昼夜节律变化对动脉粥样硬化形成的影响及其相关通路的研究进展

地球上几乎所有的生命都存在昼夜节律,控制昼夜节律的生物钟具有重要的生理功能,同时也是疾病的重要调节器.昼夜节律与动脉粥样硬化关系密切.研究表明受损的生物钟会影响造血过程和糖脂代谢,并改变局部斑块病变中的细胞功能.在分子水平上,昼夜节律可以通过Toll样受体(TLR)通路调节动脉粥样硬化炎症状态和血管重塑,通过蛋白激酶B...     

昼夜节律在病毒感染中的作用

昼夜节律是由内源性时钟调节的多个生物过程的日常振荡,调控机体的各种生理变化.节律紊乱会导致多种疾病的发生,包括代谢综合征和癌症等.最近将昼夜节律系统作用研究扩展到了感染的调控,宿主与病原体的相互作用以及由此产生的疾病结局.深入了解昼夜节律系统在调节病毒感染中的作用将为病毒性传染病的致病机理、抗病毒治疗、疫苗研发等提供新的思路.本文就昼夜节律与病毒感染的相互作用进行综述,包括昼夜节律如何影响病毒感染以及病毒如何调节节律以促进自身复制的关键发现,突出昼夜节律的重要性.     

Dissecting and modeling photic and melanopsin effects to predict sleep disturbances induced by irregular light exposure in mice

Artificial lighting, day-length changes, shift work, and transmeridian travel all lead to sleep–wake disturbances. The nychthemeral sleep–wake cycle (SWc) is known to be controlled by output from the central circadian clock in the suprachiasmatic nuclei (SCN), which is entrained to the light–dark cycle. Additionally, via intrinsically photosensitive retinal ganglion cells containing the photopigment melanopsin (Opn4), short-term light–dark alternations exert direct and acute influences on sleep and waking. However, the extent to which longer exposures typically experienced across the 24-h day exert such an effect has never been clarified or quantified, as disentangling sustained direct light effects (SDLE) from circadian effects is difficult. Recording sleep in mice lacking a circadian pacemaker, either through transgenesis (Syt10^cre/creBmal1^fl/-) or SCN lesioning and/or melanopsin-based phototransduction (Opn4^−/−), we uncovered, contrary to prevailing assumptions, that the contribution of SDLE is as important as circadian-driven input in determining SWc amplitude. Specifically, SDLE were primarily mediated (>80%) through melanopsin, of which half were then relayed through the SCN, revealing an ancillary purpose for this structure, independent of its clock function in organizing SWc. Based on these findings, we designed a model to estimate the effect of atypical light–dark cycles on SWc. This model predicted SWc amplitude in mice exposed to simulated transequatorial or transmeridian paradigms. Taken together, we demonstrate this SDLE is a crucial mechanism influencing behavior on par with the circadian system. In a broader context, these findings mandate considering SDLE, in addition to circadian drive, for coping with health consequences of atypical light exposure in our society.

