) isolated from plants have been recognized for their roles in treating different human diseases including cancers. Many NMMs exhibit effective anti-cancer activities and can be used as drugs or adjuvant agents to enhance the efficacy of chemotherapy and radiotherapy. Some NMMs, such as paclitaxel and camptothecin, have been extensively studied for decades and are now used as anti-cancer medicines due to their remarkable curative effects, such as inhibiting cancer cell proliferation and metastasis, and inducing cell death and differentiation. METHODS: After extensively reviewing papers related to NMM studies in cancers, we grouped NMMs into six categories based on their chemical structures. We summarized the anti-cancer activities of these NMMs and current knowledge of molecular mechanisms for them to exert their functions. RESULTS AND CONCLUSION: Many NMMs from plants can effectively inhibit cancer cells with low or tolerable toxicity to patients. Some NMMs have been well-characterized for their anti-cancer activities and have already been used as clinical drugs or adjuvant agents; however, the mechanisms underlying the cancer suppressive activities of most NMMs remain poorly understood. Many NMMs can be used as initial structural scaffolds to design and develop novel therapeutics against cancers. This review summarizes reports related to signaling pathways mediated by different NMMs and can provide a theoretical basis for clinical application and new drug development of NMMs.


Assuntos
Produtos Biológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Alcaloides/química , Alcaloides/uso terapêutico , Alcaloides/toxicidade , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Flavonoides/química , Flavonoides/uso terapêutico , Flavonoides/toxicidade , Humanos , Hidroxibenzoatos/química , Hidroxibenzoatos/uso terapêutico , Hidroxibenzoatos/toxicidade , Plantas/química , Plantas/metabolismo , Quinonas/química , Quinonas/uso terapêutico , Quinonas/toxicidade , Saponinas/química , Saponinas/uso terapêutico , Saponinas/toxicidade , Terpenos/química , Terpenos/uso terapêutico , Terpenos/toxicidade
10.
Toxicology ; 387: 17-26, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28645578

RESUMO

The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is the most important cellular defense mechanisms against oxidative attack. BTB and CNC homology-1 (Bach1), like Kelch-like ECH-associated protein 1 (Keap1), is one of a negative regulator of Nrf2 that control antioxidant response elements (ARE)-dependent gene expressions. In the current study, we found that quinones show greater capacity than hydroquinones in nuclear Bach1 export, as well as ubiquitin-dependent Bach1 degradation in our experimental time frame. Consistently, quinones are easier than hydroquinones in Nrf2 activation and ARE-driven antioxidant protein expressions. Considering the redox cycling potential of quinone-hydroquinone couple, we investigated the effect of transit metal oxidation on the regulation of Nrf2 activity. As shown, Fe3+ enhanced hydroquinone-induced Nrf2 activation and ARE-driven gene expressions, suggesting quinones rather than hydroquinone activate Nrf2 through Bach1 arylation. Taking together, our investigation illustrated that the electrophilic character of quinones ensure their conjugation with Bach1, which is important for the downregulation of Bach1 and the upregulation of Nrf2 signaling.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Benzoquinonas/toxicidade , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Hepatócitos/efeitos dos fármacos , Hidroquinonas/toxicidade , Quinonas/toxicidade , Elementos de Resposta Antioxidante , Fatores de Transcrição de Zíper de Leucina Básica/genética , Regulação para Baixo , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Glutationa/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Ferro/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Ligação Proteica , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Ubiquitinação/efeitos dos fármacos
11.
ACS Chem Neurosci ; 8(8): 1704-1712, 2017 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-28425704

RESUMO

Protein aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. It has been shown that lysine residues play a key role in the formation of these aggregates. Thus, the ability to disrupt aggregate formation by covalently modifying lysine residues could lead to the discovery of therapeutically relevant antiamyloidogenesis compounds. Herein, we demonstrate that an ortho-iminoquinone (IQ) can be utilized to inhibit amyloid aggregation. Using alpha-synuclein and Aß1-40 as model amyloidogenic proteins, we observed that IQ was able to react with lysine residues and reduce amyloid aggregation. We also observed that IQ reacted with free amines within the amyloid fibrils preventing their dissociation and seeding capacity.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/metabolismo , Agregação Patológica de Proteínas/tratamento farmacológico , Quinonas/farmacologia , alfa-Sinucleína/metabolismo , Animais , Catequina/análogos & derivados , Catequina/farmacologia , Catequina/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Galinhas , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Células HEK293 , Humanos , Lisina/metabolismo , Metionina/metabolismo , Camundongos , Micrococcus luteus , Proteínas Associadas aos Microtúbulos/metabolismo , Muramidase/metabolismo , Fármacos Neuroprotetores/toxicidade , Oxirredução , Agregação Patológica de Proteínas/metabolismo , Quinonas/toxicidade , Tirosina 3-Mono-Oxigenase/metabolismo
12.
PLoS One ; 12(3): e0173121, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28282460

