[Show abstract][Hide abstract] ABSTRACT: 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.
Canadian Journal of Physiology and Pharmacology 02/2014; 92(2):102-8. · 1.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thank you for your interest and your comments on our paper titled Panaxatriol saponin ameliorated liver injury by acetaminophen via restoring thioredoxin-1 and pro-caspase-12. We answered the concerns as following: It is correct that toxicity of acetaminophen depends on its metabolic activation to N-acetyl-pbenzoquinoneimine (NAPQI) by cytochrome P450 enzymes. It is well known that many substances exert powerful protective effect against acetaminophen hepatotoxicity by inhibiting its cytochrome P450-mediated biotransformation (1). This article is protected by copyright. All rights reserved.
Liver international: official journal of the International Association for the Study of the Liver 01/2014; · 3.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endoplasmic reticulum (ER) stress has been implicated in Parkinson's disease. We previously reported that thioredoxin 1(Trx-1) suppressed the ER stress by 1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP), however its molecular mechanism remains largely unknown. In the present study, we showed that 1-Methyl-4-phenylpyridinium ion(MPP(+)) induced ER stress via activating glucose-regulated protein 78(GRP78), inositol-requiring enzyme 1α(IRE 1α), tumor necrosis factor receptor associated factor 2(TRAF 2), 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 expressions of above molecules induced by MPP(+). On the contrary, overexpression of Trx-1 attenuated the ER stress and repressed the expressions of above molecules induced by MPP(+). More importantly, the overexpression of Trx-1 in transgenic mice suppressed ER stress by inhibiting the activations of these molecules. We presented for the first time, the molecular mechanism of Trx-1 suppressing endoplasmic reticulum stress in Parkinson's disease in vitro and in vivo. Based on these findings, we concluded that Trx-1 played a neuroprotective role in Parkinson's disease by suppressing ER stress through regulating the activations of GRP78, IRE 1α, TRAF 2, JNK, caspase-12 and CHOP.
Free Radical Biology & Medicine 10/2013; · 5.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acetaminophen (APAP) is widely used as an antipyretic agent which is safe at therapeutic doses. However, overdose of APAP induces fatal and non-fatal hepatic necroses. The chemical reactive metabolites of APAP initiate toxicity and inflammatory response within the liver and lead to acute liver failure. However, the mechanism underlying APAP-induced liver injury is unknown. Thioredoxin-1 (TRX-1) is an important redox regulator, which plays roles in resisting oxidative stress, regulating inflammation and inhibiting apoptosis. Panaxatriol saponin (PTS) is one of the biologically active fractions of Panax notoginseng which is a traditional Chinese medicine. The aim of this study was to investigate the mechanism on PTS protecting liver from APAP hepatotoxicity.
Mice were divided into three groups, control group, APAP group and APAP combined with PTS group. Alanine aminotransferase (ALT) and tumour necrosis factor-alpha (TNF-α) were detected by ELISA. TRX-1 and pro-caspase-12 were examined by Western blotting.
Our results showed PTS inhibited the levels of ALT and TNF-α by APAP. Pretreatment with PTS ameliorated liver injury induced by APAP. The decrease in TRX-1 expression was restored by PTS, as well as decreased pro-caspase-12 expression was inhibited by PTS. These data suggest that PTS has roles in suppressing the hepatotoxicity by APAP.
Panaxatriol saponin ameliorated liver injury by APAP through restoring the expression TRX-1 and inhibiting pro-caspase-12 decrease.
Liver international: official journal of the International Association for the Study of the Liver 09/2013; · 3.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 (β-adrenergic receptors inhibitor), but not by phenoxybenzamine (α-adrenergic receptors 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 β-adrenergic receptors/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 β-adrenergic receptors. Trx-1 may play an important role in the actions of Eph.
[Show abstract][Hide abstract] ABSTRACT: Methamphetamine (METH) is one of the most commonly abused agents by illicit-drug users. Thioredoxin-1 (Trx-1) plays important biological roles both in intra- and extracellular compartments, including in regulation of various intracellular molecules via thiol redox control. In this study, we found that Trx-1 was induced by METH in rat pheochromocytoma PC12 cells. Furthermore, PI3K/Akt pathway was involved in METH-induced increase of Trx-1 expression. An increase in phosphorylated cAMP response element-binding protein (CREB) was also observed after exposure of PC12 cells to METH, which was inhibited by a PI3K inhibitor, LY294002. In addition, the siRNA targeted toTrx-1 reduced the level of phosphorylated CREB by METH, suggesting Trx-1 is necessary for increased activity of CREB by METH. The results obtained in this study showed that Trx-1 might play a role in the actions of METH.
