DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity

Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation

Advanced lipoxidation end products (ALEs) and advanced glycation end products (AGEs) have a pathogenetic role in the development and progression of different oxidative-based diseases including diabetes, atherosclerosis, and neurological disorders. AGEs and ALEs represent a quite complex class of compounds that are formed by different mechanisms, by heterogeneous precursors and that can be formed either exogenously or endogenously. There is a wide interest in AGEs and ALEs involving different aspects of research which are essentially focused on set-up and application of analytical strategies (1) to identify, characterize, and quantify AGEs and ALEs in different pathophysiological conditions ; (2) to elucidate the molecular basis of their biological effects ; and (3) to discover compounds able to inhibit AGEs/ALEs damaging effects not only as biological tools aimed at validating AGEs/ALEs as drug target, but also as promising drugs. All the above-mentioned research stages require a clear picture of the chemical formation of AGEs/ALEs but this is not simple, due to the complex and heterogeneous pathways, involving different precursors and mechanisms. In view of this intricate scenario, the aim of the present review is to group the main AGEs and ALEs and to describe, for each of them, the precursors and mechanisms of formation

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

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Not AvailableA study was conducted to assess the impact of summer season-related heat stress and nutritional stress individually as well as simultaneously on the adaptive capability of goats. Twenty four adult Osmanabadi bucks (average body weight (BW) 16.0 kg) were divided into four groups, C (n = 6; control), HS (n = 6; heat stress), NS (n = 6; nutritional stress) and CS (n = 6; combined stress). The study was conducted for a period of 45 days. The NS and CS bucks were under restricted feed to induce nutritional stress. The HS and CS bucks were exposed to summer heat stress. The animals exhibited different physiological adaptive behavior in the morning and afternoon. Further, the higher plasma cortisol (p < 0.01) and aldosterone (p < 0.05) was recorded in CS group as compared to other groups. The highest degree of degenerative changes and hyperactivity of endocrine cells was recorded in CS group liver and adrenal gland respectively. The higher expression of adrenal and hepatic Heat Shock Protein 70 (HSP70)messenger ribonucleic acid (mRNA) was reported in CS and HS goats respectively. It can be concluded from this study that plasma cortisol and adrenal HSP70 gene expression may be considered as ideal biological markers for combined stresses in Osmanabadi bucks.Not Availabl

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Not AvailableA study was conducted to assess the impact of heat and nutritional stress simultaneously on the adaptive capability as indicated by behavioral and physiological responses, plasma heat shock protein 70 (HSP70) level, and peripheral blood mononuclear cells (PBMC) HSP70 gene expression in goats. Twenty-four adult Osmanabadi bucks (average body weight (BW) 16.0 kg) were used in the present study. The bucks were divided into four groups viz., C (n = 6; control), HS (n = 6; heat stress), NS (n = 6; nutritional stress), and CS (n = 6; combined stress). The study was conducted for a period of 45 days. C and HS bucks had ad libitum access to their feed while NS and CS bucks were under restricted feed (30 % intake of C bucks) to induce nutritional stress. The HS and CS bucks were exposed to solar radiation for 6 h a day between 10:00 a.m. and 4:00 p.m. to induce heat stress. The data was analyzed using repeated measures analysis of variance. The standing time differed significantly (P < 0.01) between ad libitum fed groups (C and HS) and restricted feeding groups (NS and CS). The highest (P < 0.01) lying time was recorded in the CS group while the lowest in the C and HS groups. The highest (P < 0.01) drinking frequency was also recorded in the CS group. Water intake recorded was significantly (P < 0.01) higher in both the HS and CS groups. The highest respiration rate (RR), pulse rate (PR), and rectal temperature (RT) during the afternoon were also recorded in the CS group. Further, skin temperature of the head, flank, and scrotum during the afternoon was also higher (P < 0.01) in the CS group. In addition, both plasma HSP70 concentration and PBMC HSP70 messenger RNA (mRNA) transcript expression were also significantly (P < 0.01) higher in the CS group. It can be concluded from this study that when two stressors occur simultaneously, they may have severe impact on adaptive capabilities of Osmanabadi bucks as compared to that would occur individually. Further, the study indicated that lying time, drinking frequency, RR, RT, plasma HSP70, and PBMC HSP70 gene expression may act as ideal biological markers for assessing the impact of CS on adaptive capabilities in bucks.ICAR-National Institute of Animal Nutrition and Physiolog

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Not AvailableA study was conducted to assess the impact of heat stress, nutritional stress and combined stresses (heat and nutritional stress) on rumen fermentation characteristics, histopathology of rumen and rumen HSP70 gene expression in goats. Twenty four adult Osmanabadi bucks were divided into four groups, C (n=6; control), HS (n=6; heat stress), NS (n=6; nutritional stress) and CS (n=6; combined stress). The study was conducted for a period of 45 days. The C and HS bucks had ad libitum access to their feed while NS and CS bucks were subjected to restricted feed (30% intake of C bucks) to induce nutritional stress. The HS and CS bucks were exposed to heat stress in an outside environment. Both feed intake and body weight were significantly (p < 0.01) lower in CS and NS groups. The carboxy methyl cellulase activities-extracellular, intracellular and total activity in the rumen fluid differed significantly (p < 0.01) between the groups. The highest concentration of ammonia nitrogen (p < 0.05) was recorded in C while the lowest in the CS group. The concentration of total nitrogen and trichloroacetic acid precipitable N, propionic acid, butyric acid, and valeric acid was lower (p < 0.01) in the restricted fed (NS and CS) bucks as compared to ad libitum fed groups (C and HS). Further, the ratio of acetate to propionate (A: P ratio) was also significantly (p < 0.01) higher in CS and NS groups. The higher expression of rumen heat shock protein 70 (HSP70) mRNA was observed in CS goats. The histopathological section of rumen revealed a reduction in the length of rumen villi and thickness in CS, whereas rumen keratinization was highest in the CS group. From the study it can be concluded that when two stresses occur simultaneously, they may have severe impact on rumen fermentation characteristics of bucks.Not Availabl

