Effect of butylated hydroxytoluene on the life span of Drosophila bipectinata

The median and the maximum life spans of Drosophila bipectinata increased after feeding with various concentrations (10 μM, 10² μM and 10³ μM) of butylated hydroxytoluene (BHT). Insects fed on the diet supplemented with 10³ μM BHT had decreased rate of lipid peroxidation (measured by thiobarbituric acid test) with respect to the controls. It is suggested that the antioxidant BHT, which scavenges free radicals, prolongs the life span of Drosophila.     

The antioxidant butylated hydroxytoluene can retard cerebellar degeneration induced transplacentally by a single low dosage of N-methyl-N-nitrosourea

Late-onset cerebellar degeneration can be induced transplacentally in mice by a single low-dose (1 mg/kg) injection of the direct-acting DNA alkylating agent N-methyl-N-nitrosourea (MNU) on day 16 of pregnancy. The offspring develop a mild ataxia that manifests by 12-16 weeks of age postnatally when the animals are challenged with a motor coordination task. Morphological evidence of degeneration includes pyknosis of Purkinje cells and abnormal foliation patterns. Additionally, these animals demonstrate a progressive retinopathy characterized by thinning of the nuclear and plexiform layers of the retina. Efforts to retard the cerebellar degeneration were undertaken in the present study. MNU-exposed and control animals were fed a standard mouse chow diet supplemented with 0.75% butylated hydroxytoluene (BHT), an antioxidant. This supplementation commenced 24 h following exposure to the teratogen and continued throughout the life of the offspring. A second group of MNU-exposed and control mice were fed a non-BHT-supplemented, standard Purina mouse chow diet. Quantitative histological evaluation of cerebellar coronal sections indicated that by 4 weeks of age BHT-fed, MNU-exposed mice had significantly fewer pyknotic Purkinje cells than non-BHT-fed, MNU-exposed animals. This was true for the vermal, paravermal, and lateral areas of the cerebellum. The findings suggest the usefulness of teratogenic models of degenerative diseases for the testing of potential intervention strategies.     

Haematological and platelet effects of butylated hydroxytoluene (BHT, E321)

Inclusion of butylated hydroxytoluene (BHT) in the diet of rats, at a dose level of 3 g/kg/day for up to 14 or 21 days, caused modest, but persistent, increases in platelet count, microcytic red blood cell count and red blood cell glutathione (up to 144%, 280% and 197% of control values respectively). These changes were directly BHT-related but unrelated to its hepatotoxicity and independent of vitamin K status. Transient increases in red blood cell count, haematocrit and haemoglobin and transient decreases in reticulocyte, white blood cell and neutrophil counts were, however, related to the early but temporary reduction in food and water intake in the initial stages of feeding the BHT-containing diet. The apparent microcytosis was not accompanied by any other evidence of haemolytic anaemia and may, therefore, have arisen as an artifactual consequence of platelet abnormalities. The cause of the increased platelet phenomenon is not yet characterised but may be an adaptive response to a BHT-related platelet dysfunction and does not appear to be life threatening since an 8-fold increase in mean platelet count has been observed without any detectable adverse effect on thrombogenesis. It is suggested that BHT, given in high doses, could prove to be a useful tool in the identification and characterisation of thrombopoietin.     

Tests for mutagenic effects of ammoniated glycyrrhizin, butylated hydroxytoluene, and gum Arabic in rodent germ cells

Ammoniated glycyrrhizin, butylated hydroxytoluene, and gum Arabic are "generally recognized as safe" (GRAS) substances that are used primarily as additives in foods. These substances were incorporated into rodent diets and fed to male rats and mice for 10 and 8 wk, respectively. The treated male mice and rats were then tested for dominant lethal effects. The mice were also tested for induced heritable translocation. Results of the rat studies indicated a statistically significant dominant lethal effect of each of the compounds tested; however, the biological significance of this response is not known. Results of the mouse dominant lethal and heritable translocation studies, on the other hand, indicated no adverse effects of the compounds tested.     

