中西医观解读时间生物学

时间生物学是一门研究生命活动节律的科学。在西方医学中,研究时间生物学是利用分子生物学实验来阐释其机制,以西医的思维方法解释时间生物学的生理及病理过程;中医对时间生物学的记载有两千多年的历史,阴阳理论、子午流注学说以及五运六气学说一直以来都在指导中医的诊断和治疗。中西医观的不同对时间生物学的研究提供了新的研究思路,同时时间生物学也为研究中西医结合提供了广阔的前景。     

Entraining effects of variations in light spectral composition on the rest-activity rhythm of a nocturnal rodent

The ability to predict and adjust physiology and behavior to recurring environmental events has been necessary for survival on Earth. Recent discoveries revealed that not only changes in irradiance but also light spectral composition can stimulate the suprachiasmatic nucleus (SCN), ensuring the body’s synchronization to the environment. Therefore, using a lighting system that modulates spectral composition during the day using combined red-green-blue (RGB) lights, we evaluated the effect of variations in light spectral composition on the rest-activity rhythm of rodents. Male Wistar rats (n = 17) were gestated and raised under different lighting conditions and exposed to a long photoperiod (16 h light: 8 h dark). The difference between groups was the presence of variations in light spectral composition during the day (RGB-v) to simulate daily changes in natural light, or not (RGB-f). After weaning, spontaneous motor activity was recorded continuously for rhythm evaluation. Our results indicated that animals under RGB-v did not present a reactive peak of activity after the beginning of the light phase, suggesting that this group successfully detected the variations aimed at mimicking daily alterations of natural light. Furthermore, RGB-v animals exhibited an earlier activity acrophase in comparison to animals under RGB-f (RGB-v = 12:16 – “hh:mm”, RGB-f = 13:02; p < 0.001), which might have been due to the capability to predict the beginning of the dark phase when exposed to variations in light spectrum. However, this earlier activity acrophase can be also explained by the blue-light peak that occurred in RGB-v. The spectral and waveform analysis of daily patterns of motor activity revealed that rats in the RGB-v group were better entrained to a circadian rhythm throughout the experiment. RGB-v showed higher interdaily stability (IS) values (29.75 ± 6.5, n = 9) than did RGB-f (t₍₁₅₎ = 2.74, p = 0.015). Besides, the highest power content (PC) on the first harmonic (circadian) was reached earlier in the RGB-v group. The circadianity index (CI) of the whole period was higher in the RGB-v group (t₍₁₅₎ = 3.47, p = 0.003). Thus, we could consider that locomotor activity rhythm was entrained to the light-dark cycle in the RGB-v rats earlier compared to the RGB-f rats. Our results provide additional evidence for the effect of variations in light spectral composition on the rest-activity pattern of nocturnal rodents. This suggests that these animals might predict the arrival of the activity phase by its advanced acrophase when exposed to RGB-v, demonstrating a better synchronization to a 24-h rhythm.     

Effects of a chronic reduction of short-wavelength light input on melatonin and sleep patterns in humans: Evidence for adaptation

Light is an important environmental stimulus for the entrainment of the circadian clock and for increasing alertness. The intrinsically photosensitive ganglion cells in the retina play an important role in transferring this light information to the circadian system and they are elicited in particular by short-wavelength light. Exposure to short wavelengths is reduced, for instance, in elderly people due to yellowing of the ocular lenses. This reduction may be involved in the disrupted circadian rhythms observed in aged subjects. Here, we tested the effects of reduced blue light exposure in young healthy subjects (n?=?15) by using soft orange contact lenses (SOCL). We showed (as expected) that a reduction in the melatonin suppressing effect of light is observed when subjects wear the SOCL. However, after chronic exposure to reduced (short wavelength) light for two consecutive weeks we observed an increase in sensitivity of the melatonin suppression response. The response normalized as if it took place under a polychromatic light pulse. No differences were found in the dim light melatonin onset or in the amplitude of the melatonin rhythms after chronic reduced blue light exposure. The effects on sleep parameters were limited. Our results demonstrate that the non-visual light system of healthy young subjects is capable of adapting to changes in the spectral composition of environmental light exposure. The present results emphasize the importance of considering not only the short-term effects of changes in environmental light characteristics.     