The nearly ubiquitous expression of circadian rhythmicity across species suggests that synchronizing physiology and behavior to Earth’s light–dark (LD) cycle is critical for survival and essential for optimal functioning and health. With increasing environmental light pollution and the introduction of new technologies such as light-emitting diodes and connected devices, human photic behavior is increasingly uncoupled from the natural LD cycle. The resulting perturbations in sleep–wake architecture have led to the increased prevalence of circadian disorders, insomnia, daytime somnolence, mood alteration, and poorer cognitive performance (1–5), stressing the need for a greater and more mechanistic understanding of the photic regulation of sleep and behavior.Light entrains the circadian pacemaker located in the suprachiasmatic nuclei (SCN), whose output signal generates an endogenous circadian sleep–wake rhythm aligned to the environmental LD cycle (6). However, light also exerts direct acute effects on sleep and waking, independent of the circadian system (7, 8). In nocturnal animals, such as most laboratory rodents, darkness administered for short periods (e.g., 1 h) acutely induces waking behavior, while the same length of light exposure promotes sleep (7). In circadian biology, these light- and/or dark-dependent changes were referred to as “masking,” as they can conceal the sleep–wake rhythm generated by the clock output signal. Therefore, this direct and noncircadian photic regulation was primarily considered through its indirect consequences on circadian function rather than a process actively imposing itself on the expression of sleep and waking in a direct and important manner (9). This highlights the need for a better understanding of the significance of the direct photic regulation of sleep and waking in comparison to clock-driven influence.The nonvisual effects of light are known to be mediated through different photoreceptive systems and neuronal pathways. Previous research led to the discovery of a novel retinal photoreceptor, melanopsin (Opn4), which is crucial for irradiance detection, maximally sensitive to blue light (480 nm), and expressed in a subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) that convey nonimage-forming light information to the brain (10–12). These melanopsin ipRGCs project to various brain targets, which are thought to mediate light influence on physiology and behavior (13–15). Clock synchronization and circadian rhythm entrainment is mediated by projections to the SCN (16–18), whereas innervation of the sleep-promoting neurons of the ventrolateral preoptic area (VLPO) (19, 20) or the subparaventricular zone are thought to mediate light''s direct effects on sleep, yet it remains to be clarified whether the SCN might also participate in mediating those direct photic effects. Moreover, the loss of melanopsin does not abolish these responses, demonstrating that other photoreceptors involved in vision, the rods and cones, also play a role (12). Furthermore, the loss of ipRGCs results in dramatic loss of nonvisual effects, indicating that these cells receive inputs from rods and cones and are also the principal conduit for nonvisual light input from these photoreceptors (12, 18, 21–23). However, the degree of overlap between these two systems for regulating nonvisual responses is not yet certain.In recent years, the development of transgenic mouse models targeting these phototransduction pathways has revealed the pronounced effects of light and dark pulses of short duration on sleep and waking (11, 12, 24). Moreover, we previously showed that this acute and direct photic influence can be observed at all times of day (12). These observations raise the question as to whether longer periods of light and dark exposure, such as those of the 24-h LD cycle, exert sustained direct noncircadian effects, that is, continuous acute effects that could be observed over longer periods of time. One could postulate that the complete absence of light (constant darkness [DD] experiments) would allow for the extrapolation of the influence of sustained direct photic effects; however, this would not consider the possibility that the absence of light would lead to circadian disruption. Thus, under standard LD cycles, the contribution of direct noncircadian photic regulation in shaping the sleep–wake cycle has to date never been properly quantified due to the difficulty in disentangling it from the circadian effects.In the current study, we sought to address three related issues: 1) the quantification of the respective contribution of circadian effects (CE) and sustained direct light effects (SDLE) in shaping the 24-h sleep–wake cycle; 2) the identification of the pathways underlying those effects (i.e., the respective role of the photoreceptive systems), melanopsin versus rods and cones, and the respective role of the SCN versus non-SCN brain relays as conduits for this direct photic regulation of the sleep–wake cycle; and 3) whether quantifying the respective contributions of CE and SDLE allows for the prediction of the nychthemeral sleep–wake distribution under unnatural LD cycles, such as those experienced during jet lag. Recording sleep in mice lacking a functional central clock either through SCN lesioning or Bmal1 tissue-specific clock gene deletion and/or melanopsin-based phototransduction, we uncovered that CE and SDLE contribute in equal proportion to shaping the nychthemeral cycle. Furthermore, analyzing sleep in melanopsin-deficient mice with or without disabled SCN revealed that SDLE are primarily (>80%) mediated through melanopsin-based phototransduction, half of which passes via the SCN, implying a noncircadian function for the brain structure comprising the master circadian clock. To further validate our findings, these data were integrated into a model that accurately predicted 24-h sleep–wake distribution in mice exposed to a simulated “jet lag” or transequatorial travel paradigm.     

234例原发性高血压患者血压昼夜节律分析

目的　探讨原发性高血压患者血压昼夜节律曲线类型和年龄、性别、血压水平、眼底小动脉、肾功能及血管内皮功能之间的关系。方法　选择初诊原发性高血压患者 2 34例 ,根据动态血压检测结果将昼夜节律曲线分为反杓型、非杓型、杓型和超杓型 4组。检测 2 4h动态血压、眼底、血液生化及血管内皮功能。结果　不同血压曲线类型组之间收缩压、舒张压、脉压、年龄以及各曲线类型组之间单纯收缩期高血压的分布有显著差异 ,其中 ,反杓型组和非杓型组的年龄显著大于杓型组 ,非杓型组中单纯收缩期高血压的比例高于杓型组 ;而不同血压曲线类型组之间性别、眼底动脉硬化程度、尿素氮、血肌酐、内皮素及一氧化氮无显著性差异。结论　 4种血压节律曲线类型与年龄明显相关 ,而与性别、眼底小动脉硬化程度、肾功能、血管内皮功能之间无明显相关关系。     

