Insulin resistance, a hallmark of type 2 diabetes, is associated with oxidative stress. However, the role of reactive oxygen species or specific antioxidant enzymes in its development has not been ...tested under physiological conditions. The objective of our study was to investigate the impact of overexpression of glutathione peroxidase 1 (GPX1), an intracellular selenoprotein that reduces hydrogen peroxide ( H2O2) in vivo, on glucose metabolism and insulin function. The GPX1-overexpressing (OE) and WT male mice (n = 80) were fed a selenium-adequate diet (0.4 mg/kg) from 8 to 24 weeks of age. Compared with the WT, the OE mice developed (P < 0.05) hyperglycemia (117 vs. 149 mg/dl), hyperinsulinemia (419 vs. 1,350 pg/ml), and elevated plasma leptin (5 vs. 16 ng/ml) at 24 weeks of age. Meanwhile, these mice were heavier (37 vs. 27 g, P < 0.001) and fatter (37% vs. 17% fat, P < 0.01) than the WT mice. At 30-60 min after an insulin challenge, the OE mice had 25% less (P < 0.05) of a decrease in blood glucose than the WT mice. Their insulin resistance was associated with a 30-70% reduction (P < 0.05) in the insulin-stimulated phosphorylations of insulin receptor (β-subunit) in liver and Akt ( Ser473and Thr308) in liver and soleus muscle. Here we report the development of insulin resistance in mammals with elevated expression of an antioxidant enzyme and suggest that increased GPX1 activity may interfere with insulin function by overquenching intracellular reactive oxygen species required for insulin sensitizing.
Nearly all patients with bipolar disorder have severely disrupted circadian rhythms. Treatment with mood stabilizers can restore these daily rhythms, and this is correlated with patient recovery. ...However, it is still uncertain whether clock abnormalities are the cause of bipolar disorder or if these rhythm disruptions are secondary to alterations in other circuits. Furthermore, the mechanism by which the circadian clock might influence mood is still unclear. With cloning and characterization of the circadian genes and recent advances in molecular biology, we are starting to understand this strong association between circadian rhythms and bipolar disorder. Recent human genetic and mouse behavioral studies indicate that the Clock gene is particularly relevant in the mood disruptions associated with this disorder. Furthermore, it appears that Clock expression outside of the central pacemaker of the suprachiasmatic nucleus (SCN) is involved in mood regulation. In this chapter, the evidence linking circadian rhythms, the Clock gene, and bipolar disorder is discussed, along with the possible biology that underlies this connection.
The plant circadian clock coordinates the responses to multiple and often simultaneous environmental challenges that the sessile plant cannot avoid. These responses must be integrated efficiently ...into dynamic metabolic and physiological networks essential for growth and reproduction. Many of the output pathways regulated by the circadian clock feed back to modulate clock function, leading to the appreciation of the clock as a central hub in a sophisticated regulatory network. In this Review, we discuss the circadian regulation of growth, flowering time, abiotic and biotic stress responses, and metabolism, as well as why temporal 'gating' of these processes is important to plant fitness.
Drug addiction is a devastating disease that affects millions of individuals worldwide. Through better understanding of the genetic variations that create a vulnerability for addiction and the ...molecular mechanisms that underlie the progression of addiction, better treatment options can be created for those that suffer from this condition. Recent studies point to a link between abnormal or disrupted circadian rhythms and the development of addiction. In addition, studies suggest a role for specific genes that make up the molecular clock in the regulation of drug sensitivity, sensitization, and reward. The influence of circadian genes and rhythms on drug-induced behaviors may be mediated through the mesolimbic dopaminergic system. This system has long been implicated in the development of addiction, and recent evidence supports a regulatory role for the brain's central pacemaker and circadian gene expression in the regulation of dopaminergic transmission. This review highlights the association between circadian genes and drug addiction, and the possible role of the mesolimbic dopaminergic system in this association.
