http://repub.eur.nl/res/aut/16102/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/30772/ 2011-10-15T00:00:00Z Background.: Preoperative fasting induces robust protection against renal ischemia/reperfusion (I/R) injury in mice but is considered overcautious and possibly detrimental for postoperative recovery in humans. Furthermore, fasting seems to conflict with reported benefits of preoperative nutritional enhancement with carbohydrate-rich drinks. Here, we investigated whether preoperative ingestion of a glucose solution interferes with fasting-induced protection against renal I/R injury. Methods.: Mice were randomized into the following groups: fasted for 3 days with access to water (fasted) or a glucose solution (fasted+glc) and fed ad libitum with water (fed) or a glucose solution (fed+glc). After induction of bilateral renal I/R injury, all animals had free access to food and water. Calorie intake, body weight, insulin sensitivity, kidney function, and animal survival were determined. Results.: Fed+glc mice had a comparable daily calorie intake as fed mice, but 50% of those calories were obtained from the glucose solution. Fasted+glc mice had a daily calorie intake of approximately 75% of the intake of both fed groups. This largely prevented the substantial body weight loss seen in fasted animals. Preoperative insulin sensitivity was significantly improved in fasted+glc mice versus fed mice. After I/R injury, kidney function and animal survival were superior in both fasted groups. Conclusions.: The benefits of fasting and preoperative nutritional enhancement with carbohydrates are not mutually exclusive and may be a clinically feasible regimen to protect against renal I/R injury. http://repub.eur.nl/res/pub/28485/ 2010-02-01T00:00:00Z Dietary restriction (DR) extends lifespan and increases resistance to multiple forms of stress, including ischemia reperfusion injury to the brain and heart in rodents. While maximal effects on lifespan require long-term restriction, the kinetics of onset of benefits against acute stress is not known. Here, we show that 2-4 weeks of 30% DR improved survival and kidney function following renal ischemia reperfusion injury in mice. Brief periods of water-only fasting were similarly effective at protecting against ischemic damage. Significant protection occurred within 1 day, persisted for several days beyond the fasting period and extended to another organ, the liver. Protection by both short-term DR and fasting correlated with improved insulin sensitivity, increased expression of markers of antioxidant defense and reduced expression of markers of inflammation and insulin/insulin-like growth factor-1 signaling. Unbiased transcriptional profiling of kidneys from mice subject to short-term DR or fasting revealed a significant enrichment of signature genes of long-term DR. These data demonstrate that brief periods of reduced food intake, including short-term daily restriction and fasting, can increase resistance to ischemia reperfusion injury in rodents and suggest a rapid onset of benefits of DR in mammals. © 2010 The Authors. Journal compilation http://repub.eur.nl/res/pub/16403/ 2009-05-20T00:00:00Z The genetic information that takes care of the proper functioning of all cell types that makes up an organism is organized in DNA. This so-called blue print of life is continuously attacked by a variety of genotoxic agents and environmental stresses that can damage the DNA (Figure 1). For instance, ultraviolet radiation (UV) causes helix-distorting lesions, cis-syn-cyclobutane pyrimidine dimers (CPDs) and pyrimidine-(6,4)-pyrimidone products (6-4PPs) (Sancar, 1996). On the other hand, ionizing radiation (IR) can cause formation of single strand breaks (SSBs) and double strand breaks (DSBs) (van Gent et al., 2001). The organism’s own metabolism generates reactive oxygen species (ROS) (including superoxide anions, hydrogen peroxide and hydroxyl radicals and their numerous subsequent reaction products) lipid peroxidation products, oestrogen metabolites, reactive carbonyl species, endogenous alkylating agents, spontaneous hydrolysis and deamination products (De Bont and van Larebeke, 2004). These result in DNA damages like oxidative DNA lesions, including 8-oxo-2’-deoxyguanosine (oxodG), thymine glycols, cyclopurines and SSBs and DSBs (Hoeijmakers, 2001). Finally, spontaneous modifications of nucleotides such as hydrolysis leading to abasic sites are common in cells. In total this adds up to 104-105 lesions per cell per day (Lindahl, 1993). The consequences of DNA damage can be severe and may lead to cellular malfunctioning caused by hampered transcription and replication, and may result in permanent cell cycle arrest (senescence) or cell death (apoptosis). If the cells don’t get replaced, and the tissue or organismal homeostasis gets lost, it can result in (premature) ageing (Mitchell et al., 2003). However, when these DNA damages result in irreversible mutations or chromosomal aberrations, and therefore replication errors, these mutations can lead to carcinogenesis (Mitchell et al., A complex network of DNA repair pathways (first found in bacteria and yeast), each selective for a specific subset of DNA lesions has evolved to overcome early onset of cancer or ageing. However, the more complex the system, the more sensitive it is to errors and deficiencies. http://repub.eur.nl/res/pub/24824/ 2009-04-07T00:00:00Z Cockayne syndrome and other segmental progerias with inborn defects in DNA repair mechanisms are thought to be due in part to hypersensitivity to endogenous oxidative DNA damage. The accelerated aging-like symptoms of this disorder include dysmyelination within the central nervous system, progressive sensineuronal hearing loss and retinal degeneration. We tested the effects of congenital nucleotide excision DNA repair deficiency on acute oxidative stress sensitivity in vivo. Surprisingly, we found mouse models of Cockayne syndrome less susceptible than wild type animals to surgically induced renal ischemia reperfusion injury, a multifactorial injury mediated in part by oxidative damage. Renal failure-related mortality was significantly reduced in Csb-/-mice, kidney function was improved and proliferation was significantly higher in the regenerative phase following ischemic injury. Protection from ischemic damage correlated with improved baseline glucose tolerance and insulin sensitivity and a reduced inflammatory response following injury. Protection was further associated with genetic ablation of a different Cockayne syndrome-associated gene, Csa. Our data provide the first functional in vivo evidence that congenital DNA repair deficiency can induce protection from acute stress in at least one organ. This suggests that while specific types of unrepaired endogenous DNA damage may lead to detrimental effects in certain tissues, they may at the same time elicit beneficial adaptive changes in others and thus contribute to the tissue specificity of disease symptoms. © 2009 The Authors Journal compilation http://repub.eur.nl/res/pub/14100/ 2006-10-30T00:00:00Z Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i) the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii) differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii) interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of "null" alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals.