Artigos de revistas: "Circadian rhythms"

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DOYLE, SUSAN E., MICHAEL S. GRACE, WILSON McIVOR e MICHAEL MENAKER. "Circadian rhythms of dopamine in mouse retina: The role of melatonin". Visual Neuroscience 19, n.º 5 (setembro de 2002): 593–601. http://dx.doi.org/10.1017/s0952523802195058.

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Both dopamine and melatonin are important for the regulation of retinal rhythmicity, and substantial evidence suggests that these two substances are mutually inhibitory factors that act as chemical analogs of day and night. A circadian oscillator in the mammalian retina regulates melatonin synthesis. Here we show a circadian rhythm of retinal dopamine content in the mouse retina, and examine the role of melatonin in its control. Using high-performance liquid chromatography (HPLC), we measured levels of dopamine and its two major metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in retinas of C3H+/+ mice (which make melatonin) and C57BL/6J mice that are genetically incapable of melatonin synthesis. In a light/dark cycle both strains of mice exhibited daily rhythms of retinal dopamine, DOPAC, and HVA content. However, after 10 days in constant darkness (DD), a circadian rhythm in dopamine levels was present in C3H, but not in C57 mice. C57 mice given ten daily injections of melatonin in DD exhibited a robust circadian rhythm of retinal dopamine content whereas no such rhythm was present in saline-injected controls. Our results demonstrate that (1) a circadian clock generates rhythms of dopamine content in the C3H mouse retina, (2) mice lacking melatonin also lack circadian rhythms of dopamine content, and (3) dopamine rhythms can be generated in these mice by cyclic administration of exogenous melatonin. Our results also indicate that circadian rhythms of retinal dopamine depend upon the rhythmic presence of melatonin, but that cyclic light can drive dopamine rhythms in the absence of melatonin.

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Brzezinski, Amnon, Seema Rai, Adyasha Purohit e Seithikurippu R. Pandi-Perumal. "Melatonin, Clock Genes, and Mammalian Reproduction: What Is the Link?" International Journal of Molecular Sciences 22, n.º 24 (8 de dezembro de 2021): 13240. http://dx.doi.org/10.3390/ijms222413240.

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Physiological processes and behaviors in many mammals are rhythmic. Recently there has been increasing interest in the role of circadian rhythmicity in the control of reproductive function. The circadian rhythm of the pineal hormone melatonin plays a role in synchronizing the reproductive responses of animals to environmental light conditions. There is some evidence that melatonin may have a role in the biological regulation of circadian rhythms and reproduction in humans. Moreover, circadian rhythms and clock genes appear to be involved in optimal reproductive performance. These rhythms are controlled by an endogenous molecular clock within the suprachiasmatic nucleus (SCN) in the hypothalamus, which is entrained by the light/dark cycle. The SCN synchronizes multiple subsidiary oscillators (clock genes) existing in various tissues throughout the body. The basis for maintaining the circadian rhythm is a molecular clock consisting of transcriptional/translational feedback loops. Circadian rhythms and clock genes appear to be involved in optimal reproductive performance. This mini review summarizes the current knowledge regarding the interrelationships between melatonin and the endogenous molecular clocks and their involvement in reproductive physiology (e.g., ovulation) and pathophysiology (e.g., polycystic ovarian syndrome).

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Powell, Weston T., Lucille M. Rich, Elizabeth R. Vanderwall, Maria P. White e Jason S. Debley. "Temperature synchronisation of circadian rhythms in primary human airway epithelial cells from children". BMJ Open Respiratory Research 9, n.º 1 (outubro de 2022): e001319. http://dx.doi.org/10.1136/bmjresp-2022-001319.

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IntroductionCellular circadian rhythms regulate immune pathways and inflammatory responses that mediate human disease such as asthma. Circadian rhythms in the lung may also contribute to exacerbations of chronic diseases such as asthma by regulating observed rhythms in mucus production, bronchial reactivity, airway inflammation and airway resistance. Primary human airway epithelial cells (AECs) are commonly used to model human lung diseases, such as asthma, with circadian symptoms, but a method for synchronising circadian rhythms in AECs has not been developed, and the presence of circadian rhythms in human AECs remains uninvestigated.MethodsWe used temperature cycling to synchronise circadian rhythms in undifferentiated and differentiated primary human AECs. Reverse transcriptase-quantitative PCR was used to measure expression of the core circadian clock genes ARNTL, CLOCK, CRY1, CRY2, NR1D1, NR1D2, PER1 and PER2.ResultsFollowing temperature synchronisation, the core circadian genes ARNTL, CRY1, CRY2, NR1D1, NR1D2, PER1 and PER2 maintained endogenous 24-hour rhythms under constant conditions. Following serum shock, the core circadian genes ARNTL, NR1D1 and NR1D2 demonstrated rhythmic expression. Following temperature synchronisation, CXCL8 demonstrated rhythmic circadian expression.ConclusionsTemperature synchronised circadian rhythms in AECs differentiated at an air–liquid interface can serve as a model to investigate circadian rhythms in pulmonary diseases.

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Gubareva, Yekaterina, Mikhail Maydin, Margarita Tyndyk, Irina Vinogradova e Andrey Panchenko. "CIRCADIAN RHYTHM OF PROLIFERATION IN INTESTINAL EPITHELIUM AND MAMMARY TUMORS IN HER-2/NEU TRANSGENIC AND FVB/N WILD TYPE MICE; THEIR CORRECTION WITH MELATONIN". Problems in oncology 65, n.º 1 (1 de janeiro de 2019): 154–58. http://dx.doi.org/10.37469/0507-3758-2019-65-1-154-158.

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Circadian rhythms and tumor development are interconnected as the factors like light pollution which disrupt circadian rhythms increase the risk of cancer, and oncological diseases are associated with changes in organism’s circadian rhythms. Circadian changes in intestinal epithelium and mammary tumors proliferation and apoptosis in HER-2/neu overexpressing FVB/N mice and assessment of melatonin’s influence on these parameters were studied in this work. It was shown by us that intestinal epithelium in mice exhibits circadian rhythm of proliferation with the peak in the morning and in tumor-bearing mice this rhythm is disrupted. Exogenous melatonin contributes to circadian rhythm of intestinal epithelium proliferation. Circadian changes in mammary tumors proliferation rate depend on melatonin secretion or supplementation time. Thus, melatonin may be considered as a perspective drug in anticancer therapy modulating circadian rhythms in cancerous and normal tissues.