Rice blast, caused by the fungus Pyricularia grisea (Cooke) Sacc., is a serious rice (Oryza sativa L.) disease causing considerable economic damage worldwide. DNA markers for rice blast resistance ...have been developed, but most are not suitable for routine use in a marker-assisted selection breeding program involving large numbers of progeny. After identifying candidate microsatellite markers from public database sources, we have mapped these markers near the blast resistance genes Pi-b, Pi-k, and Pi-ta2 on rice chromosomes 2, 11, and 12, respectively, using segregation information from hundreds of progeny in several crosses. Two microsatellite markers, RM208 and RM224, were found to cosegregate with the Pi-b and Pi-k genes, respectively, while additional microsatellites were found to closely flank these two genes and the Pi-ta2 gene. The new markers are polymorphic in the narrow crosses characteristic of applied breeding programs and appear to be ideally suited for marker assisted selection for blast resistance in rice because of their tight linkage with resistance genes and ease of use through analysis of amplification products. A dominant marker indicating the presence of the Pi-b gene, Pibdom, has also been developed on the basis of the sequence of the cloned Pi-b gene. These markers should facilitate the introgression and pyramiding of these three blast resistance genes into new rice cultivars and elite lines.
The Waxy gene (Wx) encodes the granulebound starch synthase responsible for the synthesis of amylose in rice (Oryza sativa). Recently, a polymorphic microsatellite sequence closely linked to the Wx ...gene was reported. To determine whether polymorphism in this sequence correlates with variation in apparent amylose content, we tested an extended pedigree of 92 current and historically important long-, medium- and short-grain US rice cultivars representing the efforts of many breeders over more than 80 years. Seven Wx microsatellite alleles were identified which together explained 82.9% of the variation in apparent amylose content of the 89 non-glutinous rice cultivars tested. Similar results were also obtained with 101 progeny of a cross between low- and intermediate-amylose breeding lines. An additional, unique microsatellite allele, (CT)16, was detected in one glutinous cultivar, CI 5309. However, the other glutinous cultivars, Calmochi 101 and Tatsumi mochi, were in the (CT)17 class along with three other cultivars that contained 15-16.5% amylose. We sequenced a 200-bp PCR-amplified fragment containing the CT microsatellite and the putative 5' splice site of the Wx leader intron from a subset of 42 cultivars representing all eight microsatellite alleles. All of the cultivars with 18% or less amylose had the sequence AGTTATA at the putative leader intron 5' splice site, while all cultivars with a higher proportion of amylose had AGGTATA. This single nucleotide substitution could also be assayed by AccI digestion of the amplified fragment. Overall, this single nucleotide polymorphism could explain 79.7% of the variation in the apparent amylose content of the 89 non-glutinous cultivars tested. Interestingly, cultivars in the (CT)19 microsatellite classes that differed substantially in amylose content still showed the correlation between this G-T polymorphism and apparent amylose content. The G-T polymorphism at this site was not, however, able to explain the very low amylose contents of the three glutinous cultivars tested, all of which had the sequence AGTTATA.
The weight of patients has not been demonstrated to have a consistent effect on the rate of polyethylene wear in clinical studies of total joint replacement. For this reason, we analyzed the ...relationship between quantitative activity, measured with a pedometer, and body mass index, a measure of obesity. Data were acquired for 209 individuals, 22-82 years of age; all were independent community walkers. One hundred and fifty-one had a well functioning total hip or knee replacement. Analysis of variance was used to evaluate the relationship between activity and body mass index, with adjustments for confounding variables. The 58 individuals with no total joint prosthesis averaged 7,781 steps per day, which was higher (p < 0.01) than those with a total hip (5,869 steps per day) or knee (4,597 steps per day) replacement. The subjects with no total joint prosthesis were, however, younger than the patients with a prosthesis (p < 0.01), and the body mass index of the patients with a total knee replacement was higher than that of the patients with a hip replacement and that of the subjects with no prosthesis (p < 0.01). After adjustment for differences in age, gender, and Charnley class, a higher body mass index (greater obesity) was associated with lower activity (p = 0.05). With regard to the rate of polyethylene wear, decreased ambulatory activity may counterbalance increased weight, which could, at least in part, explain why weight has not had a consistent effect on polyethylene wear in clinical studies. Wear is a function of use, not time. The effect of obesity on activity should be considered in radiographic studies of wear and other outcome assessments of total joint replacements.
Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for ...lithium's effectiveness on these mice remain unclear. Here, we find that cholecystokinin (Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockΔ19 mice. Selective knockdown of Cck expression via RNA interference in the VTA of wild-type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild-type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective antimanic agent.
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