Circadian Regulation of Drug Responses: Toward Sex-Specific and Personalized Chronotherapy

The Annual Review of Pharmacology and Toxicology, Journal Year: 2023, Volume and Issue: 64(1), P. 89 - 114

Published: Sept. 19, 2023

Today's challenge for precision medicine involves the integration of impact molecular clocks on drug pharmacokinetics, toxicity, and efficacy toward personalized chronotherapy. Meaningful improvements tolerability and/or medications through proper administration timing have been confirmed over past decade immunotherapy chemotherapy against cancer, as well commonly used pharmacological agents in cardiovascular, metabolic, inflammatory, neurological conditions. Experimental human studies recently revealed sexually dimorphic circadian responses. Dedicated randomized clinical trials should now aim to issue recommendations daily medical practice, integrating innovative technologies remote longitudinal monitoring metrics, statistical prediction clock function from single-timepoint biopsies, multiscale biorhythmic mathematical modelling. Importantly, chronofit patients with a robust function, who would benefit most chronotherapy, need be identified. Conversely, nonchronofit could emerging class chronobiotics targeting clock.

Language: Английский

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Minimal influence of estrous cycle on studies of female mouse behaviors

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 16

Published: July 4, 2023

Sex bias has been an issue in many biomedical fields, especially neuroscience. In rodent research, scientists only focused on male animals due to the belief that female estrous cycle gives rise unacceptable, high levels of variance experiments. However, even though sexual behaviors are well known be regulated by cycle, which effects other non-sexual were not always consistent previous reports. Recent reviews analyzing published literature suggested there is no evidence for larger variation than several phenotypes.To further investigate impact variability behaviors, we conducted multiple behavioral assays, including open field test, forced swimming and resident-intruder assay assess anxiety-, depression-like as social interaction respectively. We compared females estrus diestrus stages across four different mouse strains: C57BL/6, BALB/c, C3H, DBA/2.Our results found significant difference most parameters between these two stages. On hand, differences among certain strains relatively both stages, suggesting a very minimal effect detecting difference. Last, similar variations sexes.While our study successfully identified sexes, did find solid support notion influenced cycle. Additionally, observed males females. Female mice, therefore, have reason excluded future research.

Language: Английский

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Circadian rhythm disruption by PARP inhibitors correlates with treatment toxicity in patients with ovarian cancer and is a predictor of side effects

EBioMedicine, Journal Year: 2025, Volume and Issue: unknown, P. 105764 - 105764

Published: May 1, 2025

Ovarian cancer is among the most lethal malignancies in women. The advent of PARP inhibitors (PARPi) has improved outcomes. However, treatment-related toxicity remains a critical challenge, impacting patient quality life and treatment adherence. In circadian sub-study MAMOC trial-a double-blind, phase III study-42 patients (FIGO stage IIIA-IV) were randomised 2:1 ratio to receive rucaparib or placebo. subset these patients, we performed differential gene expression rhythmicity analysis on up 800 genes, including clock clock-controlled genes. Machine learning algorithms mathematical modelling employed simulate patient-specific profiles explore correlations between patterns side effects. Our revealed significant disruptions rhythms, specifically core genes BMAL1 PER2, following treatment. These strongly correlated with severity frequency effects, nausea fatigue, displaying opposite trends placebo rucaparib-treated groups. K-means clustering successfully distinguished from those receiving based profiles. addition, therapy also altered several SIRT1, BRCA1, BRCA2, TP53. Notably, our data suggest that individual differences rhythms may lead distinct 24-h patients. findings rhythm dysregulation contribute PARPi therapy. Aligning timing could mitigate adverse improve This study was funded by Dr. Rolf Schwiete Stiftung MSH Medical School Hamburg, Germany. trial (ClinicalTrials.gov: NCT04227522) Clovis Oncology, United States.

Language: Английский

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Hair Follicles as a Critical Model for Monitoring the Circadian Clock

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2407 - 2407

Published: Jan. 26, 2023

Clock (circadian) genes are heterogeneously expressed in hair follicles (HFs). The can be modulated by both the central circadian system and some extrinsic factors, such as light thyroid hormones. These participate regulation of several physiological processes HFs, including growth pigmentation. On other hand, because peripheral synchronized with clock, HFs could provide a noninvasive practical method for monitoring evaluating multiple circadian-rhythm-related conditions disorders among humans, day night shifts, sleep-wake disorders, physical activities, energy metabolism, aging. However, due to complexity biology, understanding how intrinsic oscillation operates using tissues only may insufficient. Combining HF sampling multidimensional assays detection body temperature, blood samples, or certain validated questionnaires helpful improving applications. Thus, serve critical model clock help an potential mechanisms conditions; furthermore, chronotherapy support personalized treatment scheduling based on gene expression profile HFs.

Language: Английский

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Shaping the future of precision oncology: Integrating circadian medicine and mathematical models for personalized cancer treatment

Current Opinion in Systems Biology, Journal Year: 2024, Volume and Issue: 37, P. 100506 - 100506

Published: Feb. 29, 2024

The growing numbers of cancer cases represent a medical and societal burden worldwide. More than half all patients are treated with chemotherapy. Yet, chemotherapeutic drugs kill not only cells, but also healthy tissue, causing massive adverse side effects. Recent research on circadian medicine suggests that side-effects can be reduced, treatment efficacy increased, by considering the biological clock patients. Integrating profiles molecular markers in personalized mathematical models simulate individual dynamics drug uptake, action cellular response to This requires advanced computational tools balance prediction quality overfitting. Personalized will eventually lead an optimal alignment timing inner patient, reducing effects, increasing enhancing patient well-being.