RESUMO

Many cancer types are serious diseases causing mortality, and new therapeutics with improved efficacy and safety are required. Immuno-(cell)-therapy is considered as one of the promising therapeutic strategies for curing intractable cancer. In this study, we tested R2016, a newly developed heterocyclic quinone derivative, for induction of immunogenic tumor cell death and as a possible novel immunochemotherapeutic. We studied the anti-cancer effects of R2016 against LLC, a lung cancer cell line and B16F10, a melanoma cell line. LLC (non-immunogenic) and B16F10 (immunogenic) cells were killed by R2016 in dose-dependent manner. R2016 reduced the viability of both LLC and B16F10 tumor cells by inducing apoptosis and necrosis, while it demonstrated no cytotoxicity against normal splenocytes. Expression of immunogenic death markers on the cell surface of R2016 treated tumor cells including calreticulin (CRT) and heat shock proteins (HSPs) was increased along with the induction of their genes. Increased CRT expression correlated with dendritic cell (DC) uptake of dying tumor cells: the proportion of CRT+CD11c+cells was increased in the R2016-treated group. The gene transcription of Calr3, Hspb1, and Tnfaip6, which are related to immunogenicity induction of dead cells, was up-regulated in the R2016 treated tumor cells. On the other hand, ANGPT1, FGF7, and URGCP gene levels were down-regulated by R2016 treatment. This data suggests that R2016 induced immunogenic tumor cell death, and suggests R2016 as an effective anti-tumor immunochemotherapeutic modality.


Assuntos
Apoptose/efeitos dos fármacos , Carbazóis/toxicidade , Compostos Heterocíclicos/toxicidade , Quinonas/toxicidade , Animais , Antígeno CD11c/metabolismo , Calreticulina/genética , Calreticulina/metabolismo , Carbazóis/síntese química , Carbazóis/química , Carbazóis/uso terapêutico , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/análise , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Necrose , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Quinonas/síntese química , Quinonas/química , Quinonas/uso terapêutico , Regulação para Cima/efeitos dos fármacos
13.
Chem Res Toxicol ; 30(1): 13-37, 2017 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-27617882

RESUMO

Quinones represent a class of toxicological intermediates, which can create a variety of hazardous effects in vivo including, acute cytotoxicity, immunotoxicity, and carcinogenesis. In contrast, quinones can induce cytoprotection through the induction of detoxification enzymes, anti-inflammatory activities, and modification of redox status. The mechanisms by which quinones cause these effects can be quite complex. The various biological targets of quinones depend on their rate and site of formation and their reactivity. Quinones are formed through a variety of mechanisms from simple oxidation of catechols/hydroquinones catalyzed by a variety of oxidative enzymes and metal ions to more complex mechanisms involving initial P450-catalyzed hydroxylation reactions followed by two-electron oxidation. Quinones are Michael acceptors, and modification of cellular processes could occur through alkylation of crucial cellular proteins and/or DNA. Alternatively, quinones are highly redox active molecules which can redox cycle with their semiquinone radical anions leading to the formation of reactive oxygen species (ROS) including superoxide, hydrogen peroxide, and ultimately the hydroxyl radical. Production of ROS can alter redox balance within cells through the formation of oxidized cellular macromolecules including lipids, proteins, and DNA. This perspective explores the varied biological targets of quinones including GSH, NADPH, protein sulfhydryls [heat shock proteins, P450s, cyclooxygenase-2 (COX-2), glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1, (NQO1), kelch-like ECH-associated protein 1 (Keap1), IκB kinase (IKK), and arylhydrocarbon receptor (AhR)], and DNA. The evidence strongly suggests that the numerous mechanisms of quinone modulations (i.e., alkylation versus oxidative stress) can be correlated with the known pathology/cytoprotection of the parent compound(s) that is best described by an inverse U-shaped dose-response curve.