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Yamanaka, Yujiro. "Basic concepts and unique features of human circadian rhythms: implications for human health". Nutrition Reviews 78, Supplement_3 (26 de novembro de 2020): 91–96. http://dx.doi.org/10.1093/nutrit/nuaa072.

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Abstract Most physiological functions and behaviors exhibit a robust approximately 24-hour rhythmicity (circadian rhythm) in the real world. These rhythms persist under constant conditions, but the period is slightly longer than 24 hours, suggesting that circadian rhythms are endogenously driven by an internal, self-sustained oscillator. In mammals, including humans, the central circadian pacemaker is located in the hypothalamic suprachiasmatic nucleus. The primary zeitgeber for this pacemaker is bright sunlight, but nonphotic time cues also affect circadian rhythms. The human circadian system uniquely exhibits spontaneous internal desynchronization between the sleep-wake cycle and core body temperature rhythm under constant conditions and partial entrainment of the sleep-wake cycle in response to nonphotic time cues. Experimental and clinical studies of human circadian rhythms must take into account these unique features. This review covers the basic concepts and unique features of the human circadian system, the mechanisms underlying phase adjustment of the circadian rhythms by light and nonphotic time cues (eg, physical exercise), and the effects of eating behavior (eg, chewing frequency) on the circadian rhythm of glucose metabolism.

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Zamoshchina, T. A., M. V. Meleshko, S. V. Logvinov, A. V. Matveуenko, L. N. Novitskaya e Ye V. Ivanova. "The suprahiazmatic nucleus of the forward hypothalamus destruction and circadian rhythms of moving activity, body temperature and renal excretion of Nа+, Cа2+, K+, Li+ in rats in summer solstice". Bulletin of Siberian Medicine 10, n.º 5 (28 de outubro de 2011): 50–55. http://dx.doi.org/10.20538/1682-0363-2011-5-50-55.

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In summer solstice it was established that right or left suprachiazmatic nucleus lesion breaks circadian rhythms of rat's moving activity in «open field» and lithium urine excretion. Damage of the left nuclei in a greater degree affects formation circadian rhythm of sodium renal excretion, destruction of the right nuclei - the calcium rhythm organization. The rhythms of body temperature and potassium urine excretion find weak sensitivity to reenergizing right or left suprachiazmatic nucleus. At destruction right or left suprachiazmatic nucleus are formed rhythm's desynchronization, character and expressiveness are defined by an illumination mode.

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Farr, Lynne, Catherine Todero e Lonna Boen. "Reducing Disruption of Circadian Temperature Rhythm Following Surgery". Biological Research For Nursing 2, n.º 4 (abril de 2001): 257–66. http://dx.doi.org/10.1177/109980040100200405.

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Temperature and other circadian rhythms are disrupted following surgery and other traumatic events. During recovery, coordination between temperature rhythms and other rhythmic physiologic processes is reduced. Studies of animals and humans have shown that return of synchrony is not immediate, but that it is important in the recovery process. The purpose of this study was to test a combination of cues that have been shown to adjust the timing of circadian temperature rhythm. The combined cues consisted of timed ingestion of caffeine and protein foods and adjustment of the sleep/wake cycle. The intervention was tested in 26 age-and gender-matched maxillofacial surgery patients. Patients were randomly assigned to control or experimental groups. Circadian temperature rhythm was measured by continuous monitoring with axillary probes and miniature recorders before and after surgery. Following surgery, both experimental and control subjects displayed 24-hour circadian temperature rhythms; however, the peak-to-trough difference was decreased more following surgery in the control subjects than in the subjects who had prepared for surgery by practicing the intervention. Control subjects also had less day-to-day stability in the phase of their rhythms following surgery. These results suggest that the intervention reduced circadian disruption following surgery and provides a way for patients to prepare themselves to resist rhythm changes.

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Areshidze, D. A., e L. V. Kakturskiy. "Circadian Rhythms of the Liver and Their Sexual Dimorphism: Current State of the Problem". Innovative Medicine of Kuban, n.º 2 (29 de abril de 2024): 108–14. http://dx.doi.org/10.35401/2541-9897-2024-9-2-108-114.

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The rhythmicity of life functioning processes at the cellular, organ, and system levels is one of the fundamental properties of living things. Among the wide range of biorhythms, circadian rhythms are the most important for mammals. In mammals, circadian rhythms coordinate a wide range of physiological processes with constantly changing environmental conditions, primarily with light conditions. Data on the characteristics of the circadian rhythms of the liver (the most important organ for maintaining homeostasis) are limited and sometimes even contradictory. We aim to analyze modern literature investigating the organization of circadian rhythms at the gene, cellular, and organ levels. Over the past decades, it has become known that disruption of the normal circadian rhythm of the liver underlies the development of several pathologies. This article highlights some aspects of the normal circadian rhythm functioning and the role of circadian dysfunction in the occurrence of specific pathologies. We also focus on the little-explored issue of sex differences in the circadian rhythms of the mammalian liver.

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Xiao, Yangbo, Ye Yuan, Mariana Jimenez, Neeraj Soni e Swathi Yadlapalli. "Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms". Proceedings of the National Academy of Sciences 118, n.º 28 (7 de julho de 2021): e2019756118. http://dx.doi.org/10.1073/pnas.2019756118.

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Circadian clocks regulate ∼24-h oscillations in gene expression, behavior, and physiology. While the genetic and molecular mechanisms of circadian rhythms are well characterized, what remains poorly understood are the intracellular dynamics of circadian clock components and how they affect circadian rhythms. Here, we elucidate how spatiotemporal organization and dynamics of core clock proteins and genes affect circadian rhythms in Drosophila clock neurons. Using high-resolution imaging and DNA-fluorescence in situ hybridization techniques, we demonstrate that Drosophila clock proteins (PERIOD and CLOCK) are organized into a few discrete foci at the nuclear envelope during the circadian repression phase and play an important role in the subnuclear localization of core clock genes to control circadian rhythms. Specifically, we show that core clock genes, period and timeless, are positioned close to the nuclear periphery by the PERIOD protein specifically during the repression phase, suggesting that subnuclear localization of core clock genes might play a key role in their rhythmic gene expression. Finally, we show that loss of Lamin B receptor, a nuclear envelope protein, leads to disruption of PER foci and per gene peripheral localization and results in circadian rhythm defects. These results demonstrate that clock proteins play a hitherto unexpected role in the subnuclear reorganization of core clock genes to control circadian rhythms, revealing how clocks function at the subcellular level. Our results further suggest that clock protein foci might regulate dynamic clustering and spatial reorganization of clock-regulated genes over the repression phase to control circadian rhythms in behavior and physiology.