Cellular and Molecular Neurobiology 12/2012; · 2.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 pre‑treatment 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 morphine‑induced hepatic and renal damage.
Molecular Medicine Reports 12/2012; · 1.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Attempts are being made to identify genes targeted by morphine. It is beneficial for developing new treatments that alleviate side-effects of morphine. Thioredoxin-1 is a small ubiquitous protein that has various biological activities, such as the control of redox balance, the inhibition of apoptosis and the modulation of inflammation. In this study, we found that thioredoxin-1 was induced by morphine in SH-SY5Y cells. Furthermore, opioid receptor, PI3K and ERK pathways were involved in morphine-induced increase of thioredoxin-1 expression. These results suggest that thioredoxin-1 maybe play a role in the actions of morphine. More detailed analysis could clarify cellular and molecular mechanisms involved in the actions of morphine.
[Show abstract][Hide abstract] ABSTRACT: There are few efficacious interventions to combat morphine dependence. Thioredoxin-1 (Trx-1) and heat shock protein 70 (Hsp70) are emerging as important modulators of neuronal function. They have been shown to be involved in cellular protective mechanisms against a variety of toxic stressors. This study was designed to investigate the effects of geranylgeranylacetone (GGA), a pharmacological inducer of Trx-1 and Hsp70, on morphine-induced hyperlocomotion, rewarding effect, and withdrawal syndrome. Trx-1 and Hsp70 expression was increased in the frontal cortex, hippocampus, ventral tegmental area, and nucleus accumbens of mice after GGA treatment. GGA administration reduced morphine-induced motor activity and inhibited conditioned place preference. GGA markedly attenuated the morphine-naloxone-induced withdrawal signs, including jumping, rearing, and forepaw tremor. Furthermore, the activation of cAMP-responsive element-binding protein and the expression of ΔFosB and cyclin-dependent kinase 5 were decreased in the nucleus accumbens by GGA treatment after morphine withdrawal. In the nucleus accumbens, GGA enhanced morphine-induced expression of Trx-1 and Hsp70 after morphine withdrawal. These results suggest that strengthening the expression of Trx-1 and Hsp70 in the brain by using noncytotoxic pharmacological inducers may provide a novel therapeutic strategy for morphine dependence. GGA could be a safe and novel therapeutic agent for morphine dependence.
[Show abstract][Hide abstract] ABSTRACT: Formaldehyde (FA), a common environmental pollutant, has toxic effects on central nervous system. The detailed mechanisms on FA-induced neurotoxicity have not been fully elucidated. In this study, we found that glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) expression, biomarkers of endoplasmic reticulum (ER) stress, were increased and pro-caspase-12 was decreased after PC12 cells exposure to FA. These results suggest that FA actually induces ER stress. Thioredoxin-1 (Trx-1) has various biological activities, including the control of redox balance, the modulation of ER stress and inhibition of apoptosis. In the present study, Trx-1 expression was increased at early stage, but decreased at late stage after FA treatment. Knockdown of Trx-1 expression increased the susceptibility of PC12 cells to FA-induced neurotoxicity. We also found that ginsenoside Rg1 had the potential to induce Trx-1 expression and attenuated neurotoxicity induced by FA. ER stress caused by FA was suppressed by ginsenoside Rg1. These data indicate that Trx-1 is a therapeutic candidate for protecting against FA-induced neurotoxicity.
[Show abstract][Hide abstract] ABSTRACT: Preterm delivery (PTD) is the leading cause of infant mortality and morbidity. However, the mechanism at the molecular level is still unknown. Placental inflammatory response and oxidative stress are associated with PTD. Thioredoxin-1 (TRX-1) regulates oxidative stress, inflammation, and the activities of transcription factors.
The objective was to detect in placental tissues the expressions of TRX-1 and the TRX-1-related molecules: tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), thioredoxin-1-binding protein-2 (TBP-2), hypoxia inducible transcription factor 1α (HIF-1α), and forkhead box protein O3A (FoxO3A).
