Circadian rhythms of physiology are the keys to health and fitness, as dysregulation, by genetic mutations or environmental factors, increases disease risk and aggravates progression. Molecular and ...physiological studies have shed important light on an intrinsic clock that drives circadian rhythms and serves essential roles in metabolic homoeostasis, organ physiology and brain functions. One exciting new area in circadian research is pain, including headache and neuropathic pain for which new mechanistic insights have recently emerged. For example, cluster headache is an intermittent pain disorder with an exceedingly precise circadian timing, and preliminary evidence is emerging linking several circadian components (eg, Clock and Nr1d1) with the disease. In this review, we first discuss the broad metabolic and physiological relevance of the circadian timing system. We then provide a detailed review of the circadian relevance in pain disease and physiology, including cluster headache, migraine, hypnic headache and neuropathic pain. Finally, we describe potential therapeutic implications, including existing pain medicines and novel clock‐modulating compounds. The physiological basis for the circadian rhythms in pain is an exciting new area of research with profound basic and translational impact.
The circadian clock plays a fundamental role in physiology. In particular, the heart is a target organ where the clock orchestrates various aspects of cardiac function. At the molecular level, the ...clock machinery governs daily rhythms of gene expression. Such circadian regulation is in tune with the dynamic nature of heart structure and function, and provides the foundation for chronotherapeutic applications in cardiovascular diseases. In comparison, a regulatory role of the clock in cardiac protein degradation is poorly documented. Sarcomere is the structural and functional unit responsible for cardiac muscle contraction, and sarcomere components are closely regulated by protein folding and proteolysis. Emerging evidence supports a role of the circadian clock in governing sarcomere integrity and function. Particularly, recent studies uncovered a circadian regulation of a core sarcomere component TCAP. It is possible that circadian regulation of the cardiac muscle protein turnover is a key regulatory mechanism underlying cardiac remodeling in response to physiological and environmental stimuli. While the detailed regulatory mechanisms and the molecular links to cardiac (patho)physiology remain to be further studied, therapeutic strategies targeting circadian control in the heart may markedly enhance intervention outcomes against cardiovascular disease.
Circadian timekeeping systems drive oscillatory gene expression to regulate essential cellular and physiological processes. When the systems are perturbed, pathological consequences ensue and disease ...risks rise. A growing number of small-molecule modulators have been reported to target circadian systems. Such small molecules, identified via high-throughput screening or derivatized from known scaffolds, have shown promise as drug candidates to improve biological timing and physiological outputs in disease models. In this review, we first briefly describe the circadian system, including the core oscillator and the cellular networks. Research progress on clock-modulating small molecules is presented, focusing on development strategies and biological efficacies. We highlight the therapeutic potential of small molecules in clock-related pathologies, including jet lag and shiftwork; various chronic diseases, particularly metabolic disease; and aging. Emerging opportunities to identify and exploit clock modulators as novel therapeutic agents are discussed.
The mammalian circadian clock involves a transcriptional feedback loop in which CLOCK and BMAL1 activate the Period and Cryptochrome genes, which then feed back and repress their own transcription. ...We have interrogated the transcriptional architecture of the drcadian transcriptional regulatory loop on a genome scale in mouse liver and find a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II (RNAPII) recruitment RNA expression, and chromatin states. We find that the drcadian transcriptional cycle of the clock consists of three distinct phases: a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Only 22% of messenger RNA (mRNA) cycling genes are driven by de novo transcription, suggesting that both transcriptional and posttranscriptional mechanisms underlie the mammalian circadian clock. We also find that drcadian modulation of RNAPII recruitment and chromatin remodeling occurs on a genome-wide scale far greater than that seen previously by gene expression profiling.
