Offspring's leukocyte telomere length, paternal age, and telomere elongation in sperm.

PublishedJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tThis is the final version of the article. Available from Public Library of Science via the DOI in this record.Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offspring's LTLs in 4 different cohorts. Moreover, we examined the potential cause of the paternal age on offspring's LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18-94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young (50 years) donors. Paternal age had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age. Moreover, sperm telomere length analyses were compatible with the emergence in older men of a subset of sperm with elongated telomeres. Paternal age exerts a considerable effect on the offspring's LTL, a phenomenon which might relate to telomere elongation in sperm from older men. The implications of this effect deserve detailed study.Supported by NIH grants R01-AG021593, R01-AG020132, and P01-AG0876. Support was also provided by NIH contract NOHC25195, the NHLBI cooperative agreement grants U01 HL 67893, U01 HL67894, U01 HL67895, U01 HL67896, U01 HL67897, U01 HL67898, U01 HL67899, U01 HL67900, U01 HL67901, U01 HL67902, U01 HL56563, U01 HL56564, U01 HL56565, U01 HL56566, U01 HL56567, U01 HL56568, and U01 HL56569. Also funded in part by the Wellcome Trust grant (ref 074951)

Interaction of calcium and neomycin with anionic phospholipid-lecithin liposomes : A differential scanning calorimetry study

The interactions of calcium and neomycin with liposomes of various anionic phospholipids plus lecithin were studied by differential scanning calorimetry. Phosphatidylinositol bisphosphate differed from other acidic phospholipids in its interactions with both calcium and neomycin. Calcium, at concentrations as low as 1 mM, induced the appearance of a second transition peak in phosphatidylinositol bisphosphate-enriched liposomes only. Neomycin acted antagonistically and precluded this phase separation. In addition, neomycin lowered the phase transition temperature of phosphatidylinositol bisphosphate-lecithin liposomes while it raised the transition temperature of all other anionic phospholipid-lecithin liposomes tested. This fluidizing effect of neomycin and the antagonism to calcium may induce critical alterations of properties of biological membranes. The study supports and extends our previous findings and conclusions that phosphatidylinositol bisphosphate may play a crucial role in the expression of aminoglycoside toxicity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24633/1/0000044.pd

Offspring's Leukocyte Telomere Length, Paternal Age, and Telomere Elongation in Sperm

Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offspring's LTLs in 4 different cohorts. Moreover, we examined the potential cause of the paternal age on offspring's LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18–94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young (<30 years) and older (>50 years) donors. Paternal age had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age. Moreover, sperm telomere length analyses were compatible with the emergence in older men of a subset of sperm with elongated telomeres. Paternal age exerts a considerable effect on the offspring's LTL, a phenomenon which might relate to telomere elongation in sperm from older men. The implications of this effect deserve detailed study

Characterization of aminoglycoside-lipid interactions and development of a refined model for ototoxicity testing

Aminoglycoside interactions with various phospholipids were measured in three model systems and compared with the ototoxicities of the drugs: (a) competition for [14C]neomycin binding; (b) competition for 45Ca2+ binding; and (c) effect on surface pressure of monomolecular lipid films. The efficacies of the antibiotics in displacing neomycin from phosphatidylserine, phosphatidylinositol or phosphatidylinositol bisphosphate were netilmicin &gt; neomycin [ges] gentamicin; the efficacies in displacing calcium from phosphatidylinositol, phosphatidylinositol phosphate or phosphatidylinositol bisphosphate were netilmicin &gt; gentamicin &gt; neomycin &gt; kanamycin &gt; spectinomycin. Neither measure correlated well with the ototoxicities of the drugs which were quantitated at equimolar drug concentrations in cochlear perfusions: neomycin &gt; gentamicin &gt;= tobramycin &gt; netilmicin &gt;= amikacin. When monomolecular films of phosphatidylcholine with phosphatidylserine, cardiolipin, phosphatidylinositol, or phosphatidylinositol phosphate or bisphosphate were challenged with neomycin, the phosphatidylinositol bisphosphate film showed a unique dose-dependent increase in surface pressure while the others showed a decrease or no significant effect. The abilities of aminoglycosides to increase the surface pressure of a film of phosphatidycholine : phosphatidylinositol bisphosphate (1:1 molar ratio) in the presence of 3 mM CaCl2 correlated well with their toxicities. Non-ototoxic cations increased the film pressure or left it unaffected. The results confirm the unique interactions between aminoglycosides and phosphatidylinositol bisphosphate as a possible basis of a mechanism of toxicity and development of a drug-screening system.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24664/1/0000077.pd