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Depres-Brummer, P., F. Levi, G. Metzger e Y. Touitou. "Light-induced suppression of the rat circadian system". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 268, n.º 5 (1 de maio de 1995): R1111—R1116. http://dx.doi.org/10.1152/ajpregu.1995.268.5.r1111.

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In a constant environment, circadian rhythms persist with slightly altered period lengths. Results of studies with continuous light exposure are less clear, because of short exposure durations and single-variable monitoring. This study sought to characterize properties of the oscillator(s) controlling the rat's circadian system by monitoring both body temperature and locomotor activity. We observed that prolonged exposure of male Sprague-Dawley rats to continuous light (LL) systematically induced complete suppression of body temperature and locomotor activity circadian rhythms and their replacement by ultradian rhythms. This was preceded by a transient loss of coupling between both functions. Continuous darkness (DD) restored circadian synchronization of temperature and activity circadian rhythms within 1 wk. The absence of circadian rhythms in LL coincided with a mean sixfold decrease in plasma melatonin and a marked dampening but no abolition of its circadian rhythmicity. Restoration of temperature and activity circadian rhythms in DD was associated with normalization of melatonin rhythm. These results demonstrated a transient internal desynchronization of two simultaneously monitored functions in the rat and suggested the existence of two or more circadian oscillators. Such a hypothesis was further strengthened by the observation of a circadian rhythm in melatonin, despite complete suppression of body temperature and locomotor activity rhythms. This rat model should be useful for investigating the physiology of the circadian timing system as well as to identify agents and schedules having specific pharmacological actions on this system.

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Luo, Wenxin, Zhangzheng Yin, Mingliang Zhang, Xingguo Huang e Jie Yin. "Dietary Lactobacillus delbrueckii Affects Ileal Bacterial Composition and Circadian Rhythms in Pigs". Animals 14, n.º 3 (26 de janeiro de 2024): 412. http://dx.doi.org/10.3390/ani14030412.

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Intestinal bacteria, synchronized with diet and feeding time, exhibit circadian rhythms and anticipate host gut function; however the effect of dietary probiotics on gut bacterial diurnal rhythms remains obscure. In this study, bacteria were sequenced at 6 Zeitgeber times (ZT) from a pig model of ileal T-shaped fistula to test ileal bacterial composition and circadian rhythms after Lactobacillus delbrueckii administration. The results showed that dietary L. delbrueckii enhanced ileal bacterial α-diversity at Zeitgeber time (ZT) 16, evidenced by an increased Simpson index compared with control pigs. At the phylum level, Firmicutes was identified as the largest phyla represented in pigs, but dietary L. delbrueckii only increased the abundance of Tenericutes at ZT16. At the genus level, 11/100 genera (i.e., Lactobacillus, Enterococcus, Leptotrichia, Pediococcus, Bifidobacte, Cellulosilyticum, Desulfomicrobium, Sharpea, Eubacterium, Propionivibrio, and Aerococcus) were markedly differentiated in L. delbrueckii-fed pigs and the effect was rhythmicity-dependent. Meanwhile, dietary L. delbrueckii affected six pathways of bacterial functions, such as membrane transport, metabolism of cofactors and vitamins, cell motility, the endocrine system, signaling molecules and interaction, and the nervous system. Cosinor analysis was conducted to test bacterial circadian rhythm in pigs, while no significant circadian rhythm in bacterial α-diversity and phyla composition was observed. Lactobacillus, Terrisporobacter, and Weissella exhibited significant rhythmic fluctuation in the control pigs, which was disturbed by probiotic exposure. In addition, dietary L. delbrueckii affected circadian rhythms in ileal Romboutsia, Erysipelatoclostridium, Cellulosilyticum, and Eubacterium abundances. Dietary L. delbrueckii affected both ileal bacterial composition and circadian rhythms, which might further regulate gut function and host metabolism in pigs.

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Giannetto, C., F. Fazio, A. Assenza, G. Caola, P. Pennisi e G. Piccione. "Circadian rhythms of redox states and total locomotor activity in dairy cattle". Czech Journal of Animal Science 55, No. 5 (17 de maio de 2010): 183–89. http://dx.doi.org/10.17221/306/2009-cjas.

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We want to study the circadian rhythm of dROMs and anti-oxidative power in dairy cattle during dry period and the possible involvement of the circadian organization of rest/activity cycles in the fluctuation of redox state. For this purpose we recorded TLA in five clinically healthy Bruna Italian dairy cattle by means of an actigraphy-based data logger, Actiwatch-Mini<sup>®</sup>. Blood samples were collected every 3 hours over a 48-hour period for the assessment of free radicals (dROMs) and the antioxidant power: antioxidant barrier (Oxy-ads) and thiol-antioxidant barrier (SHp). All animals were in the same productive period (dry) and they were housed in the same stable under natural photoperiod and ambient temperature. One-way repeated measure ANOVA was used to determine a statistical significant effect of time on the studied parameters. A trigonometric statistical model was applied to characterize the main rhythmic parameters according to the single cosinor procedure. A significant effect of time on all studied parameters was observed. They showed a diurnal acrophase and different degrees of robustness of rhythms. In conclusion, we can claim that there is a synergism between the dROM circadian rhythm and the circadian rhythm of anti-oxidative power. These rhythms do not have any implication for the issue of causation with the TLA circadian rhythms.

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Delorme, Tara C., Lalit K. Srivastava e Nicolas Cermakian. "Are Circadian Disturbances a Core Pathophysiological Component of Schizophrenia?" Journal of Biological Rhythms 35, n.º 4 (5 de junho de 2020): 325–39. http://dx.doi.org/10.1177/0748730420929448.

