Oxidatively damaged DNA and its repair in colon carcinogenesis

Inflammation, high fat, high red meat and low fiber consumption have for long been known as the most important etiological factors of sporadic colorectal cancers (CRC). Colon cancer originates from neoplastic transformation in a single layer of epithelial cells occupying colonic crypts, in which migration and apoptosis program becomes disrupted. This results in the formation of polyps and metastatic cancers. Mutational program in sporadic cancers involves APC gene, in which mutations occur most abundantly in the early phase of the process. This is followed by mutations in RAS, TP53, and other genes. Progression of carcinogenic process in the colon is accompanied by augmentation of the oxidative stress, which manifests in the increased level of oxidatively damaged DNA both in the colon epithelium, and in blood leukocytes and urine, already at the earliest stages of disease development. Defence mechanisms are deregulated in CRC patients: (i) antioxidative vitamins level in blood plasma declines with the development of disease; (ii) mRNA level of base excision repair enzymes in blood leukocytes of CRC patients is significantly increased; however, excision rate is regulated separately, being increased for 8-oxoGua, while decreased for lipid peroxidation derived ethenoadducts, ?Ade and ?Cyt; (iii) excision rate of ?Ade and ?Cyt in colon tumors is significantly increased in comparison to asymptomatic colon margin, and ethenoadducts level is decreased. This review highlights mechanisms underlying such deregulation, which is the driving force to colon carcinogenesis.     

Insulin resistance due to nutrient excess

It has long been known that excesses of glucose and branched chain amino acids, such as leucine, lead to insulin resistance in skeletal muscle. A recent study in incubated rat muscle suggests that both molecules may do so by virtue of their ability to downregulate the fuel sensing and signaling enzyme AMP-activated protein kinase (AMPK) and activate mTOR/p70S6 kinase (p70S6K) signaling. The results also demonstrated that inhibition of mTOR/p70S6K with rapamycin prevented the development of insulin resistance but had no effect on AMPK activity (Thr172 phosphorylation of its catalytic subunit). In contrast, activation of AMPK by both AICAR and α-lipoic acid led to the phosphorylation of specific molecules that diminished both mTOR/p70S6K signaling and insulin resistance. These findings suggest that downregulation of AMPK precedes mTOR/p70S6K activation in mediating glucose and leucine-induced insulin resistance, although the mechanism by which it does so remains to be determined. Also requiring study is how an excess of the two nutrients leads to AMPK downregulation.     

Insulin and insulin resistance

As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the complex biological mechanisms of insulin action and insulin resistance, we need to consider the dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns. Rapid globalization, urbanisation and industrialization have spawned epidemics of obesity, diabetes and their attendant co-morbidities, as physical inactivity and dietary imbalance unmask latent predisposing genetic traits.     

Insulin resistance and hypertension

Diminished insulin (Ins) sensitivity is a characteristic feature of various pathological conditions such as the cardiometabolic syndrome, Type 2 diabetes, and hypertension. Persons with essential hypertension are more prone than normotensive persons to develop diabetes, and this propensity may reflect decreased ability of Ins to promote relaxation and glucose transport in vascular and skeletal muscle tissue, respectively. There are increasing data suggesting that ANG II acting through its ANG type 1 receptor inhibits the actions of Ins in vascular and skeletal muscle tissue, in part, by interfering with Ins signally through phosphatidylinositol 3-kinase (PI3K) and its downstream protein kinase B (Akt) signaling pathways. This inhibitory action of ANG II is mediated, in part, through stimulation of RhoA activity and oxidative stress. Activated RhoA and increased reactive oxygen species inhibition of PI3K/Akt signaling results in decreased endothelial cell production of nitric oxide, increased myosin light chain activation with vasoconstriction, and reduced skeletal muscle glucose transport.     

Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis

Peroxisome proliferator-activated receptor-delta (PPAR-delta; also known as PPAR-beta) is expressed at high levels in colon tumors, but its contribution to colon cancer is unclear. We examined the role of PPAR-delta in colon carcinogenesis using PPAR-delta-deficient (Ppard(-/-)) mice. In both the Min mutant and chemically induced mouse models, colon polyp formation was significantly greater in mice nullizygous for PPAR-delta. In contrast to previous reports suggesting that activation of PPAR-delta potentiates colon polyp formation, here we show that PPAR-delta attenuates colon carcinogenesis.     

Insulin resistance and birth weight

This review article describes the scientific evidence for the relationship between birth weight and insulin resistance. Most studies demonstrate that low birth weight is closely connected to insulin resistance and later development of diabetes type II in adulthood. For this reason it is important for clinicians to focus on the personal history of the patient's birth weight. In patients with low birth weight, primary measures should be taken to prevent the development or progress of insulin resistance, and late consequences like diabetes and atherosclerotic complications.     

