Mitochondria are key players in aging and in the pathogenesis of age-related diseases. Recent mitochondrial transcriptome analyses revealed the existence of multiple small mRNAs transcribed from mitochondrial DNA (mtDNA). Humanin (HN), a peptide encoded in the mtDNA 16S ribosomal RNA region, is a neuroprotective factor. An in silico search revealed six additional peptides in the same region of mtDNA as humanin; we named these peptides small humanin-like peptides (SHLPs). We identified the functional roles for these peptides and the potential mechanisms of action. The SHLPs differed in their ability to regulate cell viability in vitro. We focused on SHLP2 and SHLP3 because they shared similar protective effects with HN. Specifically, they significantly reduced apoptosis and the generation of reactive oxygen species, and improved mitochondrial metabolism in vitro. SHLP2 and SHLP3 also enhanced 3T3-L1 pre-adipocyte differentiation. Systemic hyperinsulinemic-euglycemic clamp studies showed that intracerebrally infused SHLP2 increased glucose uptake and suppressed hepatic glucose production, suggesting that it functions as an insulin sensitizer both peripherally and centrally. Similar to HN, the levels of circulating SHLP2 were found to decrease with age. These results suggest that mitochondria play critical roles in metabolism and survival through the synthesis of mitochondrial peptides, and provide new insights into mitochondrial biology with relevance to aging and human biology.
An in vitro organ culture system for buccal ganglia of the adult snail, Helisoma, is described. The system supports: (1) maintenance of characteristic electrophysiological parameters of identified neurons over seven days of culture; (2) choline metabolism including uptake and synthesis over the same duration; (3) sprouting and growth of neurons in response to axotomy; (4) the formation of novel central electrotonic connections between identified neurons as a result of sprouting and growth. These observations on neuronal growth and the formation of connections are similar to those made with in vivo culture. The use of in vitro culture allows precise manipulations not previously possible. When buccal ganglia are cultured in vitro with the cut distal ends of peripheral nerve trunks held closely apposed, axons of neurons 5R and 5L in the nerve trunks are capable of forming electrotonic connections similar to central connections. The capability of these neurons to form electrotonic connections via their peripheral axons implies that special structures (i.e., central neurites) are not required for the formation of connections; and neither are special environments (i.e., the central neuropile) required for these connections.
A B S T R A C T The development of a vitamin D-resistant state in the course of renal failure may be responsible for reduced intestinal absorption of calcium and an impaired response of skeletal tissue. Moreover, the kidney has been shown to carry out the conversion of 25-hydroxycholecalciferol (25-OH-CC) to a highly biologically active metabolite, 1,25-dihydroxycholecalciferol (1,25-diOH-CC). In the present studies, vitamin D-deficient rats, made acutely uremic by either bilateral nephrectomy or urethral ligation, received physiological doses of cholecalciferol (vitamin D3) (CC), 25-OH-CC or 1,25-diOH-CC; 24 hr later intestinal calcium transport, in vitro, and bone calcium mobilization, in vivo, were assessed. Whereas CC and 25-OH-CC stimulated calcium transport in sham-operated controls, they were without effect in the uremic animals. In contrast, administration of 1,25-diOH-CC stimulated calcium transport in both groups of uremic animals. Administration of 1,25-diOH-CC also stimulated calcium mobilization from bone in each group of animals. However, CC and 25-OH-CC were only effective in the sham controls and the uremic group produced by urethral ligation and had little or no effect in animals without kidneys. These results indicate that renal conversion of calciferol to a
We hypothesized that ozone (O3) exposure acutely affects cardiovascular hemodynamics in humans and, in particular, in subjects with essential hypertension. We studied 10 nonmedicated hypertensive and six healthy male adults. Each subject, after catheterization of the right heart and a radial artery, was exposed in an environmentally controlled chamber to filtered air (FA) on one day and to 0.3 ppm O3 on the following day for 3 h with intermittent exercise. Relative to FA exposure, O3 exposure induced no statistically significant changes in cardiac index, ventricular performance, pulmonary artery pressure, pulmonary and systemic vascular resistances, ECG, serum cardiac enzymes, plasma catecholamines and atrial natriuretic factor, and SaO2. The overall results did not indicate major acute cardiovascular effects of O3 in either the hypertensive or the control subjects. However, mean preexposure to postexposure changes were significantly (p < 0.02) larger with O3 than with FA for rate-pressure product (1,353 beats/min/mm Hg) and for heart rate (8 beats/min); these responses were not significantly different between the hypertensive and the control subjects. Significant O3 effects were also observed for mean FEV1 (-6%), and AaPO2 (> 10 mm Hg increase), which were not significantly different between the two groups. These results suggest that O3 exposure can increase myocardial work and impair pulmonary gas exchange to a degree that might be clinically important in persons with significant preexisting cardiovascular impairment, with or without concomitant lung disease.
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