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Schizophrenia is a multifactorial disorder caused by a combination of genetic variations and exposure to environmental insults. Sleep and circadian rhythm disturbances are a prominent and ubiquitous feature of many psychiatric disorders, including schizophrenia. There is growing interest in uncovering the mechanistic link between schizophrenia and circadian rhythms, which may directly affect disorder outcomes. In this review, we explore the interaction between schizophrenia and circadian rhythms from 2 complementary angles. First, we review evidence that sleep and circadian rhythm disturbances constitute a fundamental component of schizophrenia, as supported by both human studies and animal models with genetic mutations related to schizophrenia. Second, we discuss the idea that circadian rhythm disruption interacts with existing risk factors for schizophrenia to promote schizophrenia-relevant behavioral and neurobiological abnormalities. Understanding the mechanistic link between schizophrenia and circadian rhythms will have implications for mitigating risk to the disorder and informing the development of circadian-based therapies.

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Foster, Takesha R., Kwesi A. Dadzie, Olivia Adams e Melanie R. Gubbels-Bupp. "The Effect of Malnutrition on T-cell Circadian Rhythms". Journal of Immunology 208, n.º 1_Supplement (1 de maio de 2022): 167.07. http://dx.doi.org/10.4049/jimmunol.208.supp.167.07.

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Abstract In mammals, T-cell migration is under circadian control, likely to anticipate daily rhythms in infection risk. Glucocorticoids are a major controller of circadian processes and malnutrition is associated with increased glucocorticoid secretion. Previous studies suggest malnutrition may impart a “super-quiescent” phenotype to T-cells, enabling a greater number of naïve T-cells to survive short-term malnutrition albeit with diminished function. Thus, we hypothesize that malnourished T-cells may conserve energy by disengaging from rhythmic migration under circadian control and/or foregoing migration to reside in the bone marrow instead. To test this hypothesis, the total number of nucleated cells and naïve CD4+ and CD8+ T-cells in the blood, spleen, bone marrow, and brachial and mesenteric lymph nodes were enumerated by flow cytometry every four hours over the course of one day from control and malnourished mice. Additionally, expression levels of CD127 and CXCR4 in both T-cell populations and the concentration of glucocorticoids in the blood were assessed. A better understanding of how malnutrition affects the circadian rhythm of T-cell migration will not only help identify the mechanisms of how circadian rhythms work, but also how organisms’ circadian rhythms change in response to malnutrition. This knowledge of how malnutrition disrupts the circadian rhythm of T-cells may help improve vaccination strategies in malnourished children. Supported by NSF-MRI [DBI- 1920116] NSF -RUI [IOS-1951881]

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Man, Andy W. C., Huige Li e Ning Xia. "Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis". International Journal of Molecular Sciences 22, n.º 2 (12 de janeiro de 2021): 676. http://dx.doi.org/10.3390/ijms22020676.

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Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings have suggested strong correlations between the circadian clock and cardiovascular diseases. Desynchronization between the circadian rhythm and body metabolism contributes to the development of cardiovascular diseases including arteriosclerosis and thrombosis. Circadian rhythms are involved in controlling inflammatory processes and metabolisms, which can influence the pathology of arteriosclerosis and thrombosis. Circadian clock genes are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system. The circadian machinery in the vascular system may be a novel therapeutic target for the prevention and treatment of cardiovascular diseases. The research on circadian rhythms in cardiovascular diseases is still progressing. In this review, we briefly summarize recent studies on circadian rhythms and cardiovascular homeostasis, focusing on the circadian control of inflammatory processes and metabolisms. Based on the recent findings, we discuss the potential target molecules for future therapeutic strategies against cardiovascular diseases by targeting the circadian clock.

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Kiranmai, M. Sai, e M. Raajitha. "A COMPREHENSIVE REVIEW ON CHRONOTHERAPEUTICS". International Journal of Pharmaceutical Sciences and Medicine 8, n.º 3 (30 de março de 2023): 82–108. http://dx.doi.org/10.47760/ijpsm.2023.v08i03.007.

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Chronotherapy refers to the use of circadian, ultradian, infradian & seasonal, or other rhythmic cycles in the application of therapy. There are a number of conditions that show a circadian pattern and advantages could be taken by timing and adjusting the administration of drugs according to the circadian rhythm of the disease. Chronotherapy can be divided into three categories: time-controlled systems, in which the drug release is primarily controlled by the delivery system; stimuli-induced PDDS, in which release is controlled by the stimuli, such as the pH or intestinal enzymes; or externally regulated systems, in which release is programmed by external stimuli such as magnetism, ultrasound, electrical effect, and irradiation. The symptoms of some diseases, such as asthma, arthritis, depression, ulcer, allergic rhinitis, sleep disturbances, etc., are influenced by circadian rhythms. The biological clock of the human body is based on solar and lunar adaptations. The circadian rhythm is the primary rhythm that the biological clock adheres to. The functioning of the brain, behavior, and cognition can all be significantly impacted by circadian rhythm disruption. The use of chronotherapeutics can help with this. The recent interest that has occurred in the field of chronotherapeutics is to match the circadian rhythms of the disease for the successful treatment of the disease.

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Zhang, Xiaozhao, e Ying Jie. "Importance of Circadian Rhythms in the Ocular Surface". Biomolecules 14, n.º 7 (4 de julho de 2024): 796. http://dx.doi.org/10.3390/biom14070796.

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Circadian rhythms are a ubiquitous feature throughout the organism. Accumulating evidence suggests that the dysfunction of circadian rhythms due to genetic mutations or environmental factors contributes to the genesis and progress of multiple diseases. The physiological homeostasis of the ocular surface, like any other tissue or organ, is also orchestrated by circadian rhythms. In this review, we summarize the molecular clocks and the expression of clock-controlled genes in the mammalian ocular surface. Based on the circadian expression of these genes, we conclude the diurnal oscillations of cellular biological activities in the mammalian ocular surface. Moreover, we evaluate the factors entraining circadian oscillators in the ocular surface. Finally, we further discuss the latest development of the close correlation between circadian rhythms and ocular health. Briefly, this review aimed to synthesize the previous studies to aid in understanding the importance of circadian rhythms in the ocular surface and the possible opportunities for circadian rhythm-based interventional strategies to restore the homeostasis of the ocular surface.

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Inouye, S. T., J. S. Takahashi, F. Wollnik e F. W. Turek. "Inhibitor of protein synthesis phase shifts a circadian pacemaker in mammalian SCN". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 255, n.º 6 (1 de dezembro de 1988): R1055—R1058. http://dx.doi.org/10.1152/ajpregu.1988.255.6.r1055.

