Perfect timing: circadian rhythms, sleep, and immunity — an NIH workshop summary

JCI Insight, Год журнала: 2020, Номер 5(1)

Опубликована: Янв. 15, 2020

Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate adaptive responses — ranging from leukocyte mobilization, trafficking, chemotaxis to cytokine release T cell differentiation —are mediated time of day–dependent manner. The National Institutes Health (NIH) recently sponsored an interdisciplinary workshop, “Sleep Insufficiency, Circadian Misalignment, the Immune Response,” highlight new research linking biology function identify areas high translational potential. This Review summarizes topics discussed highlights immediate opportunities delineating clinically relevant connections among biological rhythms, sleep, regulation.

Язык: Английский

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Importance of circadian timing for aging and longevity

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Май 17, 2021

Dietary restriction (DR) decreases body weight, improves health, and extends lifespan. DR can be achieved by controlling how much and/or when food is provided, as well adjusting nutritional composition. Because these factors are often combined during DR, it unclear which necessary for beneficial effects. Several drugs have been utilized that target nutrient-sensing gene pathways, many of change expression throughout the day, suggesting timing drug administration critical. Here, we discuss dietary pharmacological interventions promote a healthy lifespan influencing energy intake circadian rhythms.

Язык: Английский

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Diet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes

Cell, Год журнала: 2018, Номер 174(4), С. 831 - 842.e12

Опубликована: Июль 26, 2018

Overnutrition disrupts circadian metabolic rhythms by mechanisms that are not well understood. Here, we show diet-induced obesity (DIO) causes massive remodeling of enhancer activity in mouse liver, triggering synchronous high-amplitude both fatty acid (FA) synthesis and oxidation. SREBP expression was rhythmically induced DIO, leading to FA and, surprisingly, oxidation (FAO). DIO similarly caused a rhythm PPARα, which also required for FAO. Provision pharmacological activator PPARα abrogated the requirement FAO (but synthesis), suggesting indirectly controls via production endogenous ligands. The imparted time-of-day-dependent responsiveness lipid-lowering drugs. Thus, acquisition rhythmicity non-core clock components SREBP1 remodels gene transcription response overnutrition enables chronopharmacological approach disorders.

Язык: Английский

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Metabolic and cardiovascular consequences of shift work: The role of circadian disruption and sleep disturbances

European Journal of Neuroscience, Год журнала: 2018, Номер 51(1), С. 396 - 412

Опубликована: Окт. 25, 2018

Abstract Shift work, defined as work occurring outside typical daytime working hours, is associated with an increased risk of various non‐communicable diseases, including diabetes and cardiovascular disease. Disruption the internal circadian timing system concomitant sleep disturbances thought to play a critical role in development these health problems. Indeed, controlled laboratory studies have shown that short‐term misalignment restriction independently impair physiological processes, insulin sensitivity, energy expenditure, immune function, blood pressure cardiac modulation by autonomous nervous system. If allowed persist, acute effects may lead cardiometabolic diseases long term. Here, we discuss evidence for contributions disruption metabolic problems shift workers. Improving understanding mechanisms affected disturbance will contribute implementation strategies prevent or mitigate impact work.

Язык: Английский

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Targeting the CCL2–CCR2 axis for atheroprotection

European Heart Journal, Год журнала: 2022, Номер 43(19), С. 1799 - 1808

Опубликована: Фев. 16, 2022

Decades of research have established atherosclerosis as an inflammatory disease. Only recently though, clinical trials provided proof-of-concept evidence for the efficacy anti-inflammatory strategies with respect to cardiovascular events, thus offering a new paradigm lowering residual vascular risk. Efforts target inflammasome-interleukin-1β-interleukin-6 pathway been highly successful, but inter-individual variations in drug response, lack reduction all-cause mortality, and higher rate infections also highlight need second generation agents targeting atherosclerosis-specific immune mechanisms while minimizing systemic side effects. CC-motif chemokine ligand 2/monocyte-chemoattractant protein-1 (CCL2/MCP-1) orchestrates monocyte trafficking between bone marrow, circulation, atherosclerotic plaques by binding its cognate receptor CCR2. Adding strong body data from experimental models, coherent series recent large-scale genetic observational epidemiological studies along human relevance therapeutic potential CCL2-CCR2 axis atherosclerosis. Here, we summarize pinpointing emerging Furthermore, contextualize previous efforts interfere this pathway, scrutinize approaches vs. targeting, discuss possible pathway-intrinsic opportunities challenges related pharmacological

Язык: Английский

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Sex-dimorphic and age-dependent organization of 24-hour gene expression rhythms in humans

Science, Год журнала: 2023, Номер 379(6631), С. 478 - 483

Опубликована: Фев. 2, 2023

The circadian clock modulates human physiology. However, the organization of tissue-specific gene expression rhythms and how these depend on age sex is not defined in humans. We combined data from Genotype-Tissue Expression (GTEx) project with an algorithm that assigns phases to 914 donors, by integrating temporal information multiple tissues each individual, identify messenger RNA (mRNA) 46 tissues. Clock transcripts showed conserved timing relationships tight synchrony across body. mRNA varied breadth, covering global functions, including metabolic pathways systemic responses. structure was sexes groups. overall were highly sex-dimorphic more sustained females. Rhythmic programs generally dampened

