|
|
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result sql = Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b.
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char = i;code = 105
char = n;code = 110
char = f;code = 102
char = l;code = 108
char = a;code = 97
char = m;code = 109
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = m;code = 109
char = m;code = 109
char = u;code = 117
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = e;code = 101
char = n;code = 110
char = g;code = 103
char = e;code = 101
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = R;code = 82
char = E;code = 69
char = S;code = 83
char = U;code = 85
char = L;code = 76
char = T;code = 84
char = S;code = 83
char = ;code = 32
char = :;code = 58
char = ;code = 32
char = <;code = 60
char = /;code = 47
char = b;code = 98
char = >;code = 62
char = T;code = 84
char = e;code = 101
char = l;code = 108
char = m;code = 109
char = i;code = 105
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = n;code = 110
char = g;code = 103
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = z;code = 122
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 0;code = 48
char = .;code = 46
char = 0;code = 48
char = 4;code = 52
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = V;code = 86
char = D;code = 68
char = R;code = 82
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = A;code = 65
char = R;code = 82
char = B;code = 66
char = s;code = 115
char = ;code = 32
char = O;code = 79
char = l;code = 108
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ,;code = 44
char = ;code = 32
char = I;code = 73
char = r;code = 114
char = b;code = 98
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = V;code = 86
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = 1;code = 49
char = 0;code = 48
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = k;code = 107
char = e;code = 101
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = f;code = 102
char = u;code = 117
char = l;code = 108
char = ;code = 32
char = V;code = 86
char = D;code = 68
char = R;code = 82
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = y;code = 121
char = p;code = 112
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = -;code = 45
char = v;code = 118
char = i;code = 105
char = v;code = 118
char = o;code = 111
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = C;code = 67
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 3;code = 51
char = 0;code = 48
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = L;code = 76
char = o;code = 111
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 7;code = 55
char = 0;code = 48
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = f;code = 102
char = u;code = 117
char = l;code = 108
char = l;code = 108
char = y;code = 121
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char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = V;code = 86
char = D;code = 68
char = R;code = 82
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = e;code = 101
char = l;code = 108
char = m;code = 109
char = i;code = 105
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = m;code = 109
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char = d;code = 100
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = P;code = 80
char = P;code = 80
char = A;code = 65
char = R;code = 82
char = g;code = 103
char = a;code = 97
char = m;code = 109
char = m;code = 109
char = a;code = 97
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 0;code = 48
char = .;code = 46
char = 3;code = 51
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = i;code = 105
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = L;code = 76
char = o;code = 111
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 3;code = 51
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = I;code = 73
char = r;code = 114
char = b;code = 98
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 6;code = 54
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = O;code = 79
char = l;code = 108
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = V;code = 86
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
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char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
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char = t;code = 116
char = o;code = 111
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char = 1;code = 49
char = 2;code = 50
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char = n;code = 110
char = m;code = 109
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char = l;code = 108
char = );code = 41
char = ;code = 32
char = a;code = 97
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char = s;code = 115
char = o;code = 111
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char = s;code = 115
char = e;code = 101
char = e;code = 101
char = m;code = 109
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char = l;code = 108
char = i;code = 105
char = k;code = 107
char = e;code = 101
char = l;code = 108
char = y;code = 121
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char = t;code = 116
char = o;code = 111
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = v;code = 118
char = e;code = 101
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char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = i;code = 105
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = P;code = 80
char = P;code = 80
char = A;code = 65
char = R;code = 82
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char = m;code = 109
char = o;code = 111
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
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char = y;code = 121
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = .;code = 46
char = ;code = 32
char = O;code = 79
char = l;code = 108
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = I;code = 73
char = r;code = 114
char = b;code = 98
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
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char = (;code = 40
char = K;code = 75
char = i;code = 105
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char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
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char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
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char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 9;code = 57
char = ;code = 32
char = n;code = 110
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char = ;code = 32
char = a;code = 97
char = d;code = 100
char = d;code = 100
char = i;code = 105
char = t;code = 116
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char = o;code = 111
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char = a;code = 97
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char = l;code = 108
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = a;code = 97
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char = ;code = 32
char = a;code = 97
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char = t;code = 116
char = a;code = 97
char = g;code = 103
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = o;code = 111
char = r;code = 114
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
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char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = C;code = 67
char = C;code = 67
char = R;code = 82
char = 2;code = 50
char = b;code = 98
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = n;code = 110
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = v;code = 118
char = a;code = 97
char = l;code = 108
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
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = C;code = 67
char = C;code = 67
char = R;code = 82
char = 2;code = 50
char = b;code = 98
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
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result sql = BACKGROUND : There have been indications that common Angiotensin Receptor Blockers (ARBs) may be exerting anti-inflammatory actions by directly modulating the immune system. We decided to use molecular modelling to rapidly assess which of the potential targets might justify the expense of detailed laboratory validation. We first studied the VDR nuclear receptor, which is activated by the secosteroid hormone 1,25-dihydroxyvitamin-D. This receptor mediates the expression of regulators as ubiquitous as GnRH (Gonadatrophin hormone releasing hormone) and the Parathyroid Hormone (PTH). Additionally we examined Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma), which affects the function of phagocytic cells, and the C-CChemokine Receptor, type 2b, (CCR2b), which recruits monocytes to the site of inflammatory immune challenge.