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The suprachiasmatic nucleus (SCN) of the hypothalamus contains a circadian pacemaker that regulates many circadian rhythms in mammals. Experimental work in microorganisms and invertebrates suggests that protein synthesis is required for the function of the circadian oscillator, and recent experiments in golden hamsters suggest an acute inhibition of protein synthesis can induce phase shifts in a mammalian circadian pacemaker. To determine whether protein synthesis in the SCN region is involved in the generation of circadian rhythms in mammals, a protein synthesis inhibitor, anisomycin, was microinjected into the SCN region, and the effect on the circadian rhythm of locomotor activity of hamsters was measured. A single injection of anisomycin into the SCN region induced phase shifts in the circadian activity rhythm that varied systematically as a function of the phase of injection within the circadian cycle. These results suggest that protein synthesis may be involved in the generation of circadian rhythms in mammals and that the anatomic site of action of anisomycin is within the hypothalamic suprachiasmatic region.

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Kubištová, Aneta, Veronika Spišská, Lucie Petrželková, Leona Hrubcová, Simona Moravcová, Lenka Maierová e Zdeňka Bendová. "Constant Light in Critical Postnatal Days Affects Circadian Rhythms in Locomotion and Gene Expression in the Suprachiasmatic Nucleus, Retina, and Pineal Gland Later in Life". Biomedicines 8, n.º 12 (7 de dezembro de 2020): 579. http://dx.doi.org/10.3390/biomedicines8120579.

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The circadian clock regulates bodily rhythms by time cues that result from the integration of genetically encoded endogenous rhythms with external cycles, most potently with the light/dark cycle. Chronic exposure to constant light in adulthood disrupts circadian system function and can induce behavioral and physiological arrhythmicity with potential clinical consequences. Since the developing nervous system is particularly vulnerable to experiences during the critical period, we hypothesized that early-life circadian disruption would negatively impact the development of the circadian clock and its adult function. Newborn rats were subjected to a constant light of 16 lux from the day of birth through until postnatal day 20, and then they were housed in conditions of L12 h (16 lux): D12 h (darkness). The circadian period was measured by locomotor activity rhythm at postnatal day 60, and the rhythmic expressions of clock genes and tissue-specific genes were detected in the suprachiasmatic nuclei, retinas, and pineal glands at postnatal days 30 and 90. Our data show that early postnatal exposure to constant light leads to a prolonged endogenous period of locomotor activity rhythm and affects the rhythmic gene expression in all studied brain structures later in life.

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Bebas, Piotr, Bronislaw Cymborowski e Jadwiga M. Giebultowicz. "Circadian rhythm of acidification in insect vas deferens regulated by rhythmic expression of vacuolar H+-ATPase". Journal of Experimental Biology 205, n.º 1 (1 de janeiro de 2002): 37–44. http://dx.doi.org/10.1242/jeb.205.1.37.

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SUMMARY Recent studies have demonstrated that the peripheral tissues of vertebrates and invertebrates contain circadian clocks; however, little is known about their functions and the rhythmic outputs that they generate. To understand clock-controlled rhythms at the cellular level, we investigated a circadian clock located in the reproductive system of a male moth (the cotton leaf worm Spodoptera littoralis) that is essential for the production of fertile spermatozoa. Previous work has demonstrated that spermatozoa are released from the testes in a daily rhythm and are periodically stored in the upper vas deferens (UVD). In this paper, we demonstrate a circadian rhythm in pH in the lumen of the UVD, with acidification occurring during accumulation of spermatozoa in the lumen. The daily rhythm in pH correlates with a rhythmic increase in the expression of a proton pump, the vacuolar H+-ATPase (V-ATPase), in the apical portion of the UVD epithelium. Rhythms in pH and V-ATPase persist in light/dark cycles and constant darkness, but are abolished in constant light, a condition that disrupts clock function and renders spermatozoa infertile. Treatment with colchicine impairs the migration of V-ATPase-positive vesicles to the apical cell membrane and abates the acidification of the UVD lumen. Bafilomycin, a selective inhibitor of V-ATPase activity, also prevents the decline in luminal pH. We conclude that the circadian clock generates a rhythm of luminal acidification by regulating the levels and subcellular distribution of V-ATPase in the UVD epithelium. Our data provide the first evidence for circadian control of V-ATPase, the fundamental enzyme that provides the driving force for numerous secondary transport processes. They also demonstrate how circadian rhythms displayed by individual cells contribute to the synchrony of physiological processes at the organ level.

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Deprés-Brummer, Petra, Philippe Bourin, Nicole Pages, Gérard Metzger e Francis Lévi. "Persistent T lymphocyte rhythms despite suppressed circadian clock outputs in rats". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 273, n.º 6 (1 de dezembro de 1997): R1891—R1899. http://dx.doi.org/10.1152/ajpregu.1997.273.6.r1891.

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Circadian rhythms in circulating leukocyte and lymphocyte counts persisted with halved amplitudes in constant light (LL) of 300 lx intensity for 8 wk, whereas circadian rhythms in body temperature, locomotor activity, and plasma catecholamines were completely suppressed. Subsequent exposure to constant darkness (DD) normalized all circadian rhythms within 2 wk. Rhythms in circulating T lymphocyte subsets were studied in LL or DD using double labeling with monoclonal antibodies and flow cytometry. Circadian rhythms were suppressed for leukocytes and lymphocytes but were maintained for both T helper cells (Th) and T cytotoxic cells (Ts) lymphocytes after 11 wk in LL. A group 24-h rhythm was only validated for total lymphocytes after 16 wk in LL. However, individual total, Th, and Ts lymphocytes maintained their usual respective phase relationships in each rat. The alteration of immune cell circulatory rhythms likely stemmed from a progressive loss of circadian synchronization among rats kept in LL. Conversely, after 11 or 16 wk in DD, leukocytes and lymphocyte subsets circadian rhythms were maintained. Thus catecholamines do not drive circulatory T cell rhythms. The loss of coupling between T lymphocyte rhythms and three major outputs of the circadian system further supports the hypothesis of an independent immunologic oscillator.