Intermolecular associations determine the dynamics of the circadian KaiABC oscillator

Three proteins from cyanobacteria (KaiA, KaiB, and KaiC) can reconstitute circadian oscillations in vitro. At least three molecular properties oscillate during this reaction, namely rhythmic phosphorylation of KaiC, ATP hydrolytic activity of KaiC, and assembly/disassembly of intermolecular complexes among KaiA, KaiB, and KaiC. We found that the intermolecular associations determine key dynamic properties of this in vitro oscillator. For example, mutations within KaiB that alter the rates of binding of KaiB to KaiC also predictably modulate the period of the oscillator. Moreover, we show that KaiA can bind stably to complexes of KaiB and hyperphosphorylated KaiC. Modeling simulations indicate that the function of this binding of KaiA to the KaiB•KaiC complex is to inactivate KaiA''s activity, thereby promoting the dephosphorylation phase of the reaction. Therefore, we report here dynamics of interaction of KaiA and KaiB with KaiC that determine the period and amplitude of this in vitro oscillator.     

Effects of a one-hour light pulse on the timing of the circadian rhythm in melatonin secretion in rams

Abstract: The effects of a 1-hr light pulse on the timing of the circadian rhythm in the blood plasma concentration of melatonin were documented in Soay rams. Groups of 5 to 6 animals were transferred from short days (LD 8: 16) to constant dim red light (DD) for 6 days, and were exposed to a 1-hr light pulse at one of 16 different times throughout 24 hr on day 3. Blood samples were collected hourly for 30 hr before (day 2–3) and after the light pulse (day 5–6), and the plasma concentrations of melatonin were measured by radioimmunoassay. The animals were allocated to experimental groups based on the circadian time (CT) when the light pulse was given using two hourly blocks through the circadian day; the onset of enhanced melatonin secretion (melatonin peak) was designated as CT 12. Under DD there was a clearly defined plasma melatonin rhythm in all animals. The mean duration of the melatonin peak was 13.24 ± 0.16 hr (n = 91) and the mean period between the onset of successive melatonin peaks was 23.55 ± 0.10 hr (n = 21). The effect of the 1-hr light pulse on the time of onset of the melatonin peak varied significantly with the circadian time when the light pulse was given (ANOVA, P= 0.031). Light-induced significant (pre- vs post-pulse onset, Students t-test, P < 0.05) phase delays in the onset of the melatonin peak in the early subjective day at CT 2.5 hrs (mean ø: -1.9 hr), and in the early subjective night at CT 12.5 and 14.5 (mean ø: -2.0 hrs), but not at other times. The light pulse never induced significant phase advances. The effects of the light pulse on the offset of plasma melatonin peak did not vary significantly with the time of the light pulse (ANOVA, P= 0.780), although significant differences in the pre- and post-pulse offset occurred at CT 14.5 and 18.5 (mean ø: -1.5 hr). The differential changes in the onset and the offset of the melatonin peak resulted in changes in the duration of the peak (maximum difference between means: 3.8 hr). The results indicate that entrainment occurs under natural 24 hr LD cycles when light impinges on the early subjective night and induces a net phase delay, thus extending the period of the melatonin rhythm to 24 hr. This causes a close phase relationship between the end of the light period and the onset of the melatonin peak as occurs in sheep under natural cycles. The results are also consistent with a multiple oscillator governing melatonin secretion, and that differential entrainment of the component oscillators by light affects the duration of the melatonin peak.     

