RESUMO
Cancer has been a serious threat and impact on the health and life of human. Phototherapy is considered as a promising therapeutic method to replace the traditional treatment in clinic owing to its noninvasive nature and high efficiency. Photoinitiators have long been used in the field of photopolymerization; however, few studies have been carried out on their potential as anticancer agents under light irradiation. In this study, the effect of a photoinitiator, diphenyl (2, 4, 6-trimethylbenzoyl) phosphine oxide (TPO), on breast cancer is investigated and the related mechanism is elucidated. It is found that TPO has low dark toxicity and significant phototoxicity. TPO can inhibit cell growth and development and promote cell apoptosis through a mitochondrial pathway under light irradiation. Further studies show that cell apoptosis is induced by free radicals produced from the photolysis of TPO to activate JNK phosphorylation. Overall, we identify the antitumor effects of TPO in vitro for the first time, and provides a proof of concept for its application as a novel photolatent therapeutic drug.
Assuntos
Fotoiniciadores Dentários , Radicais Livres , Humanos , Teste de Materiais , Fotoiniciadores Dentários/química , Fotoiniciadores Dentários/efeitos da radiaçãoRESUMO
Blindness and visual impairments are heavy loads for modern society. Visual prosthesis is a promising therapy to treat these diseases. However, electric stimulation (ES)-induced damage of the optic nerve and adjacent cells are problems that must not be overlooked. In the current study, we aimed to investigate the effects of ES on cultured microglia cells and the potential protective mechanisms from a natural compound Lycium barbarum polysaccharide (LBP). Cellular injuries were induced by 9 mA bipolar pulse current in BV-2 cells for 15 min. Treatment with LBP alone or in association with either autophagic inhibitor 3-MA or autophagic agonist rapamycin was preadded for 2 h before the ES challenge. After that, morphological and molecular changes of the cells were measured at 2 h or 6 h postchallenges. We found that ES induced evident morphological and pathological changes of BV-2 cells, including oxidative stress, inflammation, and apoptosis. Pretreatment with LBP significantly attenuated these injuries with enhanced endogenous autophagy. When cellular autophagy was inhibited or enhanced by corresponding drug, the protective properties of LBP were partly inhibited or maintained, respectively. In addition, we demonstrated that ERK and p38 MAPK exerted diversified roles in the protection of LBP against ES-induced cellular damages. In conclusion, LBP improves bipolar pulse current-induced microglia cell injury through modulating autophagy and MAPK pathway.
Assuntos
Autofagia/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Lycium/metabolismo , Adenina/análogos & derivados , Adenina/toxicidade , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular , Estimulação Elétrica , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inflamação , Lycium/química , Camundongos , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microscopia de Fluorescência , Proteínas Associadas aos Microtúbulos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sirolimo/toxicidade , Imagem com Lapso de Tempo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
This study aimed to investigate the possible therapeutic effects and active components of Lycium barbarum polysaccharides (LBP) on a high fat diet-induced NASH rat model. We induced NASH in a rat model by voluntary oral feeding with a high-fat diet ad libitum for 8 weeks. After 8 weeks, 1â mg/kg LBP was orally administered for another 4 weeks with a high-fat diet. When compared with NASH rats treated for 12 weeks, therapeutic LBP treatment for 4 weeks during 12 weeks of NASH induction showed ameliorative effects on: (1) increased body and wet liver weights; (2) insulin resistance and glucose metabolic dysfunction; (3) elevated level of serum aminotransferases; (4) fat accumulation in the liver and increased serum free fatty acid (FFA) level; (5) hepatic fibrosis; (6) hepatic oxidative stress; (7) hepatic inflammatory response; and (8) hepatic apoptosis. These improvements were partially through the modulation of transcription factor NF-κB, MAPK pathways and the autophagic process. In a palmitate acid-induced rat hepatocyte steatosis cell-based model, we also demonstrated that l-arabinose and ß-carotene partially accounted for the beneficial effects of LBP on the hepatocytes. In conclusion, LBP possesses a variety of hepato-protective properties which make it a potent supplementary therapeutic agent against NASH in future clinical trials.