Reduced susceptibility of muscle-specific insulin receptor knockout mice to colon carcinogenesis

Insulin resistance is a risk factor for colon cancer, but it is not clear which of its metabolic sequelae are involved. The objective of this study was to determine whether increased adiposity and elevated circulating lipids commonly seen in insulin resistance promote colon carcinogenesis independent of changes in insulin. We made use of muscle-specific insulin receptor knockout (MIRKO) mice that exhibit elevated serum triglycerides (TG), free fatty acids (FFA), and fat mass but have similar body weights, circulating glucose, and insulin and insulin sensitivity to their wild-type littermates used as controls. Seven-week-old male MIRKO mice and controls received four weekly intraperitoneal injections of either 5 mg/kg azoxymethane (AOM) to induce aberrant crypt foci (ACF) or 10 mg/kg AOM to induce tumors and were killed at 24 or 40 wk of age, respectively. The MIRKO mice displayed hyperinsulinemia at 7 wk of age and reduced insulin sensitivity at 16 wk of age compared with controls. The previously reported MIRKO phenotype developed between 16 and 24 wk of age. By 40 wk of age, however, MIRKO mice were again insulin resistant. ACF development did not differ between MIRKO mice and controls, but MIRKO mice developed significantly fewer colon tumors. Our results suggest that circulating TG and FFA are not promoters of colon tumor development. Indeed, we show that the cumulative effects of the metabolic changes that occur with knockout of the insulin receptor in muscle are associated with reduced susceptibility to colon tumorigenesis.     

Reduced susceptibility to colitis-associated colon carcinogenesis in mice lacking plasma membrane-associated sialidase

Sialic acids are acidic monosaccharides that bind to the sugar chains of glycoconjugates and change their conformation, intermolecular interactions, and/or half-life. Thus, sialidases are believed to modulate the function of sialoglycoconjugates by desialylation. We previously reported that the membrane-associated mammalian sialidase NEU3, which preferentially acts on gangliosides, is involved in cell differentiation, motility, and tumorigenesis. The NEU3 gene expression is aberrantly elevated in several human cancers, including colon, renal, prostate, and ovarian cancers. The small interfering RNA-mediated knock-down of NEU3 in cancer cell lines, but not in normal cell-derived primary cultures, downregulates EGFR signaling and induces apoptosis. Here, to investigate the physiological role of NEU3 in tumorigenesis, we established Neu3-deficient mice and then subjected them to carcinogen-induced tumorigenesis, using a sporadic and a colitis-associated colon cancer models. The Neu3-deficient mice showed no conspicuous accumulation of gangliosides in the brain or colon mucosa, or overt abnormalities in their growth, development, behavior, or fertility. In dimethylhydrazine-induced colon carcinogenesis, there were no differences in the incidence or growth of tumors between the Neu3-deficient and wild-type mice. On the other hand, the Neu3-deficient mice were less susceptible than wild-type mice to the colitis-associated colon carcinogenesis induced by azoxymethane and dextran sodium sulfate. These results suggest that NEU3 plays an important role in inflammation-dependent tumor development.     

Bayesian hierarchical spatially correlated functional data analysis with application to colon carcinogenesis

Summary .   In this article, we present new methods to analyze data from an experiment using rodent models to investigate the role of p27, an important cell-cycle mediator, in early colon carcinogenesis. The responses modeled here are essentially functions nested within a two-stage hierarchy. Standard functional data analysis literature focuses on a single stage of hierarchy and conditionally independent functions with near white noise. However, in our experiment, there is substantial biological motivation for the existence of spatial correlation among the functions, which arise from the locations of biological structures called colonic crypts: this possible functional correlation is a phenomenon we term crypt signaling . Thus, as a point of general methodology, we require an analysis that allows for functions to be correlated at the deepest level of the hierarchy. Our approach is fully Bayesian and uses Markov chain Monte Carlo methods for inference and estimation. Analysis of this data set gives new insights into the structure of p27 expression in early colon carcinogenesis and suggests the existence of significant crypt signaling. Our methodology uses regression splines, and because of the hierarchical nature of the data, dimension reduction of the covariance matrix of the spline coefficients is important: we suggest simple methods for overcoming this problem.     

A stochastic carcinogenesis model incorporating genomic instability fitted to colon cancer data

A generalization of the two-mutation stochastic carcinogenesis model of Moolgavkar, Venzon and Knudson and certain models constructed by Little is developed; the model incorporates progressive genomic instability and an arbitrary number of mutational stages. This model is shown to have the property that, at least in the case when the parameters of the model are eventually constant, the excess relative and absolute cancer rates following changes in any of the parameters will eventually tend to zero. It is also shown that when the parameters governing the processes of cell division, death, or additional mutation (whether of the normal sort or that resulting in genomic destabilization) at the penultimate stage are subject to perturbations, there are relatively large fluctuations in the hazard function for the model, which start almost as soon as the parameters are changed. The model is fitted to US Caucasian colon cancer incidence data. A model with five stages and two levels of genomic destabilization fits the data well. Comparison with patterns of excess risk in the Japanese atomic bomb survivor colon cancer incidence data indicate that radiation might act on early mutation rates in the model; a major role for radiation in initiating genomic destabilization is less likely.     