Phototransduction cascade and circadian oscillator in chicken pineal gland

ABSTRACT: The chicken pineal gland has an endogenous circadian oscillator that controls the diurnal oscillation of N-acetyltransferase activity responsible for melatonin rhythm. It has been speculated that the chicken pineal cell contains a photoreceptive molecule that receives the environmental light signal and transmits the signal to the oscillator for resetting the phase. In spite of several lines of evidence suggesting the similarity between retinal and pineal photon-signal transducing proteins, the identity of the photoreceptive molecule had been an open question. In 1994, we isolated a pineal cDNA encoding a novel photoreceptive molecule and named it "pinopsin." The protein expressed in 293EBNA cells bound 11- cis -retinal to form a blue-sensitive pigment with an absorption maximum at about 470 nm. A putative G-protein interaction site of pinopsin shared a relatively high similarity in amino acid sequence to that of rhodopsin, implying that pinopsin functionally couples with transducin or transducin-like G-protein(s) in the pineal cells. We have cloned a cDNA for chicken pineal transducin α-subunit, and the deduced amino acid sequence contained a potential site to be ADP-ribosylated by pertussis toxin (PTX). Therefore, the transducin-mediated pathway could be blocked by PTX, though previous studies showed that treatment of the cultured chicken pineal cells with PTX had no effect on the light-induced phase-shift of the oscillator. Accordingly, it is unlikely that transducin mediates the light-input pathway to the oscillator, which may involve PTX-insensitive G-protein(s) or some unidentified component(s). The G-protein coupled receptor-mediated signaling processes regulating melatonin synthesis are discussed.     

Glucocorticoid regulation of the circadian clock modulates glucose homeostasis

Circadian clock genes are regulated by glucocorticoids; however, whether this regulation is a direct or secondary effect and the physiological consequences of this regulation were unknown. Here, we identified glucocorticoid response elements (GREs) at multiple clock genes and showed that 3 were directly regulated by the glucocorticoid receptor. We determined that a GRE within the core clock gene Per2 was continuously occupied during rhythmic expression and essential for glucocorticoid regulation of that gene in vivo. We further demonstrated that mice with a genomic deletion spanning this GRE expressed elevated leptin levels and were protected from glucose intolerance and insulin resistance on glucocorticoid treatment but not from muscle wasting. We conclude that Per2 is an integral component of a particular glucocorticoid regulatory pathway and that glucocorticoid regulation of the peripheral clock is selectively required for some actions of glucocorticoids.     

The effects of aging on the circadian rhythm of serum cortisol in the dog

The purpose of this study was to determine if aging affects the circadian rhythm of serum cortisol. Female beagle dogs belonging to three age groups were used: adult (3.3 ± 0.6 (SD) years), old (12.1 ± 0.3 years), and puppies (8.4 ± 0.2 weeks). Blood samples were collected by cephalic or jugular venipuncture at 3-h intervals during three 24-h periods and analyzed for total serum cortisol concentrations by radioimmunoassay. The circadian rhythm was present in the serum cortisol of adult animals, but no significant changes during a 24-h period could be detected in the old animals. No circadian rhythm in serum cortisol was present in the puppies. It is concluded that the circadian rhythm in plasma cortisol is disrupted in old animals and is not yet developed in puppies.     

Neonatal alcohol exposure permanently disrupts the circadian properties and photic entrainment of the activity rhythm in adult rats

BACKGROUND: Alcohol exposure during the period of rapid brain development produces structural damage in different brain regions, including the suprachiasmatic nucleus (SCN), that may have permanent neurobehavioral consequences. Thus, this study examined the long-term effects of neonatal alcohol exposure on circadian behavioral activity in adult rats. METHODS: Artificially reared Sprague-Dawley rat pups were exposed to alcohol (EtOH; 4.5 g/kg/day) or isocaloric milk formula (gastrostomy control; GC) on postnatal days 4-9. At 2 months of age, rats from the EtOH, GC, and suckle control (SC) groups were housed individually, and properties of the circadian rhythm in wheel-running behavior were continuously analyzed during exposure to a 12-hr light:12-hr dark photoperiod (LD 12:12) or constant darkness (DD). RESULTS: Neonatal alcohol exposure had distinctive effects on the rhythmic properties and quantitative parameters of adult wheel-running behavior. EtOH-treated animals were distinguished by unstable and altered entrainment to LD 12:12 such that their daily onsets of activity were highly variable and occurred at earlier times relative to control animals. In DD, circadian regulation of wheel-running behavior was altered by neonatal alcohol exposure such that the free-running period of the activity rhythm was shorter in EtOH-exposed rats than in control animals. Total amount of daily wheel-running activity in EtOH-treated rats was greater than that observed in the SC group. In addition, the circadian activity patterns of EtOH-exposed rats were fragmented such that the duration of the active phase and the number of activity bouts per day were increased. CONCLUSIONS: These data indicate that neonatal alcohol exposure produces permanent changes in the circadian regulation of the rat activity rhythm and its entrainment to LD cycles. These long-term alterations in circadian behavior, along with the developmental alcohol-induced changes in SCN endogenous rhythmicity, may have important implications in clinical sleep-wake disturbances observed in neonates, children, and adults exposed to alcohol in utero.     

