Insulin-like growth factors I and II are unable to form and maintain their native disulfides under in vivo redox conditions.
Insulin-like growth factor (IGF) I does not quantitatively form its three native disulfide bonds in the presence of 10 mM reduced and 1 mM oxidized glutathione in vitro [Hober, S. et al. (1992) Biochemistry 31, 1749-1756]. In this paper, we show (i) that both IGF-I and IGF-II are unable to form and maintain their native disulfide bonds at redox conditions that are similar to the situation in the secretory vesicles in vivo and (ii) that the presence of protein disulfide isomerase does not overcome this problem. The results indicate that the previously described thermodynamic disulfide exchange folding problem of IGF-I in vitro is also present in vivo. Speculatively, we suggest that the thermodynamic disulfide exchange properties of IGF-I and II are biologically significant for inactivation of the unbound growth factors by disulfide exchange reactions to generate variants destined for rapid clearance. (+info)
Plasmalogens as endogenous antioxidants: somatic cell mutants reveal the importance of the vinyl ether.
Exposure of plasmalogen-deficient variants of the murine cell line RAW 264.7 to short-term (0-100 min) treatment with electron transport inhibitors antimycin A or cyanide (chemical hypoxia) resulted in a more rapid loss of viability than in the parent strain. Results suggested that plasmalogen-deficient cells were more sensitive to reactive oxygen species (ROS) generated during chemical hypoxia; the mutants could be rescued from chemical hypoxia by using the antioxidant Trolox, an alpha-tocopherol analogue, and they were more sensitive to ROS generation by plumbagin or by rose bengal treatment coupled with irradiation. In addition, the use of buffers containing 2H2O greatly enhanced the cytotoxic effect of chemical hypoxia, suggesting the involvement of singlet oxygen. We used the unique enzymic deficiencies displayed by the mutants to differentially restore either plasmenylethanolamine (the major plasmalogen species normally found in this cell line) or its biosynthetic precursor, plasmanylethanolamine. Restoration of plasmenylethanolamine, which contains the vinyl ether, resulted in wild-type-like resistance to chemical hypoxia and ROS generators, whereas increasing levels of its precursor, which bears the saturated ether, had no effect on cell survival. These findings identify the vinyl ether double bond as a crucial element in cellular protection under these conditions and support the hypothesis that plasmalogens, through the vinyl ether, act as antioxidants to protect cells against ROS. These phospholipids might protect cells from ROS-mediated damage during events such as chemical hypoxia. (+info)
Divinyl ether fatty acid synthesis in late blight-diseased potato leaves.
We conducted a study of the patterns and dynamics of oxidized fatty acid derivatives (oxylipins) in potato leaves infected with the late-blight pathogen Phytophthora infestans. Two 18-carbon divinyl ether fatty acids, colneleic acid and colnelenic acid, accumulated during disease development. To date, there are no reports that such compounds have been detected in higher plants. The divinyl ether fatty acids accumulate more rapidly in potato cultivar Matilda (a cultivar with increased resistance to late blight) than in cultivar Bintje, a susceptible cultivar. Colnelenic acid reached levels of up to approximately 24 nmol (7 microgram) per g fresh weight of tissue in infected leaves. By contrast, levels of members of the jasmonic acid family did not change significantly during pathogenesis. The divinyl ethers also accumulated during the incompatible interaction of tobacco with tobacco mosaic virus. Colneleic and colnelenic acids were found to be inhibitory to P. infestans, suggesting a function in plant defense for divinyl ethers, which are unstable compounds rarely encountered in biological systems. (+info)
Low mortality rates in industrial cohort studies due to selection for work and survival in the industry.
