Chronomedicine: An old concept's fledging? A selective literature search

Chronomedicine may be conceptualized as dealing with the prevention, causation, diagnosis, and treatment of diseases in humans with a particular focus on the role "time" [Greek: chrónos] plays in our physiology, endocrinology, metabolism and behavior at many organizational levels. While it has been used as a term and somewhat pursued as a discipline for decades, it appears that chronomedicine has captured a broader interest as a promising specialty only more recently. This commentary addresses roots of chronomedicine in the 1900s and perspectives for chronomedicine in the 21st century. Classical terms of chronobiology, e.g., Zeitgeber, melatonin and circadian, may be traced back to Aschoff, Lerner, and Halberg, respectively, but who actually coined the term "chronomedicine" and used it first in a publication remains unclear. Importantly, it could be(come) rather straightforward to transfer abundant insights gained from chronobiology to strategies in chronomedicine as animal models have been increasingly developed to understand human health and disease. Perspectively, chronomedicine should comprise "clinical chronomedicine" (individual-based) and "preventive chronomedicine" (population-based). Overall, due to the "maturing" of chronomedicine as a field, the near future might bring a section dedicated to chronomedicine in existing journals, or even a "Journal of Chronomedicine" as vectors of ideas and research.     

Differential regulation of the Menkes and Wilson disease copper transporters by hormones: an integrated model of metal transport in the placenta

Copper (Cu) plays a critical role in the developing foetus, but virtually nothing is known concerning the regulation of its uptake and metabolism in the placenta. In this issue of the Biochemical Journal, Hardman and colleagues, using a model of placental trophoblasts in culture, identify differential hormonal regulation of two copper-transporting ATPases; namely, those responsible for Menkes disease (ATP7A; MNK) and Wilson disease (ATP7B; WND). Insulin and oestrogen, which are essential during gestation, up-regulate MNK and this leads to trafficking of the MNK protein from the Golgi to the basolateral membrane, resulting in increased Cu efflux. At the same time, insulin decreased WND levels, and this leads to intracellular sequestration of the protein to a perinuclear region that reduces apical Cu release. As such, this results in a concerted flux of Cu from the basolateral surface of the trophoblast that would potentially be used by the developing foetus. An integrated model of vectorized Cu transport is proposed, which involves co-ordinated expression of transporters, organelle interactions and probable protein-protein interactions. The findings have wider implications for considering general models of intracellular metal transport.     

Chronobiological evidence for an uncoupling of the Na,K-ATPase to aldosterone in normal renin hypertension

The Na,K-ATPase activity of erythrocyte membranes is markedly increased in normal-renin essential hypertensives. A temporal shift of the chronobiology of the erythrocyte-membrane-bound Na,K-ATPase in these patients is described. The disorder causes a loss of synchronism between the circadian rhythms of aldosterone and Na,K-ATPase. Such uncoupling phenomenon may explain the inversion of the day/night sodium excretion ratio and other disturbances of sodium metabolism found in essential hypertensives.     

International Society of Chronobiology: Membership Information

The International Society for Chronobiology has as its aims, furthering the study of temporal changes in living matter, including biological rhythms in development and ageing in individuals and populations; studying and defining the mechanisms of temporal changes; fostering practical applications for chronobiological findings to mankind in basic and applied biology, physiology, work hygiene and the medical sciences; promoting education in and wide understanding of chronobiology; and furthering contact between scientists in the field and providing a forum for practitioners of chronobiology.     

International Society of Chronobiology: Membership Information

The International Society for Chronobiology has as its aims, furthering the study of temporal changes in living matter, including biological rhythms in development and ageing in individuals and populations; studying and defining the mechanisms of temporal changes; fostering practical applications for chronobiological findings to mankind in basic and applied biology, physiology, work hygiene and the medical sciences; promoting education in and wide understanding of chronobiology; and furthering contact between scientists in the field and providing a forum for practitioners of chronobiology.     

Current aspects of Leydig cell function and its regulation

Recent findings on Leydig cell function and its regulation are discussed. Regulatory mechanisms at different organizational levels, i.e. at the level of the pituitary, the testis and the intracellular elements, are briefly reviewed as well as the transmission and the modulation of the hormonal signal at the Leydig cell membrane. Special emphasis is given to local paracrine and autocrine regulatory interactions operating at the level of the testis.     

Cross inhibition models for the transmission of hormonal signals.