Effects of the antioxidant butylated hydroxytoluene (BHT) on retinal degeneration induced transplacentally by a single low dosage of N-methyl-N-nitrosourea (MNU)

A 1 mg/kg dose of the DNA alkylating agent, N-methyl-N-nitrosourea (MNU), when administered on day 16 of gestation provokes a progressive retinal degeneration in CD-1 albino mice reared under standard fluorescent lighting conditions (12 hr light: 12 hr dark); this degeneration begins at about 4 weeks post-natally and worsens with age. It is accelerated by constant fluorescent light exposure but is retarded greatly by constant darkness, suggesting the importance of secondary insults in the post-natal period for development of the degenerative disease. To determine whether the secondary photochemical damage might be specifically blocked, MNU-exposed and control animals in the present study were fed an antioxidant-enriched diet of Purina mouse chow supplemented with 0.75% butylated hydroxytoluene (BHT). A second group of MNU-exposed and control animals were fed a non-BHT supplemented standard Purina mouse chow diet. Systematic measurements of the number of rows of photoreceptor cell nuclei, the thickness of the inner/outer segment layer, and the thickness of the whole retina were made, to quantify and degenerative changes in animals 2, 4, 6, and 8 weeks of age. By 8 weeks, retinas of BHT-fed, MNU-exposed animals were significantly thicker and had more rows of photoreceptor cell nuclei than regular-diet, MNU-exposed animals. Moreover, the retinas of BHT-fed animals, both for MNU-exposed and controls, demonstrated sporadic morphologic changes in the form of circular configurations composed of ganglion cells, arcades of nuclear and plexiform layers, and, in one control animal, a hyperplastic nodule. These experiments suggested that MNU-induced retinal degeneration may be retarded by a BHT-enriched diet; however, continuous high doses of this compound pre- and postnatally may induce other retinal abnormalities.     

Loss of Caenorhabditis elegans homologue of human MOB4 compromises life span,health life span and thermotolerance

Mob1/phocein family proteins are conserved from yeast to mammals. Human has four MOB genes, MOB1, 2, 3 and 4. Human MOB1 protein, which is a component of the Hippo pathway, is involved in the inhibition of yes-associated protein (YAP1) through large tumor suppressor (LATS) kinases and plays a tumor suppressive role. In contrast, MOB4 activates YAP1. Caernorhabditis elegans (C. elegans) also has four MOB genes. Moreover, C. elegans has homologues of YAP1 (Ce_YAP-1) and LATS kinases (WTS-1). Nevertheless, our previous study revealed that the Hippo pathway is not conserved in C. elegans and that heat shock activates Ce_YAP-1. We also reported that Ce_YAP-1 is involved in the regulation of life span, healthy lifespan and thermotolerance. In this study, we raised a question whether and how C. elegans homologue of MOB4 (Ce_MOB-4) is involved in the regulation of Ce_YAP-1. Ce_MOB-4 is ubiquitously expressed in adult worms. This expression pattern is similar to that of Ce_YAP-1. mob-4 loss-of-function mutants show short life span, short health life span and compromise thermotolerance. However, heat shock activates Ce_YAP-1 in mob-4 mutant. In conclusion, the role of MOB4 in the activation of YAP1 is not conserved in C. elegans.     

Effects of nutrition on disease and life span. I. Immune responses, cardiovascular pathology, and life span in MRL mice.

Mice of the autoimmune, lymphoproliferative strain MRL/lpr and the congenic, nonlymphoproliferative strain MRL/n were fed one of six diets from weaning on-ward. These mice were sacrificed at 3 or 5 months of age. Low fat diets resulted in lower cholesterol and higher triglyceride levels than did cholesterol-containing high-fat diets. Caloric restriction of MRL/lpr mice was associated with an increased plaque-forming cell response to trinitrophenylated polyacrylamide beads, less lymphoproliferation, and less severe glomerulonephritis. Diet did not affect the incidence of autoimmune vasculitis in MRL/lpr mice sacrificed at 5 months. MRL/lpr mice fed a low-fat, calorically restricted diet from 5 months of age to death lived longer than mice which were fed ad libitum a cholesterol-containing, high-fat diet. At death, MRL/lpr mice fed the former diet had the autoimmune vasculitis which had been evident in mice killed at 5 months, whereas mice fed the latter diet, in addition to the vasculitis, had a high incidence of atherosclerotic lesions of intrarenal and aortic branch arteries.     

