Genes Involved in Oxidative Stress Pathways Are Differentially Expressed in Circulating Mononuclear Cells Derived From Obese Insulin-Resistant and Lean Insulin-Sensitive Individuals Following a Single Mixed-Meal Challenge.

Background: Oxidative stress induced by nutritional overload has been linked to the pathogenesis of insulin resistance, which is associated with metabolic syndrome, obesity, type 2 diabetes and diabetic vascular complications. Postprandial changes in expression of oxidative stress pathway genes in obese vs. lean individuals, following intake of different types of meals varying in macronutrient composition have not been characterized to date. Here we aimed to test whether/how oxidative stress responses in obese vs. lean individuals are modulated by meal composition. Methods: High-carbohydrate (HC), high-fat (HF), or high-protein (HP) liquid mixed meals were administered to study subjects (lean insulin-sensitive, n = 9 and obese insulin-resistant, n = 9). Plasma levels of glucose and insulin, lipid profile, urinary F2-isoprostanes (F2-IsoP), and expression levels of genes of oxidative stress pathways were assessed in mononuclear cells (MNC) derived from fresh peripheral blood, at baseline and up to 6-h postprandial states. Differences in these parameters were compared between insulin-sensitive/resistant groups undergoing aforementioned meal challenges. Results: Obese individuals exhibited increased pro-oxidant (i.e., CYBB and CYBA) and anti-oxidant (i.e., TXN RD1) gene expression in the postprandial state, compared with lean subjects, regardless of meal type (P interaction for group × time < 0.05). By contrast, lean subjects had higher expression of NCF-4 gene (pro-oxidant) after HC meal and SOD1 gene (anti-oxidant) after HC and HF meals (P interaction for group × meal < 0.05). There was an increase in postprandial level of urinary F2-IsoP in the obese (P < 0.05) but not lean group. Conclusions: These findings may represent an adaptive oxidative response to mitigate increased stress induced by acute nutritional excess. Further, the results suggest an increased predisposition of obese subjects to oxidative stress. Chronic nutritional excess resulting in increases in body weight and adiposity might lead to decompensation leading to worsening insulin resistance and its sequel. Insights from this study could impact on nutritional recommendations for obese subjects at high-risk of cardiovascular diseases

Heredity of type 2 diabetes confers increased susceptibility to oxidative stress and inflammation.

INTRODUCTION AND OBJECTIVE: Heredity of type 2 diabetes mellitus (T2DM) is associated with greater risk for developing T2DM. Thus, individuals who have a first-degree relative with T2DM (FDRT) provide a natural model to study factors of susceptibility towards development of T2DM, which are poorly understood. Emerging key players in T2DM pathophysiology such as adverse oxidative stress and inflammatory responses could be among possible mechanisms that predispose FDRTs to develop T2DM. Here, we aimed to examine the role of oxidative stress and inflammatory responses as mediators of this excess risk by studying dynamic postprandial responses in FDRTs. RESEARCH DESIGN AND METHODS: In this open-label case-control study, we recruited normoglycemic men with (n=9) or without (n=9) a family history of T2DM. We assessed plasma glucose, insulin, lipid profile, cytokines and F2-isoprostanes, expression levels of oxidative and inflammatory genes/proteins in circulating mononuclear cells (MNC), myotubes and adipocytes at baseline (fasting state), and after consumption of a carbohydrate-rich liquid meal or insulin stimulation. RESULTS: Postprandial glucose and insulin responses were not different between groups. Expression of oxidant transcription factor NRF2 protein (p<0.05 for myotubes) and gene (pgroup=0.002, ptime×group=0.016), along with its target genes TXNRD1 (pgroup=0.004, ptime×group=0.007), GPX3 (pgroup=0.011, ptime×group=0.019) and SOD-1 (pgroup=0.046 and ptime×group=0.191) was upregulated in FDRT-derived MNC after meal ingestion or insulin stimulation. Synergistically, expression of target genes of inflammatory transcription factor nuclear factor kappa B such as tumor necrosis factor alpha (pgroup=0.001, ptime×group=0.007) was greater in FDRT-derived MNC than in non-FDRT-derived MNC after meal ingestion or insulin stimulation. CONCLUSIONS: Our findings shed light on how heredity of T2DM confers increased susceptibility to oxidative stress and inflammation. This could provide early insights into the underlying mechanisms and future risk of FDRTs for developing T2DM and its associated complications

