Xiaoshuang Zhou

The role of thioredoxin-1 in resisting methamphetamine-induced rewarding effect

Abstract Methamphetamine (METH) is a highly addictive drug of abuse which induces behavioral sensitization and rewarding effects. Thioredoxin‐1 (Trx‐1) is a redox protein and plays roles in regulating activity of transcription factor, such as cAMP responsive element‐binding protein (CREB), AP‐1, p53, is emerging as an important modulator of neuronal function. It has been reported that Trx‐1 is involved in morphine dependence. In this study, we examined the rewarding effect after METH administration by conditioned place preference (CPP) of mice, and detected the levels of dopamine and the activity of cAMP responsive element‐binding protein (CREB), the expressions of &Dgr;FosB and cyclin‐dependent kinase 5 (CDK5) in the ventral tegmental area (VTA) and nucleus accumbens (NAc) in mice. Our results showed that the expression of METH‐CPP was occluded in Trx‐1 overexpression transgenic (TG) mice. The increase of dopamine level induced by METH was not further higher in Trx‐1 TG mice. METH decreased the expression of Trx‐1 which was restored in TG mice. The activity of CREB and the expressions of &Dgr;FosB and CDK5 were increased by METH in wile‐type mice, which were not further increased in TG mice. These results suggest that overexpression of Trx‐1 may occlude the CPP induced by METH through regulating the activity of CREB and the expression of &Dgr;FosB.

The Role of Thioredoxin-1 in Suppression Sepsis Through Inhibiting Mitochondrial-induced Apoptosis in Spleen

ABSTRACT Sepsis is a serious public health issue and the leading cause of death in critically ill patients in intensive care units. Thioredoxin-1 (Trx-1) is a protein of regulating redox, as well as a modulator of inflammation and apoptosis. Our previous study reported that Trx-1 decreased endoplasmic reticulum-mediated inflammation involved in lung in a model of experimental sepsis. However, its effect on mitochondrial-mediated apoptosis in spleen has not been reported. We studied whether Trx-1 could prevent spleen cells apoptosis in sepsis. In the present study, we showed that the apoptosis in spleen was decreased in sepsis induced by cecal ligation and puncture (CLP) in Trx-1 overexpression transgenic (Tg) mice compared with wild-type mice. Colony forming units in the peritoneal cavity and the level of procalcitonin in plasma were significantly decreased in Trx-1 Tg mice 12 h after CLP. The expressions of c-jun-N-terminal kinase, Bax, caspase-9, and caspase-3 were increased in spleen, which were suppressed in Trx-1 Tg mice. However, the decreased Bcl-2 expression in sepsis was recovered in Trx-1 Tg mice. Our results suggest that overexpression of Trx-1 provides protection against sepsis through suppressing mitochondria-induced apoptosis pathway in spleen. This study may provide a new target for clinical intervention, as well potential strategies for treatment of sepsis.

Thioredoxin-1 Increases Survival in Sepsis by Inflammatory Response Through Suppressing Endoplasmic Reticulum Stress.

ABSTRACT Sepsis is the main cause of death in critically ill patients, pathogenesis of which is still unclear. The nuclear factor &kgr;B (NF-&kgr;B) inflammatory signal pathway mediated by endoplasmic reticulum stress is involved in sepsis. Thioredoxin-1 (Trx-1) is an important protein of regulating oxidative stress. It plays a crucial role in the anti-oxidation, anti-apoptosis, and anti-inflammation. However, the role and the mechanism of Trx-1 in sepsis have not been extensively studied. In the present study, we showed that the survival was longer in sepsis induced by cecal ligation and puncture in Trx-1 overexpression transgenic (Tg) mice compared with wild-type mice. Wet/dry lung weight ratio was decreased in Trx-1 Tg mice. The levels of TNF-&agr; and IL-1&bgr; in plasma and lung tissue were inhibited in Tg mice. The expressions of glucose-regulated protein 78, inositol-requiring enzyme 1&agr; (IRE1&agr;), tumor necrosis factor receptor-associated factor 2, C/EBP homologous protein, NF-&kgr;B, and inhibitors of NF-&kgr;B&agr; were increased in lung tissue. More importantly, the overexpression of Trx-1 in transgenic mice suppressed NF-&kgr;B inflammatory signal pathway by inhibiting the activation of molecules involved in ER stress. Our results suggest that Trx-1 may play protective role in extending survival in sepsis by regulating inflammatory response through suppressing ER stress.

