松果体昼夜节律生物钟分子机制的研究进展

在各种非哺乳类脊椎动物中 ,松果体起着中枢昼夜节律振荡器的作用。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视交叉上核 (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或负向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。这些过程对钟振荡器的稳定性和 /或钟导引的光输入通路有着重要的调控作用     

生物钟基因研究进展

昼夜节律是以大约24 h为周期波动的生物现象.这些节律包括血压、体温、激素水平、血中免疫细胞的数量、睡眠觉醒周期循环等.基因水平上的昼夜节律研究还只是刚起步,介绍不同物种控制昼夜行为的共同基因(如period 、timless 、clock基因等)的研究进展,特别是一些有关调控昼夜节律基因的转录因子的研究.同时讨论果蝇和人类生物钟调节的共同分子机制.     

哺乳动物卵巢生物钟的研究进展

近年来,越来越多的研究发现生物钟系统在许多生理活动中,包括心血管、内分泌、免疫、生殖等系统的生理,都起着重要作用。随着2006年卵巢生物钟的发现,生殖系统生物钟成为新的研究热点。研究发现卵巢生物钟不仅影响排卵,而且还控制类固醇激素的释放。卵巢生物钟属外围生物钟,受到中央生物钟(SCN)神经内分泌信号的调控。还发现下丘脑-垂体-卵巢(HPG)轴上各水平都存在生物钟,HPG轴上各生物钟失同步影响生殖能力,这可能导致一些疾病发生的病因。本文总结近十年的关于卵巢生物钟的研究,列举哺乳动物卵巢生物钟存在的证据,并阐述生物钟在雌鼠正常生殖生理过程,及在生殖系统疾病病理过程中的作用及其分子机制。     

生物钟机制研究进展

由生物体内源性生物钟所产生的昼夜节律是近年来生命科学的研究热点之一。几种模型生物（蓝细菌、脉孢菌、拟南芥、果蝇、小鼠）的生物钟相关基因相继被克隆和鉴定,为理解昼夜节律的分子机制奠定了基础。振荡器蛋白对其编码基因的负反馈调控可能是不同生物的生物运作普遍机制,在此基础上,不同生物有不尽相同的调控方式;隐色素可能是高等生物的共同生物钟光受体。     

蓝藻生物钟分子机理的研究进展

蓝藻是具有内源性生物钟的简单生物.虽然蓝藻生物钟具有跟真核生物同样的基础特征,但其相关基因和蛋白质与真核生物没有同源性.蓝藻生物钟的核心是kai基因簇及其编码的蛋白KaiA,KaiB和KaiC.这三种Kai蛋白相互作用调节KaiC的磷酸化状态,从而产生昼夜节律信息.KaiC的磷酸化循环是昼夜节律的起博器,调控包括kai基因在内的相关基因的节律性表达.组氨酸蛋白激酶的磷酸化传递可将环境信息输入和将节律信息输出生物钟核心.     

哺乳动物生物钟的遗传和表观遗传研究进展

生物钟对生物机体的生存与环境适应具有着重要意义,其相关研究近年来受到人们的广泛关注。生物钟的重要性质之一是内源节律的周期性,当前的研究认为这种周期性是由生物钟相关基因转录翻译的多反馈环路构成核心机制调控着近似24 h的节律振荡。哺乳动物的生物钟系统存在一个多层次的结构,包括位于视交叉上核的主时钟和外周器官和组织的子时钟。虽然主时钟和子时钟存在的组织不同,但是参与调节生物钟的分子机制是一致的。近年来,通过正向、反向遗传学方法和表观遗传学的研究方法,对生物钟的分子机制的解析和认知愈发深入。本文在简单回顾生物钟基因发现历史的基础上,重点从遗传学和表观遗传学两个方面,从振荡周期的角度,对哺乳动物生物钟分子机制的研究进展进行了综述性介绍,以期为靶向调节生物钟来改善机体的稳态系统的研究提供参考,同时希望能促进时间生物学领域与更多其他领域形成交叉研究。     

Timeless与生物钟基因

综述了timeless基因的发现、多态性和重要功能。timeless是最先被发现的两个生物钟基因之一。生物钟的昼夜节律由PER、TIM、CLOCK和CYCLE4个生物钟齿轮组成的正负反馈回路进行调节。其中TIM可以受光因子调控,它还可以与PER形成异二聚体,通过正负调控方式调节果蝇的昼夜节律行为。     

昆虫生物钟分子调控研究进展

昆虫生物钟节律的研究是人类了解生物节律的重要途径。昆虫在生理和行为上具有广泛的节律活动,如运动、睡眠、学习记忆、交配、嗅觉等节律活动,其中昼夜活动行为节律的研究广泛而深入。昆虫乃至高等动物普遍具有保守的昼夜节律系统,昼夜生物钟节律主要包括输入系统:用于接受外界光和温度等环境信号并传入核心振荡器,使得生物时钟与环境同步;核心时钟系统:自我维持的昼夜振荡器;输出系统:将生物钟产生的信号传递出去而控制生物行为和生理的节律变化。早期分子和遗传学研究主要关注昼夜节律振荡器的分子机制及神经生物学,阐明了昼夜生物钟节律的主要分子机制及相关神经网络。最近更多的研究关注生物钟信号是如何输入和输出。本文以果蝇运动节律的相关研究为主要内容,围绕生物钟输入系统、振荡器、输出系统这3个组成部分对昆虫生物钟研究进展进行总结。     

