We have demonstrated that alkaline phosphatase activity and collagen synthesis are dose-dependently stimulated by ascorbic acid in differentiated pig osteoblasts. In this study we further examined the relationship between ascorbic acid and bone metabolism by feeding young pigs large amounts of ascorbic acid. Three groups of seven 47-d-old pigs were given no ascorbic acid supplement (control), 500 (500 AA) or 1000 (1000 AA) mg ascorbic acid/kg diet for 4 mo. Calcium and P absorption and retention were evaluated by a 14-d balance trial immediately before killing in control and 1000 AA groups only (n = 6). Bones were collected at death and the bone ash and bending moment (three-point bending test) determined. Various plasma and urine indices of bone metabolism, especially those reflecting collagen degradation (hydroxyproline, deoxypyridinoline) and synthesis (carboxyterminal propeptide of type I collagen) were monitored. The plasma ascorbic acid concentrations increased with time and paralleled the dietary concentrations (P < 0.01). The Ca and P balances and the bone ash and bending moments in the ascorbic acid-supplemented pigs did not differ from those of the controls. Plasma osteocalcin was elevated (P < 0.05), whereas the other bone formation markers, alkaline phosphatase and carboxy terminal propeptide of type I collagen, were not affected by ascorbic acid. The plasma concentrations of Ca, P and 1,25-dihydroxycholecalciferol did not differ among the three groups. The unaffected urinary excretion of deoxypyridinoline and hydroxyproline in the ascorbic acid-supplemented pigs indicates that ascorbic acid does not alter bone resorption. Thus, high intakes of ascorbic acid have no positive influence on bone metabolism and bone characteristics in pigs. The in vivo long-term effects do not correlate with the short-term in vitro effects previously reported.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and function as transcription factors that regulate gene expression in numerous biological processes. Although the PPARβ/δ subtype is highly expressed in the brain, its physiological roles in neuronal function remain to be elucidated. In this study, we examined the presence of PPARβ/δ in the master circadian clock of the Syrian hamster and investigated its putative functional role in this structure. In mammals, the central circadian clock, located in the suprachiasmatic nucleus (SCN), is entrained by the light-dark (LD) cycle via photic6 signals conveyed by a direct pathway whose terminals release glutamate. Using immunocytochemical and qRT-PCR analysis, we demonstrated that the rhythmic expression of PPAR β/δ within the SCN of hamsters raised under an LD cycle was detectable only at the transcriptional level when the hamsters were maintained under constant darkness (DD). The increase in the number of immunoreactive PPARβ/δ cells observed under DD after light stimulation during the early subjective night (CT14), but not during the subjective day (CT06), demonstrated that the expression of PPARβ/δ can be up-regulated according to the photosensitive phase of the circadian clock. All of the PPARβ/δ-positive cells in the SCN also expressed the glutamate receptor NMDAR1. Moreover, we demonstrated that at the photosensitive point (CT14), the administration of L-16504, a specific agonist of PPARβ/δ, amplified the phase delay of the locomotor response induced by a light pulse. Taken together, these data suggest that PPARβ/δ activation modulates glutamate release that mediates entrainment of the circadian clock by light.
Acute exposure to cigarette smoke provokes airway hyperresponsiveness to substance P and inactivates neutral endopeptidase (NEP). To determine whether nedocromil sodium can prevent cigarette smoke-induced hyperresponsiveness to substance P, we studied two groups of anaesthetized guinea-pigs. One group of guinea-pigs was pretreated with aerosolized 0.9% NaCl solution (90 breaths), the other group was pretreated with aerosolized nedocromil sodium (10(-4) M, 90 breaths). In each animal, pretreatment was followed by either exposure to the smoke of one cigarette or exposure to air. After acute exposure to cigarette smoke or to air, we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P. In the absence of nedocromil sodium, the bronchoconstrictor responses to substance P were greater in cigarette smoke-exposed guinea-pigs than in air-exposed animals. Aerosolized nedocromil sodium had no effect on the response to substance P in air-exposed animals, but it reduced cigarette smoke-induced hyperresponsiveness to substance P. The preventive effect on cigarette smoke-induced hyperresponsiveness to substance P was observed at concentrations of aerosolized nedocromil sodium of 3 x 10(-5), 10(-4), and 3 x 10(-4) M. In vitro, cigarette smoke solution inhibited NEP activity from lung membrane preparations, but this inhibitory effect was not modified by nedocromil sodium (10(-4) M). We conclude that aerosolized nedocromil sodium reduces cigarette smoke-induced airway hyperresponsiveness to substance P in vivo. This action of nedocromil sodium is not due to a protective effect on cigarette smoke-induced inactivation of NEP in vitro.
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