Endoplasmic reticulum stress is implicated in the etiopathogenesis of Parkinson disease (PD). Our previous study has revealed that thioredoxin-1 (Trx-1) attenuated IRE1 activation in 1-methyl-4-phenylpyridinium ion (MPP+)/1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models. However, its exact mechanism has been largely unclear. In this research, it was reported for the first time that the protein levels of heat shock protein 90 (Hsp90) and phosphorylated cell division cycle 37 (p-Cdc37) were significantly decreased and the interaction of Hsp90/p-Cdc37 complex with IRE1 was disturbed in MPP+/MPTP-induced PD models. Trx-1 overexpression reversed the expression of Hsp90 and p-Cdc37 in cultured cells and the substantia nigra pars compacta of mice. More importantly, Trx-1 overexpression enhanced the interaction of Hsp90/p-Cdc37 complex with IRE1. In conclusion, our data demonstrated that Trx-1 inhibited IRE1 activation in PD by elevating the expression of Hsp90 and p-Cdc37 and strengthening the interaction of Hsp90/p-Cdc37 complex and IRE1.
Cell Cycle Proteins , Parkinson Disease , Mice , Animals , Humans , Cell Cycle Proteins/metabolism , Thioredoxins , HSP90 Heat-Shock Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism
Parkinson's disease (PD) is a common neurodegenerative disease and is a major culprit that harms the health of elderly people. The main pathological feature is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. The current mainstream therapeutic strategies include surgical treatment and medicine substitute therapy. However, these treatment methods sometimes have limitations. Subsequently, the treatment with stem cells (SCs) transplantation has been gradually established. SCs is a kind of cell with self-renewal ability and multi-directional differentiation potential. Transplantation of SCs, including embryonic stem cells, adult stem cells (neural stem cells and mesenchymal stem cells) and induced pluripotent stem cells, have the ability to mediate nerve regeneration and restoration within the lesioned midbrain tissue, bringing hope for the treatment of PD. In this paper, we summarize the progress in therapeutic strategies of different types of SCs in PD treatment, with an emphasis on the advantages and limitations.
Neural Stem Cells , Parkinson Disease , Stem Cell Transplantation , Aged , Dopaminergic Neurons/pathology , Humans , Parkinson Disease/therapy
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.
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.
Antineoplastic Agents/therapeutic use , Molecular Targeted Therapy , Neoplasms/drug therapy , Thioredoxins/antagonists & inhibitors , Humans , Neoplasms/metabolism
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.
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antioxidants/metabolism , Brain Ischemia/drug therapy , Neuroprotective Agents/therapeutic use , Thioredoxins/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Apoptosis/drug effects , Brain Ischemia/metabolism , Humans , Neuroprotective Agents/metabolism
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.
Disease Models, Animal , Neurotoxins/toxicity , Parkinson Disease/etiology , Parkinson Disease/pathology , Animals , Caenorhabditis elegans , Drosophila , Drug Administration Routes , Mice , Parkinson Disease/physiopathology , Rats , Snails , Zebrafish
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.