Environmental temperature cycles are a universal entraining cue for all circadian systems at the organismal level with the exception of homeothermic vertebrates. We report here that resistance to ...temperature entrainment is a property of the suprachiasmatic nucleus (SCN) network and is not a cell-autonomous property of mammalian clocks. This differential sensitivity to temperature allows the SCN to drive circadian rhythms in body temperature, which can then act as a universal cue for the entrainment of cell-autonomous oscillators throughout the body. Pharmacological experiments show that network interactions in the SCN are required for temperature resistance and that the heat shock pathway is integral to temperature resetting and temperature compensation in mammalian cells. These results suggest that the evolutionarily ancient temperature resetting response can be used in homeothermic animals to enhance internal circadian synchronization.
Coronavirus disease 2019 (COVID‐19), the disease resulting from infection by a novel coronavirus, SARS‐Cov2, has rapidly spread since November 2019 leading to a global pandemic. SARS‐Cov2 has ...infected over four million people and caused over 290,000 deaths worldwide. Although most cases are mild, a subset of patients develop a severe and atypical presentation of acute respiratory distress syndrome (ARDS) that is characterised by a cytokine release storm (CRS). Paradoxically, treatment with anti‐inflammatory agents and immune regulators has been associated with worsening of ARDS. We hypothesize that the intrinsic circadian clock of the lung and the immune system may regulate individual components of CRS, and thus, chronotherapy may be used to effectively manage ARDS in COVID‐19 patients.
LINKED ARTICLES
This article is part of a themed issue on The Pharmacology of COVID‐19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc
Glutamine is an essential nutrient that regulates energy production, redox homeostasis, and signaling in cancer cells. Despite the importance of glutamine in mitochondrial metabolism, the ...mitochondrial glutamine transporter has long been unknown. Here, we show that the SLC1A5 variant plays a critical role in cancer metabolic reprogramming by transporting glutamine into mitochondria. The SLC1A5 variant has an N-terminal targeting signal for mitochondrial localization. Hypoxia-induced gene expression of the SLC1A5 variant is mediated by HIF-2α. Overexpression of the SLC1A5 variant mediates glutamine-induced ATP production and glutathione synthesis and confers gemcitabine resistance to pancreatic cancer cells. SLC1A5 variant knockdown and overexpression alter cancer cell and tumor growth, supporting an oncogenic role. This work demonstrates that the SLC1A5 variant is a mitochondrial glutamine transporter for cancer metabolic reprogramming.
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•The SLC1A5 variant is a mitochondrial glutamine transporter•The SLC1A5 variant has a mitochondrial targeting sequence•Hypoxia controls SLC1A5 variant expression through HIF-2α•The SLC1A5 variant mediates mitochondrial glutamine metabolism in cancer
Despite the importance of glutamine in cancer metabolism, the mitochondrial glutamine transporter has long been unknown. Yoo et al. show that a variant of SLC1A5 has a mitochondrial targeting signal for mitochondrial localization and is induced by HIF-2α. SLC1A5 variant knockdown suppressed cancer cell growth, supporting an oncogenic role.
Dysregulation of circadian rhythms is associated with metabolic dysfunction, yet it is unclear whether enhancing clock function can ameliorate metabolic disorders. In an unbiased chemical screen ...using fibroblasts expressing PER2::Luc, we identified Nobiletin (NOB), a natural polymethoxylated flavone, as a clock amplitude-enhancing small molecule. When administered to diet-induced obese (DIO) mice, NOB strongly counteracted metabolic syndrome and augmented energy expenditure and locomotor activity in a Clock gene-dependent manner. In db/db mutant mice, the clock is also required for the mitigating effects of NOB on metabolic disorders. In DIO mouse liver, NOB enhanced clock protein levels and elicited pronounced gene expression remodeling. We identified retinoid acid receptor-related orphan receptors as direct targets of NOB, revealing a pharmacological intervention that enhances circadian rhythms to combat metabolic disease via the circadian gene network.
