Nω,Nω'-Di-Z-L-arginine

To reduce risk of coronary heart disease, replacement of saturated fats (SFAs) with polyunsaturated fats (PUFA) is recommended. Strong and concordant evidence supports this recommendation, but controversy remains. Some observational studies have reported no association between SFAs and coronary heart disease, likely because of failure to account for the macronutrient replacing SFAs, which determines the direction and strength of the observed associations. Controversy also persists about whether ω-6 (nω-6) PUFA or a high dietary ratio of nω-6 to ω-3 (nω-3) fatty acids leads to proinflammatory and pro-oxidative states. These issues are relevant to soybean oil, which is the leading edible oil consumed globally and in the United States. Soybean oil accounts for over 40% of the US intake of both essential fatty acids. We reviewed clinical and epidemiologic literature to determine the effects of soybean oil on cholesterol levels, inflammation, and oxidation. Clinical evidence indicates that soybean oil does not affect inflammatory biomarkers, nor does it increase oxidative stress. On the other hand, it has been demonstrated that when dietary SFAs are replaced with soybean oil, blood cholesterol levels are lowered. Regarding the nω-6:nω-3 dietary ratio, health agencies have consistently rejected the importance of this ratio, instead emphasizing the importance of consuming sufficient amounts of each type of fat. Thus, several lines of evidence indicate that soybean oil can positively contribute to overall health and reduction of risk of coronary heart disease.

From a catalytic point of view, the three mammalian nitric oxide synthases (NOSs) function in an almost identical way. The N-terminal oxygenase domain catalyzes the conversion of l-arginine to l-citrulline plus ·NO in two sequential oxidation steps. Once l-arginine binds to the active site positioned above the heme moiety, two consecutive monooxygenation reactions take place. In the first step, l-arginine is hydroxylated to make Nω-hydroxy-l-arginine in a process that requires 1 molecule of NADPH and 1 molecule of O2 per mol of l-arginine reacted. In the second step, Nω-hydroxy-l-arginine, never leaving the active site, is oxidized to ·NO plus l-citrulline and 1 molecule of O2 and 0.5 molecules of NADPH are consumed. Since nitric oxide is an important signaling molecule that participates in a number of biological processes, including neurotransmission, vasodilation, and immune response, synthesis and release of ·NO in vivo must be exquisitely regulated both in time and in space. Hence, NOSs have evolved introducing in their amino acid sequences subcellular targeting motifs, most of them located at their N-termini. Deletion studies performed on recombinant, purified NOSs have revealed that part of the N-terminus of all three NOS can be eliminated with the resulting mutant enzymes still being catalytically active. Likewise, NOS isoforms lacking part of their N-terminus when transfected in cells render mislocalized, active proteins. In this review we will comment on the current knowledge of these subcellular targeting signals present in nNOS, iNOS, and eNOS.

The various mediums of exposure to nickel (Ni) compounds have raised enormous public health concerns, as it has been illustrated to exert toxic effects in biological organs, including the brain. We have previously implicated the involvement of elevated nitric oxide (NO) in Ni-induced oxidative stress in the brain. Hence, the present study investigated the ameliorative potential of Nω-nitro-L-arginine (L-NA), a NO synthase inhibitor, following Ni-induced neurotoxicity. Adult male rats were divided into four groups; control (normal saline), 10 mg/kg Ni chloride (NiCl2) only, 1 mg/kg L-NA, or 2 mg/kg L-NA co-administered with NiCl2. The administration was via daily intraperitoneal injections for three weeks. Neurobehavioural assessments performed thereafter ascertained short-term spatial memory and anxiety. Furthermore, histological evaluations of the cortex, hippocampus, and striatum were carried out using routine hematoxylin and eosin technique, while the phosphotungstic acid hematoxylin method was used to express the degree of astrogliosis. Biochemical analysis of NO levels was examined along with other oxidative stress markers (superoxide dismutase, catalase, glutathione, glutathione S transferase, glutathione peroxidase, myeloperoxidase, and lipid peroxidation). The results illustrated altered behavioral responses, a higher population of degenerating neurons, and astrocytes in the NiCl2 group. There was also an elevation in the NO level and a corresponding reduction in antioxidant activities. However, these debilitating changes were ameliorated in the L-NA treated groups. These results demonstrate an association between alterations in NO synthesis pathway and Ni neurotoxicity, which may render neuronal cells susceptible to damage by oxidative stress. This may yet be another mechanism and useful therapeutic marker in deciphering Ni-induced neurotoxicity.