Victimization over the life span: a comparison of lesbian, gay, bisexual, and heterosexual siblings

Lifetime victimization was examined in a primarily European American sample that comprised 557 lesbian/gay, 163 bisexual, and 525 heterosexual adults. Lesbian, gay, and bisexual (LGB) participants were recruited via LGB e-mail lists, periodicals, and organizations; these participants recruited 1 or more siblings for participation in the study (81% heterosexual, 19% LGB). In hierarchical linear modeling analyses, sexual orientation was a significant predictor of most of the victimization variables. Compared with heterosexual participants, LGB participants reported more childhood psychological and physical abuse by parents or caretakers, more childhood sexual abuse, more partner psychological and physical victimization in adulthood, and more sexual assault experiences in adulthood. Sexual orientation differences in sexual victimization were greater among men than among women.     

Genetic variation for life span, resistance to paraquat, and spontaneous activity in unselected populations of Drosophila melanogaster: implications for transgenic rescue of life span

Genetic variation in adult life span, resistance to paraquat, resistance to DDT, and spontaneous flying activity were measured in 138 recombinant inbred lines of Drosophila melanogaster. We find that the phenotypic correlation between life span and resistance to an exogenous oxidizing agent is positive, though weak, and that there is little correlation between the two traits at the level of quantitative trait loci (QTLs). The sign of the life span-resistance correlation is haplotype-specific, suggesting a high degree of statistical interaction and dependence on genetic background. Because of the genotype-specificity in the relationship between life span and resistance phenotypes, interventions to extend life span by overexpression of antioxidant enzymes are likely to produce strain-specific results. These observations are in general agreement with the "genetic rescue" hypothesis of Sohal et al. [Sohal, R.S., Mockett, R.J., Orr, W.C., 2002. Mechanisms of aging: an appraisal of the oxidative stress hypothesis. Free Radic. Biol. Med. 33, 575-586.], though we emphasize that such statistical interaction is a normal feature of standing genetic variation, and does not imply that some genotypes are pathological. Ad hoc observation of spontaneous flying activity 5 days after emergence proved to be a much better predictor of life span than resistance to an exogenous oxidant in these populations.     

Molecular and genetic analyses of a multivariate system specifying behavior and life span

Recombinant inbred (RI) lines have been constructed by crossing the Bristol and Bergerac BO strains of the nematodeCaenorhabditis elegans. The F₁ hermaphroditic progeny are allowed to self-fertilize for 20 generations, yielding the RI lines. Heritability estimates for several behavioral traits and for life span, as well as both phenotypic and genetic covariance estimates for these traits, have been obtained. Significant heritability is detected only for forward movement. Large genetic covariances are detected between different behavioral components, corroborating earlier studies based on observations of stereotypical behaviors in nematodes. A strain distribution pattern (SDP) has been generated using genetic loci defined both by mutation and by restriction fragment length polymorphisms. Estimates of the number of loci affecting the life span range from three to six; these estimates were obtained both by classic quantitative techniques and by mapping, using the SDP for these RI lines. Thus, loci specifying life span are distributed throughout the genome rather than localized to any one region. EMS-induced, long-lived (Age) mutants were also examined. In contrast to an earlier report, these mutants ingest normal amounts of food. Theage locus of one strain, MK546, segregates independently of a behavioral alteration which was coinduced in the original mutant hunt.This work was supported in part by Department of Health and Human Services Grants AG-01236 and AG-05720 and by National Science Foundation Grant PCM-8208652. Some strains were provided by the Caenorhabditis Genetics Center, which is supported by Contract NO1-AG-9-2113 between the National Institutes of Health and the Curators of the University of Missouri.     

