Base excision repair, folate deficiency and cancer

Folate, an essential water soluble vitamin has been implicated in the etiology of many types of cancer especially colorectal cancer. Folate deficiency has been reported to incapacitate DNA repair pathways and thereby affect the genomic stability. Our lab has reported previously and here again through this research that folate deficiency affects the DNA damage inducibility of base excision repair pathway. Our study shows the differential effect folate deficiency has on the expression of the genes involved in this pathway. Further, our study shows the increase in preneoplastic lesions in the colon of mice exposed to folate deficiency in response to dimethylhydrazine, a colon and liver carcinogen. This study further supports our findings from previous studies from our lab that folate deficiency increases the susceptibility to cancer by deregulating DNA repair pathways, base excision repair in this scenario. Similarly, methionine restriction also, increases accumulation of preneoplastic lesions and incapacitates base excision repair in mice exposed to dimethylhydrazine. Since methionine restriction has shown to produce beneficial effects in laboratory rodents when the animals are exposed to long term restrictions, it would be interesting to put our animal models on methionine restriction and folate deficient diets for longer periods to test whether long term adaptations would bring about any beneficial effect

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α.

Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals

Neural Network based Modeling, Characterization and Identification of Chaotic Systems in Nature

Modeling of chaotic systems, based on the output time series, is quite promising since the output often represents the characteristic behaviour of the total system. It has been an interesting topic for researchers over the past few years. So far, some methods are developed for the identification of chaotic systems. Because of the intense complexity of chaotic systems, the performance of existing algorithms is not always satisfactory. Application of chaotic system theory to socially relevant problems like environmental studies is the need of the hour Neural networks have the required self-learning capability to tune the network parameters (i.e. weights) for identifying highly non-linear and chaotic systems. In the present work, effectiveness of modeling a chaotic system using dynamic neural networks has been demonstrated. From the rich literature available for non-linear modeling with neural networks, the Recurrent Neural Network (RNN) structure is selected. The Extended Kalman Filter (EKF) algorithm is used to train the RNN. Further, the Expectation Maximization algorithm is used to effectively arrive at the initial states and the state covariance. Particle filter algorithm with its two important variants namely Sampling Importance Resampling (SIR) and Rao Blackwellised algorithms are also used for training the given RNN. Four standard chaotic systems, Lorenz, Rossler, Chua and Chen, are modelled with the three algorithms. The best algorithm is found to be EKF-EM based on the least mean square error criterion. Validation of RNN model with EKFEM algorithm is done in time domain by Estimation of embedding dimension, Phase plots, Lyapunov Exponents, Kaplan -Yorke dimension and Bifurcation diagrams. Analysis of the chaotic systems is also performed in the transform domain using Fourier, Wavelet and Mapped Real Transforms. viii Natural chaotic systems are analyzed based on the selected model structure and training algorithm, taken for analysis. Sunspot, Venice Lagoon and North Atlantic oscillations are the three of the natural chaotic systems modelled with the selected RNN model structure and EKF-EM algorithm

doi:10.1093/nar/gkm860 SURVEY AND SUMMARY Caloric restriction and genomic stability

Caloric restriction (CR) reduces the incidence and progression of spontaneous and induced tumors in laboratory rodents while increasing mean and maximum life spans. It has been suggested that CR extends longevity and reduces age-related pathologies by reducing the levels of DNA damage and mutations that accumulate with age. This hypothesis is attractive because the integrity of the genome is essential to a cell/organism and because it is supported by observations that both cancer and immunological defects, which increase significantly with age and are delayed by CR, are associated with changes in DNA damage and/or DNA repair. Over the last three decades, numerous laboratories have examined the effects of CR on the integrity of the genome and the ability of cells to repair DNA. The majority of studies performed indicate that the age-related increase in oxidative damage to DNA is significantly reduced by CR. Early studies suggest that CR reduces DNA damage by enhancing DNA repair. With the advent of genomic technology and our increased understanding of specific repair pathways, CR has been shown to have a significant effect on major DNA repair pathways, such as NER, BER and double-strand break repair

The Timing and Duration of Folate Restriction Differentially Impacts Colon Carcinogenesis

Diet plays a crucial role in the development of colorectal cancer (CRC). Of particular importance, folate, present in foods and supplements, is a crucial modulator of CRC risk. The role of folate, and, specifically, the synthetic variant, folic acid, in the primary prevention of CRC has not been fully elucidated. Animal studies varied considerably in the timing, duration, and supplementation of folates, leading to equivocal results. Our work attempts to isolate these variables to ascertain the role of folic acid in CRC initiation, as we previously demonstrated that folate restriction conferred protection against CRC initiation in a β-pol haploinsufficient mouse model. Here we demonstrated that prior adaptation to folate restriction altered the response to carcinogen exposure in wild-type C57BL/6 mice. Mice adapted to folate restriction for 8 weeks were protected from CRC initiation compared to mice placed on folate restriction for 1 week, irrespective of antibiotic supplementation. Through analyses of mTOR signaling, DNA methyltransferase, and DNA repair, we have identified factors that may play a critical role in the differential responses to folate restriction. Furthermore, the timing and duration of folate restriction altered these pathways differently in the absence of carcinogenic insult. These results represent novel findings, as we were able to show that, in the same model and under controlled conditions, folate restriction produced contrasting results depending on the timing and duration of the intervention

A new role for oxidative stress in aging: The accelerated aging phenotype in Sod1−/− mice is correlated to increased cellular senescence

In contrast to other mouse models that are deficient in antioxidant enzymes, mice null for Cu/Zn-superoxide dismutase (Sod1−/− mice) show a major decrease in lifespan and several accelerated aging phenotypes. The goal of this study was to determine if cell senescence might be a contributing factor in the accelerated aging phenotype observed in the Sod1−/− mice. We focused on kidney because it is a tissue that has been shown to a significant increase in senescent cells with age. The Sod1−/− mice are characterized by high levels of DNA oxidation in the kidney, which is attenuated by DR. The kidney of the Sod1−/− mice also have higher levels of double strand DNA breaks than wild type (WT) mice. Expression (mRNA and protein) of p16 and p21, two of the markers of cellular senescence, which increased with age, are increased significantly in the kidney of Sod1−/− mice as is β-gal staining cells. In addition, the senescence associated secretory phenotype was also increased significantly in the kidney of Sod1−/− mice compared to WT mice as measured by the expression of transcripts for IL-6 and IL-1β. Dietary restriction of the Sod1−/− mice attenuated the increase in DNA damage, cellular senescence, and expression of IL-6 and IL-1β. Interestingly, the Sod1−/− mice showed higher levels of circulating cytokines than WT mice, suggesting that the accelerated aging phenotype shown by the Sod1−/− mice could result from increased inflammation arising from an accelerated accumulation of senescent cells. Based on our data with Sod1−/− mice, we propose that various bouts of increased oxidative stress over the lifespan of an animal leads to the accumulation of senescent cells. The accumulation of senescent cells in turn leads to increased inflammation, which plays a major role in the loss of function and increased pathology that are hallmark features of aging