关键词： infarct   mouse   ISCHEMIC-HEART-DISEASE   ACCELERATES RECOVERY   TARGETED DELETION   OXIDATIVE STRESS   IN-VIVO   CLOCK   EXPRESSION   INFARCTION   MATRIX-METALLOPROTEINASE-9   CONTRACTILITY  

摘要： Virag JA, Dries JL, Easton PR, Friesland AM, DeAntonio JH, Chintalgattu V, Cozzi E, Lehmann BD, Ding JM, Lust RM. Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2. Am J Physiol Heart Circ Physiol 298: H1088-H1095, 2010. First published January 8, 2010; doi:10.1152/ajpheart.01280.2008.-Variations in circadian rhythms are evident in the incidence of cardiovascular disease, and the risk of cardiovascular events increases when rhythms are disrupted. The suprachiasmatic nucleus is the central circadian pacemaker that regulates the daily rhythm of peripheral organs. Diurnal rhythms have more recently been shown to exist in myocardial tissue and are involved in metabolism and contractile function. Thus we sought to determine whether the functional deletion of the circadian rhythm mouse periodic gene 2 (mPer2) would protect the heart against ischemic injury. Nonreperfused myocardial infarction was induced in anesthetized, ventilated C57 (n = 17) and mPer2 mutant (mPer2-M; n = 15) mice via permanent ligation of the left anterior descending coronary artery. At 4 days post-myocardial infarction, we observed a 43% reduction of infarct area in mPer2-M mice compared with wild-type mice. This is coincident with 25% less macrophage infiltration, 43% higher capillary density, 17% increase in hypertrophy, and 15% less cardiomyocyte apoptosis in the infarct zone. Also, matrix metalloproteinase-9 was expressed in inflammatory cells in both groups, but total protein was 40% higher in wild-type mice, whereas it was not elevated in mPer2-M mice in response to injury. The functional deletion of the mPer2 gene reduces the severity of myocardial infarct injury by limiting the inflammatory response, reducing apoptosis, and inducing cardiomyocyte hypertrophy, thus preserving cardiac function. These findings collectively imply that the disruption of the circadian clock gene mPer2 is protective. Understanding the interactions between circadian

关键词： circadian rhythm   clock genes   heart rate   blood pressure   telemetry   BLOOD-PRESSURE   SUPRACHIASMATIC NUCLEUS   HEART-RATE   PRIMARY HYPERTENSION   24 H   LESIONS   CYCLE   HYPOTHALAMUS   FREQUENCY   ONSET  

摘要： Vukolic A, Antic V, Van Vliet BN, Yang Z, Albrecht U, Montani JP. Role of mutation of the circadian clock gene Per2 in cardiovascular circadian rhythms. Am J Physiol Regul Integr Comp Physiol 298: R627-R634, 2010. First published January 6, 2010; doi:10.1152/ajpregu.00404.2009.-Alterations in the circadian blood pressure pattern are frequently observed in hypertension and lead to increased cardiovascular morbidity. However, there are no studies that have investigated a possible implication of the Period2 gene, a key component of the molecular circadian clock, on the circadian rhythms of blood pressure and heart rate. To address this question, we monitored blood pressure, heart rate, and locomotor activity 24 h a day by telemetry in mice carrying a mutation in the Period2 gene and in wild-type control mice. Under a standard 12: 12-h light-dark cycle, mutant mice showed a mild cardiovascular phenotype with an elevated 24-h heart rate, a decreased 24-h diastolic blood pressure, and an attenuation of the dark-light difference in blood pressure and heart rate. Locomotor activity was similar in both groups and did not appear to explain the observed hemodynamic differences. When mice were placed under constant darkness during eight consecutive days, wildtype mice maintained 24-h rhythms, whereas there was an apparent progressive loss of 24-h rhythm of blood pressure, heart rate, and locomotor activity in mutant mice. However, a chi square periodogram revealed that circadian rhythms were preserved under complete absence of any light cue, but with shorter periods by similar to 40 min, leading to a cumulative phase shift toward earlier times of similar to 5 h and 20 min by the end of the 8th day. When heart rate, mean arterial pressure, and activity were recalculated according to the endogenous circadian periods of each individual mouse, the amplitudes of the circadian rhythms ("subjective night"-"subjective day" differences) were maintained for all variables studied. Our dat

