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  • Masao Doi
Masao Doi

Masao Doi
Kyoto University | Kyodai · Graduate School of Pharmaceutical Sciences / Faculty of Pharmaceutical Sciences

PhD

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121
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Publications

Publications (121)
Article
Designer receptors exclusively activated by designer drugs (DREADDs) are engineered G-protein-coupled receptors that afford reversible manipulation of neuronal activity in vivo. Here, we introduce size-reduced DREADD derivatives miniDq and miniDi, which inherit the basic receptor properties from the Gq-coupled excitatory receptor hM3Dq and the Gi-c...
Chapter
The circadian fluctuation of body temperature is one of the most prominent and stable outputs of the circadian clock and plays an important role in maintaining optimal day–night energy homeostasis. The body temperature of homothermic animals is not strictly constant, but it shows daily oscillation within a range of 1–3 °C, which is sufficient to sy...
Article
Full-text available
Ribosome profiling, which is based on deep sequencing of ribosome footprints, has served as a powerful tool for elucidating the regulatory mechanism of protein synthesis. However, the current method has substantial issues: contamination by rRNAs and the lack of appropriate methods to measure ribosome numbers in transcripts. Here, we overcome these...
Article
Full-text available
Unknown interactions between drugs remain the limiting factor for clinical application of drugs, and the induction and inhibition of drug-metabolizing CYP enzymes are considered the key to examining the drug–drug interaction (DDI). In this study, using human HepaRG cells as an in vitro model system, we analyzed the potential DDI based on the expres...
Article
Temperature-dependent translational control of the core clock gene Per2 plays an important role in establishing entrainment of the circadian clock to physiological body temperature cycles. Previously, we found an involvement of the phosphatidylinositol 3-kinase (PI3K) in causing Per2 protein expression in response to a warm temperature shift (WTS)...
Article
Full-text available
The circadian clock is a biological timekeeping system that oscillates with a circa-24-h period, reset by environmental timing cues, especially light, to the 24-h day–night cycle. In mammals, a “central” clock in the hypothalamic suprachiasmatic nucleus (SCN) synchronizes “peripheral” clocks throughout the body to regulate behavior, metabolism, and...
Preprint
Full-text available
Ribosome profiling, which is based on deep sequencing of ribosome footprints, has served as a powerful tool to unveil the regulatory mechanism of protein synthesis. However, the current method has substantial issues: contamination by rRNAs and the lack of appropriate means to determine overall ribosome numbers in transcripts. Here, we overcome thes...
Article
Full-text available
Body temperature in homeothermic animals does not remain constant but displays a regular circadian fluctuation within a physiological range (e.g., 35°C-38.5°C in mice), constituting a fundamental systemic signal to harmonize circadian clock-regulated physiology. Here, we find the minimal upstream open reading frame (uORF) encoded by the 5' UTR of t...
Article
Full-text available
Small extracellular vesicles (sEVs) are nano‐sized vesicles secreted from various cells that contain bioactive metabolites and function as key regulators for intercellular communication. sEVs modulate diverse biological and pathological processes in the body, and the amount of circulating sEVs has been reported to correlate with certain disease pro...
Article
The suprachiasmatic nucleus (SCN) is the master circadian clock in mammals and is properly entrained by environmental light cycle. However, the molecular mechanism(s) determining the magnitude of phase shift by light is still not fully understood. The orphan G-protein-coupled receptor Gpr176 is enriched in the SCN, controls the pace (period) of the...
Article
The epidermis is the outermost layer of the skin and the body's primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the s...
Article
Calcium signaling is pivotal to the circadian clockwork in the suprachiasmatic nucleus (SCN), particularly in rhythm entrainment to environmental light-dark cycles. Here, we show that a small G-protein Gem, an endogenous inhibitor of high-voltage-activated voltage-dependent calcium channels (VDCCs), is rapidly induced by light in SCN neurons via th...
Article
Body temperature of thermostatic animals does not stay constant but displays a regular circadian fluctuation, which has a role in maintaining homeostasis of sleep and metabolism as well as entraining the peripheral circadian clocks in the body. Following the discovery of clock genes that generate the circadian rhythm and the master clock structure...
Article
Full-text available
Canonically, hormones are produced in the endocrine organs and delivered to target tissues. However, for steroids, the concept of tissue intracrinology, whereby hormones are produced in the tissues where they exert their effect without release into circulation, has been proposed, but its role in physiology/disease remains unclear. The meibomian gla...
Article
Full-text available
Gpr19 encodes an evolutionarily conserved orphan G-protein-coupled receptor (GPCR) with currently no established physiological role in vivo. We characterized Gpr19 expression in the suprachiasmatic nucleus (SCN), the locus of the master circadian clock in the brain, and determined its role in the context of the circadian rhythm regulation. We found...
Preprint
Background and Purpose Gpr19 encodes an evolutionarily conserved orphan G-protein-coupled receptor (GPCR) with no established physiological function in vivo. The purpose of this study was to determine the role of Gpr19 in the circadian clock system.Experimental Approach We examined whether and how the master circadian clock neurons in the suprachia...
Article
Full-text available
Circadian clocks orchestrate multiple different physiological rhythms in a well-synchronized manner. However, how these separate rhythms are interconnected is not exactly understood. Here, we developed a method that allows for the real-time simultaneous measurement of locomotor activity and body temperature of mice using infrared video camera imagi...
Article
Full-text available
By the effort to identify candidate signaling molecules important for the formation of robust circadian rhythms in the suprachiasmatic nucleus (SCN), the mammalian circadian center, here we characterize the role of α2δ proteins, synaptic molecules initially identified as an auxiliary subunit of the voltage dependent calcium channel, in circadian rh...
Article
Full-text available
Hepatocellular carcinoma (HCC) is the most predominant primary malignancy in the liver. Genotoxic and genetic models have revealed that HCC cells are derived from hepatocytes, but where the critical region for tumor foci emergence is and how this transformation occurs are still unclear. Here, hyperpolyploidization of hepatocytes around the centrilo...
Preprint
Full-text available
Hepatocellular carcinoma (HCC) is the most predominant primary malignancy in the liver. Genotoxic and genetic models have revealed that HCC cells are derived from hepatocytes, but where the critical region for tumor foci emergence is and how this transformation occurs are still unclear. Here, hyperpolyploidization of hepatocytes around the centrilo...
Article
Full-text available
G-protein-coupled receptors (GPCRs) are an important source of drug targets with diverse therapeutic applications. However, there are still more than one hundred orphan GPCRs, whose ligands and functions remain unidentified. The suprachiasmatic nucleus (SCN) is the central circadian clock of the brain, directing daily rhythms in activity–rest behav...
Article
Full-text available
G-protein-coupled receptors (GPCRs) are important drug targets with diverse therapeutic applications. However, there are still more than a hundred orphan GPCRs, whose protein functions and biochemical features remain unidentified. Gpr176 encodes a class-A orphan GPCR that has a role in circadian clock regulation in mouse hypothalamus and is also im...
Article
Recently Koronowski et al. (Cell, 2019) showed that reconstitution of the liver circadian clock in otherwise genetically arrhythmic mice revives the daily program of the nicotinamide adenine dinucleotide salvage pathway and glycogenesis in vivo. This liver-autonomous metabolic cycling cannot be sustained under constant darkness, revealing the impor...
Article
Full-text available
Non-coding cis-regulatory elements are essential determinants of development, but their exact impacts on behavior and physiology in adults remain elusive. Cis-element-based transcriptional regulation is believed to be crucial for generating circadian rhythms in behavior and physiology. However, genetic evidence supporting this model is based on mut...
Article
Full-text available
Previous studies have established that fetal Leydig cells (FLCs) and adult Leydig cells (ALCs) show distinct functional characteristics. However, the lineage relationship between FLCs and ALCs has not been clarified yet. Here, we reveal that a subset of FLCs dedifferentiate at fetal stages to give rise to ALCs at the pubertal stage. Moreover, the d...
Article
Full-text available
Correction for “Two Ck1δ transcripts regulated by m6A meth-ylation code for two antagonistic kinases in the control of the circadian clock,” by Jean-Michel Fustin, Rika Kojima, Kakeru Itoh, Hsin-Yi Chang, Ye Shiqi, Bowen Zhuang, Asami Oji, Shingo Gibo, Rajesh Narasimamurthy, David Virshup, Gen Kurosawa, Masao Doi, Ichiro Manabe, Yasushi Ishihama, M...
Article
Full-text available
Significance The most abundant modification in mRNA is the N ⁶ -methylation of internal adenosines (m6A), but m6A’s physiological function is unknown for most mRNAs. Here we show that Casein Kinase 1 Delta mRNA ( Ck1δ ), coding for a critical kinase in the control of circadian rhythms, is regulated by m6A. When m6A is inhibited, the expression of t...
Article
Full-text available
Micturition behavior follows regular day/night fluctuations, and unwanted increase in micturition could occur during night in jet lag condition. To clarify the effect of jet lag on micturition behavior, we simultaneously detected circadian micturition patterns and locomotor activity rhythms of mice under experimental jet lag conditions, by applying...