Melatonin and circadian biology in human cardiovascular disease

Abstract: Diurnal rhythms influence cardiovascular physiology, i.e. heart rate and blood pressure, and they appear to also modulate the incidence of serious adverse cardiac events. Diurnal variations occur also at the molecular level including changes in gene expression in the heart and blood vessels. Moreover, the risk/benefit ratio of some therapeutic strategies and the concentration of circulating cardiovascular system biomarkers may also vary across the 24‐hr light/dark cycle. Synchrony between external and internal diurnal rhythms and harmony among molecular rhythms within the cell are essential for normal organ biology. Diurnal variations in the responsiveness of the cardiovascular system to environmental stimuli are mediated by a complex interplay between extracellular (i.e. neurohumoral factors) and intracellular (i.e. specific genes that are differentially light/dark regulated) mechanisms. Neurohormones, which are particularly relevant to the cardiovascular system, such as melatonin, exhibit a diurnal variation and may play a role in the synchronization of molecular circadian clocks in the peripheral tissue and the suprachiasmatic nucleus. Moreover, mounting evidence reveals that the blood melatonin rhythm has a crucial role in several cardiovascular functions, including daily variations in blood pressure. Melatonin has antioxidant, anti‐inflammatory, chronobiotic and, possibly, epigenetic regulatory functions. This article reviews current knowledge related to the biological role of melatonin and its circadian rhythm in cardiovascular disease.     

Sirtuins, melatonin and circadian rhythms: building a bridge between aging and cancer

Abstract:  Histone deacetylases (HDAC) have been under intense scientific investigation for a number of years. However, only recently the unique class III HDAC, sirtuins, have gained increasing investigational momentum. Originally linked to longevity in yeast, sirtuins and more specifically, SIRT1 have been implicated in numerous biological processes having both protective and/or detrimental effects. SIRT1 appears to play a critical role in the process of carcinogenesis, especially in age-related neoplasms. Similarly, alterations in circadian rhythms as well as production of the pineal hormone melatonin have been linked to aging and cancer risk. Melatonin has been found act as a differentiating agent in some cancer cells and to lower their invasive and metastatic status. In addition, melatonin synthesis and release occurs in a circadian rhythm fashion and it has been linked to the core circadian machinery genes ( Clock , Bmal1 , Periods , and Cryptochromes ). Melatonin has also been associated with chronotherapy, the timely administration of chemotherapy agents to optimize trends in biological cycles. Interestingly, a recent set of studies have linked SIRT1 to the circadian rhythm machinery through direct deacetylation activity as well as through the nicotinamide adenine dinucleotide (NAD⁺) salvage pathway. In this review, we provide evidence for a possible connection between sirtuins, melatonin, and the circadian rhythm circuitry and their implications in aging, chronomodulation, and cancer.     

The circadian nature of melatonin secretion in Japanese quail (Coturnix coturnix japonica)