Implications of a model where the formation of two mediators interacting through cross inhibition is stimulated by the same hormone or by two specific hormones are analyzed at steady'state, first in the case where no co-operative processes are involved, secondly in the case where one of the inhibitory branches presents positive co-operativity characteristics. The possible occurrence of agonist concentration-mediators response curves with extrema of opposite type, multiple steady states, hysteresis and discontinuous transitions from one functional program to another is demonstrated. When steady-state hormonal levels fluctuate, it is shown that the cross inhibitory mediators may induce a strict temporal organization of the intracellular processes and result in both amplification and frequency multiplication of the fluctuations.     

Mitochondria: The hands of the clock?

The output of the master clock to control peripheral circadian functions and temporal organization in metazoans is unknown. We recently reported a periodic dip of lipidperoxidation (PDL) at 03 h in humans by monitoring the serum levels of malondialdehyde (MDA), a marker of lipidperoxidation, over a 24-hour period and suggested that PDL may represent a redox signal of the master clock. Mitochondria are considered to be the major source of lipidperoxidation in most tissues. Their activity is known to be disrupted in many malignant tissues. To test the possible role of mitochondrial activity on the induction of the PDL, we monitored the daily MDA levels in the serum of 16 cancer patients, suffering from different kinds of malignant tumors, and compared them with those found in the healthy humans of our previous study. Discriminant analysis revealed a significant difference between both groups only at 03 h ( p = 0.000001), thus indicating the critical relevance of this time point for differences between both groups. In the light of the emerging role of the mitochondrion in cell signaling, we suggest that the signal transduction from the master clock may be related to central and peripheral mitochondrial activity and its ROS (reactive oxygen species) generation. This notion could involve nitric oxide, as a known potent regulator of mitochondrial function and as an essential part of the mitochondrial signaling pathway. The PDL could additionally be useful as a circadian phase marker in chronobiology research.     

Metabolism of Anxiolytics and Hypnotics: Benzodiazepines, Buspirone, Zoplicone, and Zolpidem

1. The benzodiazepines are among the most frequently prescribed of all drugs and have been used for their anxiolytic, anticonvulsant, and sedative/hypnotic properties. Since absorption rates, volumes of distribution, and elimination rates differ greatly among the benzodiazepine derivatives, each benzodiazepine has a unique plasma concentration curve. Although the time to peak plasma levels provides a rough guide, it is not equivalent to the time to clinical onset of effect. The importance of and half-lives in the actions of benzodiazepines is discussed.2. The role of cytochrome P450 isozymes in the metabolism of benzodiazepines and in potential pharmacokinetic interactions between the benzodiazepines and other coadministered drugs is discussed.3. Buspirone, an anxiolytic with minimal sedative effects, undergoes extensive metabolism, with hydroxylation and dealkylation being the major pathways. Pharmacokinetic interactions of buspirone with other coadministered drugs seem to be minimal.4. Zopiclone and zolpidem are used primarily as hypnotics. Both are extensively metabolized; N-demethylation, N-oxidation, and decarboxylation of zopiclone occur, and zolpidem undergoes oxidation of methyl groups and hydroxylation of a position on the imidazolepyridine ring system. Zopiclone has a chiral centre, and demonstrates stereoselective pharmacokinetics. Metabolic drug–drug interactions have been reported with zopiclone and erythromycin, trimipramine, and carbamazepine. Reports to date indicate minimal interactions of zolpidem with coadministered drugs; however, it has been reported to affect the C _max and clearance of chlorpromazepine and to decrease metabolism of the antiviral agent ritonavin. Since CYP3A4 has been reported to play an important role in metabolism of zolpidem, possible interactions with drugs which are substrates and/or inhibitors of that CYP isozyme should be considered.     

Analysis of the circadian rhythm in energy metabolism of rat liver

• 1.1. To study the temporal organization of energy metabolism in rat liver the steady state concentrations of key intermediates of carbohydrate and phosphorus metabolism were determined during 24 hr.
• 2.2. The circadian rhythm in energy metabolism of rat liver has been analysed by four different approaches. It was shown that neither apparent PEP synthesis nor crossover theorem were acceptable for the elucidation of the temporal organization of multi-enzyme systems.
• 3.3. Correlations analysis explained the temporal organization of energy metabolism most satisfactorily.
• 4.4. Based on the results of this analysis it was suggested that circadian regulation of energy metabolism in liver was realized at the level of the citric acid cycle.