Effects of in vitro potassium on ammoniagenesis in rat and canine kidney tissue

Effects of in vitro potassium on ammoniagenesis in rat and canine kidney tissue. Decreased ammonium (NH4+) excretion is associated with hyperkalemia. To determine if potassium could directly influence renal ammonia production, we investigated ammoniagenesis by rat and canine renal cortical tissues in vitro at different potassium concentrations. Renal tissue from normal and acidotic rats and normal dogs incubated in glutamine, lactate, and 7 to 10mEq/liters of potassium or 25mEq/liters of potassium produced significantly less ammonia than slices incubating in glutamine, lactate, and 4 to 5mEq of potassium. Glutamate accumulation, which follows glutamine deamidation, did not decrease and even increased at 25mEq/liters of potassium. With glutamine as the sole substrate, decreased ammoniagenesis was seen only at higher potassium concentrations (> 16mEq/liters) than when lactate was also present. The depression to glutamine ammoniagenesis by high concentrations of potassium was partially obliterated in an anaerobic environment. When glutamate replaced glutamine as the precursor, renal ammonia produced by slices in 7 and 25mEq/liters was again significantly lower than by slices incubating in 4mEq/liters. We blocked glutamine synthesis by rat kidney slices with dl-methionine dl-sulfoximine when glutamate was the renal ammonia precursor. This essentially allows glutamate deamination to produce ammonia. Potassium depressed glutamate deamination significantly at 7mEq/liters (↓ 13%) and at 25mEq/liters of potassium (↓ 35%) as compared to 4mEq/liters. The above findings are consistent with a major depressive effect of in vitro potassium on glutamate deamination in rat and canine kidneys. Other evidence, especially from rat tissue studies, suggests that potassium also may affect glutamine deamination directly. Rat kidney slices incubating in the high potassium medium of 7mEq/liter or greater also consumed less oxygen in the presence of glutamine (P < 0.01), oxidatively decarboxylated less glutamine (P < 0.02) and produced less glucose from glutamine (P < 0.01).Effet du potassium in vitro sur l'ammoniogenèse dans tissu rénal de rat et de chien. Une diminution de l'excrétion d'ammoniaque (NH4+) est associée à l'hyperkaliémie. Afin de déterminer si le potassium peut influencer directement la production rénale d'ammoniac, nous avons étudié l'ammoniogenèse dans le tissu rénal cortical de rat et de chien in vitro à différentes concentrations de potassium. Du tissu rénal provenant de rats normaux et en acidose et de chiens normaux incubés dans de la glutamine, du lactate, et 7 à 10mEq/litres de potassium ou 25mEq/litres de potassium produit significativement moins d'ammoniac que des tranches incubées dans de la glutamine, du lactate, et 4 à 5mEq/litres de potassium. L'accumulation de glutamate, consécutive à la deamination de la glutamine, n'a pas diminué et même a augmenté à 25mEq/litres de potassium. Avec la glutamine comme seul substrat, la diminution de l'ammoniogenèse n'a été observée qu'à des concentrations de potassium supérieures (> 16mEq/litres) à celle nécessaire quand le lactate est présent. La dépression de l'ammoniogenèse due à la glutamine au moyen de concentrations élevées de potassium est partiellement abolie par un environnement anaérobique. Quand la glutamine est remplacée par du glutamate, le rénale d'ammoniac produit par des tranches dans des milieux à 7mEq/litres et 25mEq/litres est là encore significativement inférieur à celui produit par des tranches incubées dans un milieu à 4mEq/litres. Nous avons bloqué la synthèse de glutamine dans les tranches de rein de rat au moyen de la dl-méthionine dl-sulfoximine quand le glutamate était le précurseur de rénale d'ammoniac. Ceci permet à la déamination du glutamate de produire de l'ammoniac. Potassium diminue significativement la déamination du glutamate à 7mEq/litres (diminution de 13%), et à 25mEq/litres (diminution de 35%) par comparaison avec les valeurs obtenues à 4mEq/litres. Ces constatations sont compatibles avec un effet dépresseur majeur du potassium in vitro sur la déamination du glutamate dans les reins de rat et de chien. D'autres arguments, tirés essentiellement des études sur le tissu de rat, suggèrent que le potassium peut aussi affecter la déamination du glutamate directement. Des tranches de rein de rat incubées dans un milieu riche en potassium (7mEq/litres ou plus) consomment moins d'oxygène en présence de glutamine (P < 0,01), décarboxylent moins de glutamine par oxydation (P < 0,02) et produisent moins de glucose à partir de la glutamine (P < 0,01)