RESULTS : Telmisartan was predicted to strongly antagonize (Ki asymptotically equal to 0.04 nmol) the VDR. The ARBs Olmesartan, Irbesartan and Valsartan (Ki asymptotically equal to10 nmol) are likely to be useful VDR antagonists at typical in-vivo concentrations. Candesartan (Ki asymptotically equal to 30 nmol) and Losartan (Ki asymptotically equal to 70 nmol) may also usefully inhibit the VDR. Telmisartan is a strong modulator of PPARgamma (Ki asymptotically equal to 0.3 nmol), while Losartan (Ki asymptotically equal to 3 nmol), Irbesartan (Ki asymptotically equal to 6 nmol), Olmesartan and Valsartan (Ki asymptotically equal to 12 nmol) also seem likely to have significant PPAR modulatory activity. Olmesartan and Irbesartan (Ki asymptotically equal to 9 nmol) additionally act as antagonists of a theoretical model of CCR2b. Initial validation of this CCR2b model was performed, and a proposed model for the Angiotensin II Type1 receptor (AT2R1) has been presented.
CONCLUSION : Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the activation of two key nuclear receptors-VDR and PPARgamma. If our simulations are confirmed by experiment, it is possible that ARBs may become useful as potent anti-inflammatory agents, in addition to their current indication as cardiovascular drugs.
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result sql = Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b.
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char = b;code = 98
char = e;code = 101
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = m;code = 109
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = A;code = 65
char = n;code = 110
char = g;code = 103
char = i;code = 105
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = R;code = 82
char = e;code = 101
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = B;code = 66
char = l;code = 108
char = o;code = 111
char = c;code = 99
char = k;code = 107
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = A;code = 65
char = R;code = 82
char = B;code = 66
char = s;code = 115
char = );code = 41
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = y;code = 121
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = e;code = 101
char = r;code = 114
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = -;code = 45
char = i;code = 105
char = n;code = 110
char = f;code = 102
char = l;code = 108
char = a;code = 97
char = m;code = 109
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = m;code = 109
char = m;code = 109
char = u;code = 117
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = y;code = 121
char = s;code = 115
char = t;code = 116
char = e;code = 101
char = m;code = 109
char = .;code = 46
char = ;code = 32
char = W;code = 87
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = c;code = 99
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = e;code = 101
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = p;code = 112
char = i;code = 105
char = d;code = 100
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = i;code = 105
char = c;code = 99
char = h;code = 104
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = a;code = 97
char = r;code = 114
char = g;code = 103
char = e;code = 101
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = t;code = 116
char = ;code = 32
char = j;code = 106
char = u;code = 117
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = f;code = 102
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = p;code = 112
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = i;code = 105
char = l;code = 108
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = l;code = 108
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = v;code = 118
char = a;code = 97
char = l;code = 108
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 = 46
char = ;code = 32
char = W;code = 87
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = i;code = 105
char = r;code = 114
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = u;code = 117
char = d;code = 100
char = i;code = 105
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = V;code = 86
char = D;code = 68
char = R;code = 82
char = ;code = 32
char = n;code = 110
char = u;code = 117
char = c;code = 99
char = l;code = 108
char = e;code = 101
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = i;code = 105
char = c;code = 99
char = h;code = 104
char = ;code = 32
char = i;code = 105
char = s;code = 115
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 = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = e;code = 101
char = c;code = 99
char = o;code = 111
char = s;code = 115
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = o;code = 111
char = i;code = 105
char = d;code = 100
char = ;code = 32
char = h;code = 104
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = 1;code = 49
char = ,;code = 44
char = 2;code = 50
char = 5;code = 53
char = -;code = 45
char = d;code = 100
char = i;code = 105
char = h;code = 104
char = y;code = 121
char = d;code = 100
char = r;code = 114
char = o;code = 111
char = x;code = 120
char = y;code = 121
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = -;code = 45
char = D;code = 68
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = d;code = 100
char = i;code = 105
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
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 = r;code = 114
char = e;code = 101
char = g;code = 103
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = u;code = 117
char = b;code = 98
char = i;code = 105
char = q;code = 113
char = u;code = 117
char = i;code = 105
char = t;code = 116
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = G;code = 71
char = n;code = 110
char = R;code = 82
char = H;code = 72
char = ;code = 32
char = (;code = 40
char = G;code = 71
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = d;code = 100