Article
Jet-lag symptoms arise from temporal misalignment between the internal circadian clock and external solar time when traveling across multiple time zones. Light is known as a strong timing cue of the circadian clock. We here examined the effect of daily light on the process of jet lag by detecting c-Fos expression in the master clock neurons in the...
Article
Full-text available
Daily body temperature rhythm (BTR) is essential for maintaining homeostasis. BTR is regulated separately from locomotor activity rhythms, but its molecular basis is largely unknown. While mammals internally regulate BTR, ectotherms, includingDrosophila, exhibit temperature preference rhythm (TPR) behavior to regulate BTR. Here, we demonstrate that...
Article
Full-text available
Day-night changes in the storage capacity of the urinary bladder are indispensable for sound sleep. Connexin 43 (Cx43), a major gap junction protein, forms hemichannels as a pathway of ATP in other cell types, and the urinary bladder utilizes ATP as a mechanotransduction signals to modulate its capacity. Here, we demonstrate that the circadian cloc...
Article
It is not known whether the endogenous mammalian core clock proteins sustain measurable oscillations in cells in culture where de novo translation is pharmacologically inhibited. We studied here the mammalian core clock protein PER2, which undergoes robust circadian oscillations in both abundance and phosphorylation. With a newly developed antibody...
Article
Full-text available
Liver metabolism undergoes robust circadian oscillations in gene expression and enzymatic activity essential for liver homeostasis, but whether the circadian clock controls homeostatic self-renewal of hepatocytes is unknown. Here we show that hepatocyte polyploidization is markedly accelerated around the central vein, the site of permanent cell sel...
Article
Full-text available
The Gm7325 gene, bioinformatically identified in the mouse genome, encodes a small protein but has not been characterized until recently. Our gene expression analysis revealed that Gm7325 transcription is remarkably upregulated in injured skeletal muscle tissues. Activated satellite cells and immature myotubes were densely decorated with positive s...
Article
G-protein-coupled receptors (GPCRs) constitute an immensely important class of drug targets with diverse clinical applications. There are still more than 120 orphan GPCRs whose cognate ligands and physiological functions are not known. A set of circadian pacemaker neurons that governs daily rhythms in behavior and physiology resides in the suprachi...
Article
Full-text available
Among nonphotic stimulants, a classic cholinergic agonist, carbachol, is known to have a strong and unique phase-resetting effect on the circadian clock: Intracerebroventricular carbachol treatment causes phase delays during the subjective early night and phase advances in the subjective late night, but the effects of this drug on the suprachiasmat...
Article
With the current societal norm of shiftwork and long working hours, maintaining a stable daily life is becoming very difficult. An irregular lifestyle disrupts circadian rhythms, resulting in the malfunction of body physiology and ultimately leading to lifestyle-related diseases, including hypertension. By analyzing completely arrhythmic Cry1/Cry2...
Article
Rationale: Cocaine-induced behaviors such as locomotor activity and self-administration show circadian rhythmicity. A previous study demonstrated the involvement of circadian clock genes in cocaine reinforcement and vulnerable use. Objective This study aims to characterize the circadian clock genes that regulate diurnal variations in locomotor act...
Article
Full-text available
G-protein-coupled receptors (GPCRs) participate in a broad range of physiological functions. A priority for fundamental and clinical research, therefore, is to decipher the function of over 140 remaining orphan GPCRs. The suprachiasmatic nucleus (SCN), the brain's circadian pacemaker, governs daily rhythms in behaviour and physiology. Here we launc...
Article
Full-text available
Measuring real-time gene activity in the brains of freely moving animals presents a challenging issue in neuroscience research. Circadian gene expression in neurons of the suprachiasmatic nucleus (SCN), a small nucleus in the hypothalamus, is reflected in behavioral rhythmicity. Cellular oscillatory gene expression is generated by a transcription-t...
Article
Comment on Azmahani et al. "Steroidogenic enzymes, their related transcription factors and nuclear receptors in human sebaceous glands under normal and pathological conditions". [J Steroid Biochem Mol Biol. 2014
Article
In the adrenal, the type I 3β-hydroxysteroid dehydrogenase (HSD3B1) is expressed exclusively in the zona glomerulosa (ZG), where aldosterone is produced. Angiotensin II (AngII) and potassium (K(+)) are the major physiological regulators of aldosterone synthesis. However, their respective roles in regulation of aldosterone synthesis are not fully de...