     

Top-down analysis of temporal hierarchy in biochemical reaction networks

The study of dynamic functions of large-scale biological networks has intensified in recent years. A critical component in developing an understanding of such dynamics involves the study of their hierarchical organization. We investigate the temporal hierarchy in biochemical reaction networks focusing on: (1) the elucidation of the existence of "pools" (i.e., aggregate variables) formed from component concentrations and (2) the determination of their composition and interactions over different time scales. To date the identification of such pools without prior knowledge of their composition has been a challenge. A new approach is developed for the algorithmic identification of pool formation using correlations between elements of the modal matrix that correspond to a pair of concentrations and how such correlations form over the hierarchy of time scales. The analysis elucidates a temporal hierarchy of events that range from chemical equilibration events to the formation of physiologically meaningful pools, culminating in a network-scale (dynamic) structure-(physiological) function relationship. This method is validated on a model of human red blood cell metabolism and further applied to kinetic models of yeast glycolysis and human folate metabolism, enabling the simplification of these models. The understanding of temporal hierarchy and the formation of dynamic aggregates on different time scales is foundational to the study of network dynamics and has relevance in multiple areas ranging from bacterial strain design and metabolic engineering to the understanding of disease processes in humans.     

Knowledge and Attitudes of American Physicians and Public About Medical Chronobiology and Chronotherapeutics. Findings of Two 1996 Gallup Surveys

Two Gallup telephone interview surveys were conducted during 1996 of 320 American primary care physicians and 1011 adults to assess their knowledge and attitudes about medical chronobiology and chronotherapeu-tics. Of the doctors, 88% claimed to possess at least some familiarity with the concept of chronobiology and circadian rhythms; however, many were not often able to identify correctly the time of day or night when common medical conditions and events most likely occur or worsen. Furthermore, a significant number of doctors believed that chronotherapies, special dosage forms that proportion medications during the day and night in synchrony to need with reference to 24h patterns in the intensity of symptoms and risk of severe medical events, were already being marketed in the United States for angina pectoris, hypertension, respiratory allergies, and other medical conditions even though this was not the case at the time of the survey. On the other hand, the doctors were relatively unaware of those chronotherapies that actually did exist to treat asthma and peptic ulcer disease. American adults also lacked knowledge of temporal patterns in disease and were seldom able to identify the clock time when asthma and myocardial infarction are of greatest risk or when blood pressure is highest. Although neither the American physicians nor adults possessed knowledge of these facts, both had a strong positive attitude toward the concept of chronotherapeutics. Overall, the findings of these Gallup surveys indicate that a massive educational effort is necessary immediately to ensure new developments in medical chronobiology and chronotherapeutics are correctly comprehended and properly incorporated by physicians into clinical medicine and wisely utilized by patients.     

The resilience of pollination interactions: importance of temporal phases

Aims The loss of species that engage in close ecological interactions, such as pollination, has been shown to lead to secondary extinctions, ultimately threatening the overall ecosystem stability and functioning. Pollination studies are currently flourishing at all possible levels of interaction organization (i.e., species, guild, group and network), and different methodological protocols aimed to define the resilience of pollination interactions have been proposed. However, the temporal dimension of the resilience of pollination interactions has been often overlooked. In the light of these considerations, we addressed the following questions: does a temporal approach help to reveal critical moments during the flowering season, when pollination interactions are less resilient to perturbations? Do pollination interactions evaluated at species, guild, group and network level show different patterns when assessed through time?     

Ethanol inhibits muscarinic receptor-stimulated phosphoinositide metabolism and calcium mobilization in rat primary cortical cultures

In recent years, it has been hypothesized that muscarinic receptor-stimulated phosphoinositide (PI) metabolism may represent a relevant target for the developmental neurotoxicity of ethanol. Age-, brain region-, and receptor-specific inhibitory effects of ethanol on this system have been found, both in vitro and after in vivo administration. As a direct consequence of this action, alterations of calcium homeostasis would be expected, through alterations of inositol trisphosphate formation, which mediates intracellular calcium mobilization. In the present study, the effects of ethanol (50–500 mM) on carbachol-stimulated PI metabolism and free intracellular calcium levels were investigated in rat primary cortical cultures, by measuring release of inositol phosphates and utilizing the two calcium probes fluo-3 and indo-1 on an ACAS (Adherent Cell Analysis and Sorting) Laser Cytometer. Ethanol exerted a concentration-dependent inhibition of carbachol-stimulated PI metabolism. In addition, ethanol's inhibitory effect paralleled the temporal development of the muscarinic receptor signal transduction system, with the strongest inhibition (25–50%) occurring when maximal stimulation by carbachol occurs (days 5–7). Ethanol also exerted a concentration-dependent decrease in free intracellular calcium levels following carbachol stimulation. Both initial calcium spike amplitude, seen in all responsive cells, as well as the total number of cells responding to carbachol, were decreased by ethanol. The inhibitory effects of ethanol seemed dependent upon preincubation time, in that a longer preincubation (30 min) with the lowest dose (50 mM), showed almost the same decrease in responding cell number and reduction in spike amplitude in responding cells, as a shorter incubation (10 min) with the highest ethanol dose (500 mM). The specificity of the response to carbachol was demonstrated by blocking the response with 10 M atropine. Moreover, experiments with carbachol in calcium-free buffer with 1 mM EGTA indicated that the initial calcium spike was due to intracellular calcium mobilization from intracellular stores. Since calcium is believed to play important roles in cell proliferation and differentiation, these results support the hypothesis that this intracellular signal-transduction pathway may be a target for ethanol, contributing to its developmental neurotoxicity.     