时间生物学—2017年诺贝尔生理或医学奖解读

时间生物学主要研究生物节律的产生及生物钟的运行机制,2017年诺贝尔生理或医学奖的颁布再次引发人们对该领域诸多科学问题的高度关注。生物钟与日月运行引起的环境信号周期性保持同步,有利于生物节律的相位和组织稳态的精确维持。本文介绍了生物节律现象的早期研究及随后生物钟理论体系建立的发展简史,并结合2017年诺贝尔生理或医学奖的解读阐述了果蝇生物钟基因的发现与分子调控机理,进而简单归纳当前时间生物学领域的前沿科学问题,阐明生物钟研究的意义。     

Association between light exposure at night and insomnia in the general elderly population: The HEIJO-KYO cohort

Chronic circadian misalignment between the internal and environmental rhythms, which is typically related to night-shift work and clock-gene variants, is associated with disruption of suprachiasmatic nucleus function and increased risk of insomnia. Under controlled laboratory conditions, light at night (LAN) suppresses melatonin secretion, delays the internal biological rhythm, and reduces sleepiness. Therefore, LAN exposure may cause circadian misalignment and insomnia, though it remains unclear in real-life situations whether LAN exposure is associated with insomnia. To evaluate an association between LAN exposure and sleep quality in home settings, we conducted a cross-sectional community-based study in 857 elderly individuals (mean age, 72.2 years). We evaluated bedroom light intensity using a light meter and subjectively and objectively measured sleep quality using the Pittsburgh Sleep Quality Index and an actigraph, respectively, along with urinary 6-sulfatoxymelatonin excretion. Compared with the lowest quartile group of LAN intensity, the highest quartile group revealed a significantly higher odds ratio (OR) for subjective insomnia in a multivariate model adjusted for age, gender, body mass index, daytime physical activity, urinary 6-sulfatoxymelatonin excretion, bedtime, rising time, and day length (adjusted OR, 1.61, 95% confidence interval, 1.05–2.45, p?=?0.029). In addition, higher OR for subjective insomnia was significantly associated with the increase in quartiles of LAN intensity (p_trend?=?0.043). Consistently, we observed significant association trends between the increase in quartiles of LAN intensity and poorer actigraphic sleep quality, including decreased sleep efficiency, prolonged sleep-onset latency, increased wake-after-sleep onset, shortened total sleep time, and delayed sleep-mid time in multivariate models adjusted for the covariates mentioned above (all p_trend?<?0.001). In conclusion, we demonstrated that LAN exposure in home settings is significantly associated with both subjectively and objectively measured sleep quality in a community-based elderly population.     

Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting

To review the interaction between melatonin and the dopaminergic system in the hypothalamus and striatum and its potential clinical use in dopamine-related disorders in the central nervous system. Medline-based search on melatonin–dopamine interactions in mammals. Melatonin, the hormone produced by the pineal gland atnight, influences circadian and seasonal rhythms, most notably the sleep–wake cycle and seasonal reproduction. The neurochemical basis of these activities is not understood yet. Inhibition of dopamine release by melatonin has been demonstrated in specific areas of the mammalian central nervous system (hypothalamus, hippocampus, medulla-pons, and retina). Antidopaminergic activities of melatonin have been demonstrated in the striatum. Dopaminergic transmission has a pivotal role in circadian entrainment of the fetus, in coordination of body movement and reproduction. Recent findings indicate that melatonin may modulate dopaminergic pathways involved in movement disorders in humans. In Parkinson patients melatonin may, on the one hand, exacerbate symptoms (because of its putative interference with dopamine release) and, on the other, protect against neurodegeneration (by virtue of its antioxidant properties and its effects on mitochondrial activity). Melatonin appears tobe effective in the treatment of tardive dyskinesia, a severe movement disorder associated with long-term blockade of the postsynaptic dopamine D₂ receptor by antipsychotic drugs in schizophrenic patients. The interaction of melatonin with the dopaminergic system may play a significant role in the nonphotic and photic entrainment of the biological clock as well as in the fine-tuning of motor coordination in the striatum. These interactions and the antioxidant nature of melatonin may be beneficial in the treatment of dopamine-related disorders.     

The effects of biological rhythms and sleep quality on benign paroxysmal positional vertigo and reflux symptom severity

Recently, there has been increased interest in chronotypes and clinical differences between them. However, there is limited information about the potential influence of the chronotypes on clinical manifestations and symptom intensity of somatic diseases. The aim of this study is to evaluate the impact of biological rhythm differences and sleep quality on benign paroxysmal positional vertigo (BPPV) and larengo pharyngeal reflux (LPR) severity. Forty-four LPR patients, 43 BBPV patients and 42 controls were included in the study. The morningness–eveningness questionnaire was used to determine chronotypes, and the Pittsburgh Sleep Quality Index was used to assess subjective sleep quality. Both patient groups reported a significantly greater tendency to eveningness diurnal preferences compared to healthy controls. As with the circadian preferences, patients with BPPV or LPR characterized by poorer sleep quality and worse insomnia than non-patient individuals. It can be concluded that the circadian rhythm and sleep quality are related to the severity of LPR and BPPV.     

