研究者詳細 - 廣田　毅

論文 - 廣田　毅

分割表示 69 件中 21 - 40 件目／全件表示 >>

概日時計を標的とした化合物と創薬の最前線招待有り

飯田夢惟、廣田毅

Medical Science Digest 47 巻頁： 23 - 25 2021年

A N-terminally deleted form of the CK2α' catalytic subunit is sufficient to support cell viability. 査読有り国際誌

Borgo C, D'Amore C, Cesaro L, Itami K, Hirota T, Salvi M, Pinna LA

Biochemical and biophysical research communications 531 巻 ( 3 ) 頁： 409 - 415 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

Viable clones of C2C12 myoblasts where both catalytic subunits of protein kinase CK2 had been knocked out by the CRISPR/Cas9 methodology have recently been generated, thus challenging the concept that CK2 is essential for cell viability. Here we present evidence that these cells are still endowed with a residual “CK2-like” activity that is able to phosphorylate Ser-13 of endogenous CDC37. Searching for a molecular entity accounting for such an activity we have identified a band running slightly ahead of CK2α′ on SDS-PAGE. This band is not detectable by in-gel casein kinase assay but it co-immuno-precipitates with the β-subunit being downregulated by specific CK2α′ targeting siRNA treatment. Its size and biochemical properties are consistent with those of CK2α′ mutants deleted upstream of Glu-15 generated during the knockout process. This mutant sheds light on the role of the CK2 N-terminal segment as a regulator of activity and stability. Comparable cytotoxic efficacy of two selective and structurally unrelated CK2 inhibitors support the view that survival of CK2α/α’−/− cells relies on this deleted form of CK2α′, whose discovery provides novel perspectives about the biological role of CK2.

DOI： 10.1016/j.bbrc.2020.07.112

An Isoform-Selective Modulator of Cryptochrome 1 Regulates Circadian Rhythms in Mammals. 査読有り国際誌

Miller S, Aikawa Y, Sugiyama A, Nagai Y, Hara A, Oshima T, Amaike K, Kay SA, Itami K, Hirota T

Cell chemical biology 27 巻 ( 9 ) 頁： 1192 - 1198 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cell Chemical Biology

Cryptochrome 1 (CRY1) and CRY2 are core regulators of the circadian clock, and the development of isoform-selective modulators is important for the elucidation of their redundant and distinct functions. Here, we report the identification and functional characterization of a small-molecule modulator of the mammalian circadian clock that selectively controls CRY1. Cell-based circadian chemical screening identified a thienopyrimidine derivative KL201 that lengthened the period of circadian rhythms in cells and tissues. Functional assays revealed stabilization of CRY1 but not CRY2 by KL201. A structure-activity relationship study of KL201 derivatives in combination with X-ray crystallography of the CRY1-KL201 complex uncovered critical sites and interactions required for CRY1 regulation. KL201 bound to CRY1 in overlap with FBXL3, a subunit of ubiquitin ligase complex, and the effect of KL201 was blunted by knockdown of FBXL3. KL201 will facilitate isoform-selective regulation of CRY1 to accelerate chronobiology research and therapeutics against clock-related diseases.

DOI： 10.1016/j.chembiol.2020.05.008

Small Molecules Modulating Mammalian Biological Clocks: Exciting New Opportunities for Synthetic Chemistry 査読有り

Amaike Kazuma, Oshima Tsuyoshi, Skoulding Nicola Stephanie, Toyama Yoshifumi, Hirota Tsuyoshi, Itami Kenichiro

CHEM 6 巻 ( 9 ) 頁： 2186 - 2198 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Chem

Challenges and opportunities: • Increasing opportunities for the discovery of new circadian clock modulators, which are attractive drug candidates for clock-related diseases in pharmaceutical industry, and to enhance crop yield in agriculture. • Development of new reactions for rapid access to hit compound derivatives, accelerating structure-activity relationship studies, which are generally time consuming. • New approaches for target identification of clock-modulating small molecules, which is still challenging, enable molecular-level understanding and new structural designs.

DOI： 10.1016/j.chempr.2020.08.011

低分子化合物を用いた概日時計機能の操作招待有り

廣田毅

日本薬理学会年会要旨集 93 巻 ( 0 ) 頁： 1-S12-3 - S12-3 2020年

担当区分：筆頭著者,　責任著者記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：公益社団法人日本薬理学会