Language: Английский

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The association of mixed multi-metal exposure with sleep duration and self-reported sleep disorder: A subgroup analysis from the National Health and Nutrition Examination Survey (NHANES)

Environmental Pollution, Journal Year: 2024, Volume and Issue: 361, P. 124798 - 124798

Published: Aug. 27, 2024

Sleep disorders significantly affect sleep duration and constitute a major public health issue. However, the relationship between metal exposure is not fully elucidated. This study utilized publicly available data from National Health Nutrition Examination Survey (NHANES) to measure blood concentrations of seven metals-copper (Cu), zinc (Zn), selenium (Se), manganese (Mn), mercury (Hg), cadmium (Cd), lead (Pb)-in cohort 4263 American adults. The self-reported disorder risk was analyzed using single models like logistic linear regression mixedexposure such as weighted quantile sum (WQS) Bayesian kernel machine (BKMR). results indicated an absence statistically significant findings in model. In contrast, mixed model revealed positive correlation levels across entire population. A "U-shaped" association identified copper males, females, individuals aged 60 above. Moreover, trend observed Additionally, elevated mixtures were associated with reduced among females. Sensitivity analyses corroborated these findings. conclusion, within context mixtures, may be factor for general Manganese unique older Copper have "U" shaped link specific population subgroups. Finally, accumulation mainly due mercury, reduce duration. Further research necessary validate

Language: Английский

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Chronotype-Dependent Sleep Loss Is Associated with a Lower Amplitude in Circadian Rhythm and a Higher Fragmentation of REM Sleep in Young Healthy Adults

Brain Sciences, Journal Year: 2023, Volume and Issue: 13(10), P. 1482 - 1482

Published: Oct. 19, 2023

In modern society, the time and duration of sleep on workdays are primarily determined by external factors, e.g., alarm clock. This can lead to a misalignment intrinsically timing, which is dependent individual chronotype, resulting in reduced quality. Although this highly relevant given high incidence disorders, little known about effect architecture. Using Fitbit trackers questionnaire surveys, our study aims elucidate architecture, subjective quality young healthy adults (n = 59) under real-life conditions (average 82.4 ± 9.7 days). Correlations between variables were calculated identify direction relationships. On workdays, midpoint was earlier, shorter, tiredness upon waking higher than free days. A discrepancy days associated with lower stability circadian rhythm REM also fragmentation sleep. Similarly, days, thus timing conditions, proportion suggests that extrinsically affects architecture stages, particularly sleep, closely connected

Language: Английский

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Sex-specific regulation of the cortical transcriptome in response to sleep deprivation

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: March 5, 2024

Multiple studies have documented sex differences in sleep behaviour, however, the molecular determinants of such remain unknown. Furthermore, most addressing mechanisms been performed only males, leaving current state knowledge biased towards male sex. To address this, we studied transcriptome cerebral cortex and female C57Bl/6 J mice after 6 h deprivation. We found that several genes, including neurotrophin growth factor Bdnf, immediate early genes Fosb Fosl2, adenylate cyclase Adcy7 are differentially upregulated males compared to females. identified androgen-receptor activating transcription EZH2 as upstream regulatory element specifying deprivation transcriptome. propose pathways downstream these transcripts, which impact on cellular re-organisation, synaptic signalling, learning may underpin differential response two sexes.

Language: Английский

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Time matters: chrono-pharmacotherapy as precision medicine

Asia-Pacific Journal of Pharmacotherapy & Toxicology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

The circadian clock and its inherent rhythms serve as the foundation for regulating many of body’s vital processes. Recent advances in medicine have leveraged these natural cycles through chronotherapy, practice timing drug administration to align with body's internal clock, enhance treatment outcomes. Endogenous clocks not only dictate physiological but also influence how drugs are absorbed, distributed, metabolized, excreted, thereby affecting both their therapeutic efficacy potential toxicity. When disrupted, resulting imbalance has been linked a range disorders, such cancer cardiovascular diseases, highlighting growing need time-sensitive strategies. Technological breakthroughs, including wearable sensors, digital health platforms, sophisticated machine learning techniques, now allow continuous, real-time monitoring biomarkers, which turn helps optimize regimens. In oncology, example, synchronizing chemotherapy, therapy, immunotherapy anti-inflammatory patient’s cycle shown effectiveness improve tolerability. Moreover, observed sex-based differences responses emphasize importance tailoring individual patient profiles. Emerging research is focusing on directly targeting molecular components, showing treating metabolic oncological conditions. However, fully integrating chronopharmacology into clinical will require development standardized protocols, regulatory backing, large-scale trials that incorporate biomarkers. Ultimately, merging biology strategies promises efficacy, minimize side effects, Future studies must address inter-individual variability, sex differences, misalignment harness chronotherapy’s personalized medicine.

Language: Английский

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Sex-specific attenuation of constant light-induced memory impairment and Clock gene expression in brain in hepatic Npas2 knockout mice

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 11, 2025

Abstract NPAS2 (Neuronal PAS Domain Protein 2) is a component of the core circadian clock and coordinated activity between central brain peripheral liver proteins postulated to be instrumental for linking behaviour metabolism. We investigated conditional liver-specific knockout mouse model ( Npas 2-/- or cKO) explore its function in activity, rhythms cognition (novel object recognition-NOR). Circadian showed no genotype differences. Constant-light reduced NOR floxxed controls but remarkably not mice, particularly females. Consistent with entrainment systemic biology, N pas mice altered expression gene Clock frontal cortex. Sex differences independent were found genes , Bmal1 Reverb-b brain. absent mice. Females greater period length phase response constant light independently genotype. The data suggest that role light-induced memory impairment females, potential mediation by cortical expression, merit further investigation. These findings have implications interaction clocks, sex deleterious effects on cognition.

Language: Английский

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