The overexpression of Thioredoxin-1 suppressing inflammation induced by methamphetamine in spleen

BACKGROUND Methamphetamine (METH) is an addictive psychostimulant and has been shown to induce oxidative stress and inflammation in various tissues. Thioredoxin-1 (Trx-1) plays the roles in regulating redox and inhibiting inflammation. Whether Trx-1 is involved in METH-induced inflammation is still unknown. METHODS The present study was designed to investigate inflammatory factors in spleen of wild type and Trx-1 overexpression transgenic mice after METH treatment. RESULTS We found the mRNA level of Trx-1 was decreased and mRNA level of Trx-1 binding protein-2 (TBP-2) was increased. The mRNA levels of tumor necrosis factor-α (TNF-α), interferon-γ(IFN-γ), interleukin-2 (IL-2), T-bet and signal transducer and activators of transcription 4 (STAT 4) were increased and the mRNA levels of IL-10, GA-TA-binding protein-3 (GATA-3) and STAT 6 were decreased. Overexpression of Trx-1 reversed the above effects induced by METH. CONCLUSION The present study showed for the first time that Trx-1 overexpression suppressed the inflammation induced by METH.

The induction of thioredoxin-1 by epinephrine withdraws stress via interaction with β-arrestin-1

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 β-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 β-arrestin-1 expression through interaction with β-arrestin-1. Consequently, the downregulation of β-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/β-arrestin-1 interaction may represent a novel endogenous mechanism on protecting against stress.

Nicotine suppresses the neurotoxicity by MPP+/MPTP through activating α7nAChR/PI3K/Trx-1 and suppressing ER stress

&NA; Parkinsons disease (PD) is a neurodegenerative disease. Nicotine has been reported to have the role in preventing Parkinsons disease. However, its mechanism is still unclear. In present study we found that nicotine suppressed 1‐methyl‐4‐phenylpyridinium ion(MPP+) toxicity in PC12 cells by MTT assay. The expression of thioredoxin‐1(Trx‐1) was decreased by MPP+, which was restored by nicotine. The nicotine suppressed expressions of Glucose‐regulated protein 78(GRP78/Bip) and C/EBP homologous protein (CHOP) induced by MPP+. The methyllycaconitine (MLA), the inhibitor of &agr;7nAChR and LY294002, the inhibitor of phosphatidylinositol 3‐kinase (PI3K) blocked the suppressions of above molecules, respectively. Consistently, pretreatment with nicotine ameliorated the motor ability, restored the declines of Trx‐1 and tyrosine hydroxylase (TH), and suppressed the expressions of Bip and CHOP induced by 1‐Methy‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) in mice. Our results suggest that nicotine plays role in resisting MPP+/MPTP neurotoxicity through activating the &agr;7nAChR/PI3K/Trx‐1 pathway and suppressing ER stress. Graphical abstract Figure. No caption available. HighlightsNicotine suppressed the ER stress induced by MPP+/MPTP.Nicotine induced Trx‐1 expression.Nicotine activated &agr;7 nAChR/ PI3K pathways.

Overexpression of Thioredoxin-1 Blocks Morphine-Induced Conditioned Place Preference Through Regulating the Interaction of γ-Aminobutyric Acid and Dopamine Systems

Morphine is one kind of opioid, which is currently the most effective widely utilized pain relieving pharmaceutical. Long-term administration of morphine leads to dependence and addiction. Thioredoxin-1 (Trx-1) is an important redox regulating protein and works as a neurotrophic cofactor. Our previous study showed that geranylgeranylaceton, an inducer of Trx-1 protected mice from rewarding effects induced by morphine. However, whether overexpression of Trx-1 can block morphine-induced conditioned place preference (CPP) in mice is still unknown. In this study, we first examined whether overexpression of Trx-1 affects the CPP after morphine training and further examined the dopamine (DA) and γ-aminobutyric acid (GABA) systems involved in rewarding effects. Our results showed that morphine-induced CPP was blocked in Trx-1 overexpression transgenic (TG) mice. Trx-1 expression was induced by morphine in the ventral tegmental area (VTA) and nucleus accumbens (NAc) in wild-type (WT) mice, which was not induced in Trx-1 TG mice. The DA level and expressions of tyrosine hydroxylase (TH) and D1 were induced by morphine in WT mice, which were not induced in Trx-1 TG mice. The GABA level and expression of GABABR were decreased by morphine, which were restored in Trx-1 TG mice. Therefore, Trx-1 may play a role in blocking CPP induced by morphine through regulating the expressions of D1, TH, and GABABR in the VTA and NAc.

