Drug efficacy - considering circadian rhythms and time of day

1994 ◽  
Vol &NA; (943) ◽  
pp. 19
Author(s):  
&NA;
Keyword(s):  
Circadian Rhythms ◽  
Drug Efficacy ◽  
Time Of Day

scholarly journals MON-015 Pregnancy Adapts Circadian Rhythms in the Reproductive Axis: Impact on Labor Regulating Drug Efficacy

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Hanne Mette Hoffmann ◽  
Thu V Duong ◽  
Duong Nguyen ◽  
Asad Muhammed ◽  
Alexandra M Yaw
Keyword(s):  
Transcription Factors ◽  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Ex Vivo ◽  
Drug Efficacy ◽  
Time Of Day ◽  
Receptor Expression ◽  
Behavioral Activity ◽  
Reproductive Tissues ◽  
Reproductive Axis

Abstract Molecular and behavioral timekeeping is regulated by the circadian system represented on the cellular level by clock transcription factors, including Period2 (PER2), Bmal1, Clock and Cry. These transcription factors drive a daily ~24h rhythm in gene expression leading to tissue specific receptor expression optimizing sensitivity to hormones and drugs dependent on the time of day. To synchronize circadian rhythms in the body to the time of day, the brain’s suprachiasmatic nucleus (SCN) translates environmental light information into neuronal and endocrine signals allowing circadian rhythm synchrony. Despite the critical role of circadian rhythms in fertility, it remains unknown how circadian rhythms change within reproductive tissues during pregnancy, and how these adaptations might impact drug efficacy. Monitoring wheel-running patterns in circadian PER2::luciferase (PER2::LUC) reporter mice, we confirmed that pregnancy is associated with reductions of activity and identified a correlation between delayed onset of behavioral activity during late pregnancy and ex vivo SCN PER2::LUC period, whereas no correlation between arcuate nucleus PER2::LUC rhythms was identified. The time of day of peak PER2::LUC expression provides a time-stamp as to the circadian phase of a tissue. Pregnancy impacted circadian synchrony in the reproductive axis, with the most dramatic change within the uterus. To understand how circadian rhythms responded to input during pregnancy, we performed a pharmacology study and found that circadian rhythm generation in the uterus responded differentially to hormones regulating pregnancy and labor depending on gestational age and the time of day of drug administration. To test for functional changes in uterine contraction capacity, we recorded ex vivo uterine contractions. Our preliminary data reveal a circadian change in uterine function in the mouse, which impacted labor regulating drug efficacy depending on the time of day. Together our data show that pregnancy is associated with behavioral changes in locomotor activity patterns, as well as adaptations in phase-relationships in reproductive tissues. Our chrono-pharmacology study indicates that a better understanding of labor-regulating drug efficacy can potentially allow increased efficacy of currently used drugs in the clinic to both induce labor as well as halt preterm labor.

296 Sex differences in sleep and wakefulness of police officers working shifts: evidence from a field study

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A118-A118
Author(s):  
Gabriela Caetano ◽  
Laura Kervezee ◽  
Fernando Gonzales-Aste ◽  
Philippe Boudreau ◽  
Diane Boivin
Keyword(s):  
Sex Differences ◽  
Circadian Rhythms ◽  
Shift Work ◽  
Police Officers ◽  
Field Studies ◽  
Time Of Day ◽  
Cycle Phase ◽  
Shift Workers ◽  
Work Related ◽  
Time Awake