New insights into the history of domesticated and wild apricots and its contribution to Plum pox virus resistance

Studying domesticated species and their wild relatives allows understanding of the mechanisms of population divergence and adaptation, and identifying valuable genetic resources. Apricot is an important fruit in the Northern hemisphere, where it is threatened by the Plum pox virus (PPV), causing the sharka disease. The histories of apricot domestication and of its resistance to sharka are however still poorly understood. We used 18 microsatellite markers to genotype a collection of 230 wild trees from Central Asia and 142 cultivated apricots as representatives of the worldwide cultivated apricot germplasm; we also performed experimental PPV inoculation tests. The genetic markers revealed highest levels of diversity in Central Asian and Chinese wild and cultivated apricots, confirming an origin in this region. In cultivated apricots, Chinese accessions were differentiated from more Western accessions, while cultivated apricots were differentiated from wild apricots. An approximate Bayesian approach indicated that apricots likely underwent two independent domestication events, with bottlenecks, from the same wild population. Central Asian native apricots exhibited genetic subdivision and high frequency of resistance to sharka. Altogether, our results contribute to the understanding of the domestication history of cultivated apricot and point to valuable genetic diversity in the extant genetic resources of wild apricots.     

Genome-wide association and fine mapping of genetic loci predisposing to colon carcinogenesis in mice

To identify the genetic determinants of colon tumorigenesis, 268 male mice from 33 inbred strains derived from different genealogies were treated with azoxymethane (AOM; 10 mg/kg) once a week for six weeks to induce colon tumors. Tumors were localized exclusively within the distal colon in each of the strains examined. Inbred mouse strains exhibit a large variability in genetic susceptibility to AOM-induced colon tumorigenesis. The mean colon tumor multiplicity ranged from 0 to 38.6 (mean = 6.5 ± 8.6) and tumor volume ranged from 0 to 706.5 mm(3) (mean = 87.4 ± 181.9) at 24 weeks after the first dose of AOM. AOM-induced colon tumor phenotypes are highly heritable in inbred mice, and 68.8% and 71.3% of total phenotypic variation in colon tumor multiplicity and tumor volume, respectively, are attributable to strain-dependent genetic background. Using 97,854 single-nucleotide polymorphisms, we carried out a genome-wide association study (GWAS) of AOM-induced colon tumorigenesis and identified a novel susceptibility locus on chromosome 15 (rs32359607, P = 6.31 × 10(-6)). Subsequent fine mapping confirmed five (Scc3, Scc2, Scc12, Scc8, and Ccs1) of 16 linkage regions previously found to be associated with colon tumor susceptibility. These five loci were refined to less than 1 Mb genomic regions of interest. Major candidates in these loci are Sema5a, Fmn2, Grem2, Fap, Gsg1l, Xpo6, Rabep2, Eif3c, Unc5d, and Gpr65. In particular, the refined Scc3 locus shows high concordance with the human GWAS locus that underlies hereditary mixed polyposis syndrome. These findings increase our understanding of the complex genetics of colon tumorigenesis, and provide important insights into the pathways of colorectal cancer development and might ultimately lead to more effective individually targeted cancer prevention strategies.     

Chemopreventive effect of chitosan oligosaccharide against colon carcinogenesis

Chitosan oligosaccharide (COS, 3 kDa相似文献   

Review. Kuru and its contribution to medicine

The solution of kuru led us to the solution of Creutzfeldt-Jakob disease and to the elucidation, in humans and other species, of previously unknown mechanisms of infection. These require very close three-dimensional matching, which determines infectious nucleant or prion activity. Evidence for nucleation processes is found widely in the organic and inorganic worlds and in the interactions between them: in the formation of amyloid fibrils; in the biochemistry of silicon; in cave formations deep in the Earth; and in outer space. Kuru in its location in Papua New Guinea has also led to an understanding of the cultural achievements of the Palaeo-Melanesians, with deep roots in human history.     

Social neuroscience and its potential contribution to psychiatry

Most mental disorders involve disruptions of normal social behavior. Social neuroscience is an interdisciplinary field devoted to understanding the biological systems underlying social processes and behavior, and the influence of the social environment on biological processes, health and well‐being. Research in this field has grown dramatically in recent years. Active areas of research include brain imaging studies in normal children and adults, animal models of social behavior, studies of stroke patients, imaging studies of psychiatric patients, and research on social determinants of peripheral neural, neuroendocrine and immunological processes. Although research in these areas is proceeding along largely independent trajectories, there is increasing evidence for connections across these trajectories. We focus here on the progress and potential of social neuroscience in psychiatry, including illustrative evidence for a rapid growth of neuroimaging and genetic studies of mental disorders. We also argue that neuroimaging and genetic research focused on specific component processes underlying social living is needed.