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Mauvieux, Benoît, Laurent Gouthière, Bruno Sesboüe e Damien Davenne. "Etudes comparées des rythmes circadiens et reflet actimétrique du sommeil de sportifs et de sédentaires en poste régulier de nuit". Canadian Journal of Applied Physiology 28, n.º 6 (1 de dezembro de 2003): 831–87. http://dx.doi.org/10.1139/h03-062.

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The aim of this study was to show the resistance and persistence of the circadian rhythm of temperature (T°) and the sleep quality of athletic subjects and sedentary subjects engaged in night work, and attempt to explain the mechanisms that influence these differences. The effects of night work on biological rhythms have been studied extensively in the past few years. The contradictory situations for the night workers irrefutably affect their biological systems. Individuals with high amplitudes in their circadian rhythms have been found to be more tolerant to shift work and this results in a greater stability of circadian rhythms. This seems beneficial in coping with frequent rhythm disturbances. The physical training program seems to improve several mechanisms of the human biological system: amplitudes of circadian rhythms were increased and the circadian rhythm period was more resistant to an environment extreme (night work, shift work, sleep deprivation, or jet lag). To test this hypothesis, athletes and sedentary subjects who were engaged in regular night work were selected in the PSA Peugeot Citroën Automobiles Group in French Normandy country. The circadian rhythm of the T° for both groups was studied with a specific methodology and with extensive spectral analysis, especially the spectral elliptic inverse method. Study models of the rhythm of the T° were determined and the characteristic parameters were exposed. A complementary actigraphic study showed the physical training program's effects on the sleep quality. The results revealed a large stability in the rhythm of circadian variation of T° for the athletes: the amplitude was still large but for the sedentary subjects the amplitude of the T° decreased and it was difficult to adjust a period on the rhythm of T°. The stability and persistent quality of the athletes' circadian rhythm was confirmed. We observed that the actigraphic sleep was greater for athletes than for sedentary subjects, and the acrophase time for the athletes was later than for the sedentary subjects during the night shift. Key words: circadian rhythm of temperature, actimetry, sleep quality, exercise, night work, methodology of rhythms analysis

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Menaker, M. "CIRCADIAN RHYTHMS: Circadian Photoreception". Science 299, n.º 5604 (10 de janeiro de 2003): 213–14. http://dx.doi.org/10.1126/science.1081112.

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Shevelev, Oleg A., Marina V. Petrova, Mikhail Yu Yuriev, Elias M. Mengistu, Inna Z. Kostenkova, Maria A. Zhdanova, Sergey G. Vesnin e Igor Goryanin. "Study of Brain Circadian Rhythms in Patients with Chronic Disorders of Consciousness and Healthy Individuals Using Microwave Radiometry". Diagnostics 12, n.º 8 (22 de julho de 2022): 1777. http://dx.doi.org/10.3390/diagnostics12081777.

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The study of circadian rhythms in the human body using temperature measurements is the most informative way to assess the viability of the body’s rhythm-organizing systems. Pathological processes can affect circadian rhythm dynamics in damaged organs. Severe brain damage that caused the development of disorders of consciousness (DOC) (strokes, traumatic brain injury) disrupts the activity of central oscillators, by directly damaging or destroying the periphery links, and the level of preservation of circadian rhythms and the dynamics of their recovery can be informative diagnostic criteria for patient’s condition assessment. This study examined 23 patients with DOC by using a non-invasive method for obtaining body and cerebral cortex temperature to compare with healthy controls. Measurements were made with a 4 h interval for 52 h beginning at 08:00 on day 1 and ending at 08:00 on day 3. The profile of patients with DOC showed complete disruption compared to healthy controls with rhythmic patterns. The results indicate that the mechanisms for maintaining brain circadian rhythms are different from general homeostasis regulation of the body. Use of microwave radio thermometry for the identification of rehabilitation potential in patients with DOC is a promising area of investigation.

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Jaeger, Cassie, Ali Q. Khazaal, Canxin Xu, Mingwei Sun, Stacey L. Krager e Shelley A. Tischkau. "Aryl Hydrocarbon Receptor Deficiency Alters Circadian and Metabolic Rhythmicity". Journal of Biological Rhythms 32, n.º 2 (27 de março de 2017): 109–20. http://dx.doi.org/10.1177/0748730417696786.

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PAS domain–containing proteins can act as environmental sensors that capture external stimuli to allow coordination of organismal physiology with the outside world. These proteins permit diverse ligand binding and heterodimeric partnership, allowing for varied combinations of PAS-dependent protein-protein interactions and promoting crosstalk among signaling pathways. Previous studies report crosstalk between circadian clock proteins and the aryl hydrocarbon receptor (AhR). Activated AhR forms a heterodimer with the circadian clock protein Bmal1 and thereby functionally inhibits CLOCK/Bmal1 activity. If physiological activation of AhR through naturally occurring, endogenous ligands inhibits clock function, it seems plausible to hypothesize that decreased AhR expression releases AhR-induced inhibition of circadian rhythms. Because both AhR and the clock are important regulators of glucose metabolism, it follows that decreased AhR will also alter metabolic function. To test this hypothesis, rhythms of behavior, metabolic outputs, and circadian and metabolic gene expression were measured in AhR-deficient mice. Genetic depletion of AhR enhanced behavioral responses to changes in the light-dark cycle, increased rhythmic amplitude of circadian clock genes in the liver, and altered rhythms of glucose and insulin. This study provides evidence of AhR-induced inhibition that influences circadian rhythm amplitude.

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Meléndez-Fernández, O. Hecmarie, Jennifer A. Liu e Randy J. Nelson. "Circadian Rhythms Disrupted by Light at Night and Mistimed Food Intake Alter Hormonal Rhythms and Metabolism". International Journal of Molecular Sciences 24, n.º 4 (8 de fevereiro de 2023): 3392. http://dx.doi.org/10.3390/ijms24043392.