Abstract Introduction National reports of work-related injuries found the excess risk of work injury attributed to shift work to be significantly higher among women. The Working Time Society (WTS) concluded that male sex is one of the few factors that is “consistently associated with perceived or actual shift work tolerance”. However, it is unclear if physiological parameters are involved. Laboratory-controlled studies report sex differences in circadian rhythms (body temperature, melatonin). In sleep deprivation protocols, alertness and cognitive performances were affected by sex, menstrual cycle phase and hormonal contraceptives [HC] use. Nevertheless, field studies that compare male and female shift workers are scarce. Methods An observational study including 76 police officers working on patrol: 56 males and 20 females (11 using [HC], 6 not using [non-HC] and 3 with unknown use of hormonal contraception) aged 32.0 ± 5.3 years. Participants were followed throughout a month-long work cycle (1,457 morning, evening, night, or other shifts, plus rest days). They filled out time-stamped questionnaires (Samn-Perelli, KSS, Visual Analogue Scales, ~5/day; sleep and work-related information, ~1–2/day), completed 5-min Psychomotor Vigilance Tasks (PVT, ~2/day), and wore an actigraph to collect activity data. Linear mixed-effects models were used to analyze the effects of group, time awake and time-of-day on fatigue, sleepiness, alertness, mood and PVT measures. Results Self-reported measures and psychomotor performance significantly varied with time awake and time-of-day. Fatigue and sleepiness levels were significantly higher among female compared to male police officers, both with time awake and across the 24-h day. These variations were similar between non-HC females and the other groups. Compared to males, HC females were more fatigued and less alert, both with time awake and across the 24-h day, and sleepier with time awake. Having children at home did not explain these differences. Conclusion The results of this study expand our knowledge on the sex differences in the sleep and circadian physiology and demonstrate a critical effect of HC on women fatigue, sleepiness and alertness when working shifts. Sex and hormonal parameters must be considered in occupational medicine as well as in future laboratory and field studies on shift workers and circadian rhythms. Support (if any) IRSST, FRQS.

scholarly journals Daily rhythms of both host and parasite affect antimalarial drug efficacy

2021 ◽  
Author(s):  
Alíz T Y Owolabi ◽  
Sarah E Reece ◽  
Petra Schneider
Keyword(s):  
Drug Treatment ◽  
Developmental Stage ◽  
Antimalarial Drug ◽  
Drug Sensitivity ◽  
Drug Efficacy ◽  
Time Of Day ◽  
Parasite Development ◽  
Daily Rhythms ◽  
Parasite Plasmodium

Abstract Background and objectives Circadian rhythms contribute to treatment efficacy in several non-communicable diseases. However, chronotherapy (administering drugs at a particular time-of-day) against infectious diseases has been overlooked. Yet, the daily rhythms of both hosts and disease-causing agents can impact the efficacy of drug treatment. We use the rodent malaria parasite Plasmodium chabaudi, to test if the daily rhythms of hosts, parasites, and their interactions, affect sensitivity to the key antimalarial, artemisinin. Methodology Asexual malaria parasites develop rhythmically in the host’s blood, in a manner timed to coordinate with host daily rhythms. Our experiments coupled or decoupled the timing of parasite and host rhythms, and we administered artemisinin at different times of day to coincide with when parasites were either at an early (ring) or later (trophozoite) developmental stage. We quantified the impacts of parasite developmental stage, and alignment of parasite and host rhythms, on drug sensitivity. Results We find that rings were less sensitive to artemisinin than trophozoites, and this difference was exacerbated when parasite and host rhythms were misaligned, with little direct contribution of host time-of-day on its own. Furthermore, the blood concentration of haem at the point of treatment correlated positively with artemisinin efficacy but only when parasite and host rhythms were aligned. Conclusions and implications Parasite rhythms influence drug sensitivity in vivo. The hitherto unknown modulation by alignment between parasite and host daily rhythms suggests that disrupting the timing of parasite development could be a novel chronotherapeutic approach. Lay Summary We reveal that chronotherapy (providing medicines at a particular time-of-day) could improve treatment for malaria infections. Specifically, parasites’ developmental stage at the time of treatment and the coordination of timing between parasite and host both affect how well antimalarial drug treatment works.

scholarly journals Time-of-day-dependent responses of cyanobacterial cellular viability against oxidative stress

2019 ◽  
Author(s):  
Kenya Tanaka ◽  
Ginga Shimakawa ◽  
Shuji Nakanishi
Keyword(s):  
Oxidative Stress ◽  
Circadian Rhythms ◽  
Cell Viability ◽  
Circadian Clock ◽  
Stress Tolerance ◽  
Time Of Day ◽  
Circadian Oscillation ◽  
Subjective Time ◽  
Rhythmic Pattern ◽  
Oxidative Stress Tolerance