关键词： 节律基因   细胞周期   DNA损伤   磷酸化  

摘要： 昼夜节律钟与细胞周期是两个重要的生物过程。昼夜节律钟是机体的分子时间调节系统;而细胞分裂周期调节细胞的发展和细胞更新。一些细胞周期相关基因的表达在节律钟的调控下被其复合物所调节。其中包括NPAS2/CLOCK和BMAL1/CLOCK二聚体复合物。这些复合物调节PER1/PER2的转录。近期的研究表明,节律基因PER1和PER2在DNA损伤反应通路中表现明显,诱导PER1和PER2在癌细胞中可以抑制细胞增殖和提高调亡率。另外在人类的许多癌症中存在PER1和PER2蛋白的丢失和失调。最新研究证实PER1和PER2参与了ATM-chk1/chk2的DNA损伤反应通路,并且预示作为一肿瘤抑制因子起作用。现将PER1和PER2在肿瘤的研究进展综述如下。

关键词： 基因   血压   高血压   血压昼夜节  

摘要： 目的研究血管紧张素转换酶(ACE)、醛固酮合成酶(CYP11B2),α-内收蛋白((α-adducin)基因多态性与高血压患者血压昼夜节律变化的关系。方法根据动态血压昼夜节律变化,将238例高血压患者分为杓型与非杓型两组,分析ACE、CYP11B2、α-adducin基因不同基因型在杓型血压组和非杓型血压组的分布;统计学处理用卡方检验和方差分析。结果杓型组与非杓型组ACE基因多态性的分布存在显著差异,P<0.05;杓型组以II型的分布频率为主,而卡方分割表明非杓型组ID+DD基因型的分布高于杓型组(P<0.01);而CYP11B2、α-adducin基因多态性与高血压患者血压节律变化无关联。结论ACE(I/D)基因多态性与高血压患者昼夜血压节律变化有关,携带D等位基因的患者可能更易发生夜间血压升高。

关键词： Neuropeptide-Y   Y2 receptors   Y4 receptors   Circadian pattern   Locomotion   Exploration   Feeding   Drinking   Energy intake   Energy expenditure   Energy homeostasis   2 ANIMAL-MODELS   REDUCED ANXIETY   BODY-WEIGHT   NPY   BEHAVIOR   STRESS   SYSTEM   PHASE   DEPRESSION   SUBTYPES  

摘要： Members of the neuropeptide-Y (NPY) family acting via Y2 and/or Y4 receptors have been proposed to participate in the control of ingestive behaviour and energy homeostasis. Since these processes vary between day and night, we explored the circadian patterns of locomotor, exploratory and ingestive behaviour in mice with disrupted genes for Y2 (Y2-/-) or Y4 (Y4-/-) receptors. To this end, the LabMaster system was used and its utility for the analysis of changes in circadian activity and ingestion caused by gene knockout evaluated. Female animals, aged 27 weeks on average, were housed singly in cages fitted with sensors for water and food intake and two infrared frames for recording ambulation and rearing under a 12 h light/dark cycle for 4 days. Relative to WT animals, diurnal locomotion, exploration, drinking and feeding were reduced, whereas nocturnal locomotion was enhanced in Y2-/- mice. In contrast, Y4-/- mice moved more but ate and drank less during the photophase, while they ate more and explored less during the scotophase. Both Y2-/- and Y4-/- mice weighed more than WT mice. These findings attest to a differential role of Y2 and Y4 receptor signalling in the circadian control of behaviours that balance energy intake and energy expenditure. These phenotypic traits can be sensitively and continuously recorded by the LabMaster system. (C) 2009 Elsevier Ltd, All rights reserved.

关键词： 老老年   高血压   动态血压   颈动脉硬化   认知功能  

摘要： 目的探讨80岁以上老老年原发性高血压患者24 h动态血压节律及颈动脉粥样硬化对认知功能损害的影响。方法老老年原发性高血压受试者196例进行24 h动态血压及颈动脉超声监测,使用中文版简易智能状态检查表(MMSE)对受试者进行认知功能调查,MMSE总分范围为0～30分。结果血压昼夜节律与颈动脉粥样硬化对MMSE得分有显著影响,且有交互作用(F=5.937,P<0.05)。颈动脉粥样硬化者MMSE得分低于颈动脉非粥样硬化者[(19.5±2.1)比(23.1±3.0),P<0.01]。血压昼夜非杓型节律者MMSE得分低于血压昼夜杓型节律者[(19.7±2.3)比(22.9±3.1),P<0.01]。杓型血压昼夜节律与颈动脉硬化对MMSE中注意力和计算力及回忆力方面,有显著的交互作用(P<0.01),但对定向力、记忆力及语言表达能力方面无交互作用。结论血压昼夜节律减弱或消失及颈动脉粥样硬化,对老老年原发性高血压患者的认知功能损害有协同作用。

关键词： 高血压   昼夜节律   颈动脉粥样硬化斑块  

摘要： 高血压病是老年人群的常见疾病,与动脉粥样硬化的发生密切相关.颈动脉是全身中型动脉的代表,其硬化程度可间接反映冠状动脉、外周动脉等的硬化程度,可作为一个良好的窗口来监测体内动脉粥样硬化的进展,有效评估高血压患者靶器官损伤程度[1-2].动态血压监测(ambulatory blood pressure monitoring, ABPM)可如实反映患者血压的波动和昼夜节律变化等,对高血压病的诊治及预后判断具有较大意义[3-4].因此,本研究联合应用颈动脉超声结合ABPM技术探讨老年高血压病患者的昼夜节律变化与颈动脉粥样硬化斑块的相关性,为老年高血压病患者靶器官损害的防治提供依据.