Exploring the role of circadian clock gene and association with cancer pathophysiology

ABSTRACT

Most of the processes that occur in the mind and body follow natural rhythms. Those with a cycle length of about one day are called circadian rhythms. These rhythms are driven by a system of self-sustained clocks and are entrained by environmental cues such as light-dark cycles as well as food intake. In mammals, the circadian clock system is hierarchically organized such that the master clock in the suprachiasmatic nuclei of the hypothalamus integrates environmental information and synchronizes the phase of oscillators in peripheral tissues.

The circadian system is responsible for regulating a variety of physiological and behavioral processes, including feeding behavior and energy metabolism. Studies revealed that the circadian clock system consists primarily of a set of clock genes. Several genes control the biological clock, including BMAL1, CLOCK (positive regulators), CRY1, CRY2, PER1, PER2, and PER3 (negative regulators) as indicators of the peripheral clock.

Circadian has increasingly become an important area of medical research, with hundreds of studies pointing to the body’s internal clocks as a factor in both health and disease. Thousands of biochemical processes from sleep and wakefulness to DNA repair are scheduled and dictated by these internal clocks. Cancer is an example of health problems where chronotherapy can be used to improve outcomes and deliver a higher quality of care to patients.

In this article, we will discuss knowledge about molecular mechanisms of the circadian clock and the role of clocks in physiology and pathophysiology of concerns.     

Avian circannual clocks: adaptive significance and possible involvement of energy turnover in their proximate control

Endogenous circannual clocks are found in many long-lived organisms, but are best studied in mammal and bird species. Circannual clocks are synchronized with the environment by changes in photoperiod, light intensity and possibly temperature and seasonal rainfall patterns. Annual timing mechanisms are presumed to have important ultimate functions in seasonally regulating reproduction, moult, hibernation, migration, body weight and fat deposition/stores. Birds that live in habitats where environmental cues such as photoperiod are poor predictors of seasons (e.g. equatorial residents, migrants to equatorial/tropical latitudes) rely more on their endogenous clocks than birds living in environments that show a tight correlation between photoperiod and seasonal events. Such population-specific/interspecific variation in reliance on endogenous clocks may indicate that annual timing mechanisms are adaptive. However, despite the apparent adaptive importance of circannual clocks, (i) what specific adaptive value they have in the wild and (ii) how they function are still largely untested. Whereas circadian clocks are hypothesized to be generated by molecular feedback loops, it has been suggested that circannual clocks are either based upon (i) a de-multiplication ('counting') of circadian days, (ii) a sequence of interdependent physiological states, or (iii) one or more endogenous oscillators, similar to circadian rhythms. We tested the de-multiplication of days (i) versus endogenous regulation hypotheses (ii) and (iii) in captive male and female house sparrows (Passer domesticus). We assessed the period of reproductive (testicular and follicular) cycles in four groups of birds kept either under photoperiods of LD 12L:12D (period length: 24h), 13.5L:13.5D (27 h), 10.5L:10.5D (23 h) or 12D:8L:3D:1L (24-h skeleton photoperiod), respectively, for 15 months. Contrary to predictions from the de-multiplication hypothesis, individuals experiencing 27-h days did not differ (i.e. did not have longer) annual reproductive rhythms than individuals from the 21- or 24-h day groups. However, in line with predictions from endogenous regulation, birds in the skeleton group had significantly longer circannual period lengths than all other groups. Birds exposed to skeleton photoperiods experienced fewer light hours per year than all other groups (3285 versus 4380) and had a lower daily energy expenditure, as tested during one point of the annual cycle using respirometry. Although our results are tantalizing, they are still preliminary as birds were only studied over a period of 15 months. Nevertheless, the present data fail to support a 'counting of circadian days' and instead support hypotheses proposing whole-organism processes as the mechanistic basis for circannual rhythms. We propose a novel energy turnover hypothesis which predicts a dependence of the speed of the circannual clock on the overall energy expenditure of an organism.     

Circannual Variation of Cell Proliferation in Lymphoid Organs and Bone Marrow of Dbf1 Male Mice on Three Lighting Regimens

The case of a 40-year-old sighted woman with free-running sleep-wake and melatonin rhythms is presented. The subject was studied for 102 days. During the pre-treatment period, both the sleep-wake and melatonin rhythms had a period of 25.1 hr, similar to the average period of humans living in temporal isolation. Treatment consisted of bright artifical light exposure (2500 lx Vita-Lite) for 2 hr each day upon awakening. Clock time of light exposure was held constant for 6 days and then slowly advanced until the subject was arising at her desired time of day. The subject continued the light treatment at home and was able to live on a 24-hr day for the 30-day follow-up study. While other factors may be operating in this situation, it is possible that the light treatment caused the stabilization of the free-running rhythms, advancement to a normal phase and entrainment to the 24-hr day. We suspect that the tendency to free-run was related to sleep onsets that were abnormally delayed relative to the circadian phase response curve for light. By scheduling a 2-hr pulse of bright light each morning, this tendency to delay would be counteracted by light-induced advances, resulting in normal entrainment.     