char = a;code = 97
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = p;code = 112
char = h;code = 104
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = h;code = 104
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = h;code = 104
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = P;code = 80
char = a;code = 97
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = r;code = 114
char = o;code = 111
char = i;code = 105
char = d;code = 100
char = ;code = 32
char = H;code = 72
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = P;code = 80
char = T;code = 84
char = H;code = 72
char = );code = 41
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = d;code = 100
char = d;code = 100
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = P;code = 80
char = e;code = 101
char = r;code = 114
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = s;code = 115
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = ;code = 32
char = P;code = 80
char = r;code = 114
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = f;code = 102
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = -;code = 45
char = A;code = 65
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 = e;code = 101
char = d;code = 100
char = ;code = 32
char = R;code = 82
char = e;code = 101
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = G;code = 71
char = a;code = 97
char = m;code = 109
char = m;code = 109
char = a;code = 97
char = ;code = 32
char = (;code = 40
char = P;code = 80
char = P;code = 80
char = A;code = 65
char = R;code = 82
char = g;code = 103
char = a;code = 97
char = m;code = 109
char = m;code = 109
char = a;code = 97
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = i;code = 105
char = c;code = 99
char = h;code = 104
char = ;code = 32
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
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
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = g;code = 103
char = o;code = 111
char = c;code = 99
char = y;code = 121
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = C;code = 67
char = -;code = 45
char = C;code = 67
char = C;code = 67
char = h;code = 104
char = e;code = 101
char = m;code = 109
char = o;code = 111
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = R;code = 82
char = e;code = 101
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = y;code = 121
char = p;code = 112
char = e;code = 101
char = ;code = 32
char = 2;code = 50
char = b;code = 98
char = ,;code = 44
char = ;code = 32
char = (;code = 40
char = C;code = 67
char = C;code = 67
char = R;code = 82
char = 2;code = 50
char = b;code = 98
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = i;code = 105
char = c;code = 99
char = h;code = 104
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = r;code = 114
char = u;code = 117
char = i;code = 105
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = n;code = 110
char = o;code = 111
char = c;code = 99
char = y;code = 121
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = f;code = 102
char = l;code = 108
char = a;code = 97
char = m;code = 109
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = m;code = 109
char = m;code = 109
char = u;code = 117
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = e;code = 101
char = n;code = 110
char = g;code = 103
char = e;code = 101
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = R;code = 82
char = E;code = 69
char = S;code = 83
char = U;code = 85
char = L;code = 76
char = T;code = 84
char = S;code = 83
char = ;code = 32
char = :;code = 58
char = ;code = 32
char = <;code = 60
char = /;code = 47
char = b;code = 98
char = >;code = 62
char = T;code = 84
char = e;code = 101
char = l;code = 108
char = m;code = 109
char = i;code = 105
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = n;code = 110
char = g;code = 103
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = z;code = 122
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 0;code = 48
char = .;code = 46
char = 0;code = 48
char = 4;code = 52
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char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = V;code = 86
char = D;code = 68
char = R;code = 82
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = A;code = 65
char = R;code = 82
char = B;code = 66
char = s;code = 115
char = ;code = 32
char = O;code = 79
char = l;code = 108
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ,;code = 44
char = ;code = 32
char = I;code = 73
char = r;code = 114
char = b;code = 98
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = V;code = 86
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = 1;code = 49
char = 0;code = 48
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = k;code = 107
char = e;code = 101
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = f;code = 102
char = u;code = 117
char = l;code = 108
char = ;code = 32
char = V;code = 86
char = D;code = 68
char = R;code = 82
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = y;code = 121
char = p;code = 112
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = -;code = 45
char = v;code = 118
char = i;code = 105
char = v;code = 118
char = o;code = 111
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = C;code = 67
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 3;code = 51
char = 0;code = 48
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = L;code = 76
char = o;code = 111
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 7;code = 55
char = 0;code = 48
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = f;code = 102
char = u;code = 117
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = V;code = 86
char = D;code = 68
char = R;code = 82
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = e;code = 101
char = l;code = 108
char = m;code = 109
char = i;code = 105