The Microbial Communities in Male First Catch Urine Are Highly Similar to Those in Paired Urethral Swab Specimens

Urine is the CDC-recommended specimen for STI testing. It was unknown if the bacterial communities (microbiomes) in urine reflected those in the distal male urethra. We compared microbiomes of 32 paired urine and urethral swab specimens obtained from adult men attending an STD clinic, by 16S rRNA PCR and deep pyrosequencing. Microbiomes of urine and swabs were remarkably similar, regardless of STI status of the subjects. Thus, urine can be used to characterize urethral microbiomes when swabs are undesirable, such as in population-based studies of the urethral microbiome or where multiple sampling of participants is required

The HY5-PIF regulatory module coordinates light and temperature control of photosynthetic gene transcription

The ability to interpret daily and seasonal alterations in light and temperature signals is essential for plant survival. This is particularly important during seedling establishment when the phytochrome photoreceptors activate photosynthetic pigment production for photoautotrophic growth. Phytochromes accomplish this partly through the suppression of phytochrome interacting factors (PIFs), negative regulators of chlorophyll and carotenoid biosynthesis. While the bZIP transcription factor long hypocotyl 5 (HY5), a potent PIF antagonist, promotes photosynthetic pigment accumulation in response to light. Here we demonstrate that by directly targeting a common promoter cis-element (G-box), HY5 and PIFs form a dynamic activation-suppression transcriptional module responsive to light and temperature cues. This antagonistic regulatory module provides a simple, direct mechanism through which environmental change can redirect transcriptional control of genes required for photosynthesis and photoprotection. In the regulation of photopigment biosynthesis genes, HY5 and PIFs do not operate alone, but with the circadian clock. However, sudden changes in light or temperature conditions can trigger changes in HY5 and PIFs abundance that adjust the expression of common target genes to optimise photosynthetic performance and growth

Current and future economic burden of diabetes among working-age adults in Asia: conservative estimates for Singapore from 2010-2050

Abstract Background Diabetes not only imposes a huge health burden but also a large economic burden worldwide. In the working-age population, cost of lost productivity can far exceed diabetes-related medical cost. In this study, we aimed to estimate the current and future indirect and excess direct costs of diagnosed type 2 diabetes among the working-age population in Singapore. Methods A previously-published epidemiological model of diabetes was adapted to forecast prevalence among working-age patients with diagnosed type 2 diabetes in the absence of interventions. The current methodology of the American Diabetes Association was adopted to estimate the costs of diabetes for this population. Diabetes-related excess direct medical costs were obtained from a local cost study while indirect costs were calculated using the human capital approach applied to local labor force statistics. These cost were estimated conservatively from a societal perspective on a per patient basis and projected to the overall Singapore population from 2010 to 2050. Results In 2010, total economic costs per working-age patient were estimated to be US$5,646 (US$4,432-US$10,612), of which 42$7,791 (US$5,741-US$12,756) in 2050, with the share of indirect costs rising to 65 %. Simultaneous increases in prevalence imply that the total economic costs of diabetes for the entire working-age population will increase by 2.4 fold from US$787 million in 2010 to US$1,867 million in 2050. Conclusions By current projections, diabetes in Singapore represents a growing economic burden. Among the working-age population, the impact of productivity loss will become increasingly significant. Prevention efforts to reduce overall prevalence should also engage stakeholders outside the health sector who ultimately bear the indirect burden of disease

PER2 Variation is Associated with Diurnal Preference in a Korean Young Population

The PER2 gene has been reported to influence diurnal preference. In this study, we have attempted to characterize the associations between the PER2 gene polymorphisms and diurnal preference in a population of healthy young subjects, controlling for the social and environmental confounding factors. Subjects were 299 students in a college, carefully selected to be mentally and physically healthy. All subjects completed the 13-item composite scale for morningness (CSM). PER2 gene polymorphisms were genotyped by PCR-based methods. Genotype and allele carrier status of a PER2 G3853A polymorphism (rs934945) were associated with CSM scores. Carriers of the 3853G allele showed significantly higher CSM scores (P = 0.004, P = 0.009, and P = 0.001; total, morningness, and activity plan, respectively). There were no significant differences on CSM scores among genotypes and allele status of PER2 rs2304672. This result indicates that rs934945 of PER2 may be associated with diurnal preference in a Korean healthy population

