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  • A potential weakness of the

    2020-07-02

    A potential weakness of the present study is that it involved population controls rather than family controls, which are a better way of controlling the effects of population stratification (e.g. ethnic group differences in allele frequencies). On the other hand, general population samples do have their own advantages (Jorm & Easteal, 2000). They are not affected by the referral biases of clinic samples and not subject to transmission ratio distortion (Paterson & Petronis, 1999), which can produce spurious associations with family controls. In conclusion, the present study failed to find support for the predicted association of DBH and AR polymorphisms with P, despite the large sample size. However, we cannot rule out that there are very small associations or that other polymorphisms of these CCG 203971 have associations with P.
    Acknowledgements
    Introduction -Hydroxy-l-arginine (NOHA) is an intermediate in the oxidation of l-arginine to nitric oxide (NO) catalyzed by NO-synthases (NOS) [1], [2]. In mammals, NO is an important mediator that displays key roles in the cardiovascular, nervous and immune systems [3]. NOHA can be released from NOS during catalysis and has been found to display biological activities distinct from that of NO. For instance, NOHA is an endogenous inhibitor of the enzyme arginase and can react with NO to form long-lasting NO-donors [4], [5]. The reactive function of NOHA is its N-hydroxyguanidine (NOHG) moiety and most of the biological properties of NOHA are linked to this functional group. N-Hydroxyguanidines display interesting pharmacological properties with cardioprotective, antihypertensive and vasorelaxant activities [6], [7], [8]. Several NOHG are potent antiviral, cytotoxic and antitumor agents [9], [10], and they also act as antioxidant molecules by reacting with superoxide and peroxynitrite [11], [12]. Furthermore, some of them are alternate substrates for NOS and are able to release NO upon oxidation at the active site of NOS [13], [14]. Recently, we have shown that N-aryl-N′-hydroxyguanidines 1a–d are efficient reducing co-substrates for Dopamine β-Hydroxylase (DBH), a copper-containing monooxygenase that catalyses the oxidation of the important neurotransmitter dopamine into norepinephrine [15], [16], [17], [18]. A specific recognition of these co-substrates occurred during their oxidation by DBH and the corresponding nitrosoamidines 4a–d were found to be the predominant organic products of the reaction [15]. Even though various endogenous compounds such as ascorbate have been shown to act as reducing co-substrates for DBH [19], [20], [21], their interaction at the active site of DBH remains poorly known mainly because of the absence of a crystallographic structure and of an active recombinant form of the enzyme. Spectroscopic studies have shown that two copper ions are present at the active site of DBH with different coordination spheres in the oxidized and reduced states [22], [23], [24]. Recently, the water-soluble Cu(II) complex Py2SMeCu(II) 8 has emerged as a good model of the N3S coordination sphere of the CuB center of DBH with a reactivity mimicking that of the enzyme [25]. The oxidation of some monosubstituted NOHG has been previously investigated. The nature of the resulting products strongly depends upon the nature of the oxidant and complex mixtures are often obtained. Monoelectronic oxidants, such as lead tetra-acetate or silver carbonate, predominantly give the corresponding cyanamide 6 whereas mixtures of cyanamides 6 and ureas 5 were obtained in the presence of hydroperoxides [26], [27]. Reactivity of NOHG in the presence of copper sulfate as an oxidant was recently addressed by Cho et al. [28]. These authors evidenced reduction of copper(II) to copper(I) using bathocuproine disulfonic acid and they identified the oxidation products of an alkyl-NOHG to the corresponding cyanamide and a N-nitrosoguanidine that was further characterized by X-ray crystallography [28].