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Availability of artificial light and light-emitting devices have altered human temporal life, allowing 24-hour healthcare, commerce and production, and expanding social life around the clock. However, physiology and behavior that evolved in the context of 24 h solar days are frequently perturbed by exposure to artificial light at night. This is particularly salient in the context of circadian rhythms, the result of endogenous biological clocks with a rhythm of ~24 h. Circadian rhythms govern the temporal features of physiology and behavior, and are set to precisely 24 h primarily by exposure to light during the solar day, though other factors, such as the timing of meals, can also affect circadian rhythms. Circadian rhythms are significantly affected by night shift work because of exposure to nocturnal light, electronic devices, and shifts in the timing of meals. Night shift workers are at increased risk for metabolic disorder, as well as several types of cancer. Others who are exposed to artificial light at night or late mealtimes also show disrupted circadian rhythms and increased metabolic and cardiac disorders. It is imperative to understand how disrupted circadian rhythms alter metabolic function to develop strategies to mitigate their negative effects. In this review, we provide an introduction to circadian rhythms, physiological regulation of homeostasis by the suprachiasmatic nucleus (SCN), and SCN-mediated hormones that display circadian rhythms, including melatonin and glucocorticoids. Next, we discuss circadian-gated physiological processes including sleep and food intake, followed by types of disrupted circadian rhythms and how modern lighting disrupts molecular clock rhythms. Lastly, we identify how disruptions to hormones and metabolism can increase susceptibility to metabolic syndrome and risk for cardiovascular diseases, and discuss various strategies to mitigate the harmful consequences associated with disrupted circadian rhythms on human health.

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McGoogan, Jennifer M., e Vincent M. Cassone. "Circadian regulation of chick electroretinogram: effects of pinealectomy and exogenous melatonin". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 277, n.º 5 (1 de novembro de 1999): R1418—R1427. http://dx.doi.org/10.1152/ajpregu.1999.277.5.r1418.

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Melatonin is an important component of the avian circadian system. This study investigates the effects of pinealectomy (Pin-X) and melatonin implantation (Mel) on electroretinogram (ERG) rhythms in chicks. Feeding rhythms were monitored to obtain a phase reference for ERG recordings. Pin-X and Mel had little or no effect on feeding rhythms. Sham-operated Pin-X and vehicle implantation had no effect on ERG rhythms in the light-dark (LD) cycle or constant darkness (DD). ERG a- and b-wave amplitudes were higher during the day than during the night. The a- and b-wave implicit times were shorter during the day than during the night. a-Wave sensitivity was higher during the night than during the day, whereas b-wave sensitivity was not rhythmic. Pin-X abolished the circadian rhythm of b-wave amplitude and implicit time in DD but had no effect on a-wave rhythmicity. Mel abolished the rhythm of b-wave amplitude and of a- and b-wave implicit time in DD. Neither treatment affected ERG in LD. These results suggest that the circadian system regulates rhythmic visual function in the retina at least partially through Mel. The role played by the pineal gland and Mel may be specific to some physiological modalities (e.g., vision) while not influencing others (e.g., feeding).

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Turek, Fred W. "Circadian Rhythms". Hormone Research in Paediatrics 49, n.º 3-4 (1998): 109–13. http://dx.doi.org/10.1159/000023155.

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SAMPLES, JULIE F., MARY LOU VAN COTT, CHARLENE LONG, IMOGENE M. KING e ANGELA KERSENBROCK. "Circadian Rhythms". Nursing Research 34, n.º 6 (novembro de 1985): 377???379. http://dx.doi.org/10.1097/00006199-198511000-00021.

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Hines, P. J. "Circadian Rhythms". Science Signaling 7, n.º 319 (1 de abril de 2014): ec87-ec87. http://dx.doi.org/10.1126/scisignal.2005313.

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Eichner, E. Randy. "Circadian Rhythms". Physician and Sportsmedicine 22, n.º 10 (outubro de 1994): 82–93. http://dx.doi.org/10.1080/00913847.1994.11710504.

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Lakin-Thomas, Patricia L. "Circadian rhythms". Trends in Genetics 16, n.º 3 (março de 2000): 135–42. http://dx.doi.org/10.1016/s0168-9525(99)01945-9.

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Persson, Pontus B., e Anja Bondke Persson. "Circadian rhythms". Acta Physiologica 225, n.º 1 (4 de dezembro de 2018): e13220. http://dx.doi.org/10.1111/apha.13220.

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Merrow, Martha. "Circadian rhythms". FEBS Letters 585, n.º 10 (28 de abril de 2011): 1383. http://dx.doi.org/10.1016/j.febslet.2011.04.055.

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Vaze, Koustubh M., e Vijay Kumar Sharma. "Circadian rhythms". Resonance 18, n.º 7 (julho de 2013): 662–72. http://dx.doi.org/10.1007/s12045-013-0085-4.

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Nikhil, K. L., e Vijay Kumar Sharma. "Circadian rhythms". Resonance 18, n.º 9 (setembro de 2013): 832–44. http://dx.doi.org/10.1007/s12045-013-0107-2.

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Vaze, Koustubh M., e Vijay Kumar Sharma. "Circadian rhythms". Resonance 18, n.º 11 (novembro de 2013): 1032–50. http://dx.doi.org/10.1007/s12045-013-0129-9.

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Vaze, Koustubh M., K. L. Nikhil e Vijay Kumar Sharma. "Circadian rhythms". Resonance 19, n.º 2 (fevereiro de 2014): 175–89. http://dx.doi.org/10.1007/s12045-014-0020-3.

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Aronson, B. "Circadian rhythms". Brain Research Reviews 18, n.º 3 (dezembro de 1993): 315–33. http://dx.doi.org/10.1016/0165-0173(93)90015-r.

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McFadden, E. R. "Circadian rhythms". American Journal of Medicine 85, n.º 1 (julho de 1988): 2–5. http://dx.doi.org/10.1016/0002-9343(88)90230-6.

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Abbott, Sabra M., e Phyllis C. Zee. "Circadian Rhythms". Neurologic Clinics 37, n.º 3 (agosto de 2019): 601–13. http://dx.doi.org/10.1016/j.ncl.2019.04.004.

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Thompson, Chris. "Circadian Rhythms". British Journal of Psychiatry 146, n.º 5 (maio de 1985): 557–58. http://dx.doi.org/10.1192/bjp.146.5.557.

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Chan, Ming-Cheng, Peter M. Spieth, Kieran Quinn, Matteo Parotto, Haibo Zhang e Arthur S. Slutsky. "Circadian rhythms". Critical Care Medicine 40, n.º 1 (janeiro de 2012): 246–53. http://dx.doi.org/10.1097/ccm.0b013e31822f0abe.

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Visan, Ioana. "Circadian rhythms". Nature Immunology 13, n.º 10 (18 de setembro de 2012): 946. http://dx.doi.org/10.1038/ni.2441.