生物钟与肠道菌群调控哺乳动物能量代谢研究进展

生物钟作为哺乳动物进化过程中产生的一种适应机体内外环境昼夜变化的内在机制,控制着机体的睡眠-觉醒及进食等生理活动,使生物体在每个昼夜周期的能量需求和营养供给呈现出与环境相适应的节律性变化。哺乳动物的肝脏、骨骼肌、胰腺、心血管等组织的葡萄糖代谢、脂质代谢和激素分泌等都受到生物钟的调控。作为宿主特殊的“器官”,肠道菌群在共同进化过程中与宿主微环境(组织、细胞、代谢产物)构成了一个微生态系统,在宿主对营养物质的消化和吸收过程中发挥重要作用。近年来的一些研究证据表明,肠道菌群的构成、数量、定植以及功能活动均具有显著的昼夜节律性变化,而这与生物钟调控下的各种生理功能变化是密切相关的。此外,有研究发现肠道菌群可通过分解宿主无法消化的膳食纤维等营养物质产生短链脂肪酸等代谢产物,部分代谢产物具有调节宿主生物钟并影响代谢的功能。本文将重点阐述生物钟与肠道菌群的互作及其对哺乳动物能量代谢的影响,以期为代谢性疾病的预防和治疗提供新的线索和思路。     

节律性转录因子驱动哺乳动物昼夜节律生物钟简

生物体通过内在的昼夜节律生物钟调整生理行为和代谢生化反应来适应昼夜环境周期性变化。哺乳动物的昼夜节律生物钟核心连锁环通过驱动特异性的转录因子来维持整个基因组转录的节律性。生物钟与代谢的内稳态密切相关,生物钟的紊乱会引起各种疾病,该领域的研究能够促进时间疗法的发展来维持生命的健康,甚至可以延缓衰老。     

Morphine withdrawal produces circadian rhythm alterations of clock genes in mesolimbic brain areas and peripheral blood mononuclear cells in rats

Previous studies have shown that clock genes are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus, other brain regions, and peripheral tissues. Various peripheral oscillators can run independently of the SCN. However, no published studies have reported changes in the expression of clock genes in the rat central nervous system and peripheral blood mononuclear cells (PBMCs) after withdrawal from chronic morphine treatment. Rats were administered with morphine twice daily at progressively increasing doses for 7 days; spontaneous withdrawal signs were recorded 14 h after the last morphine administration. Then, brain and blood samples were collected at each of eight time points (every 3 h: ZT 9; ZT 12; ZT 15; ZT 18; ZT 21; ZT 0; ZT 3; ZT 6) to examine expression of rPER1 and rPER2 and rCLOCK . Rats presented obvious morphine withdrawal signs, such as teeth chattering, shaking, exploring, ptosis, and weight loss. In morphine-treated rats, rPER1 and rPER2 expression in the SCN, basolateral amygdala, and nucleus accumbens shell showed robust circadian rhythms that were essentially identical to those in control rats. However, robust circadian rhythm in rPER1 expression in the ventral tegmental area was completely phase-reversed in morphine-treated rats. A blunting of circadian oscillations of rPER1 expression occurred in the central amygdala, hippocampus, nucleus accumbens core, and PBMCs and rPER2 expression occurred in the central amygdala, prefrontal cortex, nucleus accumbens core , and PBMCs in morphine-treated rats compared with controls. rCLOCK expression in morphine-treated rats showed no rhythmic change, identical to control rats. These findings indicate that withdrawal from chronic morphine treatment resulted in desynchronization from the SCN rhythm, with blunting of rPER1 and rPER2 expression in reward-related neurocircuits and PBMCs.     

Modulation of circadian clocks by nutrients and food factors

Daily activity rhythms that are dominated by internal clocks are called circadian rhythms. A central clock is located in the suprachiasmatic nucleus of the hypothalamus, and peripheral clocks are located in most mammalian peripheral cells. The central clock is entrained by light/dark cycles, whereas peripheral clocks are entrained by feeding cycles. The effects of nutrients on the central and peripheral clocks have been investigated during the past decade and much interaction between them has come to light. For example, a high-fat diet prolongs the period of circadian behavior, a ketogenic diet advances the onset of locomotor activity rhythms, and a high-salt diet advances the phase of peripheral molecular clocks. Moreover, some food factors such as caffeine, nobiletin, and resveratrol, alter molecular and/or behavioral circadian rhythms. Here, we review nutrients and food factors that modulate mammalian circadian clocks from the cellular to the behavioral level.     

