RESUMO
Oxidative stress plays an important role in many diseases and hydrogen peroxide (H2O2) plays a central role in the stress. Gensenoside Rb1 is the one of active ingredients in the traditional Chinese medicine Panax notoginseng. It has been reported that gensenoside Rb1 possesses various pharmacological activities. Here we report that gensenoside Rb1 exhibits potent protective effects against oxidative injury induced by H2O2 through inhibiting endoplasmic reticulum stress in PC12 cells. Cell viability assay demonstrated that incubation with H2O2 for 24 h led to a significant loss of cultured rat PC12 cells, and the cell viability was pronouncedly increased by pretreatment of gensenoside Rb1 for 24 h. H2O2-induced endoplasmic reticulum stress pathway was also suppressed after gensenoside Rb1 pretreatment, which was related with thioredoxin-1 (Trx-1) induction. Trx-1 siRNA abolished the protective effects of gensenoside Rb1. Our results of the present study demonstrate that gensenoside Rb1 shows a potent anti-oxidative effect on cultured PC12 cells by inducing Trx-1 expression.
Assuntos
Antioxidantes/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ginsenosídeos/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Tiorredoxinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citoproteção , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio/toxicidade , Neurônios/metabolismo , Neurônios/patologia , Oxidantes/toxicidade , Células PC12 , Interferência de RNA , Ratos , Tiorredoxinas/genética , TransfecçãoRESUMO
Panax notoginseng, a traditional Chinese medicine, has been used for thousands of years to treat ischemic patients. More than 20 saponin components have been isolated from P. notoginseng root and identified chemically. However, these different chemical components have different roles. In this study we compared the neuroprotective mechanisms of ginsenosides Rg1, Rb1, Rg1/Rb1, and panax notoginsenoside (PNS) against injuries caused by cerebral ischemia-reperfusion (I/R). Our results show that all of these treatments significantly reduced infarction volume and alleviated neurological deficits caused by cerebral I/R. The increase in malondialdehyde (MDA) concentration was inhibited by these treatments in the hippocampus. The decreased expressions of thioredoxin-1 (Trx-1), copper-zinc superoxide dismutase (SOD-1), protein kinase B (PKB/Akt), and nuclear factor-kappa B (NF-κB) caused by cerebral I/R were restored by these treatments. The expression of heat shock protein 70 (HSP70) was enhanced in the middle cerebral artery occlusion (MCAO) group, as well as in all of the treatment groups. These results suggest that Rg1 and Rb1 have similar roles in protecting the brain from ischemic damage; however, neither Rg1/Rb1 nor PNS have synergistic effects, thus either Rg1 or the Rb1 monomer should be considered as a pharmacological neuroprotective strategy for use in the case of ischemic stroke.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Ginsenosídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Panax notoginseng , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/etiologia , Ginsenosídeos/análise , Ginsenosídeos/uso terapêutico , Infarto da Artéria Cerebral Média/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/uso terapêutico , Fitoterapia , Raízes de Plantas , Traumatismo por Reperfusão/etiologiaRESUMO
Long-term administration of morphine for the management of chronic pain will result in tolerance to its analgesic effect and could even cause drug dependence. Numerous studies have demonstrated significant redox alteration in morphine dependence and addiction. Thioredoxin-1 (Trx-1) play important roles in controlling the cellular redox balance. In recent years, several recent studies have demonstrated that Trx-1 may be a promising novel therapeutic target for morphine addiction. In this article, we firstly review the redox alteration in morphine addiction. We also summarize the expression and the protective roles of Trx-1 in morphine dependence. We further highlight the protection of geranylgeranylacetone (GGA), a noncytotoxic pharmacological inducer of Trx-1, in morphine-induced conditioned place preference. In conclusion, Trx-1 may be very promising for clinical therapy of morphine addiction in the future.
RESUMO
PURPOSE: Cancer, a major public health problem, exhibits significant redox alteration. Thioredoxin (Trx) system, including Trx and Trx reductase (TrxR), as well as Trx-interacting protein (TXNIP) play important roles in controlling the cellular redox balance in cancer cells. In most cancers, Trx and TrxR are usually overexpressed and TXNIP is underexpressed. In recent years, some agents targeting Trx, TrxR, and TXNIP were used to explore a therapy approach for cancer patients. METHODS: A systematic search of PMC and the PubMed Database was conducted to summarize the potential of Trx system inhibitors for cancer treatment. RESULTS: In this article, we first summarize the functions of Trx, TrxR, and TXNIP in cancers. We also review some small molecule inhibitors of Trx/TrxR and D-allose (TXNIP inducer) and discuss their antitumor mechanisms. We highlight the combined inhibition of Trx system and GSH system in cancer therapy. We expect that a highly specific and selective antitumor agent with no cytotoxicity on human normal cells could be developed in the future. CONCLUSION: In conclusion, Trx system may be very promising for clinical therapy of cancer in the future.
Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Tiorredoxinas/antagonistas & inibidores , Humanos , Neoplasias/metabolismoRESUMO
Parkinson disease (PD) is the second most common neurodegenerative movement disorder. Pharmacological animal models are invaluable tools to study the pathological mechanisms of PD. Currently, invertebrate and vertebrate animal models have been developed by using several main neurotoxins, such as 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, paraquat, and rotenone. These models achieve to some extent to reproduce the key features of PD, including motor defects, progressive loss of dopaminergic neurons in substantia nigra pars compacta, and the formation of Lewy bodies. In this review, we will highlight the pathogenic mechanisms of those neurotoxins and summarize different neurotoxic animal models with the hope to help researchers choose among them accurately and to promote the development of modeling PD.
Assuntos
Modelos Animais de Doenças , Neurotoxinas/toxicidade , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Animais , Caenorhabditis elegans , Drosophila , Vias de Administração de Medicamentos , Camundongos , Doença de Parkinson/fisiopatologia , Ratos , Caramujos , Peixe-ZebraRESUMO
BACKGROUND: Cerebral ischemia is a common cause of disability and death. Ischemic brain injury results from complex pathological processes, including oxidative stress, inflammation, and apoptosis. Thioredoxin( Trx) is an important multifunctional protein, which regulates cellular redox status. Increasing studies have demonstrated that Trx provides a neuroprotective role against cerebral ischemia-induced injury. METHODS: A systematic search of PMC and the PubMed Database was conducted to summarize the protective effects of Trx against cerebral ischemia. RESULTS: This article reviews the understanding of potential effects and mechanisms of Trx against cerebral ischemia, including the anti-oxidant, anti-apoptotic and anti-inflammatory effects, as well as the activation of prosurvival pathway. We also summarize that some natural compounds induce the expression of Trx, which is involved in their anti-ischemic effects. CONCLUSION: In conclusion, Trx has a potential neuroprotection in cerebral ischemia and may be very promising for clinical therapy of ischemic stroke in the future.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/metabolismo , Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Tiorredoxinas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Apoptose/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Humanos , Fármacos Neuroprotetores/metabolismoRESUMO
It has been 200 years since Parkinson disease (PD) was described by Dr. Parkinson in 1817. The disease is the second most common neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although the pathogenesis of PD is still unknown, the research findings from scientists are conducive to understand the pathological mechanisms. It is well accepted that both genetic and environmental factors contribute to the onset of PD. In this review, we summarize the mutations of main seven genes (α-synuclein, LRRK2, PINK1, Parkin, DJ-1, VPS35 and GBA1) linked to PD, discuss the potential mechanisms for the loss of dopaminergic neurons (dopamine metabolism, mitochondrial dysfunction, endoplasmic reticulum stress, impaired autophagy, and deregulation of immunity) in PD, and expect the development direction for treatment of PD.
RESUMO
Diabetes mellitus is considered as a risk factor of Alzheimer's disease (AD), the front runner of neurodegenerative disorders. Streptozotocin (STZ) is a toxin for pancreatic ß-cell, which can construct a model of insulin deficient diabetes through intraperitoneal or intravenous injection. A model generated by intracerebroventricular STZ (icv-STZ) also shows numerous aspects of sporadic AD. The protective roles of tea polyphenols epigallocatechin-3-gallate (EGCG) on both two diseases were researched by some scientists. This review highlights the link between diabetes and AD and recent studies on STZ injection-induced models, and also discusses the protection of EGCG to clarify its treatment in STZ-induced diabetes and AD.
RESUMO
Stress, a state of perceived threat to homeostasis, regulates a panel of important physiological functions. The human mind and body respond to stress by activating the sympathetic nervous system and secreting the catecholamines epinephrine and norepinephrine in the "fight-or-flight" response. However, the protective mechanism of acute stress is still unknown. In the present study, an acute stress mouse model was constructed by intraperitoneal injection of epinephrine (0.2 mg kg(-1)) for 4 h. Epinephrine treatment induced heat shock 70(Hsp70) expression in the stress responsive tissues, such as the cortex, hippocampus, thymus, and kidney. Further, the expression of thioredoxin-1(Trx-1), a cytoprotective protein, was also upregulated in these stress responsive tissues. In addition, the phosphorylation of cAMP-response element binding protein (CREB), a transcription factor of Trx-1, was increased after treatment with epinephrine. The block of CREB activation by H89 inhibited the acute epinephrine stress-induced Trx-1 and Hsp70 expression. Taken together, our data suggest that acute stimuli of epinephrine induced Trx-1 expression through activating CREB and may represent a protective role against stress.