PTD was defined as gestation of <37 weeks and term delivery (TD) as ≥37 weeks. The expressions of TRX-1 and TRX-1-related molecules were examined in placental tissues by real-time polymerase chain rection and western blot.
The expressions of TRX-1, TNF-α, COX-2, HIF-1α, and FoxO3A in the placenta of PTD were significantly higher as compared with TD, but no difference was observed in TBP-2 expression.
These results indicate that TRX-1 may be adaptively induced by the effects of inflammation and oxidative stress, suggesting protective roles for TRX-1 against these effects in the placenta of PTD.
Redox report: communications in free radical research 01/2012; 17(5):187-93. · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Panaxatriol saponins (PTS), the main constituents extracted from Panax notoginseng, a Chinese herbal medicine, has been shown to be an effective agent on various diseases. Our previous study has demonstrated that PTS is an inducer of thioredoxin-1 (Trx-1) and has a possible potential as a therapeutic agent for Parkinson's disease (PD). However, the effect of PTS on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in vivo is unknown.
Using locomotor activity test and traction test, we detected the effect of PTS on MPTP-induced behavioral impairment. Tyrosine hydroxylase, Trx-1, cyclooxygenase-2, pro-caspase-9, pro-caspase-12 and caspase-3 expressions in the anatomical region of substantia nigra pars compacta (SNc) were tested by Western blot.
PTS provided neuroprotection against the loss of dopaminergic neurons and behavioral impairment caused by MPTP. MPTP-induced neuronal death in the SNc was suppressed by PTS through increasing Trx-1 expression, suppressing cyclooxygenase-2 over-expression and inhibiting mitochondria-mediated apoptosis.
PTS, an inducer of Trx-1, has pluripharmacological properties in the protection against PD including enhancing antioxidant activity, acting as neurotrophic factor, modulating inflammation and inhibiting mitochondria-mediated apoptosis.
Journal of ethnopharmacology 10/2010; 133(2):448-53. · 2.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thioredoxin-1 has various biologic activities, including the control of redox balance and the inhibition of apoptosis. The current study was designed to examine the effects of panaxatriol saponins (PTS) extracted from Panax notoginseng on thioredoxin-1 expression and 1-methyl-4-phenylpyridinium ion-induced injury.
Using PC12 cells and Kunming mice, we test thioredoxin-1 expression after PTS treatment by Western blot. The protective effect of PTS against 1-methyl-4-phenylpyridinium ion-induced injury was assessed by MTT assay and LDH release assay.
PTS induced thioredoxin-1 expression in vitro and in vivo, and attenuated 1-methyl-4-phenylpyridinium ion-induced cell death of PC12 cells.
PTS is a new inducer of thioredoxin-1 and has a possible potential as a therapeutic agent for neurodegenerative diseases including Parkinson's disease.
Journal of ethnopharmacology 10/2009; 127(2):419-23. · 2.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thioredoxin (TRX) is a redox-active protein which is induced by oxidative stresses and shows a variety of biological activities including cytoprotection against oxidative stress. We recently reported that geranylgeranylacetone (GGA), an anti-ulcer drug, induces TRX in rat hepatocytes. In this study, we demonstrate that GGA promotes induction and secretion of TRX in rat gastric mucosal cells and human peripheral blood lymphocytes (PBLs). Western blotting and a sensitive sandwich ELISA showed that TRX was induced by GGA in the cell lysates and culture supernatants of rat gastric mucosal RGM-1 cells and human PBLs. LDH releasing assay showed that GGA protected rat gastric mucosal RGM-1 cells from ethanol-induced cytotoxicity. Moreover, exogenous recombinant wild type TRX decreased 51Cr release from primary cultured rat gastric mucosal cells incubated with ethanol or hydrogen peroxide in a dose-dependent manner, whereas recombinant mutant TRX (C32S/C35S), in which the two cysteines were replaced with serines in its active site, did not. These results indicate that GGA promotes the induction and secretion of TRX in a variety of types of cells and suggest that induced or secreted TRX may play an important role in the cytoprotective action of GGA on gastric mucosal cells.
