Circadian regulation of cardiac metabolism

Circadian rhythm evolved to allow organisms to coordinate intrinsic physiological functions in anticipation of recurring environmental changes. The importance of this coordination is exemplified by the tight temporal control of cardiac metabolism. Levels of metabolites, metabolic flux, and response to nutrients all oscillate in a time-of-day–dependent fashion. While these rhythms are affected by oscillatory behavior (feeding/fasting, wake/sleep) and neurohormonal changes, recent data have unequivocally demonstrated an intrinsic circadian regulation at the tissue and cellular level. The circadian clock — through a network of a core clock, slave clock, and effectors — exerts intricate temporal control of cardiac metabolism, which is also integrated with environmental cues. The combined anticipation and adaptability that the circadian clock enables provide maximum advantage to cardiac function. Disruption of the circadian rhythm, or dyssynchrony, leads to cardiometabolic disorders seen not only in shift workers but in most individuals in modern society. In this Review, we describe current findings on rhythmic cardiac metabolism and discuss the intricate regulation of circadian rhythm and the consequences of rhythm disruption. An in-depth understanding of the circadian biology in cardiac metabolism is critical in translating preclinical findings from nocturnal-animal models as well as in developing novel chronotherapeutic strategies.     

松果体昼夜节律生物钟分子机制的研究进展

在下丘脑视交叉上核(SCN)的调控下，哺乳类松果体通过合成褪黑素(MEL)而表达输出效应。松果体作为一个神经内分泌器官，也在各种非哺乳类脊椎动物中起着中枢昼夜节律振荡器的作用。在多数情况下，松果体振荡器均保持与光信号输入通路和内分泌输出通路的密切联系。近来，在鸟类松果体中相继发现了几种钟基因，如Per、Cry、Clock和Bmal等，其表达的时间变化规律与哺乳类SCN的非常相似。钟的振荡由其自身调控反馈环路的转录和翻译组成，鸟类松果体和哺乳类SCN似乎具有共同的钟振荡基本分子构架；若干钟基因产物作为正向(CLOCK／BNAL)或负向(PER／CRY)调节子影响钟的振荡；昼夜性的控时机制同时也需要翻译后事件的参与，包括蛋白移位、降解和磷酸化等过程。这些过程对钟振荡器稳定的24小时周期和／或钟导引的光输入通路有着重要的调控作用。     

Analysis of the mechanisms of the drug-drug interaction from a view of pharmacogenomics]

A wide variety of transporters and enzymes are involved in the disposition and metabolism of therapeutic drugs. Any compounds interacting with these proteins may inhibit uptake, efflux and/or metabolism of drugs and therefore alter the bioavailability and/or clearance of them. Progress in pharmacogenomics throws light on the clarification of mechanisms on drug-drug interaction. Various mutation and polymorphisms in drug transporters and metabolic enzymes were identified and some of which alter function of the proteins. The steroid and xenobiotic receptor, SXR, coordinately regulated CYP3A4, a major drug metabolizing enzyme and P-glycoprotein, a broad-specificity efflux pump. Now we are in the face of new period of study on drug interaction. With the help of pharmacogenomics, it might be possible to someday predict, avoid or manipulate potential cause of drug-drug interactions.     

Extracellular electron transfer mediated by a cytocompatible redox polymer to study the crosstalk among the mammalian circadian clock,cellular metabolism,and cellular redox state

The circadian clock is an endogenous biological timekeeping system that controls various physiological and cellular processes with a 24 h rhythm. The crosstalk among the circadian clock, cellular metabolism, and cellular redox state has attracted much attention. To elucidate this crosstalk, chemical compounds have been used to perturb cellular metabolism and the redox state. However, an electron mediator that facilitates extracellular electron transfer (EET) has not been used to study the mammalian circadian clock due to potential cytotoxic effects of the mediator. Here, we report evidence that a cytocompatible redox polymer pMFc (2-methacryloyloxyethyl phosphorylcholine-co-vinyl ferrocene) can be used as the mediator to study the mammalian circadian clock. EET mediated by oxidized pMFc (ox-pMFc) extracted intracellular electrons from human U2OS cells, resulting in a longer circadian period. Analyses of the metabolome and intracellular redox species imply that ox-pMFc receives an electron from glutathione, thereby inducing pentose phosphate pathway activation. These results suggest novel crosstalk among the circadian clock, metabolism, and redox state. We anticipate that EET mediated by a redox cytocompatible polymer will provide new insights into the mammalian circadian clock system, which may lead to the development of new treatments for circadian clock disorders.

Cytocompatible redox polymer pMFc altered the cellular redox state and metabolism, resulting in a longer circadian period.     

