char = D;code = 68
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char = e;code = 101
char = r;code = 114
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = c;code = 99
char = h;code = 104
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char = i;code = 105
char = s;code = 115
char = m;code = 109
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = a;code = 97
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = t;code = 116
char = ,;code = 44
char = ;code = 32
char = M;code = 77
char = P;code = 80
char = P;code = 80
char = +;code = 43
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = r;code = 114
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = c;code = 99
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = :;code = 58
char = ;code = 32
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = d;code = 100
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = o;code = 111
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = s;code = 115
char = p;code = 112
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = -;code = 45
char = 3;code = 51
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = .;code = 46
result sql = Divergent mechanisms of paraquat, MPP+, and rotenone toxicity: oxidation of thioredoxin and caspase-3 activation.
Divergent mechanisms of paraquat, MPP+, and rotenone toxicity: oxidation of thioredoxin and caspase-3 activation.
char = P;code = 80
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char = a;code = 97
char = q;code = 113
char = u;code = 117
char = a;code = 97
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char = ,;code = 44
char = ;code = 32
char = N;code = 78
char = -;code = 45
char = m;code = 109
char = e;code = 101
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char = y;code = 121
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char = 2;code = 50
char = ,;code = 44
char = 3;code = 51
char = ,;code = 44
char = 6;code = 54
char = ;code = 32
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char = e;code = 101
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char = r;code = 114
char = a;code = 97
char = h;code = 104
char = y;code = 121
char = d;code = 100
char = r;code = 114
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char = p;code = 112
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char = i;code = 105
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = e;code = 101
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char = ;code = 32
char = a;code = 97
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char = ;code = 32
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char = e;code = 101
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char = o;code = 111
char = n;code = 110
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char = b;code = 98
char = e;code = 101
char = e;code = 101
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char = ;code = 32
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char = o;code = 111
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char = t;code = 116
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char = p;code = 112
char = r;code = 114
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char = d;code = 100
char = u;code = 117
char = c;code = 99
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char = ;code = 32
char = s;code = 115
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char = v;code = 118
char = e;code = 101
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char = a;code = 97
char = l;code = 108
char = ;code = 32
char = f;code = 102
char = e;code = 101
char = a;code = 97
char = t;code = 116
char = u;code = 117
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char = e;code = 101
char = s;code = 115
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char = f;code = 102
char = ;code = 32
char = P;code = 80
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char = r;code = 114
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char = n;code = 110
char = ';code = 39
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char = ;code = 32
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char = s;code = 115
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = i;code = 105
char = m;code = 109
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = c;code = 99
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char = l;code = 108
char = l;code = 108
char = ;code = 32
char = c;code = 99
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char = l;code = 108
char = t;code = 116
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = m;code = 109
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char = d;code = 100
char = e;code = 101
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char = s;code = 115
char = .;code = 46
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char = A;code = 65
char = l;code = 108
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char = h;code = 104
char = o;code = 111
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char = g;code = 103
char = h;code = 104
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = e;code = 101
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = e;code = 101
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char = i;code = 105
char = c;code = 99
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char = l;code = 108
char = s;code = 115
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char = a;code = 97
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = k;code = 107
char = n;code = 110
char = o;code = 111
char = w;code = 119
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = p;code = 112
char = e;code = 101
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char = u;code = 117
char = r;code = 114
char = b;code = 98
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = p;code = 112
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = n;code = 110
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char = ;code = 32
char = h;code = 104
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = o;code = 111
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char = t;code = 116