<p>In mammals, circadian rhythms are generated through transcriptional regulatory networks of the clock genes. To search for novel clock modifiers, we applied chemical biology approaches. From hundreds of thousands of small molecules with diverse structure, we identified a number of compounds that potently change the period of the circadian clock in human cells. Among the period lengthening compounds, we previously discovered the first small molecule targeting the core clock protein CRY. The compound KL001 interacts with FAD-binding pocket of CRY and inhibits FBXL3-dependent degradation. By analyzing KL001 derivatives, we found 10 times more potent compound KL044. KL001 and KL044 share carbazole group and act on both CRY1 and CRY2. We further identified novel period lengthening compounds KL101 and TH301 that do not have carbazole group. Surprisingly, we discovered that KL101 is selective against CRY1 while TH301 shows much higher effect on CRY2. To understand molecular basis of the CRY1/CRY2 selectivity, we determined the X-ray crystal structures of CRY1-KL101, CRY1-TH301, CRY2-TH301, and CRY1-KL044 complexes. In this presentation, I will discuss these unique compounds that will enable atomic-level dissection of the functional difference between CRY1 and CRY2 proteins and their selective manipulation.</p>

DOI： 10.1254/jpssuppl.93.0_1-s12-3

"Janus" efficacy of CX-5011: CK2 inhibition and methuosis induction by independent mechanisms. 査読有り国際誌

D'Amore C, Moro E, Borgo C, Itami K, Hirota T, Pinna LA, Salvi M

Biochimica et biophysica acta. Molecular cell research 1867 巻 ( 11 ) 頁： 118807 - 118807 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biochimica et Biophysica Acta - Molecular Cell Research

Methuosis has been described as a distinctive form of cell death characterized by the displacement of large fluid-filled vacuoles derived from uncontrolled macropinocytosis. Its induction has been proposed as a new strategy against cancer cells. Small molecules, such as indole-based calchones, have been identified as methuosis inducers and, recently, the CK2 inhibitor CX-4945 has been shown to have a similar effect on different cell types. However, the contribution of protein kinase CK2 to methuosis signalling is still controversial. Here we show that methuosis is not related to CK2 activity since it is not affected by structurally unrelated CK2 inhibitors and genetic reduction/ablation of CK2 subunits. Interestingly, CX-5011, a CK2 inhibitor related to CX-4945, behaves as a CK2-independent methuosis inducer, four times more powerful than its parental compound and capable to promote the formation on enlarged cytosolic vacuoles at low micromolar concentrations. We show that pharmacological inhibition of the small GTPase Rac-1, its downregulation by siRNA treatment, or the over-expression of the dominant-negative mutated form of Rac-1 (Rac-1 T17N), impairs CX-5011 ability to induce methuosis. Furthermore, cell treatment with CX-5011 induces a durable activation of Rac-1 that persists for at least 24 h. Worthy of note, CX-5011 is able to promote macropinocytosis not only in mammalian cells, but also in an in-vivo zebrafish model. Based on these evidences, CX-5011 is, therefore, proposed as a potential promising compound for cancer therapies for its dual efficacy as an inhibitor of the pro-survival kinase CK2 and inducer of methuosis.

DOI： 10.1016/j.bbamcr.2020.118807

Pharmacological Interventions to Circadian Clocks and Their Molecular Bases. 査読有り国際誌

Miller S, Hirota T

Journal of molecular biology 432 巻 ( 12 ) 頁： 3498 - 3514 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Molecular Biology

Daily physiological rhythms are regulated by the body's internal timekeeper known as the circadian clock. Expression, post-translational modification, and degradation of clock proteins constituting the circadian clock are precisely controlled in a rhythmic manner. Perturbation of these processes by nature and nurture results in physiological dysfunction and diseases. Small-molecule modulators of clock or clock-related proteins can adjust clock functions, and thus represent a promising method of therapeutic treatment for a range of clock-related diseases. In this review, we will introduce the identification and development of small-molecule compounds that target clock proteins, as well as X-ray crystal structures of protein-compound complexes that facilitate the understanding of clock protein regulation and drug derivatization. Furthermore, we describe the effects of these compounds in a diseased setting and discuss the therapeutic potential of clock modulators.

DOI： 10.1016/j.jmb.2020.01.003

Isoform-selective regulation of mammalian cryptochromes. 査読有り国際誌

Miller S, Son YL, Aikawa Y, Makino E, Nagai Y, Srivastava A, Oshima T, Sugiyama A, Hara A, Abe K, Hirata K, Oishi S, Hagihara S, Sato A, Tama F, Itami K, Kay SA, Hatori M, Hirota T

Nature chemical biology 16 巻 ( 6 ) 頁： 676 - 685 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Chemical Biology

CRY1 and CRY2 are essential components of the circadian clock controlling daily physiological rhythms. Accumulating evidences indicate distinct roles of these highly homologous proteins, in addition to redundant functions. Therefore, the development of isoform-selective compounds represents an effective approach towards understanding the similarities and differences of CRY1 and CRY2 by controlling each isoform individually. We conducted phenotypic screenings of circadian clock modulators, and identified KL101 and TH301 that selectively stabilize CRY1 and CRY2, respectively. Crystal structures of CRY–compound complexes revealed conservation of compound-binding sites between CRY1 and CRY2. We further discovered a unique mechanism underlying compound selectivity in which the disordered C-terminal region outside the pocket was required for the differential effects of KL101 and TH301 against CRY isoforms. By using these compounds, we found a new role of CRY1 and CRY2 as enhancers of brown adipocyte differentiation, providing the basis of CRY-mediated regulation of energy expenditure. [Figure not available: see fulltext.]