AbstractAs an adaptation to periodic fluctuations of environmental light, photosynthetic organisms have evolved a circadian clock. Control by the circadian clock of many cellular physiological functions, including antioxidant enzymes, metabolism and the cell cycle, has attracted attention in the context of oxidative stress tolerance. However, since each physiological function works in an integrated manner to deal with oxidative stress, whether or not cell responses to oxidative stress are under circadian control remains an open question. In fact, circadian rhythms of oxidative stress tolerance have not yet been experimentally demonstrated. In the present work, we applied an assay using methyl viologen (MV), which generates reactive oxygen species (ROS) under light irradiation, and experimentally verified the circadian rhythms of oxidative stress tolerance in photosynthetic cells of the cyanobacterium Synechococcus elongatus PCC7942, a standard model species for investigation of the circadian clock. Here, we report that ROS generated by MV treatment causes damage to stroma components and not to the photosynthetic electron transportation chain, leading to reduced cell viability. The degree of decrease in cell viability was dependent on the subjective time at which oxidative stress was applied. Thus, oxidative stress tolerance was shown to exhibit circadian rhythms. In addition, the rhythmic pattern of oxidative stress tolerance disappeared in mutant cells lacking the essential clock genes. Notably, ROS levels changed periodically, independent of the MV treatment. Thus, we demonstrate for the first time that in cyanobacterial cells, oxidative stress tolerance shows circadian oscillation.

scholarly journals Free-running circadian breathing rhythms are eliminated by suprachiasmatic nucleus lesion

2020 ◽  
Vol 129 (1) ◽  
pp. 49-57
Author(s):  
Benton S. Purnell ◽  
Gordon F. Buchanan
Keyword(s):  
Sleep Apnea ◽  
Circadian Rhythms ◽  
Suprachiasmatic Nucleus ◽  
Time Of Day ◽  
Sudden Unexpected Death ◽  
Constant Darkness ◽  
Unexpected Death ◽  
Treatment And Prevention ◽  
Free Running

It has long been appreciated that breathing is altered by time of day. This study demonstrates that rhythmicity in breathing persists in constant darkness but is dependent on the suprachiasmatic nucleus in the hypothalamus. Understanding circadian rhythms in breathing may be important for the treatment and prevention of diseases such as sleep apnea and sudden unexpected death in epilepsy.

scholarly journals INTEREST GROUP SESSION—SLEEP, CIRCADIAN RHYTHMS AND AGING INTEREST GROUP: SLEEP, PHYSICAL ACTIVITY, AND BRAIN AGING

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S402-S403
Author(s):  
Christopher N Kaufmann ◽  
Katie L Stone
Keyword(s):  
Circadian Rhythms ◽  
Sleep Disturbance ◽  
Interest Group ◽  
Cognitive Aging ◽  
Brain Aging ◽  
Disease Risk ◽  
Activity Patterns ◽  
Time Of Day ◽  
Daytime Activity ◽  
Dementia Prevention

Abstract As the US population ages, the prevalence of Alzheimer’s Disease (AD) and related dementias is expected to increase, making dementia prevention efforts a major public health priority. Impaired sleep and circadian rhythms, along with other lifestyle factors, have emerged as important modifiable disease risk factors—recent studies demonstrate the importance of sleep in preventing the development of key biomarkers for AD/dementia pathology. In this symposium, we will highlight findings on the associations of sleep, circadian rhythm disruptions, and daytime activity patterns on development of cognitive decline and dementia, exploring not only the mechanisms driving these associations, but the potential impact of sleep and lifestyle interventions in promoting healthy brain aging. The symposium consists of four presentations which use data from large national cohort studies. First, we will present analyses on patterns of 24-hour (circadian) activity rhythms (e.g., usual time of day for peak activity, regularity of circadian patterns) and incident dementia risk. The second presentation will present findings pertaining to understanding the link between sleep disturbance and inflammation (a substantial contributor to cognitive aging). The third will examine whether detailed daytime activity patterns associate with imaging-based brain volumes, independent of sleep disturbance. The final presentation will explore whether initiation of sleep disorder treatments may have the potential to change trajectories of cognitive performance as individuals age. Overall, the symposium will highlight the importance of sleep and activity patterns to brain health and stimulate discussion about improving sleep and circadian disruption as a target for dementia prevention efforts.

