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Hong-Juan Wu,
Chuan Liu,
Wei-Xia Duan, Shang-Cheng Xu,
Min-Di He,
Chun-Hai Chen,
Yan Wang,
Zhou Zhou,
Zheng-Ping Yu,
Lei Zhang,
Yu Chen
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ABSTRACT: Bisphenol A (BPA) is a well-known endocrine-disrupting chemical (EDC) that has received particular attention because of its widespread distribution in humans. Due to its chemical similarity to diethylstilbestrol, which is carcinogenic to mammals, the possible genotoxicity of BPA has already largely been evaluated. However, the results are still inconclusive and controversial. To investigate the genotoxic effects of BPA in rat germ cells and the potential protective action of melatonin against these effects, adult male Sprague-Dawley rats were orally administered BPA at a dose of 200mg/kg body weight per day for ten consecutive days with or without melatonin pretreatment. The thiobarbituric acid reactive substances (TBARS) level and superoxide dismutase (SOD) activity in the testes were evaluated. Subsequently, their spermatocytes were isolated, and DNA damage was assessed using an alkaline comet assay and the meiotic spread method. BPA administration did not significantly affect the weights of rats and their reproductive organs, and no alteration in sperm count was found. However, we demonstrated that BPA administration induced a significant increase in TBARS levels and a decrease in SOD activity that were concomitant with an increase in DNA migration within male germ cells and γH2AX foci formation on the autosomes of pachytene spermatocytes. Furthermore, a decrease in the proportion of 4C-cells was observed. These BPA effects were significantly alleviated by melatonin pretreatment. Nevertheless, the genotoxic effects of BPA were not accompanied by apoptosis in germ cells and morphological changes in the testes. These results indicate that BPA exposure may induce DNA damage accumulation in germ cells via oxidative stress. Moreover, melatonin may be a promising pharmacological candidate for preventing the potential genotoxicity of BPA following occupational or environmental exposure.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 04/2013; 752(1-2):57-67. · 2.85 Impact Factor
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ABSTRACT: Tau protein, a microtubule-associated protein involved in a number of neurological disorders such as Alzheimer's disease (AD), may undergo modifications under both physiological and pathological conditions. However, the signaling pathways that couple tau protein to neuronal physiology such as synaptic plasticity have not yet been elucidated. Here we report that tau protein is involved in morphological plasticity in response to brain derived neurotrophic factor (BDNF). Stimulation of the cultured rat hippocampal neurons with BDNF resulted in increased tau protein expression, as detected by Western blotting. Furthermore, tau protein accumulated in the distal region of the neurite when treated with taxol or taxol plus BDNF. The increased tau protein also protected neurons against nocodazole-induced dendrite loss. Moreover, BDNF promoted spine growth as well as tau protein over-expression. Knockdown of tau protein using specific short-hairpin RNA (shRNA) significantly decreased the spine density. And BDNF could not increase the spine density of tau-knockdown neurons. These results highlight a possible role for tau protein in the dynamic rearrangement of cytoskeletal fibers vital for BDNF-induced synaptic plasticity.
Neurochemistry International 02/2012; 60(3):233-42. · 2.86 Impact Factor
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Shang-Cheng Xu,
Yong-Biao Chen,
Heng Lin,
Hui-Feng Pi,
Ni-Xian Zhang,
Chang-Chun Zhao,
Ling Shuai,
Min Zhong,
Zheng-Ping Yu,
Zhou Zhou,
Ping Bie
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ABSTRACT: Oxidative stress and mitochondrial dysfunction are involved in the pathogenesis of chronic liver cholestasis. Mitochondrial DNA (mtDNA) is highly susceptible to oxidative stress and mtDNA damage leads to mitochondrial dysfunction. This study aimed to investigate the mtDNA alterations that occurred during liver injury in patients with extrahepatic cholestasis. Along with an increase in malondialdehyde (MDA) levels and a decrease in ATP levels, extrahepatic cholestatic patients presented a significant increase in mitochondrial 8-hydroxydeoxyguanosine (8-OHdG) levels and decreases in mtDNA copy number, mtDNA transcript levels, and mtDNA nucleoid structure. In L02 cells, glycochenodeoxycholic acid (GCDCA) induced similar damage to the mtDNA and mitochondria. In line with the mtDNA alterations, the mRNA and protein levels of mitochondrial transcription factor A (TFAM) were significantly decreased both in cholestatic patients and in GCDCA-treated L02 cells. Moreover, overexpression of TFAM could efficiently attenuate the mtDNA damage induced by GCDCA in L02 cells. However, without its C-tail, ΔC-TFAM appeared less effective against the hepatotoxicity of GCDCA than the wild-type TFAM. Overall, our study demonstrates that mtDNA damage is involved in liver damage in extrahepatic cholestatic patients. The mtDNA damage is attributable to the loss of TFAM. TFAM has mtDNA-protective effects against the hepatotoxicity of bile acid during cholestasis.
