Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock

Cancer Discovery, Journal Year: 2019, Volume and Issue: 9(11), P. 1556 - 1573

Published: Aug. 27, 2019

Abstract Glioblastomas are highly lethal cancers, containing self-renewing glioblastoma stem cells (GSC). Here, we show that GSCs, differentiated (DGC), and nonmalignant brain cultures all displayed robust circadian rhythms, yet GSCs alone exquisite dependence on core clock transcription factors, BMAL1 CLOCK, for optimal cell growth. Downregulation of or CLOCK in induced cell-cycle arrest apoptosis. Chromatin immunoprecipitation revealed preferentially bound metabolic genes was associated with active chromatin regions compared neural cells. Targeting attenuated mitochondrial function reduced expression tricarboxylic acid cycle enzymes. Small-molecule agonists two independent BMAL1–CLOCK negative regulators, the cryptochromes REV-ERBs, downregulated factors GSC Combination cryptochrome REV-ERB synergistic antitumor efficacy. Collectively, these findings co-opt regulators beyond canonical circuitry to promote stemness maintenance metabolism, offering novel therapeutic paradigms. Significance: Cancer malignant tumor-cell populations. We demonstrate selectively depend increased binding promoting tumor metabolism. Supporting clinical relevance, pharmacologic targeting networks specifically disrupted cancer growth self-renewal. This article is highlighted In Issue feature, p. 1469

Language: Английский

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Circadian control of the secretory pathway maintains collagen homeostasis

Nature Cell Biology, Journal Year: 2020, Volume and Issue: 22(1), P. 74 - 86

Published: Jan. 1, 2020

Language: Английский

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The hepatocyte clock and feeding control chronophysiology of multiple liver cell types

Science, Journal Year: 2020, Volume and Issue: 369(6509), P. 1388 - 1394

Published: July 30, 2020

The hepatocyte clock and food availability control gene expression metabolism in nonhepatocytic cells the liver.

Language: Английский

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Chronic low-dose REV-ERBs agonist SR9009 mitigates constant light-induced weight gain and insulin resistance via adipogenesis modulation

Biomedical Journal, Journal Year: 2025, Volume and Issue: unknown, P. 100830 - 100830

Published: Jan. 1, 2025

Obesity and circadian rhythm disruption are significant global health concerns, contributing to an increased risk of metabolic disorders. Both adipose tissue rhythms play critical roles in maintaining energy homeostasis, their dysfunction is closely linked obesity. This study aimed assess the effects chronic low-dose SR9009, a REV-ERB ligand, on induced by constant light exposure mice. Mice were exposed for eight weeks (LL mice), resulting body weight, insulin resistance, white fat mass, altered clock gene expression. Low-dose SR9009 (10 mg/kg daily) was administered chronically its impact these disruptions. LL mice treated with showed reduced weight gain, mass but no overall homeostasis. suppressed Bmal1 expression restored Rev-erbα Rev-erbβ brown (WAT BAT). In vitro studies using 3T3-L1 cells indicated that inhibited adipogenesis, leading further investigation vivo. ChREBP1a Srebp-1c BAT did not affect inflammatory cytokine or adipokine expression, nor it restore Fasn, Pparγ, Prom1 both WAT BAT. These findings suggest may be potential therapeutic preventing gain resistance caused disruptions, likely through adipogenesis inhibition, though other pathways remain limited at low doses.

Language: Английский

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Targeting REV-ERBα for therapeutic purposes: promises and challenges

Theranostics, Journal Year: 2020, Volume and Issue: 10(9), P. 4168 - 4182

Published: Jan. 1, 2020

REV-ERBα (NR1D1) is a circadian clock component that functions as transcriptional repressor.Due to its role in direct modulation of metabolic genes, regarded an integrator cell metabolism with clock.Accordingly, first proposed drug target for treating sleep disorders and syndromes (e.g., dyslipidaemia, hyperglycaemia obesity).Recent years studies uncover rather broad pathological conditions including local inflammatory diseases, heart failure cancers.Moreover, involved regulation has implications chronopharmacology.In the meantime, recent have witnessed discovery array new ligands most which pharmacological activities vivo.In this article, we review regulatory various types diseases discuss underlying mechanisms.We also describe newly discovered old ones together their targeting potential.Despite well-established effects animals (preclinical studies), no progress been made regarding translation clinical trials.This implies certain challenges associated development ligands.In particular, potential related safety (or adverse effects) bioavailability.For development, it advocated should be targeted treat locally distributed, avoiding on other tissues.