scholarly journals Physiological responses to food intake throughout the day

2014 ◽  
Vol 27 (1) ◽  
pp. 107-118 ◽  
Author(s):  
Jonathan D. Johnston
Keyword(s):  
Circadian Rhythms ◽  
Unmet Need ◽  
Time Of Day ◽  
Research Field ◽  
Biological Data ◽  
Model Systems ◽  
Physiological Processes ◽  
Circadian Timing System ◽  
Glucose Profiles ◽  
Molecular Components

Circadian rhythms act to optimise many aspects of our biology and thereby ensure that physiological processes are occurring at the most appropriate time. The importance of this temporal control is demonstrated by the strong associations between circadian disruption, morbidity and disease pathology. There is now a wealth of evidence linking the circadian timing system to metabolic physiology and nutrition. Relationships between these processes are often reciprocal, such that the circadian system drives temporal changes in metabolic pathways and changes in metabolic/nutritional status alter core molecular components of circadian rhythms. Examples of metabolic rhythms include daily changes in glucose homeostasis, insulin sensitivity and postprandial response. Time of day alters lipid and glucose profiles following individual meals whereas, over a longer time scale, meal timing regulates adiposity and body weight; these changes may occur via the ability of timed feeding to synchronise local circadian rhythms in metabolically active tissues. Much of the work in this research field has utilised animal and cellular model systems. Although these studies are highly informative and persuasive, there is a largely unmet need to translate basic biological data to humans. The results of such translational studies may open up possibilities for using timed dietary manipulations to help restore circadian synchrony and downstream physiology. Given the large number of individuals with disrupted rhythms due to, for example, shift work, jet-lag, sleep disorders and blindness, such dietary manipulations could provide widespread improvements in health and also economic performance.

scholarly journals The Role of Colony Temperature in the Entrainment of Circadian Rhythms of Honey Bee Foragers

2020 ◽  
Author(s):  
Manuel A. Giannoni-Guzmán ◽  
Emmanuel Rivera ◽  
Janpierre Aleman-Rios ◽  
Alexander M. Melendez Moreno ◽  
Melina Perez Ramos ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Honey Bee ◽  
Honey Bees ◽  
Temperature Oscillation ◽  
Time Of Day ◽  
Temperature Cycle ◽  
Large Individual ◽  
Endogenous Rhythms ◽  
Honey Bee Foragers

AbstractHoney bees utilize their circadian rhythms to accurately predict the time of day. This ability allows foragers to remember the specific timing of food availability and its location for several days. Previous studies have provided strong evidence toward light/dark cycles being the primary Zeitgeber for honey bees. Recent work in our laboratory described large individual variation in the endogenous period length of honey bee foragers from the same colony and differences in the endogenous rhythms under different constant temperatures. In this study, we further this work by examining temperature inside the honey bee colony. By placing temperature and light data loggers at different locations inside the colony we uncovered that temperature oscillates with a 24-hour period at the periphery of the colony. We then simulated this temperature oscillation in the laboratory and found that using the temperature cycle as a Zeitgeber, foragers present large individual differences in the phase of locomotor rhythms with respect to temperature. Moreover, foragers successfully entrain to these simulated temperature cycles and advancing the cycle by six hours, resulted in changes in the phase of locomotor activity for the most foragers in the assay. The results shown in this study highlight the importance of temperature as a potential Zeitgeber in the field. Future studies will examine the possible functional and evolutionary role of the observed phase differences of circadian rhythms.

scholarly journals Rhythmic regulation of DNA methylation factors and core-clock genes in brain structures activated by cocaine or sucrose

2021 ◽  
Author(s):  
Lamis Saad ◽  
Andries Kalsbeek ◽  
Jean Zwiller ◽  
Patrick Anglard
Keyword(s):  
Dna Methylation ◽  
Circadian Rhythms ◽  
Cytosine Methylation ◽  
Drugs Of Abuse ◽  
Clock Genes ◽  
Chronic Administration ◽  
Reward System ◽  
Brain Structures ◽  
Time Of Day ◽  
Dependent Manner