Free radical biology & medicine 01/2012; 52(9):1543-51. · 5.42 Impact Factor
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ABSTRACT: Recent studies suggest that oxidative stress and mitochondrial dysfunction play important roles in the neurotoxicity of nickel. Because mitochondrial DNA (mtDNA) is highly vulnerable to oxidative stress and melatonin can efficiently protect mtDNA against oxidative damage in various pathological conditions, the aims of this study were to determine whether mtDNA oxidative damage was involved in the neurotoxicity of nickel and to assay the neuroprotective effects of melatonin in mtDNA. In this study, we exposed mouse neuroblastoma cell lines (Neuro2a) to different concentrations of nickel chloride (NiCl(2), 0.125, 0.25, and 0.5 mm) for 24 hr. We found that nickel significantly increased reactive oxygen species (ROS) production and mitochondrial superoxide levels. In addition, nickel exposure increased mitochondrial 8-hydroxyguanine (8-OHdG) content and reduced mtDNA content and mtDNA transcript levels. Consistent with this finding, nickel was found to destroy mtDNA nucleoid structure and decrease protein levels of Tfam, a key protein component for nucleoid organization. However, all the oxidative damage to mtDNA induced by nickel was efficiently attenuated by melatonin pretreatment. Our results suggest that oxidative damage to mtDNA may account for the neurotoxicity of nickel. Melatonin has great pharmacological potential in protecting mtDNA against the adverse effects of nickel in the nervous system.
Journal of Pineal Research 05/2011; 51(4):426-33. · 5.79 Impact Factor
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Min-Di He, Shang-Cheng Xu,
Yong-Hui Lu,
Li Li,
Min Zhong,
Yan-Wen Zhang,
Yuan Wang,
Min Li,
Ju Yang,
Guang-Bin Zhang,
Zheng-Ping Yu,
Zhou Zhou
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ABSTRACT: Mitochondrial dysfunction is thought to be a part of the mechanism underlying nickel-induced neurotoxicity. L-carnitine (LC), a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine in all mammalian species, manifests its neuroprotective effects by improving mitochondrial energetics and function. The purpose of this study was to investigate whether LC could efficiently protect against nickel-induced neurotoxicity. Here, we exposed a mouse neuroblastoma cell line (Neuro-2a) to different concentrations of nickel chloride (NiCl₂) (0.25, 0.5, 1, and 2 mM) for 24 h, or to 0.5 mM and 1 mM NiCl₂ for various periods (0, 3, 6, 12, or 24 h). We found that nickel significantly increased the cell viability loss and lactate dehydrogenase (LDH) release in Neuro-2a cells. In addition, nickel exposure significantly elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels, disrupted the mitochondrial membrane potential (ΔΨ(m)), reduced adenosine-5'-triphosphate (ATP) concentrations and decreased mitochondrial DNA (mtDNA) copy numbers and mtRNA transcript levels. However, all of the cytotoxicities and mitochondrial dysfunctions that were triggered by nickel were efficiently attenuated by pretreatment with LC. These protective effects of LC may be attributable to its role in maintaining mitochondrial function in nickel-treated cells. Our results suggest that LC may have great pharmacological potential in protecting against the adverse effects of nickel in the nervous system.
Toxicology and Applied Pharmacology 03/2011; 253(1):38-44. · 4.45 Impact Factor
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ABSTRACT: Nickel is a potential neurotoxic pollutant. Oxidative stress is supposed to be involved in the mechanism underlying nickel-induced neurotoxicity. Melatonin has efficient protective effects against various oxidative damages in nervous system. The purpose of this study was to investigate whether melatonin could efficiently protect against neurotoxicity induced by nickel. Here, we exposed primary cultured cortical neurons and mouse neuroblastoma cell lines (neuro2a) to different concentrations of nickel chloride (NiCl(2)) (0.125, 0.25, 0.5, and 1 mm) for 12 hr or 0.5 mm NiCl(2) for various periods (0, 3, 6, 12, and 24 hr). We found that nickel significantly increased reactive oxygen species production and caused the loss of cell viability both in cortical neurons and neuro2a cells. In addition, nickel exposure obviously inhibited the mitochondrial function, disrupted the mitochondrial membrane potential (DeltaPsim), reduced ATP production, and decreased mitochondrial DNA (mtDNA) content. However, each of these oxidative damages was efficiently attenuated by melatonin pretreatment. These protective effects of melatonin may be attributable to its roles in reducing oxidative stress and improving mitochondrial function in nickel-treated nerve cells. Our results suggested that melatonin may have great pharmacological potential in protecting against the adverse effects of nickel in the nervous system.
Journal of Pineal Research 08/2010; 49(1):86-94. · 5.79 Impact Factor