Trx-1 ameliorates learning and memory deficits in MPTP-induced Parkinson's disease model in mice

Abstract Parkinsons disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), characteristic motor symptoms and cognitive impairment. Thioredoxin‐1 (Trx‐1) is a redox protein and protects neurons from various injuries. Our previous study has shown that Trx‐1 overexpression attenuates movement disorder in PD. However, whether Trx‐1 ameliorates cognitive deficits in PD is still unknown. In the present study, we investigated the effects of Trx‐1 on learning and memory in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD model in mice. We demonstrated that deficits in learning and memory were induced by MPTP in mice through the elevated plus‐maze test. We found that the retention transfer latency time was shorten, escape latency was decreased and the number of platform crossings was increased in the Morris water maze (MWM) in Trx‐1 transgenic (TG) mice when compared with wild type mice. The expressions of tyrosine hydroxylase (TH) and dopamine D1 receptor (D1R) were decreased by MPTP, which were restored in Trx‐1 TG mice. The expression of N‐methyl‐D‐aspartate receptor 2B subunit (NR2B), the levels of phosphorylation of extracellular signal‐regulated kinase (ERK1/2) and cAMP‐response element binding protein (CREB) in the hippocampus were decreased by MPTP, which were reversed in Trx‐1 TG mice. These results suggest that Trx‐1 ameliorates learning and memory deficits in MPTP‐induced PD model in mice via modulating the D1R and the NMDAR‐ERK1/2‐CREB pathway. Trx‐1 may be a therapy target for learning and memory deficits in PD. Graphical abstract Figure. No Caption available. HighlightsTrx‐1 ameliorates learning and memory deficits in MPTP‐induced PD model in mice.Trx‐1 modulates the D1R activation in hippocampus.Trx‐1 regulates the NMDAR‐ERK1/2‐CREB pathway in hippocampus.

The decreased expression of thioredoxin-1 in brain of mice with experimental autoimmune myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disease caused by circulating antibodies that block acetylcholine receptor (AchR) at the neuromuscular junction. There is the cognitive and memory impairment in patients with MG. However, the molecular mechanisms underlying the alteration of central nervous system in MG remain unknown. In the present study, we found that the level of malondialdehyde (MDA) was increased in the brain of experimental autoimmune myasthenia gravis (EAMG). Furthermore, the expression of thioredoxin-1 (Trx-1) and the activity of cAMP response element-binding protein (CREB) were significantly decreased in frontal lobe and hippocampus of mice with EAMG. We also found that the expression of pro-apoptotic C/EBP homologous protein (CHOP) was increased in the frontal lobe and hippocampus of mice. However, the expressions of glucose regulated protein 78 (GRP78/Bip) was not changed in same areas. Inversely, the expressions of pro-caspase-12, pro-caspase-3 and pro-caspase-9 were decreased. These data indicate that Trx-1 mediated endoplasmic reticulum and mitochondria pathways are involved in brain damage in MG. Trx-1 may be a pivotal target for brain protective treatment in MG.

Thioredoxin-1 downregulation in the nucleus accumbens promotes methamphetamine-primed reinstatement in mice

ABSTRACT Relapse of drug abuse after abstinence is a major challenge to the treatment of addicts. Thioredoxin‐1 (Trx‐1) is an important regulator of neuroprotection, and inhibits morphine‐induced hyperlocomotion, reward and withdrawal signs, as well as blocks methamphetamine (METH)‐induced conditioned place preference (CPP). The nucleus accumbens (NAc) is essential for relapse like behavior in reinstatement animal models. In the present study, we aimed to investigate the role of Trx‐1 in the NAc in METH‐primed reinstatement by using a reinstatement procedure in mice. Adeno‐associated virus vectors expressing shRNA‐mTrx‐1 (AAV‐shRNA‐mTrx‐1) were bilaterally microinjected into the NAc after METH‐CPP extinction. The results showed that Trx‐1 downregulation in the NAc promoted the reinstatement of METH‐CPP. We also examined the expression of N‐methyl‐D‐asparate (NMDA) receptor 2B subunit (GluN2b), the levels of phosphorylated extracellular signal‐regulated kinase (p‐ERK) and phosphorylated cAMP‐response element binding protein (p‐CREB) in the NAc by western blot analysis, and found that the GluN2b expression, p‐ERK and p‐CREB levels were increased in the NAc in response to low‐dose METH in AAV‐shRNA‐mTrx‐1 mice, but were not changed in control and AAV‐vehicle mice. These data indicate that the increased GluN2b expression, and p‐ERK and p‐CREB levels in the NAc of AAV‐shRNA‐mTrx‐1 mice may be responsible for the METH‐primed reinstatement. Thus, we suggest that downregulation of Trx‐1 in the NAc may make mice more sensitive to METH reinstatement. HIGHLIGHTSTrx‐1 downregulation in NAc may make mice more sensitive to METH.Trx‐1 downregulation in NAc promotes the reinstatement of METH‐CPP.Trx‐1 downregulation in NAc promotes the activation of GluN2b/ERK/CREB pathway induced by METH.