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Not AvailableA study was conducted to assess the combined effects of heat and nutritional stress on body weight changes and HSP70 gene expressionin Osmanabadi goats. Twenty four adult Osmanabadi bucks were divided into four groups of six animals each viz. C (control), HS (heat stress), NS (nutritional stress) and CS (combined stress). The C and HS bucks had ad libitum access to their feed while NS and CS bucks were subjected to restricted feed (30% intake of C bucks) to induce nutritional stress. The HS and CS bucks were exposed to heat stress in outside environment for six hours a day between 10:00 h to 16:00 h. Both C and HS groups showed significantly higher (P<0.01) body weight and body condition scoring as compared to NS and CS groups. The highest plasma growth hormone (P<0.01) was recorded in CS group and the lowest in all stress groups (C, HS and NS). The higher (P<0.05) expression of testicular Heat Shock Protein 70 (HSP70) mRNA was reported in HS groups. It can be concluded from this study that when nutrition is not compromised Osmanabadi goats were able to withstand heat stress without compromising productionICA

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Not AvailableLivestock is an integral part of any agricultural system all over the world. Optimized livestock production is depended upon many factors like environmental stresses, climatic factors, health status, nutrient availability, and genetic potential. In the changing climate scenario, nutritional stress act as the most important indirect stress affecting livestock leading to decreased performance, lower efficiency, increased mortality and it also affects the immune system. The animals in tropics faces the problem of low feed availability during summer and this leads to severe nutritional stress to livestock grazing in the low pasture lands. Under nutrition reduces the quality and quantity of milk production, effects growth potential and reduces body condition score (BCS), induces seasonal weight loss (SWL) and it also declines the reproductive capacity of the animals, it reduces the fertility rate, embryo quality, expression of oestrus behaviour, altering follicular development, compromising oocyte competence, and inhibiting embryonic development, reduced calf birth weight, reduced sperm output, decreased sperm motility and an increased proportion of morphologically abnormal spermatozoa in the ejaculate. The reduced nutrient availability also alters the endocrine and hormonal activity in livestock leading to physiological changes and decline in reproductive efficiency. The animals exposed to environmental stress are found to cope up with the adverse effects of the stress when the nutritional requirements are not compromised. Thus in order to sustain the productivity, suitable nutritional interventions are to be adopted like management of forage for the dry period, utilization of the non-conventional feed resources as alternatives, antioxidant supplementations during the stress period, and also water management strategies for both surface and ground water resources, at both local and national levels, as fresh and contamination free water is crucial for animal production. These efforts will ensure economically viable returns in livestock farms in the changing climate scenario..Not Availabl

Adaptation of livestock to environmental challenges

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Ameliorative Strategies to Sustain Livestock Production during Heat Stress

Not AvailableIn the changing climate scenario, heat stress is of major concern among livestock owners as it affects drastically livestock production which otherwise contributes 40% of world agriculture GDP (gross domestic product). Hence there is an urgent need for reviewing the various strategies to counter the heat stress impact on livestock production. THI (temperature humidity index) may not be the ideal index to quantify heat stress impact on livestock as it does not take into account solar radiation and wind velocity. Hence, more appropriate agro-ecological zone specific indices like Dairy Heat Load Index (DHLI) which takes into account all cardinal weather parameters is the need of hour. Development of appropriate heat abatement strategies depends on the type of dairy operation practiced in a particular livestock farm. During heat stress, management strategies such as providing shade, sprinklers, fans, cold water, minimum handling, grazing during early morning and late evening hours might be very beneficial to improve livestock production. Considerable efforts are needed to modify the existing housing condition according to the changing climatic condition to improve the livestock production. Apart from management strategies, nutritional strategies also must be given equal importance which not only will help the animal to survive the stress but also it will ensure optimum energy for production processes. Nutritional interventions such as additional concentrate supplementation, re-formulation of diet that accounts for reduced DMI, fat, minerals, vitamins and antioxidants supplementation are very vital for ensuring optimum production in livestock during heat stress condition. Appropriate health service measures needs to be taken to counter the emergence of sudden disease outbreaks during heat stress condition. Geographic information system (GIS) has to be integrated with disease surveillance program to create the hazardous maps of sudden disease outbreaks and correlating them with climate and other information might be very useful for future predictions. In addition, predictive modeling system can also be used as an effective tool to forecast the probability of a disease outbreak. Advanced technological development need to be integrated with suitable breeding programs using marker assisted selection to develop agro-ecological zone specific thermo-tolerant breeds of livestock. The developed strategies should be user friendly and economically feasible if farmers have to adopt those strategies to improve livestock production in the changing climatic condition.Not Availabl