Language: Английский

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Transcriptional Control of Circadian Rhythms and Metabolism: A Matter of Time and Space

Endocrine Reviews, Journal Year: 2020, Volume and Issue: 41(5), P. 707 - 732

Published: May 11, 2020

All biological processes, living organisms, and ecosystems have evolved with the Sun that confers a 24-hour periodicity to life on Earth. Circadian rhythms arose from evolutionary needs maximize daily organismal fitness by enabling organisms mount anticipatory adaptive responses recurrent light-dark cycles associated environmental changes. The clock is conserved feature in nearly all forms of life, ranging prokaryotes virtually every cell multicellular eukaryotes. mammalian comprises transcription factors interlocked negative feedback loops, which generate circadian expression genes coordinate rhythmic physiology. In this review, we highlight previous recent studies advanced our understanding transcriptional architecture clock, specific focus epigenetic mechanisms, transcriptomics, 3-dimensional chromatin architecture. addition, discuss reciprocal ways metabolism regulate each other metabolic rhythms. We also implications biology human health, genetic environment disruptions novel therapeutic opportunities for medicine. Finally, explore remaining fundamental questions future challenges advancing field forward.

Language: Английский

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SR9009 administered for one day after myocardial ischemia-reperfusion prevents heart failure in mice by targeting the cardiac inflammasome

Communications Biology, Journal Year: 2019, Volume and Issue: 2(1)

Published: Oct. 3, 2019

Abstract Reperfusion of patients after myocardial infarction (heart attack) triggers cardiac inflammation that leads to infarct expansion and heart failure (HF). We previously showed the circadian mechanism is a critical regulator reperfusion injury. However, whether pharmacological targeting using medicine limits injury protects against HF unknown. Here, we show short-term driver REV-ERB with SR9009 benefits long-term repair post-myocardial ischemia in mice. Gain loss function studies demonstrate specificity Treatment for just one day abates NLRP3 inflammasome, decreasing immunocyte recruitment, thereby allowing vulnerable heal. Therapy given vivo, reperfusion, promotes efficient repair. This study presents downregulation inflammasome fibroblasts as cellular target SR9009, inviting more targeted therapeutic investigations future.

Language: Английский

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NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis

Cell Death and Disease, Journal Year: 2020, Volume and Issue: 11(2)

Published: Feb. 18, 2020

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia, pannus formation, and cartilage bone destruction. Nuclear receptor subfamily 1 group D member (NR1D1) functions as transcriptional repressor plays vital role in inflammatory reactions. However, whether NR1D1 involved inflammation joint destruction during the pathogenesis of RA unknown. In this study, we found that expression was increased tissues from patients with decreased Fibroblast-like synoviocytes (FLSs) stimulated IL-1β vitro. We showed activation proinflammatory cytokines matrix metalloproteinases (MMPs), while silencing exerted opposite effect. Furthermore, reduced reactive oxygen species (ROS) generation production nuclear transcription factor E2-related 2 (Nrf2)-associated enzymes. Mitogen-activated protein kinase (MAPK) κB (NF-κB) pathways were blocked agonist SR9009 but activated silencing. also inhibited M1 macrophage polarization suppressed osteoclastogenesis osteoclast-related genes expression. Treatment collagen-induced (CIA) mouse significantly hyperplasia synovial, infiltration cell bone. Our findings demonstrate an important for suggest its therapeutic potential.

Language: Английский

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Interconnections between circadian clocks and metabolism

Journal of Clinical Investigation, Journal Year: 2021, Volume and Issue: 131(15)

Published: Aug. 1, 2021

Circadian rhythms evolved through adaptation to daily light/dark changes in the environment; they are believed be regulated by core circadian clock interlocking feedback loop. Recent studies indicate that each component executes general and specific functions metabolism. Here, we review current understanding of role these genes regulation metabolism using various genetically modified animal models. Additionally, emerging evidence shows exposure environmental stimuli, such as artificial light, unbalanced diet, mistimed eating, exercise, remodels physiological processes causes metabolic disorders. This Review summarizes reciprocal between metabolism, highlights remaining gaps knowledge about examines potential applications human health disease.

Language: Английский

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Circadian Rhythms, Disease and Chronotherapy

Journal of Biological Rhythms, Journal Year: 2021, Volume and Issue: 36(6), P. 503 - 531

Published: Sept. 22, 2021

Circadian clocks are biological timing mechanisms that generate 24-h rhythms of physiology and behavior, exemplified by cycles sleep/wake, hormone release, metabolism. The adaptive value is evident when internal body daily environmental mismatched, such as in the case shift work jet lag or even mistimed eating, all which associated with physiological disruption disease. Studies animal human models have also unraveled an important role functional circadian modulating cellular organismal responses to cues (ex., food intake, exercise), pathological insults (e.g. virus parasite infections), medical interventions medication). With growing knowledge molecular underlying pathophysiology, it becoming possible target for disease prevention treatment. In this review, we discuss recent advances research potential therapeutic applications take patient into account treating

Language: Английский

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