Circadian regulation of sinoatrial nodal cell pacemaking function: Dissecting the roles of autonomic control, body temperature, and local circadian rhythmicity

PLoS Computational Biology, Год журнала: 2024, Номер 20(2), С. e1011907 - e1011907

Опубликована: Фев. 26, 2024

Strong circadian (~24h) rhythms in heart rate (HR) are critical for flexible regulation of cardiac pacemaking function throughout the day. While this flexibility HR is sustained diverse conditions, it declines with age, accompanied by reduced maximal performance. The intricate involves orchestration autonomic nervous system (ANS), body temperature (CRBT), and local rhythmicity (LCR), which has not been fully understood. Here, we developed a mathematical model describing ANS, CRBT, LCR sinoatrial nodal cells (SANC) that accurately captures distinct patterns adult aged mice. Our underscores how alliance among achieves to cover wide range firing rates SANC, performance achieve rates, while preserving robustness generate rhythmic irrespective external conditions. Specifically, ANS dominates promoting SANC performance, CRBT act as primary secondary boosters, respectively, further enhance Disruption age results impaired but robustness. This unexpected outcome primarily attributed age-related reduction parasympathetic activities, maintains compromising flexibility. work sheds light on regulating time-of-day dysfunction, offering insights into novel therapeutic targets prevention treatment arrhythmias.

Язык: Английский

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Translating around the clock: Multi-level regulation of post-transcriptional processes by the circadian clock

Cellular Signalling, Год журнала: 2020, Номер 80, С. 109904 - 109904

Опубликована: Дек. 25, 2020

Язык: Английский

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MYC Ran Up the Clock: The Complex Interplay between MYC and the Molecular Circadian Clock in Cancer

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(14), С. 7761 - 7761

Опубликована: Июль 20, 2021

The MYC oncoprotein and its family members N-MYC L-MYC are known to drive a wide variety of human cancers. Emerging evidence suggests that has bi-directional relationship with the molecular clock in cancer. is responsible for circadian (~24 h) rhythms most eukaryotic cells organisms, as mechanism adapt light/dark cycles. Disruption rhythms, such through shift work, may serve risk factor cancer, but connections oncogenic drivers were previously not well understood. In this review, we examine recent cancer can disrupt clock; conversely, disruption deregulate elevate MYC. Since control many same processes, then consider competition between several select aspects tumor biology, including chromatin state, global transcriptional profile, metabolic rewiring, immune infiltrate tumor. Finally, discuss how be monitored or diagnosed tumors, inhibition could potentially restore function. Further study reveal unsuspected vulnerabilities which lead new treatment strategies.

Язык: Английский

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Bibliometric analysis of global research status and trends of circadian rhythms in cancer from 2004 to 2024

Chronobiology International, Год журнала: 2025, Номер unknown, С. 1 - 13

Опубликована: Янв. 31, 2025

Research linking circadian dysregulation to cancer development has received increasing attention recently. However, a comprehensive understanding of research hotspots and trends in this area remains limited. International studies on the rhythms were retrieved downloaded from Web Science database. Bibliometric analysis visualization performed using VOSviewer, CiteSpace, HistCite. Three thousand three hundred eighteen English articles 2004 2024 screened evaluated. The increase publications citations reflected rapid expansion field. Scholars institutions United States have relatively high academic productivity impact. Chronobiology is most popular journal. Key clustering identified six themes: biochemistry molecular biology, physiology immunomodulation, night shift work health effects, physiological mental health, tumor therapy research, oxidative stress cancer-related mechanisms. Keyword burst regulation cells microenvironment as frontiers. role immunotherapy was current hotspot by reference co-citation analysis. This study reveals status predicts future trends. These findings provide new ideas for developing novel prevention treatment strategies.

Язык: Английский

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Device Development: The Future

Опубликована: Янв. 1, 2025

Язык: 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, Год журнала: 2025, Номер unknown, С. 105764 - 105764

Опубликована: Май 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.