Assuntos
Citoproteção , Citotoxinas , Quinonas , Animais , Citotoxinas/química , Citotoxinas/farmacologia , Citotoxinas/toxicidade , Humanos , Quinonas/química , Quinonas/farmacologia , Quinonas/toxicidade
14.
Nat Prod Commun ; 12(4): 477-478, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30520574

RESUMO

Using various chromatographic methods, one new sesquiterpene quinone named smenohaimien F (1) and five known, neodactyloquinone (2), dactyloquinone C (3), dactyloquinone D (4), isoamijiol (5), and amijiol (6), were isolated from the marine sponge Smenospongia cerebriformis Duchassaing & Michelotti, 1864. Their structures were elucidated by ID-, 2D-NMR spectroscopic analysis, HR-ESI-MS, and by comparing with the NMR data reported in the literature. The cytotoxic activities of the all compounds were evaluated on five human cancer cell lines, LU-1, HL-60, SK-Mel-2, HepG-2, and MCF-7. Compound 4 was found to exhibit significant cytotoxic activities on all tested human cancer cell lines with IC50 values ranging from 0.7 to 1.6 µg/mL.


Assuntos
Diterpenos/química , Diterpenos/toxicidade , Poríferos/química , Quinonas/química , Quinonas/toxicidade , Sesquiterpenos/química , Sesquiterpenos/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/isolamento & purificação , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Quinonas/isolamento & purificação , Sesquiterpenos/isolamento & purificação
15.
BMC Pharmacol Toxicol ; 17(1): 60, 2016 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-27998305

RESUMO

BACKGROUND: Cancer is a major public health concern globally and chemotherapy remains the principal mode of the treatment of various malignant diseases. METHODS: This study was designed to investigate the cytotoxicity of 14 naturally occurring quinones including; 3 anthraquinones, 1 naphthoquinone and 10 benzoquinones against 6 human carcinoma cell lines and normal CRL2120 fibroblasts. The neutral red uptake (NR) assay was used to evaluate the cytotoxicity of the compounds, whilst caspase-Glo assay was used to detect caspases activation. Cell cycle and mitochondrial membrane potential (MMP) were all analyzed via flow cytometry meanwhile levels of reactive oxygen species (ROS) were measured by spectrophotometry. RESULTS: Anthraquinone: emodin (2), naphthoquinone: plumbagin (4), and benzoquinones: rapanone (9), 2,5-dihydroxy-3-pentadecyl-2,5-cyclohexadiene-1,4-dione (10), 5-O-methylembelin (11), 1,2,4,5-tetraacetate-3-methyl-6-(14-nonadecenyl)-cyclohexadi-2,5-diene (13), as well as doxorubicin displayed interesting activities with IC50 values below 100 µM in the six tested cancer cell lines. The IC50 values ranged from 37.57 µM (towards breast adenocarcinoma MCF-7 cells) to 99.31 µM (towards small cell lung cancer A549 cells) for 2, from 0.06 µM (MCF-7 cells) to 1.14 µM (A549 cells) for 4, from 2.27 µM (mesothelioma SPC212 cells) to 46.62 µM (colorectal adenocarcinoma DLD-1 cells) for 9, from 8.39 µM (SPC212 cells) to 48.35 µM (hepatocarinoma HepG2 cells) for 10, from 22.57 µM (MCF-7 cells) to 61.28 µM (HepG2 cells) for 11, from 9.25 µM (MCF-7 cells) to 47.53 µM (A549 cells) for 13, and from 0.07 µM (SPC212 cells) to 1.01 µM (A549 cells) for doxorubicin. Compounds 4 and 9 induced apoptosis in MCF-7 cells mediated by increased ROS production and MMP loss, respectively. CONCLUSION: The tested natural products and mostly 2, 4, 9, 10, 11 and 13 are potential cytotoxic compounds that deserve more investigations towards developing novel antiproliferative drugs against human carcinoma.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Benzoquinonas/toxicidade , Naftoquinonas/toxicidade , Extratos Vegetais/toxicidade , Quinonas/toxicidade , Células A549 , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Benzoquinonas/química , Benzoquinonas/isolamento & purificação , Células CACO-2 , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Células Hep G2 , Humanos , Quênia/epidemiologia , Células MCF-7 , Naftoquinonas/química , Naftoquinonas/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Quinonas/química , Quinonas/isolamento & purificação
16.
J Toxicol Sci ; 41(6): 775-781, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27853106

RESUMO

While it has long been believed that benzenes and naphthalenes are unable to activate the aryl hydrocarbon receptor (AhR) because they are poor ligands, we recently reported that these quinoid metabolites upregulated cytochrome P450 1A1 (CYP1A1) in Hepa1c1c7 cells (Abiko et al., 2015). In the current study, AhR activation, measured with a bioluminescence-based cell free assay, was induced by 1,2-naphthoquinone (1,2-NQ), a metabolite of naphthalene. Consistent with this, 1,4-benzoquinone (1,4-BQ), tert-butyl-1,4-BQ, and 1,4-NQ, as well as 1,2-NQ, all electrophilic mono- and bi-cyclic quinones, upregulated CYP1A1 mRNA and protein in HepG2 cells, whereas their parent aromatic hydrocarbons had little effect. Furthermore, immunofluorescence analysis confirmed that these quinones enhanced translocation of AhR to the nucleus.


Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Citocromo P-450 CYP1A1/biossíntese , Hepatócitos/efeitos dos fármacos , Quinonas/toxicidade , RNA Mensageiro/biossíntese , Receptores de Hidrocarboneto Arílico/agonistas , Transporte Ativo do Núcleo Celular , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Benzoquinonas/toxicidade , Citocromo P-450 CYP1A1/genética , Relação Dose-Resposta a Droga , Indução Enzimática , Imunofluorescência , Células Hep G2 , Hepatócitos/enzimologia , Humanos , Naftoquinonas/toxicidade , RNA Mensageiro/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transfecção
17.
Parasitology ; 143(4): 507-17, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26887285

RESUMO

Human toxocarosis is a chronic tissue parasitosis most often caused by Toxocara canis. The seroprevalence can reach up to 50%, especially among children and adolescents. The anthelmintics used in the treatment have moderate efficacy. The aim of this study was to evaluate the in vitro and in vivo anthelmintic activity of quinones and their derivatives against T. canis larvae and the cytotoxicity of the larvicidal compounds. The compounds were evaluated at 1 mg mL(-1) concentration in microculture plates containing third stage larvae in an Roswell Park Memorial Institute (RPMI) 1640 environment, incubated at 37 °C in 5% CO2 tension for 48 h. Five naphthoxiranes were selected for the cytotoxicity analysis. The cell viability evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays using murine peritoneal macrophages isolated from C57BL/6 mice revealed that the naphthoxiranes (1 and 3) were less cytotoxic at a concentration of 0.05 mg mL(-1). The efficacy of naphthoxiranes (1 and 3) was examined in murine toxocarosis also. The anthelmintic activity was examined by evaluating the number of larvae in the brain, carcass, liver, lungs, heart, kidneys and eyes. Compound (3) demonstrated anthelmintic activity similar to that of albendazole by decreasing the number of larvae in the organs of mice and thus could form the basis of the development of a new anthelmintic drug.


Assuntos
Anti-Helmínticos/farmacologia , Quinonas/farmacologia , Toxocara canis/efeitos dos fármacos , Toxocaríase/tratamento farmacológico , Albendazol/farmacologia , Albendazol/uso terapêutico , Animais , Anti-Helmínticos/química , Anti-Helmínticos/uso terapêutico , Anti-Helmínticos/toxicidade , Feminino , Larva/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Quinonas/química , Quinonas/uso terapêutico , Quinonas/toxicidade , Toxocaríase/parasitologia
18.
J Biol Chem ; 291(9): 4763-78, 2016 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-26728460

RESUMO

Identification of factors contributing to the development of chronic obstructive pulmonary disease (COPD) is crucial for developing new treatments. An increase in the levels of protein-disulfide isomerase (PDI), a multifaceted endoplasmic reticulum resident chaperone, has been demonstrated in human smokers, presumably as a protective adaptation to cigarette smoke (CS) exposure. We found a similar increase in the levels of PDI in the murine model of COPD. We also found abnormally high levels (4-6 times) of oxidized and sulfenilated forms of PDI in the lungs of murine smokers compared with non-smokers. PDI oxidation progressively increases with age. We begin to delineate the possible role of an increased ratio of oxidized PDI in the age-related onset of COPD by investigating the impact of exposure to CS radicals, such as acrolein (AC), hydroxyquinones (HQ), peroxynitrites (PN), and hydrogen peroxide, on their ability to induce unfolded protein response (UPR) and their effects on the structure and function of PDIs. Exposure to AC, HQ, PN, and CS resulted in cysteine and tyrosine nitrosylation leading to an altered three-dimensional structure of the PDI due to a decrease in helical content and formation of a more random coil structure, resulting in protein unfolding, inhibition of PDI reductase and isomerase activity in vitro and in vivo, and subsequent induction of endoplasmic reticulum stress response. Addition of glutathione prevented the induction of UPR, and AC and HQ induced structural changes in PDI. Exposure to PN and glutathione resulted in conjugation of PDI possibly at active site tyrosine residues. The findings presented here propose a new role of PDI in the pathogenesis of COPD and its age-dependent onset.