Assuntos
Fármacos Antiobesidade/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Apoptose , Arabinose/farmacologia , Autofagia , Sobrevivência Celular , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Feminino , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Sistema de Sinalização das MAP Quinases , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/tratamento farmacológico , Estresse Oxidativo , Ratos Sprague-Dawley , beta Caroteno/farmacologiaRESUMO
Lycium barbarum has been used as a traditional Chinese medicine to nourish liver, kidneys and the eyes. However, the underlying mechanisms of its hepatic-protective properties remain uncertain. In this study, we aimed to investigate whether thioredoxin-interacting protein (TXNIP) and NOD-like receptor 3 (NLRP3) inflammasome mediated the attenuation of ethanol-induced hepatic injury by Lycium barbarum polysaccharide (LBP). Rat normal hepatocyte line BRL-3A was pre-treated with LBP prior to ethanol incubation. Hepatic damages, including apoptosis, inflammation, and oxidative stress, were measured. Then the inhibition of endogenous TXNIP expression was achieved by using its specific siRNA to test its possible involvement in the injury attenuation. We found that 50µg/ml LBP pre-treatment significantly alleviated 24-h ethanol exposure-induced overexpression of TXNIP, increased cellular apoptosis, secretion of inflammatory cytokines, activation of NLRP3 inflammasome, production of ROS, and reduced antioxidant enzyme expression. Silence of TXNIP suppressed the activated NLRP3 inflammasome, increased oxidative stress and worsened apoptosis in the cells. Further addition of LBP did not influence the effects of TXNIP inhibition on the cells. In conclusion, inhibition of hepatic TXNIP by LBP contributes to the reduction of cellular apoptosis, oxidative stress and NLRP3 inflammasome-mediated inflammation.
Assuntos
Proteínas de Transporte/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Medicamentos de Ervas Chinesas/farmacologia , Etanol/efeitos adversos , Inflamassomos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular , Linhagem Celular , Citoproteção/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Estresse Oxidativo/efeitos dos fármacos , RatosRESUMO
In the current study, the therapeutic effects of zeaxanthin dipalmitate (ZD) on a rat alcoholic fatty liver disease (AFLD) model were evaluated. After-treatment with ZD from the 5th week to the 10th week in a 10-week ethanol intragastric administration in rats significantly alleviated the typical AFLD symptoms, including reduction in rat body weight, accumulation of hepatic fat droplets, occurrence of oxidative stress, inflammation, chemoattractive responses and hepatic apoptosis in the liver. The reduction of liver function abnormalities by ZD was partly through lower expression level of cytochrome P450 2E1 (CYP2E1), diminished activity of nuclear factor kappa B (NF-κB) through the restoration of its inhibitor kappa B alpha (IκBα), and the modulation of MAPK pathways including p38 MAPK, JNK and ERK. ZD treatment alone did not pose obvious adverse effect on the healthy rat. In the cellular AFLD model, we also confirmed the inhibition of p38 MAPK and ERK abolished the beneficial effects of ZD. These results provide a scientific rationale for the use of zeaxanthin and its derivatives as new complementary agents for the prevention and treatment of alcoholic liver diseases.
Assuntos
Antioxidantes/farmacologia , Etanol/administração & dosagem , Fígado Gorduroso Alcoólico/tratamento farmacológico , Palmitatos/farmacologia , Substâncias Protetoras/farmacologia , Xantofilas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose/efeitos dos fármacos , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Feminino , Regulação da Expressão Gênica , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Redução de Peso/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
Ionomycin in conjunction with phorbol-12,13-dibutyrate (PDBu) is conventionally used as a stimulator to activate cells, especially original T cells. But we accidently found it had an entirely opposite action on malignant tumor cells derived from T cells. Thus, influence of ionomycin on human leukemia Jurkat T cell behaviors and its preliminary mechanistic process were explored in the presence of PDBu. Ionomycin could remarkably inhibit colony formation of the cells, and inhibitory rate of the cell proliferation was increased with ionomycin treatment in a dose- or time-related relationship, following the reduction of ERK1/2 and phosphorylated-ERK1/2 levels. However, a high dose of ionomycin might moderately repress mid-stage activation of the cells. It also blocked the cell entry at S-phase and G2/M-phase with the attenuation of transforming growth factor-ß (TGF-ß) level in the cells, and promoted the cell apoptosis following the augment of caspase-3 and cleaved caspase-3 in the cells. The dramatic elevation of [Ca2(+)]i and intracellular pH (pHi) was simultaneously followed by the above alteration of the cell behaviors. These results indicate that ionomycin may strongly inhibit human acute T lymphocyte leukemia progress in the presence of PDBu through the inhibition of ERK1/2 signaling, the activation of caspase-3 and the attenuation of TGF-ß mediated by the [Ca2(+)]i and pHi enhancement, providing a novel insight into function and potential application of both ionomycin and PDBu.