Phase I and Phase II enzyme polymorphisms and childhood cancer.

Childhood cancers continue to be challenging clinical entities whose etiology, demographic characteristics, clinical progression, treatment efficacy, and outcomes remain incompletely understood. Research suggests that multiple environmental and genetic factors may play crucial roles in the pathophysiology of many of these malignancies. Recent attention has been directed to the role of carcinogen metabolizing enzymes in the etiology and progression of cancer in both adults and children due to their multitude of polymorphic variants and their intimate interaction with environmental factors. In particular, xenobiotic metabolizing enzymes (XME), which are intimately involved in the activation and deactivation of many environmental carcinogens, have become an area of significant interest. Traditionally, these enzymes have been classified into either phase I or phase II enzymes depending on their substrates, activity, and occasionally based on their sequence in the metabolic pathways, and have been demonstrated to have numerous polymorphic variants. Phase I enzymes predominantly consist of cytochrome enzymes responsible for mixed function oxidase activity, whereas phase II enzymes are frequently conjugation reactions necessary for drug metabolism or the further metabolism of phase I enzyme products. Current research has discovered numerous interactions between polymorphisms in these enzymes and changes in cancer susceptibility, treatment efficacy, and clinical outcomes in childhood cancer. Furthermore, studies of polymorphisms in these enzymes have demonstrated to have synergistic/antagonistic interactions with other XME polymorphisms and demonstrate variable influences on disease pathophysiology depending on the patient's ethnic background and environmental milieu. Continuing research on the role of polymorphisms in phase I and phase II enzymes will likely further elucidate the intimate role of these polymorphisms with environmental factors in the etiology of childhood cancer.     

Expression of glutathione-dependent enzymes and cytochrome P450s in freshly isolated and primary cultures of proximal tubular cells from human kidney

The expression of glutathione (GSH)-dependent enzymes and cytochrome P450 (P450) proteins in freshly isolated proximal tubular cells from human kidney (hPT), and the effect of primary culture on these enzymes, were determined. Freshly isolated hPT cells had relatively high activities of gamma-glutamyltransferase, gamma-glutamylcysteine synthetase, glutathione S-transferase (GST), glutathione disulfide reductase, and GSH peroxidase. Cytochrome P450 4A11 was detected in freshly isolated hPT cells, whereas CYP2E1 was not. Freshly isolated hPT cells also expressed GSTA, GSTP, and GSTT but not GSTM. Primary cultures of hPT cells maintained their epithelial-like nature and diploid status, based on measurements of morphology, cytokeratin expression, and flow cytometric analysis. hPT cells retained GSH-dependent enzyme activities during primary culture, whereas cells that had undergone subsequent passage exhibited a loss of activities of most GSH-dependent enzymes and no longer expressed P450s or GSTs. CYP4A11 expression in primary cultures of hPT cells was significantly increased after treatment for 48 h with either ethanol (50 mM) or dexamethasone (7 nM). GSTA, GSTP, and GSTT contents, although still detectable, were decreased compared with those of freshly isolated hPT cells. Our data show that hPT cells express enzymes involved in xenobiotic disposition, and that they thus provide a model suitable for studies of human renal drug metabolism. Furthermore, primary cultures of hPT cells may afford the opportunity to study factors regulating P450 enzyme expression in human kidney.     

Human clock genes

Rhythmic variations in physiological and behavioural processes are mediated by both endogenous and exogenous factors. Endogenous factors include self-sustaining biological pacemakers or clocks which in the absence of strong external influences self-sustain periodic rhythms in such diverse physiological and psychological processes as core body temperature, food intake, cognitive performance and mood. Clocks with endogenous periods near or at 24 h (called circadian clocks from the Latin, circa dies, meaning about one day) have been documented from prokaryotes to single cell eukaryotes to multi-cellular, complex animals such as flies, rodents and humans. Over the past few years, a revolution in the understanding of the molecular basis of these clocks has led to the identification of a number of core clock genes and their proteins, and the development of elegant feedback models to explain the molecular gears of circadian clocks. At least eight human orthologs of mouse core clock genes have been identified, and polymorphisms in two of these, hClock and hPer2, have been implicated in human sleep disorders. Remarkably, knowledge of these core clock genes and the development of sophisticated reporter systems to monitor clock gene promoter activity have led to the astonishing observation that our body is actually composed of millions of cellular clocks and oscillators whose co-ordinated activity gives rise to pronounced daily, monthly, and seasonal rhythms in physiology and behaviour. An idea that is gaining favour is that our physical and mental well-being is probably determined by the appropriate phasing of these millions of cellular clocks with recurring, meaningful events in the environment.