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = P;code = 80
char = P;code = 80
char = A;code = 65
char = R;code = 82
char = g;code = 103
char = a;code = 97
char = m;code = 109
char = m;code = 109
char = a;code = 97
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 0;code = 48
char = .;code = 46
char = 3;code = 51
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = i;code = 105
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = L;code = 76
char = o;code = 111
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 3;code = 51
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = I;code = 73
char = r;code = 114
char = b;code = 98
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 6;code = 54
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = O;code = 79
char = l;code = 108
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = V;code = 86
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 1;code = 49
char = 2;code = 50
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
char = ;code = 32
char = s;code = 115
char = e;code = 101
char = e;code = 101
char = m;code = 109
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = k;code = 107
char = e;code = 101
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = i;code = 105
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = P;code = 80
char = P;code = 80
char = A;code = 65
char = R;code = 82
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = .;code = 46
char = ;code = 32
char = O;code = 79
char = l;code = 108
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = I;code = 73
char = r;code = 114
char = b;code = 98
char = e;code = 101
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = K;code = 75
char = i;code = 105
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = y;code = 121
char = m;code = 109
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 9;code = 57
char = ;code = 32
char = n;code = 110
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = );code = 41
char = ;code = 32
char = a;code = 97
char = d;code = 100
char = d;code = 100
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
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char = a;code = 97
char = s;code = 115
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char = a;code = 97
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = o;code = 111
char = r;code = 114
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = C;code = 67
char = C;code = 67
char = R;code = 82
char = 2;code = 50
char = b;code = 98
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = n;code = 110
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = v;code = 118
char = a;code = 97
char = l;code = 108
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 = s;code = 115
char = ;code = 32
char = C;code = 67
char = C;code = 67
char = R;code = 82
char = 2;code = 50
char = b;code = 98
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = e;code = 101
char = d;code = 100
char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = A;code = 65
char = n;code = 110
char = g;code = 103
char = i;code = 105
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = I;code = 73
char = I;code = 73
char = ;code = 32
char = T;code = 84
char = y;code = 121
char = p;code = 112
char = e;code = 101
char = 1;code = 49
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = (;code = 40
char = A;code = 65
char = T;code = 84
char = 2;code = 50
char = R;code = 82
char = 1;code = 49
char = );code = 41
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = C;code = 67
char = O;code = 79
char = N;code = 78
char = C;code = 67
char = L;code = 76
char = U;code = 85
char = S;code = 83
char = I;code = 73
char = O;code = 79
char = N;code = 78
char = ;code = 32
char = :;code = 58
char = ;code = 32
char = <;code = 60
char = /;code = 47
char = b;code = 98
char = >;code = 62
char = M;code = 77
char = o;code = 111
char = l;code = 108
char = e;code = 101
char = c;code = 99
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result sql = BACKGROUND : There have been indications that common Angiotensin Receptor Blockers (ARBs) may be exerting anti-inflammatory actions by directly modulating the immune system. We decided to use molecular modelling to rapidly assess which of the potential targets might justify the expense of detailed laboratory validation. We first studied the VDR nuclear receptor, which is activated by the secosteroid hormone 1,25-dihydroxyvitamin-D. This receptor mediates the expression of regulators as ubiquitous as GnRH (Gonadatrophin hormone releasing hormone) and the Parathyroid Hormone (PTH). Additionally we examined Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma), which affects the function of phagocytic cells, and the C-CChemokine Receptor, type 2b, (CCR2b), which recruits monocytes to the site of inflammatory immune challenge.
RESULTS : Telmisartan was predicted to strongly antagonize (Ki asymptotically equal to 0.04 nmol) the VDR. The ARBs Olmesartan, Irbesartan and Valsartan (Ki asymptotically equal to10 nmol) are likely to be useful VDR antagonists at typical in-vivo concentrations. Candesartan (Ki asymptotically equal to 30 nmol) and Losartan (Ki asymptotically equal to 70 nmol) may also usefully inhibit the VDR. Telmisartan is a strong modulator of PPARgamma (Ki asymptotically equal to 0.3 nmol), while Losartan (Ki asymptotically equal to 3 nmol), Irbesartan (Ki asymptotically equal to 6 nmol), Olmesartan and Valsartan (Ki asymptotically equal to 12 nmol) also seem likely to have significant PPAR modulatory activity. Olmesartan and Irbesartan (Ki asymptotically equal to 9 nmol) additionally act as antagonists of a theoretical model of CCR2b. Initial validation of this CCR2b model was performed, and a proposed model for the Angiotensin II Type1 receptor (AT2R1) has been presented.