char = a;code = 97
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char = i;code = 105
char = s;code = 115
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char = ;code = 32
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char = u;code = 117
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char = e;code = 101
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char = i;code = 105
char = c;code = 99
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char = c;code = 99
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char = l;code = 108
char = l;code = 108
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char = d;code = 100
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char = a;code = 97
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char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = m;code = 109
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char = e;code = 101
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char = u;code = 117
char = l;code = 108
char = a;code = 97
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char = o;code = 111
char = f;code = 102
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char = a;code = 97
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char = o;code = 111
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char = a;code = 97
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char = e;code = 101
char = ;code = 32
char = n;code = 110
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char = ;code = 32
char = w;code = 119
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char = l;code = 108
char = l;code = 108
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = f;code = 102
char = i;code = 105
char = n;code = 110
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char = d;code = 100
char = .;code = 46
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char = W;code = 87
char = e;code = 101
char = ;code = 32
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char = e;code = 101
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char = l;code = 108
char = y;code = 121
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char = t;code = 116
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char = a;code = 97
char = q;code = 113
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char = a;code = 97
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char = u;code = 117
char = i;code = 105
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char = e;code = 101
char = ;code = 32
char = f;code = 102
char = u;code = 117
char = n;code = 110
char = c;code = 99
char = t;code = 116
char = i;code = 105
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char = n;code = 110
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = p;code = 112
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = t;code = 116
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char = a;code = 97
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char = s;code = 115
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char = P;code = 80
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result sql = Paraquat, N-methyl-4-phenyl-1,2,3,6 tetrahydropyridine, and rotenone have been shown to reproduce several features of Parkinson's disease in animal and cell culture models. Although these chemicals are known to perturb dopamine homeostasis and induce dopaminergic cell death, their molecular mechanisms of action are not well defined. We have previously shown that paraquat does not require functional dopamine transporter and does not inhibit mitochondrial complex I in order to mediate its toxic action (Richardson et al., 2005). In this study, we show that paraquat specifically oxidized the cytosolic form of thioredoxin and activated Jun N-terminal kinase (JNK), followed by caspase-3 activation. Conversely, 1-methyl-4-phenylpyridinium (MPP(+)) and rotenone oxidized the mitochondrial form of thioredoxin but did not activate JNK-mitogen-activated protein kinase and caspase-3. Loading cells with exogenous dopamine did not exacerbate the toxicity of any of these compounds. These data suggest that oxidative modification of cytosolic proteins is critical to paraquat toxicity, while oxidation of mitochondrial proteins is important for MPP(+) and rotenone toxicity. In addition, intracellular dopamine does not seem to exacerbate the toxicity of these dopaminergic neurotoxicants in this model.

Publication: Toxicol. Sci. 2007 Jan ;95(1)::163-71.
Publication Date: 2007 Jan
Study Author(s): Ramachandiran, Sampath;Hansen, Jason M;Jones, Dean P;Richardson, Jason R;Miller, Gary W;
Institution: Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, Georgia 30322, USA.
Shortcut link to this study:
Paraquat, N-methyl-4-phenyl-1,2,3,6 tetrahydropyridine, and rotenone have been shown to reproduce several features of Parkinson's disease in animal and cell culture models. Although these chemicals are known to perturb dopamine homeostasis and induce dopaminergic cell death, their molecular mechanisms of action are not well defined. We have previously shown that paraquat does not require functional dopamine transporter and does not inhibit mitochondrial complex I in order to mediate its toxic action (Richardson et al., 2005). In this study, we show that paraquat specifically oxidized the cytosolic form of thioredoxin and activated Jun N-terminal kinase (JNK), followed by caspase-3 activation. Conversely, 1-methyl-4-phenylpyridinium (MPP(+)) and rotenone oxidized the mitochondrial form of thioredoxin but did not activate JNK-mitogen-activated protein kinase and caspase-3. Loading cells with exogenous dopamine did not exacerbate the toxicity of any of these compounds. These data suggest that oxidative modification of cytosolic proteins is critical to paraquat toxicity, while oxidation of mitochondrial proteins is important for MPP(+) and rotenone toxicity. In addition, intracellular dopamine does not seem to exacerbate the toxicity of these dopaminergic neurotoxicants in this model.
PMID: 17018646

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