Life and death: metabolic rate, membrane composition, and life span of animals

Maximum life span differences among animal species exceed life span variation achieved by experimental manipulation by orders of magnitude. The differences in the characteristic maximum life span of species was initially proposed to be due to variation in mass-specific rate of metabolism. This is called the rate-of-living theory of aging and lies at the base of the oxidative-stress theory of aging, currently the most generally accepted explanation of aging. However, the rate-of-living theory of aging while helpful is not completely adequate in explaining the maximum life span. Recently, it has been discovered that the fatty acid composition of cell membranes varies systematically between species, and this underlies the variation in their metabolic rate. When combined with the fact that 1) the products of lipid peroxidation are powerful reactive molecular species, and 2) that fatty acids differ dramatically in their susceptibility to peroxidation, membrane fatty acid composition provides a mechanistic explanation of the variation in maximum life span among animal species. When the connection between metabolic rate and life span was first proposed a century ago, it was not known that membrane composition varies between species. Many of the exceptions to the rate-of-living theory appear explicable when the particular membrane fatty acid composition is considered for each case. Here we review the links between metabolic rate and maximum life span of mammals and birds as well as the linking role of membrane fatty acid composition in determining the maximum life span. The more limited information for ectothermic animals and treatments that extend life span (e.g., caloric restriction) are also reviewed.     

Modulation of cognition and mood following administration of single doses of Ginkgo biloba,ginseng, and a ginkgo/ginseng combination to healthy young adults

It has previously been demonstrated in separate studies that single doses of Ginkgo biloba, Panax ginseng, and a combination of the two extracts can improve different aspects of cognitive performance in healthy young volunteers. The present study directly compared the effects of single doses of G. biloba, ginseng, and a product combining the two on aspects of mood and cognitive performance in the same cohort of healthy, young adult volunteers. The study followed a randomised placebo-controlled, double-blind, balanced, cross-over design. Twenty participants received 360 mg of ginkgo, 400 mg of ginseng, 960 mg of a product combining the two extracts, and a matching placebo. Treatment order was dictated by random allocation to a Latin square, with a 7-day wash-out period between treatments. Cognitive testing comprised completion of the Cognitive Drug Research (CDR) computerised assessment battery and two serial subtraction mental arithmetic tasks. Mood was assessed with Bond-Lader visual analogue scales. Following a baseline cognitive assessment, further test sessions took place 1, 2.5, 4, and 6 h after the day's treatment was taken. The results largely supported previous findings. All three treatments were associated with improved secondary memory performance on the CDR battery, with the ginseng condition evincing some improvement in the speed of performing memory tasks and in the accuracy of attentional tasks. Following ginkgo and the ginkgo/ginseng combination performance of both the Serial Threes and Serial Sevens, subtraction tasks was also improved at the later testing sessions. No modulation of the speed of performing attention tasks was evident. Improvements in self-rated mood was also found following ginkgo and to a lesser extent the combination product.     

Refocusing of B-cell responses following a single amino acid substitution in an antigen

Intranasal immunization of BALB/c strain mice was carried out using baculovirus-derived human chorionic gonadotrophin (hCG) beta-chain, together with Escherichia coli heat-labile enterotoxin. Gonadotrophin-reactive immunoglobulin A (IgA) was induced in a remote mucosal site, the lung, in addition to a systemic IgG response. The extensive sequence homology with luteinizing hormone (LH) results in the production of LH cross-reactive antibodies when holo-hCG is used as an immunogen. In contrast to wild-type hCGbeta, a mutated hCGbeta-chain containing an arginine to glutamic acid substitution at position 68 did not induce the production of antibodies which cross-react with LH. Furthermore, the epitopes utilized in the B-cell response to the mutated hCGbeta shifted away from the immunodominant region of the parent wild-type molecule towards epitopes within the normally weakly immunogenic C terminus. This shift in epitope usage was also seen following intramuscular immunization of rabbits. Thus, a single amino acid change, which does not disrupt the overall structure of the molecule, refocuses the immune response away from a disadvantageous cross-reactive epitope region and towards a normally weakly immunogenic but antigen-unique area. Similar mutational strategies for epitope-refocusing may be applicable to other vaccine candidate molecules.     