Hypercaloric diet and chronic stress desynchronizes the temporal pattern of rats’ insulin release

This study evaluated the effects of the association between obesity and chronic stress on the temporal pattern of serum levels of biochemical and hormonal markers. Obesity model was achieved by hypercaloric diet exposure. Wistar rats were divided into four groups: standard chow (C), hypercaloric diet (HD), stress + standard chow (S), and stress + hypercaloric diet (SHD) and analysed at three time points: ZT0, ZT12 and ZT18. Chronic stress was performed 1 h/per day, 5 days/per week, during 80 days. The presence of temporal pattern in naïve animals’ insulin release was accomplished. Hypercaloric diet induced obesity, increasing rats’ insulin and glucose levels; while chronic stress reduced insulin levels. There were interactions between chronic stress and obesity in serum insulin and glucose levels; and between time points and obesity in insulin levels. In conclusion, long exposure to hypercaloric diet and chronic stress were able to desynchronize temporal pattern of insulin release, contributing to the pathophysiology of obesity and its complications.     

The metabolic organization of a primitive air-breathing fish, the Florida gar (Lepisosteus platyrhincus)

The metabolic organization of the air-breathing Florida gar, Lepisosteus platyrhincus, was assessed by measuring the maximal activities of key enzymes in several metabolic pathways in selected tissues, concentrations of plasma metabolites including nonesterified fatty acids (NEFA), free amino acids (FAA) and glucose as well as tissue FAA levels. In general, L. platyrhincus has an enhanced capacity for carbohydrate metabolism as indicated by elevated plasma glucose levels and high activities of gluconeogenic and glycolytic enzymes. Based upon these properties, glucose appears to function as the major fuel source in the Florida gar. The capacity for lipid metabolism in L. platyrhincus appears limited as plasma NEFA levels and the activities of enzymes involved in lipid oxidation are low relative to many other fish species. L. platyrhincus is capable of oxidizing both D- and L-beta-hydroxybutyrate, with tissue-specific preferences for each stereoisomer, yet the capacity for ketone body metabolism is low compared with other primitive fishes. Based on enzyme activities, the metabolism of the air-breathing organ more closely resembles that of the mammalian lung than a fish swim bladder. The Florida gar sits phylogenetically and metabolically in an intermediate position between the "primitive" elasmobranchs and the "advanced" teleosts. The apparently unique metabolic organization of the gar may have evolved in the context of a bimodal air-breathing environmental adaptation.     

Chronobiologic organization of sleep

Interrelations between sleep and chronobiology as been studied in isolated experimental situations. A succession of hormonal regulations has been described to explain these mechanisms. Some disruptions of these regulations might be at the beginning of a lot of sleep pathologies (jet lag syndrome, burn out syndrome, insomnia...).     

Clock genes in cell clocks: roles, actions, and mysteries

Cellular events must be organized in the time dimension as well as in the space dimension for many proteins to perform their cellular functions effectively. The intracellular molecular oscillating loops that compose the cell's circadian clock coordinate the timing of the expression of a variety of genes with basic or specific cellular functions. In mammals, the temporal pattern of clock gene expression generated in each SCN neuron is coupled to those of other cells and, amplified, spreads its signals through the brain and then, via feeding behavior, glucocorticoids, and sympathetic nerves, to peripheral organs. These peripheral organs have their own circadian clocks. In some tissues, such as liver, there is also a clock-regulating cell cycle, which interacts strongly with the components and temporal organization of the circadian clock. Some tissues, however, such as testis, express clock genes whose function, if any, remains unclear. Furthermore, circadian clock function may be suspended in differentiating tissue. Thus, the prominence of circadian organization may not apply equally to all tissues under all conditions.