Assuntos
Radicais Livres/toxicidade , Pulmão/enzimologia , Isomerases de Dissulfetos de Proteínas/metabolismo , Doença Pulmonar Obstrutiva Crônica/enzimologia , Mucosa Respiratória/enzimologia , Fumar/efeitos adversos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Acroleína/toxicidade , Animais , Câmaras de Exposição Atmosférica , Linhagem Celular , Sobrevivência Celular , Indução Enzimática/efeitos dos fármacos , Feminino , Humanos , Peróxido de Hidrogênio/toxicidade , Hidroxilação , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos Endogâmicos C57BL , Oxirredução , Ácido Peroxinitroso/toxicidade , Conformação Proteica , Isomerases de Dissulfetos de Proteínas/antagonistas & inibidores , Isomerases de Dissulfetos de Proteínas/química , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Quinonas/toxicidade , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia
19.
Ukr Biochem J ; 87(4): 45-53, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26547963

RESUMO

The effects of α-tocopherol with shortened to 6 carbon atoms side chain (α-Toc-C6), α-tocopherol succinate (α-TS) and quinonimine 2,6-dichlorophenolindophenol (DCPIP) on DT-diaphorase activity and viability of rat thymocytes, splenocytes and hepatocytes were investigated. It was shown that the lowest basal activity of the enzyme is inherent in splenocytes. In comparison to splenocytes, DT-diaphorase activity was 1.4 and 5 times higher in thymocytes and hepatocytes, respectively. It was found that the sensitivity of cells to the cytotoxic effect of DCPIP was inversely proportional to the basal level of DT-diaphorase activity and accompanied by its activation with subsequent inhibition at non-toxic and toxic concentrations, respectively. Hepatocytes were least sensitive to the cytotoxic effect of α-Toc-C6. In thymocytes and splenocytes α-Toc-C6 exerts inhibitory effects on DT-diaphorase, whereas in hepatocytes an increased activity of the enzyme was observed, which probably caused their high survival rate. Simultaneous induction of cytochrome P450 enzyme expression by α-Toc-C6 in hepatocytes is also possible. Cytotoxic effect of α-TS does not depend on the basal level of DT-diaphorase activity in cells, is not accompanied by its induction and it is most likely determined by the non-specific esterase activity.


Assuntos
Citotoxinas/toxicidade , Iminas/toxicidade , NAD(P)H Desidrogenase (Quinona)/metabolismo , Quinonas/toxicidade , alfa-Tocoferol/toxicidade , 2,6-Dicloroindofenol/toxicidade , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/enzimologia , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Especificidade de Órgãos , Cultura Primária de Células , Ratos , Timócitos/citologia , Timócitos/efeitos dos fármacos , Timócitos/enzimologia , alfa-Tocoferol/análogos & derivados
20.
Bioorg Med Chem ; 23(21): 6930-42, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26476666

RESUMO

A series of eighteen derivatives of marine sesquiterpene quinone avarone and its model system tert-butylquinone with amino acids has been synthesized by nucleophilic addition of amino acids to the quinones. In vitro cytotoxic activity toward human cancer cell lines (HeLa, A549, Fem-X, K562, MDA-MB-453) and normal MRC-5 cell line was determined. Several compounds showed very strong inhibitory activity with IC50 values less than 10 µM. Avarone derivatives were more active than the corresponding tert-butylquinone derivatives. The results of the cytofluorimetric analysis of cell cycle of HeLa cells showed that apoptosis might be one of possible mechanism of action of these compounds in cancer cells. In order to examine the influence of caspases on cell death, the apoptotic mechanisms induced by the tested compounds were determined using specific caspases 3, 8 and 9 inhibitors. For all compounds antibacterial activities against six strains of Gram-positive and four strains of Gram-negative bacteria were determined, as well as antifungal activity against three fungal species.


Assuntos
Aminoácidos/química , Antibacterianos/síntese química , Cicloexenos/química , Sesquiterpenos/química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cicloexenos/síntese química , Cicloexenos/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células HeLa , Humanos , Células K562 , Testes de Sensibilidade Microbiana , Quinonas/síntese química , Quinonas/química , Quinonas/toxicidade , Sesquiterpenos/síntese química , Sesquiterpenos/toxicidade , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...