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•High-throughput screening identified Nobiletin as a clock amplitude enhancer•Nobiletin potently protects against metabolic syndrome in a clock-dependent manner•Nobiletin remodels circadian and metabolic gene expression•Nobiletin is an agonist for the ROR nuclear receptors in the circadian oscillator
In a high-throughput chemical screen, He et al. identify the small molecule Nobiletin (NOB), a naturally occurring compound enriched in citrus peels, as a circadian clock amplitude enhancer, which protects against metabolic disease. NOB is an agonist for the ROR nuclear receptors in the circadian oscillator.
The wide range of fascinating supramolecular architectures found in nature, from DNA double helices to giant protein shells, inspires researchers to mimic the diverse shapes and functions of natural ...systems. Thus, a variety of artificial molecular platforms have been developed by assembling DNA-, peptide-, and protein-based building blocks for medicinal and biological applications. There has also been a significant interest in the research of non-natural oligomers (i.e., foldamers) that fold into well-defined secondary structures analogous to those found in proteins, because the assemblies of foldamers are expected not only to form biomimetic supramolecular architectures that resemble those of nature but also to display unique functions and unprecedented topologies at the same time due to their different folding propensities from those of natural building blocks. Foldamer-based supramolecular architectures have been reported in the form of nanofibers, nanochannels, nanosheets, and finite three-dimensional (3D) shapes. We have developed a new class of crystalline peptidic materials termed “foldectures” (a compound of foldamer and architecture) with unprecedented topological complexity derived from the rapid and nonequilibrium aqueous phase self-assembly of foldamers. In this Account, we discuss the morphological features, molecular packing structures, physical properties, and potential applications of foldectures. Foldectures exhibit well-defined, microscale, homogeneous, and finite structures with unique morphologies such as windmill, tooth, and trigonal bipyramid shapes. The symmetry elements of the morphologies vary with the foldamer building blocks and are retained upon surfactant-assisted shape evolution. Structural characterization by powder X-ray diffraction (PXRD) revealed the molecular packing structures, suggesting how the foldamer building blocks assembled in the 3D structure. The analysis by PXRD showed that intermolecular hydrogen bonding connects foldamers in head-to-tail fashion, while hydrophobic attraction plays a role in arranging foldamers in parallel, antiparallel, or cholesteric phase-like manners. Each packing structure from the foldamer building blocks possesses distinct symmetry elements that are directly expressed in the 3D morphologies. Because of their well-ordered molecular packing structures, foldectures exhibit facet-dependent surface characteristics and anisotropic magnetic susceptibility. The facet-dependent surface property was harnessed to synthesize anisotropic metal nanoparticle–foldecture composites, and the anisotropic magnetic susceptibility enables foldectures to undergo real-time alignment and rotating motion in response to an external magnetic field. By means of their unusual shapes and properties, foldectures have been demonstrated to mimic the functionality of natural systems such as magnetosomes or carboxysomes. Further development of foldectures using higher-order building units, complicated packing motifs, and functional moieties could provide a novel biocompatible platform rivaling 3D biological architectures in natural systems.
Flexible piezoelectric acoustic sensors have been developed to generate multiple sound signals with high sensitivity, shifting the paradigm of future voice technologies. Speech recognition based on ...advanced acoustic sensors and optimized machine learning software will play an innovative interface for artificial intelligence (AI) services. Collaboration and novel approaches between both smart sensors and speech algorithms should be attempted to realize a hyperconnected society, which can offer personalized services such as biometric authentication, AI secretaries, and home appliances. Here, representative developments in speech recognition are reviewed in terms of flexible piezoelectric materials, self‐powered sensors, machine learning algorithms, and speaker recognition.
Flexible piezoelectric acoustic sensors and machine learning for speech processing can change the paradigm of voice technologies for the hyperconnected society, offering personalized intelligent services such as biometric authentication, AI secretaries, and Internet‐of‐Things (IoT) appliances. The recent advances in the fields of self‐powered flexible acoustic sensors and machine learning algorithms for speech recognition are comprehensively summarized.
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