Interferon-gamma (IFNG), a pro-inflammatory cytokine, increases concentrations of neopterin, a stable pteridine derivative, due to IFNG-induced transcriptional activation of the rate-limiting enzyme of pteridines biosynthesis. Neopterin concentrations were reported to correlate with metabolic syndrome (MetS), the cause of increased mortality risk, in subjects of European ancestry. We were interested to assessed neopterin correlations with clinical markers of MetS and mortality risk in population with a different genetic background, i.e., Puerto Ricans residents of Boston. Since inflammation is associated with pyridoxal-5′-phosphate (PLP) deficiency, we assessed correlations of neopterin with PLP. Plasma neopterin concentrations were evaluated in 592 adult (45-75 years of age) participants of Boston Puerto Rican Health Study. Neopterin concentrations correlated with abdominal obesity (waist circumference, r = 0.085, p < 0.038), HDL cholesterol (r = −0.15, p < 0.0001), insulin resistance (HOMA-IR, r = 0.08, P < 0.03), and plasma pyridoxal-5′-phosphate (PLP (r = −0.13, P = 0.002). Neopterin concentrations of >16 nmol/L at baseline were associated with the increased risk of mortality in 113 subjects followed for 6 years. The present results together with previously reported data in European subjects suggest a similar pattern of neopterin correlations with MetS and mortality risk in population with different genetic backgrounds. PLP is a cofactor of IFNG-induced key enzymes of tryptophankynurenine metabolism. Since PLP deficiency is associated with the increased production of diabetogenic kynurenine derivative, xanthurenic acid, our results suggest that up-regulated IFNG production might contribute to the development of insulin resistance. Assessment of neopterin concentrations might help to monitor the activity of IFNG-inducible inflammation associated with aging-associated medical and psychiatric disorders.
It is generally accepted that antioxidant properties of melatonin significantly contribute to its antiaging effect. Antioxidant effects of N‐acetylserotonin (NAS), a melatonin precursor and metabolite, might predict its antiaging action as well. The antiaging effect of NAS was studied in female retired breeders and male C3H mice. Both NAS and melatonin administered with drinking water prolonged life span in male animals by about 20% versus control animals (p < 0.01) but did not affect the life span of female mice. Antioxidative activity was evaluated by determining the malonaldehyde + 4‐hydroxynonenal (MDA + 4‐HNE) and cellular glutathion peroxidase (GPx) levels in male, 11‐month‐old, C57Bl/6J mice with very limited (if any) capacity to convert pineal NAS into melatonin. NAS increased the antioxidant capacity of kidney. Both NAS and melatonin (four weeks daily i.p. injections) increased the antioxidant capacity of brain as demonstrated by decreased MDA + 4‐HNE and increased GPx levels. NAS‐treated C57Bl/6J mice experienced a weight loss of 9%, whereas the saline and melatonin groups only 3%. NAS‐ and melatonin‐treated animals had healthy and luxuriant fur coats with some gray fur in the melatonin group; animals in the saline group had large areas of baldness. This study demonstrates, for the first time, the antiaging effect of NAS. This effect needs to be confirmed in animals with impaired capacity to convert NAS into melatonin.
The effect of bacterial lipopolysaccharide (LPS) injection on the lipid peroxidation process in Fischer (F344N) rats, spontaneously hypertensive (SHR) rats, and BALB/c mice was studied. Lipid peroxidation, as measured by malondialdehyde + 4-hydroxyalkenals (MDA + HAE) levels, was decreased in brain, kidney, and liver homogenates of F344N rats injected with lower LPS doses of 0.5, 1.0, and 2.0 mg/kg, but was increased with the highest dose of 10 mg/kg body weight. The dose of 10 mg/kg LPS decreased the MDA + HAE levels in SHR brain homogenates and increased levels in the liver homogenates. MDA + HAE levels in the brain and liver but not kidney homogenates in BALB/c mice also increased after administration of LPS at the highest dose (10 mg/kg body weight). The effect of melatonin, N-acetylserotonin (NAS), and GR-135,531 (a melatonin ligand with high affinity for MT3 receptor) on the survival of BALB/c mice injected with lethal dose of LPS was also tested. A single dose of 5 mg/kg of melatonin or NAS simultaneously injected with LPS (25 mg/kg body weight) markedly protected mice from the lethal effect of LPS with survival rates of 90% and 95% for melatonin and NAS, respectively, and 59% for mice injected with just LPS after 24 hours; a survival rate of 50% for both melatonin and NAS, and 32% was obtained for mice injected with just LPS after five days. GR-135,531 did not show protection against a lethal dose of LPS. Our results indicated that the effect of LPS on lipid peroxidation is dose-, time-, and species-dependent, and that melatonin and NAS are equally effective in protecting mice from lethality caused by LPS.
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