Life's 24-hour clock: molecular control of circadian rhythms in animal cells

Our sleep–wake cycles and many other 24-hour rhythms of behavior and physiology persist in the absence of environmental cues. Genetic and biochemical studies have shown that such rhythms are controlled by internal molecular clocks. These are assembled from the cycling RNA and protein products of a small group of genes that are conserved throughout the animal kingdom.     

Wrist actimetry circadian rhythm as a robust predictor of colorectal cancer patients survival

The disruption of the circadian timing system (CTS), which rhythmically controls cellular metabolism and proliferation, accelerated experimental cancer progression. A measure of CTS function in cancer patients could thus provide novel prediction information for outcomes, and help to identify novel specific therapies. The rest-activity circadian rhythm is a reliable and non-invasive CTS biomarker, which was monitored using a wrist watch accelerometer for 2 days in 436 patients with metastatic colorectal cancer. The relative percentage of activity in-bed versus out-of-bed (I?<?O) constituted the tested CTS measure, whose prognostic value for overall survival (OS) and progression-free survival (PFS) was determined in a pooled analysis of three patient cohorts with different treatment exposures. Median OS was 21.6 months [17.8–25.5] for patients with I?<?O above the median value of 97.5% as compared to 11.9 months [10.4–13.3] for those with a lower I?<?O (Log-rank p?<?0.001). Multivariate analyses retained continuous I?<?O as a joint predictor of both OS and PFS, with respective hazard ratios (HR) of 0.954 (p?<?0.001) and 0.970 (p?<?0.001) for each 1% increase in I?<?O. HRs had similar values in all the patient subgroups tested. The circadian physiology biomarker I?<?O constitutes a robust and independent quantitative predictor of cancer patient outcomes, that can be easily and cost-effectively measured during daily living. Interventional studies involving 24-h schedules of clock-targeted drugs, light intensity, exercise and/or meals are needed for testing the relevance of circadian synchronization for the survival of patients with disrupted rhythms.     

The circadian conidiation rhythm inNeurospora crassa

The filamentous fungusNeurospora crassais one of the best organisms for analysing the molecular basis of the circadian rhythm observed in asexual spore formation, conidiation. Many clock mutants in which the circadian conidiation rhythm has different characteristics compared to those in the wild-type strain have been isolated since the early 1970s. With the cloning of one of these clock genes,frq, the molecular basis of the circadian clock inNeurosporahas become gradually clearer. Physiological and pharmacological studies have also contributed to our understanding of the physiological basis of the circadian clock inNeurospora. These studies strongly indicate that the circadian clock is based on or is closely related to a network of metabolic processes for cellular activities. Based on these studies, it may be possible to isolate new types of clock mutants which should contribute to a better understanding of the molecular basis of the circadian clock inNeurospora.     

Interactions of polymorphisms in different clock genes associated with circadian phenotypes in humans

Several studies have shown that mutations and polymorphisms in clock genes are associated with abnormal circadian parameters in humans and also with more subtle non-pathological phenotypes like chronotypes. However, there have been conflicting results, and none of these studies analyzed the combined effects of more than one clock gene. Up to date, association studies in humans have focused on the analysis of only one clock gene per study. Since these genes encode proteins that physically interact with each other, combinations of polymorphisms in different clock genes could have a synergistic or an inhibitory effect upon circadian phenotypes. In the present study, we analyzed the combined effects of four polymorphisms in four clock genes (Per2, Per3, Clock and Bmal1) in people with extreme diurnal preferences (morning or evening). We found that a specific combination of polymorphisms in these genes is more frequent in people who have a morning preference for activity and there is a different combination in individuals with an evening preference for activity. Taken together, these results show that it is possible to detect clock gene interactions associated with human circadian phenotypes and bring an innovative idea of building a clock gene variation map that may be applied to human circadian biology.     

A circadian rhythm of thermal preference in the ant Camponotus mus: masking and entrainment by temperature cycles

Abstract. Along a stable temperature gradient and under a LD 12:12 h cycle, nurse workers of the ant Camponotus mus Roger 1863 (Hymenoptera: Formicidae) select for the brood two different temperatures daily: 30.8°C at the middle of the light period (circadian phase = 90°), and 27.5°C 8 h later, during the dark period (circadian phase = 210°), this rhythm being of endogenous nature.When a 24 h temperature cycle was superimposed along the thermal gradient, so that the immobile brood experienced a temperature transition as they receive when translocated by nurses (8 h at 30.8°C and 16 h at 27.5°C), no brood translocations occurred.The thermal cycle masked the rhythm of brood translocation when temperature fitted the daily pattern expected by nurses.When the same temperature cycle was presented with a phase-advance, nurses did not tolerate the early thermal increase and removed the brood as temperature rose.However, when workers experienced this new phase relationship between light and temperature cycles for more than 10 days, brood translocations were suppressed.Records under constant conditions of light and temperature indicated that the overt rhythm was locked-on to the expected early increase in temperature, so that the temperature cycle dominated over the LD cycle in resetting brood-carrying activity.