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Arechiga, Hugo. "Circadian rhythms". Current Opinion in Neurobiology 3, n.º 6 (dezembro de 1993): 1005–10. http://dx.doi.org/10.1016/0959-4388(93)90174-w.

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Yin, Yueci. "Study on the Correlation Between the Genetics of Circadian Rhythms and Neurodegenerative Diseases". BIO Web of Conferences 124 (2024): 02010. http://dx.doi.org/10.1051/bioconf/202412402010.

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In the context of global population aging, the increasing incidence of neurodegenerative diseases presents a serious challenge to healthcare systems worldwide. This article meticulously reviews the genetic links between circadian rhythms and neurodegenerative diseases, revealing their complex interactions and potential implications for disease management and prevention. The foundational mechanisms of circadian rhythms, the roles of related genes, and the genetic basis of neurodegenerative diseases are explored. The relationship between circadian rhythm gene variations and neurodegenerative diseases is thoroughly discussed, and the risks posed by disruptions in the Circadian Rhythms are elucidated. Understanding the influence of circadian rhythms on neurodegenerative diseases may provide new directions for the development of therapeutic strategies, marking a step towards alleviating the burden of these diseases.

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von Gall, Charlotte. "The Effects of Light and the Circadian System on Rhythmic Brain Function". International Journal of Molecular Sciences 23, n.º 5 (3 de março de 2022): 2778. http://dx.doi.org/10.3390/ijms23052778.

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Life on earth has evolved under the influence of regularly recurring changes in the environment, such as the 24 h light/dark cycle. Consequently, organisms have developed endogenous clocks, generating 24 h (circadian) rhythms that serve to anticipate these rhythmic changes. In addition to these circadian rhythms, which persist in constant conditions and can be entrained to environmental rhythms, light drives rhythmic behavior and brain function, especially in nocturnal laboratory rodents. In recent decades, research has made great advances in the elucidation of the molecular circadian clockwork and circadian light perception. This review summarizes the role of light and the circadian clock in rhythmic brain function, with a focus on the complex interaction between the different components of the mammalian circadian system. Furthermore, chronodisruption as a consequence of light at night, genetic manipulation, and neurodegenerative diseases is briefly discussed.

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Smolensky, Michael H. "Circadian Rhythms in Medicine". CNS Spectrums 6, n.º 6 (junho de 2006): 467–82. http://dx.doi.org/10.1017/s1092852900008026.

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AbstractCircadian (24-hour) rhythms are important to the practice of medicine. The phasing and amplitude of key physiologic and biochemical circadian rhythms contribute to predict in-time patterns in the manifestation and exacerbation of most medical conditions. Moreover, body rhythms can significantly affect responses of patients to diagnostic tests and medications. Rhythmicity in the pathophysiology of medical conditions is the rationale for chronotherapeutics—the purposeful variance of the concentration of medicines in synchrony with biological rhythm-determinants of disease activity—to optimize treatment outcomes. This article discusses the concept of biological time structure and its relevance to the practice of medicine, with a focus on neurologic issues.

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Dearry, A., e R. B. Barlow. "Circadian rhythms in the green sunfish retina." Journal of General Physiology 89, n.º 5 (1 de maio de 1987): 745–70. http://dx.doi.org/10.1085/jgp.89.5.745.

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We investigated the occurrence of circadian rhythms in retinomotor movements and retinal sensitivity in the green sunfish, Lepomis cyanellus. When green sunfish were kept in constant darkness, cone photoreceptors exhibited circadian retinomotor movements; rod photoreceptors and retinal pigment epithelium (RPE) pigment granules did not. Cones elongated during subjective night and contracted during subjective day. These results corroborate those of Burnside and Ackland (1984. Investigative Ophthalmology and Visual Science. 25:539-545). Electroretinograms (ERGs) recorded in constant darkness in response to dim flashes (lambda = 640 nm) exhibited a greater amplitude during subjective night than during subjective day. The nighttime increase in the ERG amplitude corresponded to a 3-10-fold increase in retinal sensitivity. The rhythmic changes in the ERG amplitude continued in constant darkness with a period of approximately 24 h, which indicates that the rhythm is generated by a circadian oscillator. The spectral sensitivity of the ERG recorded in constant darkness suggests that cones contribute to retinal responses during both day and night. Thus, the elongation of cone myoids during the night does not abolish the response of the cones. To examine the role of retinal efferents in generating retinal circadian rhythms, we cut the optic nerve. This procedure did not abolish the rhythms of retinomotor movement or of the ERG amplitude, but it did reduce the magnitude of the nighttime phases of both rhythms. Our results suggest that more than one endogenous oscillator regulates the retinal circadian rhythms in green sunfish. Circadian signals controlling the rhythms may be either generated within the eye or transferred to the eye via a humoral pathway.

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Thurley, Kevin, Christopher Herbst, Felix Wesener, Barbara Koller, Thomas Wallach, Bert Maier, Achim Kramer e Pål O. Westermark. "Principles for circadian orchestration of metabolic pathways". Proceedings of the National Academy of Sciences 114, n.º 7 (3 de fevereiro de 2017): 1572–77. http://dx.doi.org/10.1073/pnas.1613103114.

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Circadian rhythms govern multiple aspects of animal metabolism. Transcriptome-, proteome- and metabolome-wide measurements have revealed widespread circadian rhythms in metabolism governed by a cellular genetic oscillator, the circadian core clock. However, it remains unclear if and under which conditions transcriptional rhythms cause rhythms in particular metabolites and metabolic fluxes. Here, we analyzed the circadian orchestration of metabolic pathways by direct measurement of enzyme activities, analysis of transcriptome data, and developing a theoretical method called circadian response analysis. Contrary to a common assumption, we found that pronounced rhythms in metabolic pathways are often favored by separation rather than alignment in the times of peak activity of key enzymes. This property holds true for a set of metabolic pathway motifs (e.g., linear chains and branching points) and also under the conditions of fast kinetics typical for metabolic reactions. By circadian response analysis of pathway motifs, we determined exact timing separation constraints on rhythmic enzyme activities that allow for substantial rhythms in pathway flux and metabolite concentrations. Direct measurements of circadian enzyme activities in mouse skeletal muscle confirmed that such timing separation occurs in vivo.

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