Язык: Английский

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Exploring the link between chronobiology and drug delivery: effects on cancer therapy

Journal of Molecular Medicine, Год журнала: 2021, Номер 99(10), С. 1349 - 1371

Опубликована: Июль 2, 2021

Язык: Английский

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Efficacy and safety of chronomodulated irinotecan, oxaliplatin, 5‐fluorouracil and leucovorin combination as first‐ or second‐line treatment against metastatic colorectal cancer: Results from the International EORTC 05011 Trial

International Journal of Cancer, Год журнала: 2020, Номер 148(10), С. 2512 - 2521

Опубликована: Дек. 3, 2020

Abstract The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing safety efficacy profiles with circadian‐based administration (chronoIFLO5) either first‐ or second‐line treatment, within the time‐finding EORTC 05011 trial. Five‐day chronoIFLO5 was administered every 3 weeks patients PS 0, 1 2. It consisted chronomodulated irinotecan (180 mg/sqm), (80 mg/sqm) fluorouracil‐leucovorin (2800 1200 mg/sqm, respectively). For our study, toxicity antitumour activity were evaluated separately settings. Primary endpoints included Grade 3‐4 rates, best objective response rate (ORR), progression‐free survival (PFS) overall (OS). One‐hundred forty‐nine 44 treated first‐line settings, respectively, a total 1138 cycles median relative dose intensities about 90%. Demographics comparable two groups. Thirty‐six (24.7%) 10 (22.2%) experienced least one episode severe first line second line, respectively. Frontline yielded ORR 62.3% [95% CI: 54.2‐70.4] resulted PFS OS 8.7 months [7.5‐9.9] 19.9 [15.4‐24.5]. Corresponding figures 37.5% [22.5‐52.5], 6.7 [4.8‐8.9] 16.3 [11.8‐20.8]. International prospective evaluation revealed favourable chronoIFLO5, both treatment against cancer. In particular, encouraging observed, limited haematological toxicity.

Язык: Английский

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Clock at the Core of Cancer Development

Biology, Год журнала: 2021, Номер 10(2), С. 150 - 150

Опубликована: Фев. 14, 2021

To synchronize various biological processes with the day and night cycle, most organisms have developed circadian clocks. This evolutionarily conserved system is important in temporal regulation of behavior, physiology metabolism. Multiple pathological changes associated disruption support importance clocks mammals. Emerging links revealed interplay between signaling networks cancer. Understanding cross-talk clock tumorigenesis imperative for its prevention, management development effective treatment options. In this review, we summarize role one metabolic pathway, insulin/IGF1/PI3K/mTOR signaling, how dysregulation pathway could lead to uncontrolled cancer cell proliferation growth. Targeting rhythms either recently discovered pharmaceutical agents or through environmental cues a new direction chronotherapy. Combining approach traditional methods, such as radiation, chemotherapy developed, immunotherapy, may improve tumor response, while simultaneously minimizing adverse effects commonly therapies.

Язык: Английский

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Controlled Release Technologies for Chronotherapy: Current Status and Future Perspectives

Current Pharmaceutical Design, Год журнала: 2023, Номер 29(14), С. 1069 - 1091

Опубликована: Апрель 1, 2023

Abstract: The expression “as sure as night follows a day” emulates those certain cycles in the environment that are always stable. Circadian rhythms group of processes occur within body synchronisation with external factors 24 h cycle. Changes lifestyle and work shifts have disrupted these stable rhythms, which is leading cause diseases. Associations between biological clocks diseases abundant. However, it also known drugs more efficiently minimum toxicity when given during particular phase circadian Chronotherapeutics focuses on treating according to endogenous mediate xenobiotic metabolism drug response at cellular level. Therefore, treatment show aggravation symptoms time highly beneficial by chronotherapy. In this article, we emphasised how changes caused chronotherapeutic approaches such controlled release technologies can be better option for manipulations seem influence all types disease conditions.

Язык: Английский

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