Abstract: Plasma melatonin concentrations were measured in Japanese quail held under different photoperiods and constant darkness (<1 lux). When subjected to LD6:18 (6 hr light: 18 hr darkness), levels rose ～2 hr after lights-off, attained a peak level 8 hr after lights off, and subsequently declined to low daytime levels before the next lights-on signal. This generated a distinct daily rhythm in melatonin secretion with a duration of ～13 h. On exposing quail to a range of photoperiods, containing 6, 9, 11, 12, 13, 15, 18, or 20 hr of light per day, the onset of melatonin secretion remained essentially similar with the rise occurring soon after lights-off. However, the offset of melatonin secretion was suppressed by the light of the next day and thus a much truncated rhythm was produced under long (> 12 hr) photoperiods. Importantly, between night lengths of 4 to 18 hr (i.e., LD 20:4 to LD 6:18) a linear relationship existed between the duration of night-length and secretion of melatonin with the duration increasing by about 0.8 hr for each additional hour of darkness. If quail were released into darkness following a short (LD 6:18) or long (LD 20:4) day schedule, the rhythm persisted for at least two cycles with peaks occurring at about 24 hr intervals. In those quail coming into darkness from long days (LD 20:4), the rhythm of melatonin secretion decompressed rapidly on both sides of the peak, indicating that both the onset and offset of melatonin secretion were suppressed under long days. The endogenous nature of melatonin secretion was tested further by exposing birds to LD 6:30 for 4 cycles and then releasing into darkness. The rhythm in melatonin secretion persisted for at least three cycles before beginning to damp-out. The circadian nature of the rhythm in melatonin secretion was also examined by subjecting quail to T-cycles and then releasing into darkness. Both under the T-cycles and darkness following T-cycle treatments, the phase of the melatonin rhythm was advanced by > 3 hr under T = 27 hr cycles (LD 3:24) compared with T = 24 hr cycles (LD 3:21). This property is consistent with the melatonin oscillator being a circadian rhythm.     

高血压病心血管重构与血压昼夜节律性

目的 :研究血压昼夜节律性变化对高血压病患者心脏和大动脉重构的影响。方法 :对 64例 1～ 2级高血压病患者进行 2 4h动态血压监测 ,并以超声检测心脏结构指标及主动脉、股动脉、月国动脉管腔内径、内膜中层厚度等动脉结构指标及反映动脉顺应性或扩张性的功能指标。以协方差分析校正可能的混杂因素影响后 ,对比动态血压昼夜节律呈杓型和非杓型的高血压病患者心血管重构指标的差异 ,并以 3 6例正常血压者作对照。结果 :血压昼夜节律异常的非杓型组高血压病患者与正常血压对照组相比 ,左房内径、左室壁厚度、左室肌重量明显增加 ,主动脉、股动脉及月国动脉内膜中层厚度及面积增大 ,内膜中层厚度 /腔径比值及内膜中层面积 /管腔面积比值显著增高 ;主动脉还有管腔内径及面积增大 ,脉搏波速度明显增快 ,差异有统计学显著性 ,经协方差分析校正年龄、性别、体重指数、心率、吸烟情况、血糖血脂水平等可能对心血管重构的影响后 ,显著性仍然存在 ,仅股动脉重构性指标统计学显著性降低。而昼夜节律正常的杓型高血压组与正常血压对照组相比 ,心脏和血管重构性变化指标多无显著性差异 ,结论 :轻中度高血压病时 ,血压昼夜节律异常可能对心脏和大动脉重构有不利影响     

Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock

In mammals, multiple physiological, metabolic, and behavioral processes are subject to circadian rhythms, adapting to changing light in the environment. Here we analyzed circadian rhythms in the fecal microbiota of mice using deep sequencing, and found that the absolute amount of fecal bacteria and the abundance of Bacteroidetes exhibited circadian rhythmicity, which was more pronounced in female mice. Disruption of the host circadian clock by deletion of Bmal1, a gene encoding a core molecular clock component, abolished rhythmicity in the fecal microbiota composition in both genders. Bmal1 deletion also induced alterations in bacterial abundances in feces, with differential effects based on sex. Thus, although host behavior, such as time of feeding, is of recognized importance, here we show that sex interacts with the host circadian clock, and they collectively shape the circadian rhythmicity and composition of the fecal microbiota in mice.The composition of intestinal microbiota is influenced by host genetics (1), aging (2), antibiotic exposure (3), lifestyle (4), diet (5), pet ownership (6), and concomitant disease (7, 8). The impact of diet in shaping the composition of the microbiota has been well established in both humans and mice (9, 10). The type of food consumed and also the feeding behavior of the host influence the microbiota. For example, a 24-h fast increases the abundance of Bacteroidetes and reduces that of Firmicutes in mouse cecum, without altering the communal microbial diversity (11). Bacteroidetes are also dominant in the microbiota of the fasted Burmese python, whereas ingestion of a meal shifts the intestinal composition toward Firmicutes (12).The rotation of the earth results in the oscillation of light during the 24-h cycle. Organisms adapted to this cycle by developing a circadian rhythm, an endogenous and entrainable mechanism that times daily events such as feeding, temperature, sleep-wakefulness, hormone secretion, and metabolic homeostasis (13, 14). In mammals, this rhythm is controlled by a master clock that resides in the suprachiasmatic nucleus of the hypothalamus. It responds to the changing light cycle and signals this information to peripheral clocks in most tissues (15). The core mammalian clock is comprised of activators BMAL1 and CLOCK as well as repressors PERIOD (PER) and CRYPTOCHROME (CRY), forming an interlocked regulatory loop (14).Circadian rhythms also exist in fungi and cyanobacteria (16). For example, a pacemaker in cyanobacteria transduces the oscillating daylight signal to regulate gene expression and to time cell division (17, 18). Hence, the synchronization of endogenous circadian rhythms with the environment is crucial for the survival of the bacteria as well as metazoa.Recent studies show that the intestinal microbiota undergo diurnal oscillation under the control of host feeding time, and that ablation of the host molecular clock Per genes causes dysbiosis (19, 20). Here, we report that microbial composition and its oscillation are influenced by the host clock, including the Bmal1-dependent forward limb of the signaling pathway. We also find that rhythmicity is conditioned by the sex of the host, being more pronounced in females than in males.     