Assuntos
Epinefrina/fisiologia , Expressão Gênica , Tiorredoxinas/genética , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Epinefrina/farmacologia , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Células PC12 , Ratos , Estresse Psicológico/metabolismo , Tiorredoxinas/metabolismo , Ativação TranscricionalRESUMO
Epinephrine is a stress hormone which is sharply increased in response to acute stress and is continuously elevated during persistent stress. Thioredoxin-1 (Trx-1) is a redox regulating protein and is induced under various stresses. Our previous study has shown that epinephrine induces the expression of Trx-1. Tyrosine hydroxylase (TH) is the major rate-limiting enzyme in catecholamine biosynthesis in response to stress. However, how TH is regulated by epinephrine is still unknown. In the present study, we found that epinephrine increased the expression of TH in a dose- and time-dependent manner in PC12 cells, which was inhibited by propranolol (ß-adrenergic receptor inhibitor), but not by phenoxybenzamine (α-adrenergic receptor inhibitor). The increase of TH was also inhibited by SQ22536 (adenylyl cyclase inhibitor), H-89(PKA inhibitor) and LY294002 (phosphatidylinositol 3 kinase inhibitor). More importantly, overexpression of Trx-1 significantly enhanced the expression of TH, while Trx-1 siRNA suppressed TH expression induced by epinephrine. These results suggest that Trx-1 is involved in TH expression induced by epinephrine in PC12 cells.
Assuntos
Epinefrina/farmacologia , Tiorredoxinas/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Células PC12 , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Receptores Adrenérgicos alfa/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Endoplasmic reticulum (ER) stress has been implicated in Parkinson disease. We previously reported that thioredoxin 1 (Trx-1) suppressed the ER stress caused by 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine; however, its molecular mechanism remains largely unknown. In the present study, we showed that 1-methyl-4-phenylpyridinium ion (MPP(+)) induced ER stress by activating glucose-regulated protein 78 (GRP78), inositol-requiring enzyme 1α (IRE1α), tumor necrosis factor receptor-associated factor 2 (TRAF2), c-Jun N-terminal kinase (JNK), caspase-12, and C/EBP homologous protein (CHOP) in PC12 cells. The downregulation of Trx-1 aggravated the ER stress and further increased the expression of the above molecules induced by MPP(+). In contrast, overexpression of Trx-1 attenuated the ER stress and repressed the expression of the above molecules induced by MPP(+). More importantly, the overexpression of Trx-1 in transgenic mice suppressed ER stress by inhibiting the activation of these molecules. We present, for the first time, the molecular mechanism of Trx-1 suppression of endoplasmic reticulum stress in Parkinson disease in vitro and in vivo. Based on our findings, we conclude that Trx-1 plays a neuroprotective role in Parkinson disease by suppressing ER stress by regulating the activation of GRP78, IRE1α, TRAF2, JNK, caspase-12, and CHOP.
Assuntos
Estresse do Retículo Endoplasmático/genética , Intoxicação por MPTP/genética , Tiorredoxinas/genética , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/análogos & derivados , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , 1-Metil-4-fenilpiridínio/farmacologia , Animais , Caspase 12/genética , Caspase 12/metabolismo , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/genética , Endorribonucleases/metabolismo , Regulação da Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Intoxicação por MPTP/induzido quimicamente , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/fisiopatologia , Camundongos , Camundongos Transgênicos , Células PC12 , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Transdução de Sinais , Fator 2 Associado a Receptor de TNF/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Tiorredoxinas/metabolismo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismoRESUMO
Stress regulates a panel of important physiological functions and disease states. Epinephrine is produced under stresses threaten to homeostasis. Thioredoxin-1(Trx-1) is a redox regulating protein which is induced to resist stresses and related with various diseases. Thus, it is important to examine whether Trx-1 is induced by epinephrine and to understand the underlying molecular mechanisms that Trx-1 modulates epinephrine stress. Here, we show that the expression of Trx-1 was induced by epinephrine via ß-adrenergic receptor/Cyclic AMP/protein kinase A (PKA) signaling pathway in PC12 cells. The down-regulation of Trx-1 by siRNA aggravated accumulation of γ-H2AX and further decreased expression of p53 by epinephrine. Accordingly, Trx-1 overexpression alleviated accumulation of γ-H2AX and restored the expressions of p53 and C/EBP homologous protein (CHOP) in the cortex, hippocampus and thymus of mice. Moreover, Trx-1 overexpression reduced the malondialdehyde concentration by epinephrine. We further explored the mechanism on p53 and γ-H2AX regulated by Trx-1. We found that overexpression of Trx-1 suppressed ß-arrestin-1 expression through interaction with ß-arrestin-1. Consequently, the downregulation of ß-arrestin-1 suppressed the cell viability and the expressions of γ-H2AX and cyclin D1, and increased p53 expression. Taken together, our data suggest that Trx-1/ß-arrestin-1 interaction may represent a novel endogenous mechanism on protecting against stress.