Entrainment of A Free-Running Human with Bright Light?

The case of a 40-year-old sighted woman with free-running sleep-wake and melatonin rhythms is presented. The subject was studied for 102 days. During the pre-treatment period, both the sleep-wake and melatonin rhythms had a period of 25.1 hr, similar to the average period of humans living in temporal isolation. Treatment consisted of bright artifical light exposure (2500 lx Vita-Lite) for 2 hr each day upon awakening. Clock time of light exposure was held constant for 6 days and then slowly advanced until the subject was arising at her desired time of day. The subject continued the light treatment at home and was able to live on a 24-hr day for the 30-day follow-up study. While other factors may be operating in this situation, it is possible that the light treatment caused the stabilization of the free-running rhythms, advancement to a normal phase and entrainment to the 24-hr day. We suspect that the tendency to free-run was related to sleep onsets that were abnormally delayed relative to the circadian phase response curve for light. By scheduling a 2-hr pulse of bright light each morning, this tendency to delay would be counteracted by light-induced advances, resulting in normal entrainment.     

Daily variations of immunoreactive melatonin in the visual system of crayfish

In crustaceans, melatonin has been detected in the central nervous system and some other organs. The aim of this study was to analyze the melatonin content in the visual system of Procambarus clarkii, by means of radioimmunoassay, at different day-night phases. We have also studied the action of exogenous melatonin on the main properties of the electroretinogram (ERG) circadian rhythm. Experiments were conducted with 25 specimens maintained under controlled conditions of 16°C and 12 h of light alternating with 12 h of darkness. Eyes where cut in dim red light and shock frozen with liquid nitrogen and pulverized in a mortar until a homogenous powder was obtained. Melatonin was extracted with acetone, followed by centrifugation, diluted with an equal volume of equa bidest to ensure freezing at ?80°C for at least 90 min and lyophilization at the same temperature. Lyophilizates, after having been dissolved in RIA buffer, were used for determinations of melatonin. Long-term recordings of electrical responses to light (ERG) were obtained for 10 or more consecutive days. At the 5th day, a single dose of melatonin was injected and its effects on amplitude and period of the ERG circadian rhythm were measured. Melatonin concentrations differed considerably depending on the circadian time and attained a maximum during dark phase. Among the crustaceans, Procambarus clarkii represents the first case in which melatonin peaks during the night following the typical pattern known in the majority of organisms. After melatonin injection, period and amplitude of the ERG circadian rhythm were increased. This effect suggests the involvement of melatonin in the oscillators underlying the generation and expression of circadian rhythms in crayfish.     

A complex rhythm problem: The possibility of a lunar modulation of plant function

Abstract

The analysis of long temporal series of gas exchange of seeds in moist atmosphere or of root lengths of seedlings reveals the existence of non‐random fluctuations. Several observations allow us to envisage the presence of rhythmicities with modulated periods.

The plant material was kept in darkness at stabilised temperature and humidity. The experiments were conducted on different plant species, in various conditions of temperature and humidity in different years. The gas exchange was measured with the Warburg apparatus; the roots on seedlings after 72 h of germination on Petri glasses. We compared the rhythmicities of the biological material with some periodicities of the geophysical environment. We chose as a reference the passages of the moon and of the sun at the meridian.

An analogy is observed between several of the observed rhythmicities and the circadian and low‐frequency rhythmicities of the geophysical environment. It seems as if submultiples of those natural periods would be generated. We consider the probable existence of modulated synchronisation and we propose an hypothesis for deriving the observed periodicities from three basic circadian rhythms: solar, lunar and "circadian”;.

A model is proposed and a theoretical curve elaborated which is in reasonal concordance with, the experimental curve. We point out that appropriate mathe‐. matical methods for modulated periods and amplitudes should be useful.     

Activity rhythms of enzymes in human red blood cell suspensions

Abstract

We have established the presence of a rhythm in the activity of 4 enzymes in in‐vitro cell suspensions of human red blood cells. Glucose 6‐phosphate dehydrogenase and glutamate oxaloacetate transaminase demonstrated semicircadian patterns of activity, while acid phosphatese and acetylcholine esterase exhibited circadian activity rhythms. The ratios between the highest to lowest activities varied from 2:1 to 10:1 among the various enzymes. The affinity of glucose 6 phosphate dehydrogenase to its substrate and coenzyme remained constant throughout the cycle. No evidence was obtained for the presence of a soluble inhibitor at the lower levels of the activity. Sonication of hemolysates with low glucose 6 phosphate dehydrogense activity yielded additional activity comparable to that of the peak activity. Sonication of hemolysates from the time of the peak activity did not change the original activity. The observations point to a role of the cell membrane in the biological clock.