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

Prevention of hepatorenal toxicity with Sonchus asper in gentamicin treated rats

<p>Abstract</p> <p>Background</p> <p><it>Sonchus asper </it>possesses antioxidant capacity and is used in liver and kidney disorders. We have investigated the preventive effect of methanolic extract of <it>Sonchus asper </it>(SAME) on the gentamicin induced alterations in biochemical and morphological parameters in liver and kidneys of Sprague-Dawley male rat.</p> <p>Methods</p> <p>Acute oral toxicity studies were performed for selecting the therapeutic dose of SAME. 30 Sprague-Dawley male rats were equally divided into five groups with 06 animals in each. Group I received saline (0.5 ml/kg bw; 0.9% NaCl) while Group II administered with gentamicin 0.5 ml (100 mg/kg bw; i.p.) for ten days. Animals of Group III and Group IV received gentamicin and SAME 0.5 ml at a dose of 100 mg/kg bw and 200 mg/kg bw, respectively while Group V received only SAME at a dose of 200 mg/kg bw. Biochemical parameters including aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyltransferase (γ-GT), total cholesterol, triglycerides, total protein, albumin, creatinine, blood urea nitrogen (BUN), total bilirubin and direct bilirubin were determined in serum collected from various groups. Urinary out puts were measured in each group and also assessed for the level of protein and glucose. Lipid peroxides (TBARS), glutathione (GSH), DNA injuries and activities of antioxidant enzymes; catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD) were determined in liver and renal samples. Histopathological studies of liver and kidneys were also carried out.</p> <p>Results</p> <p>On the basis of acute oral toxicity studies, 2000 mg/kg bw did not induce any toxicity in rats, 1/10^thof the dose was selected for preventive treatment. Gentamicin increased the level of serum biomarkers; AST, ALT, ALP, LDH, γ-GT, total cholesterol, triglycerides, total protein, albumin, creatinine, BUN, total and direct bilirubin; as were the urinary level of protein, glucose, and urinary output. Lipid peroxidation (TBARS) and DNA injuries increased while GSH contents and activities of antioxidant enzymes; CAT, POD, SOD decreased with gentamicin in liver and kidney samples. SAME administration, dose dependently, prevented the alteration in biochemical parameters and were supported by low level of tubular and glomerular injuries induced with gentamicin.</p> <p>Conclusion</p> <p>These results suggested the preventive role of SAME for gentamicin induced toxicity that could be attributed by phytochemicals having antioxidant and free radical scavenging properties.</p

Inhibition of polyphosphoinositide phosphodiesterase by aminoglycoside antibiotics

The calcium-activated phosphodiesteratic hydrolysis of 32 P-labeled phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 4-phosphate in prelabeled nerve ending membranes is inhibited by the aminoglycosides neomycin and gentamicin, and to a lesser extent, by streptomycin. The inhibition is overcome by increasing concentrations of Ca 2+ , indicating that the aminoglycosides exert their effect by displacing Ca 2+ from lipid.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45401/1/11064_2004_Article_BF00965878.pd