Free Radical Research 07/2009; 35(1):23-30. · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We show that 1-methyl-4-phenylpyridinium ion (MPP(+)), an active metabolite of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), induces cytotoxicity via endoplasmic reticulum (ER)- and mitochondria-mediated pathways, and thioredoxin-1 (TRX-1), a redox-active protein, prevents MPTP-induced neurotoxicity. TRX-1 overexpression suppressed reactive oxygen species and the ATP decline caused by MPP(+) in HepG2 cells. MPP(+) activated caspase-12 in PC12 cells and induced cytotoxicity in HeLa-rho(0) cells lacking mitochondrial DNA, as well as in the parental HeLa-S3 cells. TRX-1-transgenic mice demonstrated significant resistance to caspase-12 activation and the apoptotic decrease of dopaminergic neurons after MPTP administration, compared with wild-type C57BL/6 mice.
Antioxidants and Redox Signaling 06/2007; 9(5):603-8. · 7.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exposure to excessive light induces retinal photoreceptor cell damage, leading to development and progression of various retinal diseases. We tested the effect of geranylgeranylacetone (GGA), an acyclic polyisoprenoid, on light-induced retinal damage in mice. Oral treatment with GGA (1.0 mg/d) for 5 d induced thioredoxin (Trx) and heat shock protein 72 (Hsp72) predominantly in the retinal pigment epithelium (RPE). After white light exposure (8000 lux for 2 h), the percentage of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive photoreceptor cells decreased significantly at 24 and 96 h, and the number of photoreceptor cell nuclei at 96 h and the electroretinographic amplitudes of the a- and b-waves at 4 and 10 d increased significantly in GGA-pretreated mice compared with saline-pretreated mice. Light-induced upregulations of 8-hydroxy-2-deoxyguanosine and 4-hydroxy-2-nonenal-modified protein, markers of oxidative stress, were inhibited by GGA pretreatment. To elucidate the cytoprotective mechanism of GGA and Trx, we used human K-1034 RPE cells and mouse photoreceptor-derived 661W cells. In K-1034 cells, GGA (10 microM) induced intracellular Trx, Hsp72, and extracellular Trx but not extracellular Hsp72. Extracellular Trx (0.75 nM) attenuated H2O2 (200 microM)-induced cell damage in 661W cells. Pretreatment with GGA and overexpression of Trx in K-1034 cells counteracted H2O2 (50 microM)-induced attenuation of cellular latex bead incorporation. Protection of phagocytotic activity through induction of Trx and possibly Hsp72 in RPE cells and elimination of oxidative stress in the photoreceptor layer through release of Trx from RPE cells may be mechanisms of GGA-mediated cytoprotection. Therefore, Trx is a neurotrophic factor released from RPE cells and plays a crucial role in maintaining photoreceptor cell integrity.
Journal of Neuroscience 04/2005; 25(9):2396-404. · 6.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 1-Methyl-4-phenylpyridinium ion (MPP(+)), an active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, induces cell death and inhibition of cell proliferation in various cells. However, the mechanism whereby MPP(+) inhibits cell proliferation is still unclear. In this study, we found that MPP(+) suppressed the proliferation with accumulation in G(1) phase without inducing cell death in p53-deficient MG63 osteosarcoma cells. MPP(+) induced hypophosphorylation of retinoblastoma protein and rapidly down-regulated the protein but not mRNA levels of cyclin D1 in MG63 cells. The down-regulation of cyclin D1 protein was suppressed by a proteasome inhibitor, MG132. The cyclin D1 down-regulation by MPP(+) was also observed in p53-positive PC12, HeLa S3, and HeLa rho(0) cells, which are a subclone of HeLa S3 lacking mitochondrial DNA. Moreover, MPP(+) dephosphorylated Akt in PC12 cells, which was rescued by the pretreatment with nerve growth factor. In addition, the pretreatment with nerve growth factor or lithium chloride, a glycogen synthase kinase-3beta inhibitor, suppressed the cyclin D1 down-regulation caused by MPP(+). Our results demonstrate that MPP(+) induces cell cycle arrest independently of its mitochondrial toxicity or the p53 status of the target cells, but rather through the proteasome- and phosphatidylinositol 3-Akt-glycogen synthase kinase-3beta-dependent cyclin D1 degradation.
Journal of Biological Chemistry 10/2004; 279(37):38710-4. · 4.65 Impact Factor