Abstract The circadian system interacts with the mesocorticolimbic reward system to modulate reward and memory in a time-of-day dependent manner. The circadian discrimination of reward however remains difficult to address between natural reinforcers and drugs of abuse. Circadian rhythms control cocaine sensitization and conversely cocaine causes long-term alteration in circadian periodicity in part through the serotonergic neurotransmission. Since neural circuits activated by cocaine and natural reinforcers do not completely overlap, we compared the effect of cocaine with that of sucrose, a strong reinforcer in rodents, by using passive chronic administration. The expression of fifteen genes playing a major role in DNA methylation (Dnmts, Tets), circadian rhythms (Clock, Bmal1, Per1/2, Cry1/2, Rev-Erbβ, Dbp1), appetite and satiety (Orexin, Npy) was analyzed in dopamine projection areas like the prefrontal cortex, the caudate putamen, and the hypothalamus interconnected with the reward system. The corresponding proteins of two genes (Orexin, Per2) were examined by IHC. For many factors controlling various biological functions, striking opposite responses were found between the two reinforcers. Global DNA methylation analysis showed that cocaine increased, while sucrose decreased the cytosine methylation content. The data are consistent with a repression of critical core-clock genes by cocaine, suggesting that consequently both agents differentially modulate day/night cycles. Whether cocaine-induced changes are long lasting, or contribute to the establishment of drug addiction requires further neuroepigenetic investigation. Understanding the mechanisms dissociating drugs of abuse from natural reinforcers remains a prerequisite for the design of selective therapeutic tools for compulsive behaviors.

scholarly journals CLOCK-induced upregulated HMGB1 resulting in circadian rhythms disruption of inflammatory microglia contributes to non-dipper hypertension in stressed rats

2020 ◽  
Author(s):  
Shutian Zhang ◽  
Li Hu ◽  
Chunmei Xia
Keyword(s):  
Oxidative Stress ◽  
Circadian Rhythms ◽  
Time Of Day ◽  
Diurnal Rhythms ◽  
Ventrolateral Medulla ◽  
Inflammatory Factors ◽  
Inflammatory Factor ◽  
List Type ◽  
Sirt1 Expression ◽  
Induced Hypertension

AbstractIncreased microglia activation and neuroinflammation within autonomic brain regions have been implicated in stress-induced hypertension (SIH). The circadian clock affects physiological cellular and biological processes, including blood pressure (BP) control, but the mechanisms remain unclear. Microglia possess endogenous timekeeping mechanisms regulate immune responses. Here, we explore whether SIH is associated with disrupted diurnal rhythms in microglia proinflammatory factors (PICs) releasing. We found that SIH exhibit diminished BP circadian rhythms, which showed non-dipper hypertension. Microglia isolated from the rostral ventrolateral medulla (RVLM) of SIH rats had aberrant PICs releasing and CLOCK rhythms, while microglia from control rats exhibited robust rhythms of PICs expression both ex vivo and in vivo. In the RVLM, stress upregulated CLOCK expression which is independent of time of day in comparison with that of control. We further identified that upregulated CLOCK depressed sirt1 expression thereby increased oxidative stress-related HMGB1-PICs releasing in microglia in RVLM of SIH rats. In conclusion, the disrupts intrinsic circadian rhythms of microglia-derived PICs releasing involves in pathogeneses of non-dipper hypertension in stressed rats.HighlightsThe aberrant rhythms CLOCK gene induced increased HMGB expression in microglia in the RVLM of stress-induced hypertension rats.Aberrant CLOCK depressed sirt1 expression, which resulted in oxidative stress initiated inflammatory HMGB1 activation in microglia in RVLM of stress-induced hypertension rats.The disrupts intrinsic circadian rhythms of microglia-derived inflammatory factor releasing in the RVLM involving in pathogeneses of non-dipper hypertension.Graphical abstractAbnormal CLOCK-sirt1-HMGB1 caused the aberrant circadian rhythms of microglial inflammatory factors releasing contributes to non-dipper hypertension. The disrupted circadian of CLOCK resulted in HMGB1 activation via sirt1-dependent oxidative stress in the RVLM.

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