Peripheral circadian clock for the cuticle deposition rhythm in Drosophila melanogaster

Insect endocuticle thickens after adult emergence by daily alternating deposition of two chitin layers with different orientation. Although the cuticle deposition rhythm is known to be controlled by a circadian clock in many insects, the site of the driving clock, the photoreceptor for entrainment, and the oscillatory mechanism remain elusive. Here, we show that the cuticle deposition rhythm is regulated by a peripheral oscillator in the epidermis in Drosophila melanogaster. Free-running and entrainment experiments in vitro reveal that the oscillator for the cuticle deposition rhythm is independent of the central clock in the brain driving the locomotor rhythms. The cuticle deposition rhythm is absent in null and dominant-negative mutants of clock genes (i.e., period, timeless, cycle, and Clock), indicating that this oscillator is composed of the same clock genes as the central clock. Entrainment experiments with monochromatic light-dark cycles and cry(b) flies reveal that a blue light-absorbing photoreceptor, cryptochrome (CRY), acts as a photoreceptor pigment for the entrainment of the cuticle deposition rhythm. Unlike other peripheral rhythms in D. melanogaster, the cuticle deposition rhythm persisted in cry(b) and cry(OUT) mutant flies, indicating that CRY does not play a core role in the rhythm generation in the epidermal oscillator.     

Exogenous melatonin modifies the circadian rhythm but does not increase the level of some immune parameters in the chicken

The effect of daily injection of the pineal hormone melatonin and naltrexone, an opioid antagonist, on the circadian rhythm and the level of immune parameters (plaque forming cell [PFC] number, serum agglutinin titer, lymphoid gland weight, total white blood cells (WBC) and their fraction number, and serum lysozyme [LZ] content) was examined in White Leghorn cockerels and female BALB/c mice kept in LD 12:12. Animals were immunized ip with sheep red blood cells (SRBC) to stimulate their immune system. Subcutaneous injections of melatonin, naltrexone, or both drugs together were made 2 hr before the end of light, for 4 or 5 days, beginning on the day of immunization. The day following the fifth injection, chickens were sacrificed over a 24 hr period every 4 hr (experiment I) or twice daily, i.e., at the beginning of light and dark phases (experiment II). Mice were killed on the day following the fourth injection at the beginning of light, and splenic PFC number was determined (experiment III). In experiment I, the existence of the diurnal rhythm was evaluated by cosinor analysis. Melatonin injections entrained the circadian rhythm in anti-SRBC serum agglutinins, but it did not influence circadian rhythmicity in other parameters examined. The circadian rhythm in total WBC number and their fractions was entrained by naltrexone treatment. Melatonin injections did not affect either the diurnal mean of parameters examined or the weight of lymphoid organs. Splenic PFC number in chickens was diminished by both melatonin and naltrexone injections, whereas in mice it was increased by melatonin, and naltrexone antagonized that effect.(ABSTRACT TRUNCATED AT 250 WORDS)