Язык: Английский

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Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(2)

Опубликована: Янв. 3, 2023

Hepatocellular carcinoma (HCC) remains a global health challenge whose incidence is growing worldwide. Previous evidence strongly supported the notion that circadian clock controls physiological homeostasis of liver and plays key role in hepatocarcinogenesis. Despite progress, cellular molecular mechanisms underpinning this HCC-clock crosstalk remain unknown. Addressing knowledge gap, we show here although human HCC cells Hep3B, HepG2, Huh7 displayed variations rhythm profiles, all relied on master transcription factors, BMAL1 CLOCK, for sustained cell growth. Down-regulating Bmal1 or Clock induced apoptosis arrested cycle at G 2 /M phase. Mechanistically, found inhibiting / dysregulation regulators Wee1 p21 which cooperatively contribute to tumor death. knockdown caused downregulation led activation upregulation Collectively, our results suggest CLOCK promote proliferation by controlling levels, thereby preventing arrest. Our findings shed light impact proteins maintaining oncogenesis provide proof-of-principle developing cancer therapy based modulation clock.

Язык: Английский

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Tumor circadian clock strength influences metastatic potential and predicts patient prognosis in luminal A breast cancer

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(7)

Опубликована: Фев. 6, 2024

Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular rhythms noncancerous cancerous human tissues their clinical relevance are largely unknown. We reconstructed informatically, integrating locally collected, time-stamped biopsies with public datasets. For tissue, inflammatory, epithelial–mesenchymal transition (EMT), estrogen responsiveness pathways show modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes organization. Luminal A organoids informatic ordering of luminal samples exhibit continued, albeit dampened reprogrammed rhythms. CYCLOPS magnitude, a measure global rhythm strength, varied widely among samples. Cycling EMT pathway genes was markedly increased high-magnitude tumors. Surprisingly, patients tumors had reduced 5-y survival. Correspondingly, 3D cultures invasion following disruption. This study links cancer EMT, metastatic potential, prognosis.

Язык: Английский

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Why does circadian timing of administration matter for immune checkpoint inhibitors’ efficacy?

British Journal of Cancer, Год журнала: 2024, Номер 131(5), С. 783 - 796

Опубликована: Июнь 4, 2024

Abstract Background Tolerability and antitumour efficacy of chemotherapy radiation therapy can vary largely according to their time administration along the 24-h scale, due moderation molecular cellular mechanisms by circadian rhythms. Recent clinical data have highlighted a striking role dosing for cancer immunotherapy, thus calling critical evaluation. Methods Here, we review analyse through which rhythms influence outcomes on ICI therapies. We examine how rhythm disorders affect tumour immune microenvironment, as main mechanism linking clock cycles in ICIs efficacy. Results Real-life from 18 retrospective studies revealed that early time-of-day (ToD) infusion checkpoint inhibitors (ICIs) could enhance progression-free and/or overall survival up fourfold compared late ToD dosing. The involved total 3250 patients with metastatic melanoma, lung, kidney, bladder, oesophageal, stomach or liver 9 countries. Such large consistent differences effects only result previously ignored robust chronobiological mechanism. timing system coordinates cellular, tissue whole-body physiology timescale. Circadian are generated at level involves 15 specific genes. disruption trigger accelerate carcinogenesis, contribute treatment failure, possibly evasion resulting immunosuppressive microenvironment. Conclusions perspective emerging understanding regulation immunity now calls randomised trials establish recommendations personalised chrono-immunotherapies current forthcoming drugs.

Язык: Английский

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Universal method for robust detection of circadian state from gene expression

Proceedings of the National Academy of Sciences, Год журнала: 2018, Номер 115(39)

Опубликована: Сен. 10, 2018

Circadian clocks play a key role in regulating vast array of biological processes, with significant implications for human health. Accurate assessment physiological time using transcriptional biomarkers found blood can significantly improve diagnosis circadian disorders and optimize the delivery therapeutic treatments. To be useful, such test must accurate, minimally burdensome to patient, readily generalizable new data. A major obstacle development gene expression biomarker tests is diversity measurement platforms inherent variability data, often resulting predictors that perform well original datasets but cannot universally applied samples collected other settings. Here, we introduce TimeSignature, an algorithm robustly infers from expression. We demonstrate its application data three independent studies distinct microarrays further validate it against set profiled by RNA-sequencing. Our results show TimeSignature more accurate efficient than competing methods, estimating within 2 h majority samples. Importantly, once trained on single study, predictor yield highly differences study population, patient protocol, or assay platform without renormalizing retraining. This feature unique among expression-based addresses challenge generalizable, clinically useful tests.

Язык: Английский

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