Chapter
Full-text available
The chapter begins with explaining the effects of deleting of Cry genes which causes complete loss of circadian rhythms and leads to hyperaldosteronism and salt-sensitive hypertension. Aldosterone induces reabsorption of ions and water in the kidneys, thereby increasing blood volume, leading to higher blood pressure. Since primary aldosteronism (PA...
Article
It has become important to evaluate the possible involvement of 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) and 2 (HSD3B2) isoforms in aldosterone-producing adenoma (APA). In this study, we studied 67 and 100 APA cases using real-time quantitative PCR (qPCR) and immunohistochemistry, respectively. Results of qPCR analysis demonstrated that HSD3...
Article
The expressions of steroidogenic enzymes to produce aldosterone like CYP11B1, CYP11B2, 3BHSD1 and 3BHSD2 remain to be clarified to confirm pathological subclassification between aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Furthermore, we examined the correlation between APA tumor size and the status of intratumoral...
Article
Full-text available
The 3β-hydroxysteroid dehydrogenase (3β-HSD) is an enzyme crucial for steroid synthesis. Two different 3β-HSD isoforms exist in humans. Classically, HSD3B2 was considered the principal isoform present in the adrenal. However, we recently showed that the alternative isoform, HSD3B1, is expressed specifically within the adrenal zona glomerulosa (ZG),...
Article
The sebaceous gland is a major site of steroid synthesis in human skin, but details of the status of steroidogenic enzymes and their regulation in human sebaceous glands under normal and pathological conditions have rarely been reported. Therefore, in this study, we examined the status of steroidogenic enzymes, sex steroid receptors and transcripti...
Article
Recent advances in circadian biology strongly suggest that there are still genes involved in the generation and maintenance of biological rhythms that remain to be identified. It has been generally appreciated that circadian rhythms are generated intracellularly through transcription/translation-based autoregulatory feedback circuits of the clock g...
Article
Full-text available
Context: Therapeutic management of primary aldosteronism requires accurate differentiation between aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). However, little is known about the molecular features that delineate the difference between APA and IHA. Two different isoforms of 3β-hydroxysteroid dehydrogenase (HSD3B1 an...
Article
Full-text available
The eukaryotic biological clock involves a negative transcription-translation feedback loop in which clock genes regulate their own transcription and that of output genes of metabolic significance. While around 10% of the liver transcriptome is rhythmic, only about a fifth is driven by de novo transcription, indicating mRNA processing is a major ci...
Article
Full-text available
The eukaryotic biological clock involves a negative transcription-translation feedback loop in which clock genes regulate their own transcription and that of output genes of metabolic significance. While around 10% of the liver transcriptome is rhythmic, only about a fifth is driven by de novo transcription, indicating mRNA processing is a major ci...
Article
Although aldosterone has an essential role in controlling electrolyte and body fluid homeostasis, aldosterone also exerts certain pathological effects on the kidney. Several previous studies have attempted to examine these deleterious effects. However, the majority of these studies were performed using various injury models, including high-salt tre...
Article
Full-text available
Jet-lag symptoms arise from temporal misalignment between the internal circadian clock and external solar time. We found that circadian rhythms of behavior (locomotor activity), clock gene expression, and body temperature immediately reentrained to phase-shifted light-dark cycles in mice lacking vasopressin receptors V1a and V1b (V1a–/–V1b–/–). Nev...
Article
The enzyme 3β -hydroxysteroid dehydrogenase/isomerase (3β -HSD) is essential for the biosynthesis of all active steroid hormones, such as those secreted from the adrenal gland, testis, ovary, skin and placenta. The 3β-HSD enzymes exist in multiple isoforms in humans and rodents. To date, six different isoforms have been identified in the mouse, and...
Conference Paper
Purpose . The circadian clock is a molecular oscillator system consisting of a group of genes formulating transcription-translation feedback loops, and exists in most body cells and organs. Involvement of the circadian clock is reported in the normal and pathological physiology of various organs, including brain, heart, liver, adrenal grand, and ot...
Article
Full-text available
One of the most significant conceptual changes brought about by the analysis of circadian clock-deficient mice is that abnormalities in the circadian clock are linked not only to sleep arousal disorder but also to a wide variety of common diseases, including hypertension, diabetes, obesity, and cancer. It has recently been shown that the disruption...
Article
Full-text available
Nocturnal enuresis in children and nocturia in the elderly are two highly prevalent clinical conditions characterized by a mismatch between urine production rate in the kidneys and storage in the urinary bladder during the sleep phase. Here we demonstrate, using a novel method for automated recording of mouse micturition, that connexin43, a bladder...