关键词： STEM-CELL ACTIVATION   REV-ERB   EXPRESSION   SKIN   TRANSCRIPTION   COMPONENT   PROLIFERATION   MECHANISM   BMAL1   TIME  

摘要： Hair follicles undergo recurrent cycling of controlled growth (anagen), regression (catagen), and relative quiescence (telogen) with a defined periodicity. Taking a genomics approach to study gene expression during synchronized mouse hair follicle cycling, we discovered that, in addition to circadian fluctuation, CLOCK-regulated genes are also modulated in phase with the hair growth cycle. During telogen and early anagen, circadian clock genes are prominently expressed in the secondary hair germ, which contains precursor cells for the growing follicle. Analysis of Clock and Bmal1 mutant mice reveals a delay in anagen progression, and the secondary hair germ cells show decreased levels of phosphorylated Rb and lack mitotic cells, suggesting that circadian clock genes regulate anagen progression via their effect on the cell cycle. Consistent with a block at the G1 phase of the cell cycle, we show a significant upregulation of p21 in Bmal1 mutant skin. While circadian clock mechanisms have been implicated in a variety of diurnal biological processes, our findings indicate that circadian clock genes may be utilized to modulate the progression of non-diurnal cyclic processes.

关键词： MICROARRAY ANALYSIS   KEY PATHWAYS   EXPRESSION   TIME   MOUSE   LIVER   RHYTHMS   CLOCK   FIBROBLASTS   ENTRAINMENT  

摘要： The circadian clock is a molecular and cellular oscillator found in most mammalian tissues that regulates rhythmic physiology and behavior. Numerous investigations have addressed the contribution of circadian rhythmicity to cellular, organ, and organismal physiology. We recently developed a method to look at transcriptional oscillations with unprecedented precision and accuracy using high-density time sampling. Here, we report a comparison of oscillating transcription from mouse liver, NIH3T3, and U2OS cells. Several surprising observations resulted from this study, including a 100-fold difference in the number of cycling transcripts in autonomous cellular models of the oscillator versus tissues harvested from intact mice. Strikingly, we found two clusters of genes that cycle at the second and third harmonic of circadian rhythmicity in liver, but not cultured cells. Validation experiments show that 12-hour oscillatory transcripts occur in several other peripheral tissues as well including heart, kidney, and lungs. These harmonics are lost ex vivo, as well as under restricted feeding conditions. Taken in sum, these studies illustrate the importance of time sampling with respect to multiple testing, suggest caution in use of autonomous cellular models to study clock output, and demonstrate the existence of harmonics of circadian gene expression in the mouse.

关键词： Dykhuizen-Hartl effect   Gene duplication   Positive selection   Negative selection   Neofunctionalization   Subfunctionalization   DETECTING POSITIVE SELECTION   CODON-SUBSTITUTION MODELS   DNA-BINDING   PERIPHERAL-TISSUES   LIKELIHOOD METHOD   INDIVIDUAL SITES   RECOMBINATION   SEQUENCES   GENETICS   PROTEIN  

摘要： Circadian rhythms, that are governed physiologically and behaviorally by endogenous clock, have been described in many species. Living organisms use this endogenous circadian clock to anticipate environmental transitions, perform activities at biologically advantageous times during the day, and undergo characteristic seasonal responses. Gene duplication is one of the most important mechanisms in the evolution of gene diversity. After duplication, one or both of duplicates can accumulate amino acid changes, thereby promoting functional divergence through the action of natural selection. The circadian system, like many other multigene families, has undergone this genetic revolution, and so circadian genes that are found in single copies in insects are duplicated in vertebrates. We analyzed six groups of genes involved in vertebrates' circadian rhythm pathway to find signatures of molecular evolutionary processes such as gene duplication, natural selection, recombination, and functional divergence. The obtained results, then, were used to determine what evolutionary forces have influenced the fates of duplicated genes of each group. We showed in this research that recombination has not been widespread during the evolution of circadian genes and that purifying selection has been the prominent natural pressure operating on circadian genes. We also showed that the evolution of circadian genes has been depended on gene duplication and functional divergence. Finally, we put forward models best describing the evolutionary fates of circadian duplicates. (c) 2008 Elsevier B.V. All rights reserved.