Pathophysiology and pathogenesis of circadian rhythm sleep disorders

Metabolic, physiological and behavioral processes exhibit 24-hour rhythms in most organisms, including humans. These rhythms are driven by a system of self-sustained clocks and are entrained by environmental cues such as light-dark cycles as well as food intake. In mammals, the circadian clock system is hierarchically organized such that the master clock in the suprachiasmatic nuclei of the hypothalamus integrates environmental information and synchronizes the phase of oscillators in peripheral tissues. The transcription and translation feedback loops of multiple clock genes are involved in the molecular mechanism of the circadian system. Disturbed circadian rhythms are known to be closely related to many diseases, including sleep disorders. Advanced sleep phase type, delayed sleep phase type and nonentrained type of circadian rhythm sleep disorders (CRSDs) are thought to result from disorganization of the circadian system. Evaluation of circadian phenotypes is indispensable to understanding the pathophysiology of CRSD. It is laborious and costly to assess an individual's circadian properties precisely, however, because the subject is usually required to stay in a laboratory environment free from external cues and masking effects for a minimum of several weeks. More convenient measurements of circadian rhythms are therefore needed to reduce patients' burden. In this review, we discuss the pathophysiology and pathogenesis of CRSD as well as surrogate measurements for assessing an individual's circadian phenotype

The utility of Aspirin in dukes C and high risk dukes B colorectal cancer - The ASCOLT study: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>High quality evidence indicates that aspirin is effective in reducing colorectal polyps; and numerous epidemiological studies point towards an ability to prevent colorectal cancer. However the role of Aspirin as an adjuvant agent in patients with established cancers remains to be defined. Recently a nested case-control study within the Nurses Health cohort suggested that the initiation of Aspirin <it>after </it>the diagnosis of colon cancer reduced overall colorectal cancer specific mortality. Although this data is supportive of Aspirin's biological activity in this disease and possible role in adjuvant therapy, it needs to be confirmed in a randomized prospective trial.</p> <p>Methods/Design</p> <p>We hypothesize through this randomized, placebo-controlled adjuvant study, that Aspirin in patients with dukes C or high risk dukes B colorectal cancer (ASCOLT) can improve survival in this patient population over placebo control. The primary endpoint of this study is Disease Free Survival and the secondary Endpoint is 5 yr Overall Survival. This study will randomize eligible patients with Dukes C or high risk Dukes B colorectal cancer, after completion of surgery and standard adjuvant chemotherapy (+/- radiation therapy for rectal cancer patients) to 200 mg Aspirin or Placebo for 3 years. Stratification factors include study centre, rectal or colon cancer stage, and type of adjuvant chemotherapy (exposed/not exposed to oxaliplatin). After randomization, patient will be followed up with 3 monthly assessments whilst on study drug and for a total of 5 years. Patients with active peptic ulcer disease, bleeding diathesis or on treatment with aspirin or anti-platelet agents will be excluded from the study.</p> <p>Discussion</p> <p>This study aims to evaluate Aspirin's role as an adjuvant treatment in colorectal cancer. If indeed found to be beneficial, because aspirin is cheap, accessible and easy to administer, it will positively impact the lives of many individuals in Asia and globally.</p> <p>Trials Registration</p> <p>Clinicaltrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00565708">NCT00565708</a></p

Amplification of a Zygosaccharomyces bailii DNA Segment in Wine Yeast Genomes by Extrachromosomal Circular DNA Formation

We recently described the presence of large chromosomal segments resulting from independent horizontal gene transfer (HGT) events in the genome of Saccharomyces cerevisiae strains, mostly of wine origin. We report here evidence for the amplification of one of these segments, a 17 kb DNA segment from Zygosaccharomyces bailii, in the genome of S. cerevisiae strains. The copy number, organization and location of this region differ considerably between strains, indicating that the insertions are independent and that they are post-HGT events. We identified eight different forms in 28 S. cerevisiae strains, mostly of wine origin, with up to four different copies in a single strain. The organization of these forms and the identification of an autonomously replicating sequence functional in S. cerevisiae, strongly suggest that an extrachromosomal circular DNA (eccDNA) molecule serves as an intermediate in the amplification of the Z. bailii region in yeast genomes. We found little or no sequence similarity at the breakpoint regions, suggesting that the insertions may be mediated by nonhomologous recombination. The diversity between these regions in S. cerevisiae represents roughly one third the divergence among the genomes of wine strains, which confirms the recent origin of this event, posterior to the start of wine strain expansion. This is the first report of a circle-based mechanism for the expansion of a DNA segment, mediated by nonhomologous recombination, in natural yeast populations