Assuntos
Arrestinas/metabolismo , Epinefrina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tiorredoxinas/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/metabolismo , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ciclina D1/metabolismo , Regulação para Baixo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Malondialdeído/análise , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células PC12 , RNA Interferente Pequeno/metabolismo , Ratos , Receptores Adrenérgicos beta/metabolismo , Tiorredoxinas/antagonistas & inibidores , Tiorredoxinas/genética , Timo/metabolismo , Fator de Transcrição CHOP/metabolismo , beta-Arrestina 1 , beta-ArrestinasRESUMO
Ephedrine (Eph) is one of alkaloids that has been isolated from the ancient herb ephedra (ma huang) and is used as the treatment of asthma, hypotension and fatigue. However, its molecular mechanism remains unknown. Thioredoxin-1 (Trx-1) is a redox regulating protein, which has various biological activities, including regulating transcription factor DNA binding activity and neuroprotection. In this study, we found that Eph induced Trx-1 expression, which was inhibited by propranolol (ß-adrenergic receptor inhibitor), but not by phenoxybenzamine (α-adrenergic receptor inhibitor) in rat pheochromocytoma PC12 cells. Moreover, the increase of Trx-1 expression was inhibited by SQ22536 (adenylyl cyclase inhibitor) and H-89 (protein kinase A inhibitor). Interestingly, the effect of Eph on dopamine- and cyclic AMP-regulated phosphoprotein (DARPP-32) was similar to Trx-1. Thus, the relationship between Trx-1 and DARPP-32 was further studied. The DARPP-32 siRNA significantly reduced Trx-1 expression, but Trx-1 siRNA did not exchange DARPP-32. These results suggested that Eph induced the Trx-1 expression through ß-adrenergic receptor/cyclic AMP/PKA/DARPP-32 signaling pathway. Furthermore, Eph induced PKA-mediated cyclic AMP response element-binding protein (CREB) phosphorylation. Down-regulation of DARPP-32 expression decreased phosphorylated CREB. In addition, Eph had a significant effect on the viability of the rat pheochromocytoma PC12 cells through ß-adrenergic receptors. Trx-1 may play an important role in the actions of Eph.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Dopamina/metabolismo , Efedrina/farmacologia , Expressão Gênica/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Tiorredoxinas/metabolismo , Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Proteína de Ligação a CREB/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Fosfoproteína 32 Regulada por cAMP e Dopamina/antagonistas & inibidores , Fosfoproteína 32 Regulada por cAMP e Dopamina/genética , Regulação para Baixo , Isoquinolinas/farmacologia , Células PC12 , Fenoxibenzamina/farmacologia , Fosforilação , Propranolol/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Receptores Adrenérgicos beta/química , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Tiorredoxinas/antagonistas & inibidores , Tiorredoxinas/genéticaRESUMO
The acute or chronic administration of opioid drugs may induce oxidative damage and cellular apoptosis in the liver and kidney, and hence result in hepatic and renal damage. Thioredoxin-1 (Trx-1) and heat shock protein 70 (Hsp70) are emerging as important modulators of cellular functions. They have been shown to be involved in cellular protective mechanisms against a variety of toxic stressors. The present study was designed to investigate the effects of geranylgeranylacetone (GGA), a pharmacological inducer of Trx-1 and Hsp70, on morphine-induced hepatic and renal damage. Morphine induced apoptosis in the liver and kidney through the mitochondria-mediated apoptosis pathway, but not the endoplasmic reticulum-mediated pathway. The activation of caspases-9 and -3 was attenuated by pretreatment with GGA. In addition, the morphine-induced increase of malondialdehyde (MDA) levels was suppressed by GGA. Furthermore, GGA enhanced morphine-induced expression of Trx-1 and Hsp70 in the liver and kidney. The findings of this study suggest that GGA may be a safe and novel therapeutic agent for morphineinduced hepatic and renal damage.