Occupational groups are often described as being relatively healthy because their mortality rates are lower than those of the national average. Although correct this confuses the issue for those who are interested in assessing the effects of exposure to a particular chemical. In a further analysis of data collected in a study of all men ever exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain, three factors have been shown to contribute to the low mortality rates that were observed. The three factors: the selection of a healthy population for employment, the survival in the industry of the healthier men, and the length of time that this population has been pursued, have been quantified. The mortality experience within five years of entering this industry was shown to be as low as 37% of that expected; for circulatory disease and respiratory disease it was as low as 21%. There was a progressive increase in standardized mortality ratio with the length of time since entry so that the effect had almost disappeared 15 years after entry. To avoid confounding the selection effect with the survival effect the latter was measured by separating men who survived 15 years after entering the industry according to whether or not they were still in the industry after this period. Those who had left experienced an overall standardized mortality ratio some 50% higher than those still in the industry. This effect, although consistent in the age groups between 25 and 74 years and for all cause groups studied, was greatest in those aged between 25 and 44 years and for lung cancer and respiratory disease. (+info)
A multicentre efficacy and safety study of the single contraceptive implant Implanon. Implanon Study Group.
An open, multicentre study was performed to assess efficacy, safety and acceptability of the single-rod contraceptive implant Implanon. The study involved 635 young healthy women, who were sexually active and of childbearing potential. The women were followed up every 3 months over the entire study period. Originally the study was designed for 2 years, but was extended to 3 years in a group of 147 women from two centres. Altogether, 21 centres in nine different countries participated. The average age of the women was 29 years (range 18-42 years), of whom 83.5% had been pregnant in the past. No pregnancy occurred during treatment with Implanon, resulting in a Pearl Index of 0 (95% confidence interval: 0.0-0.2). In the first 2 years, 31% had discontinued the treatment. Of the 147 women in the study extension, nine discontinued (6%) treatment. Bleeding irregularities was the main reason for discontinuation during the first 2 years of use (17.2%) and adverse experiences in the third year (3.4%). Implant insertion and removal were fast and uncomplicated in the vast majority (97%) of cases. Return of fertility was prompt. In conclusion, Implanon has excellent contraceptive action during its lifetime of 3 years. The safety profile is acceptable and not essentially different from progestogens in general. (+info)
Dose-dependent fate of vinyl chloride and its possible relationship to oncogenicity in rats.
Studies on the fate of 14C-labeled vinyl chloride (VC) following oral administration and inhalation exposure in rats demonstrated that the disposition of VC in the body is a function of the dose. More importantly, from the data available, it appears that a correlation exists between doses of VC which cause tumors and those that saturate metabolic or detoxifying pathways. Additional studies characterized the depression of liver non-protein sulfhydryl content (primarily GSH) with the duration and concentration of exposure to VC. The results of these investigations indicate that statistical projections utilizing data collected from rats exposed to high doses of VC are invalid for predicting the hazard of low level exposure, because such projections violate a priori assumption that the dynamics governing the fate of VC in the body are unaltered. (+info)
Mortality and cancer morbidity in a group of Swedish VCM and PCV production workers.
The cohort of workers employed in a Swedish vinyl chloride/poly(vinyl chloride) plant since its start in the early 1940's has been followed for mortality and cancer morbidity patterns. Only 21 of the 771 persons could not be traced. Difficulties in establishing exposure levels at different work areas in the past makes an evaluation of dose-effect relationships impossible. A four- to fivefold excess of pancreas/liver tumors was found, including two cases later classified as angiosarcomas of the liver. The number of brain tumors and suicide do not deviate significantly from expected. Cardiovascular and cerebrovascular diseases, on the other hand, differ significantly from the expected. The discrepancies between previous reports on VCM/PVC workers and this report are discussed. The possible etiology of the cardiovascular deaths is also discussed. (+info)
Studies on the metabolism of vinyl chloride.
Vinyl chloride (VCM) is not carcinogenic by itself, it is bioactivated to the highly reactive alkylating oxirane chloroethylene oxide. Further metabolism, apparently, leads via an interaction of the primary alkylating metabolites with glutathion to S-(2-carboxy-methyl)-cysteine and thiodiacetic acid which are eliminated with the urine. Up to now, it has not been ascertained whether the oxirane alone is the essential carcinogenic factor or whether other metabolites are also involved in carcinogenicity. Likewise, it is still unknown whether the metabolites excreted in the urine might be used as biological criteria for exposure to VCM, because these metabolites probably can originate from a series of substances other than VCM. This problem could stimulate investigations on the possible carcinogenic activity of these substances. (+info)