Meloxicam: a review of its pharmacokinetics,efficacy and tolerability following intramuscular administration

Inflammation Research - This paper reviews published studies on the intramuscular use of meloxicam in acute rheumatic conditions. Data were obtained from 68 healthy volunteers and &;gt;800...     

Coronary arteriopathy in monkeys following administration of CI-1020, an endothelin A receptor antagonist

A selective non-peptide endothelin A (ETA) receptor antagonist, CI-1020, was administered to cynomolgus monkeys intravenously (i.v.) for 2 or 4 wk and orally for 4 wk. Groups consisting of 3 animals of each sex received CI-1020 at 1, 5, and 10 mg/kg/hr (i.v.) or orally at 250, 500, and 750 mg/kg body weight for 4 wk. Control animals received the vehicle only. In a separate experiment, 1 male was infused with 10 mg/kg/hr for 2 wk, and Monastral blue dye was administered i.v. to facilitate localization of lesions to the vascular walls. One female was administered saline and the dye and served as a control. One female at 1 mg/kg/hr was found dead at week 2, and 1 female at 5 mg/kg/hr was euthanatized during week 4 as a result of severe thigh swelling at the catheter site. Macroscopically, extramural coronary arteries appeared thickened and nodular in the 4-wk i.v. study in the female found dead at 1 mg/kg/hr, in 1 male and 1 female at 5 mg/kg/hr, and in 2 females at 10 mg/kg/hr. Histologically, Monastral blue pigment trapped in the walls of coronary arteries with arteriopathy was observed in the male treated with CI-1020 at 10 mg/kg/hr for 2 wk. Extramural coronary arteriopathy occurred at all doses in the 4-wk i.v. study, with higher incidence occurring in females than in males (7 of 9 treated females compared with 3 of 9 treated males). In the oral study, 1 female at 500 mg/kg/day and 1 male and 2 females at 750 mg/kg/day had coronary arteriopathy. Histological changes after 2 wk of treatment were characterized by intimal thickening, fragmentation of the internal elastic lamina, necrosis and edema of the media, and mixed inflammatory-cell infiltrates in the intima, media, and adventitia. After 4 wk of i.v. administration, arteriopathy was characterized by segmental disruption of the elastic lamina and intimal and medial fibrosis with complete replacement of smooth muscle with fibrous tissue. The adventitia was thickened as a result of fibrosis and mixed or mononuclear inflammatory-cell infiltrates. CI-1020 concentrations were higher in males (1.57 to 29 micrograms/ml) than in females (0.974 to 24.4 micrograms/ml) in the i.v. study. Transient systemic exposure with high maximum plasma concentration (Cmax) (120-352 micrograms/ml) in the oral study was insufficient to provoke arterial changes of the same magnitude as those noted with continuous i.v. administration. The regeneration of the media by fibrous tissue and the disruption of the elastic lamina may weaken the arterial wall and increase the susceptibility of the artery to the development of aneurysm.     

Daydreaming,attentional processes,and curiosity in white Americans: Religious,educational, economic,and residency influences for a life span sample

A sample of 580 white men and 773 white women 17-92 years old were scored on the 33 factors of the Imaginal Processes Inventory. These Ss were categorized further according to Place/Population of Residency, Religious Preference, Type of Highest Degree, Level of Highest Degree, Annual Family Income, Self-described Socio-Economic Status, and Years of Education. Sex × Age × Demographic Variable ANOV As were performed on each of the 33 factors. Main effects due to Demographic variables were found to be significant in 22 cases; the Sex × Demographic Variable interaction was significant in 13 cases, the Age × Demographic Variable interaction was significant in 20 cases; and the Sex × Age × Demographic Variable interaction was significat in 11 cases.