CONCLUSION : Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the activation of two key nuclear receptors-VDR and PPARgamma. If our simulations are confirmed by experiment, it is possible that ARBs may become useful as potent anti-inflammatory agents, in addition to their current indication as cardiovascular drugs.
Publication: Theor Biol Med Model 2006 ;3:1.
Publication Date: 2006
Study Author(s): Marshall, Trevor G;Lee, Robert E;Marshall, Frances E;
Institution: Autoimmunity Research Foundation, Thousand Oaks, California 91360, USA. [email protected]
Shortcut link to this study:
Publication Date: 2006
Study Author(s): Marshall, Trevor G;Lee, Robert E;Marshall, Frances E;
Institution: Autoimmunity Research Foundation, Thousand Oaks, California 91360, USA. [email protected]
Shortcut link to this study:
BACKGROUND : There have been indications that common Angiotensin Receptor Blockers (ARBs) may be exerting anti-inflammatory actions by directly modulating the immune system. We decided to use molecular modelling to rapidly assess which of the potential targets might justify the expense of detailed laboratory validation. We first studied the VDR nuclear receptor, which is activated by the secosteroid hormone 1,25-dihydroxyvitamin-D. This receptor mediates the expression of regulators as ubiquitous as GnRH (Gonadatrophin hormone releasing hormone) and the Parathyroid Hormone (PTH). Additionally we examined Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma), which affects the function of phagocytic cells, and the C-CChemokine Receptor, type 2b, (CCR2b), which recruits monocytes to the site of inflammatory immune challenge.
RESULTS : Telmisartan was predicted to strongly antagonize (Ki asymptotically equal to 0.04 nmol) the VDR. The ARBs Olmesartan, Irbesartan and Valsartan (Ki asymptotically equal to10 nmol) are likely to be useful VDR antagonists at typical in-vivo concentrations. Candesartan (Ki asymptotically equal to 30 nmol) and Losartan (Ki asymptotically equal to 70 nmol) may also usefully inhibit the VDR. Telmisartan is a strong modulator of PPARgamma (Ki asymptotically equal to 0.3 nmol), while Losartan (Ki asymptotically equal to 3 nmol), Irbesartan (Ki asymptotically equal to 6 nmol), Olmesartan and Valsartan (Ki asymptotically equal to 12 nmol) also seem likely to have significant PPAR modulatory activity. Olmesartan and Irbesartan (Ki asymptotically equal to 9 nmol) additionally act as antagonists of a theoretical model of CCR2b. Initial validation of this CCR2b model was performed, and a proposed model for the Angiotensin II Type1 receptor (AT2R1) has been presented.
CONCLUSION : Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the activation of two key nuclear receptors-VDR and PPARgamma. If our simulations are confirmed by experiment, it is possible that ARBs may become useful as potent anti-inflammatory agents, in addition to their current indication as cardiovascular drugs.
RESULTS : Telmisartan was predicted to strongly antagonize (Ki asymptotically equal to 0.04 nmol) the VDR. The ARBs Olmesartan, Irbesartan and Valsartan (Ki asymptotically equal to10 nmol) are likely to be useful VDR antagonists at typical in-vivo concentrations. Candesartan (Ki asymptotically equal to 30 nmol) and Losartan (Ki asymptotically equal to 70 nmol) may also usefully inhibit the VDR. Telmisartan is a strong modulator of PPARgamma (Ki asymptotically equal to 0.3 nmol), while Losartan (Ki asymptotically equal to 3 nmol), Irbesartan (Ki asymptotically equal to 6 nmol), Olmesartan and Valsartan (Ki asymptotically equal to 12 nmol) also seem likely to have significant PPAR modulatory activity. Olmesartan and Irbesartan (Ki asymptotically equal to 9 nmol) additionally act as antagonists of a theoretical model of CCR2b. Initial validation of this CCR2b model was performed, and a proposed model for the Angiotensin II Type1 receptor (AT2R1) has been presented.
CONCLUSION : Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the activation of two key nuclear receptors-VDR and PPARgamma. If our simulations are confirmed by experiment, it is possible that ARBs may become useful as potent anti-inflammatory agents, in addition to their current indication as cardiovascular drugs.
PMID: 16403216
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