DOI： 10.1038/s41589-020-0505-1

Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing. 査読有り国際誌

Fribourgh JL, Srivastava A, Sandate CR, Michael AK, Hsu PL, Rakers C, Nguyen LT, Torgrimson MR, Parico GCG, Tripathi S, Zheng N, Lander GC, Hirota T, Tama F, Partch CL

eLife 9 巻 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：eLife

Mammalian circadian rhythms are generated by a transcription-based feedback loop in which CLOCK:BMAL1 drives transcription of its repressors (PER1/2, CRY1/2), which ultimately interact with CLOCK:BMAL1 to close the feedback loop with ~24-hour periodicity. Here we pinpoint a key difference between CRY1 and CRY2 that underlies their differential strengths as transcriptional repressors. Both cryptochromes bind the BMAL1 transactivation domain similarly to sequester it from coactivators and repress CLOCK:BMAL1 activity. However, we find that CRY1 is recruited with much higher affinity to the PAS domain core of CLOCK:BMAL1, allowing it to serve as a stronger repressor that lengthens circadian period. We discovered a dynamic serine-rich loop adjacent to the secondary pocket in the photolyase homology region (PHR) domain that regulates differential binding of cryptochromes to the PAS domain core of CLOCK:BMAL1. Notably, binding of the co-repressor PER2 remodels the serine loop of CRY2, making it more CRY1-like and enhancing its affinity for CLOCK:BMAL1.

DOI： 10.7554/eLife.55275

化合物を使って体内時計を操る招待有り

廣田毅

化学 75 巻頁： 66 - 67 2020年

Identification of pathways that regulate circadian rhythms using a larval zebrafish small molecule screen. 査読有り国際誌

Mosser EA, Chiu CN, Tamai TK, Hirota T, Li S, Hui M, Wang A, Singh C, Giovanni A, Kay SA, Prober DA

Scientific reports 9 巻 ( 1 ) 頁： 12405 - 12405 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

The circadian clock ensures that behavioral and physiological processes occur at appropriate times during the 24-hour day/night cycle, and is regulated at both the cellular and organismal levels. To identify pathways acting on intact animals, we performed a small molecule screen using a luminescent reporter of molecular circadian rhythms in zebrafish larvae. We identified both known and novel pathways that affect circadian period, amplitude and phase. Several drugs identified in the screen did not affect circadian rhythms in cultured cells derived from luminescent reporter embryos or in established zebrafish and mammalian cell lines, suggesting they act via mechanisms absent in cell culture. Strikingly, using drugs that promote or inhibit inflammation, as well as a mutant that lacks microglia, we found that inflammatory state affects circadian amplitude. These results demonstrate a benefit of performing drug screens using intact animals and provide novel targets for treating circadian rhythm disorders.

DOI： 10.1038/s41598-019-48914-7

その他リンク： http://orcid.org/0000-0003-4876-3608

Casein kinase 1 family regulates PRR5 and TOC1 in the Arabidopsis circadian clock. 査読有り国際誌

Uehara TN, Mizutani Y, Kuwata K, Hirota T, Sato A, Mizoi J, Takao S, Matsuo H, Suzuki T, Ito S, Saito AN, Nishiwaki-Ohkawa T, Yamaguchi-Shinozaki K, Yoshimura T, Kay SA, Itami K, Kinoshita T, Yamaguchi J, Nakamichi N

Proceedings of the National Academy of Sciences of the United States of America 116 巻 ( 23 ) 頁： 11528 - 11536 2019年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America

The circadian clock provides organisms with the ability to adapt to daily and seasonal cycles. Eukaryotic clocks mostly rely on lineage-specific transcriptional-translational feedback loops (TTFLs). Posttranslational modifications are also crucial for clock functions in fungi and animals, but the posttranslational modifications that affect the plant clock are less understood. Here, using chemical biology strategies, we show that the Arabidopsis CASEIN KINASE 1 LIKE (CKL) family is involved in posttranslational modification in the plant clock. Chemical screening demonstrated that an animal CDC7/CDK9 inhibitor, PHA767491, lengthens the Arabidopsis circadian period. Affinity proteomics using a chemical probe revealed that PHA767491 binds to and inhibits multiple CKL proteins, rather than CDC7/CDK9 homologs. Simultaneous knockdown of Arabidopsis CKL-encoding genes lengthened the circadian period. CKL4 phosphorylated transcriptional repressors PSEUDO-RESPONSE REGULATOR 5 (PRR5) and TIMING OF CAB EXPRESSION 1 (TOC1) in the TTFL. PHA767491 treatment resulted in accumulation of PRR5 and TOC1, accompanied by decreasing expression of PRR5- and TOC1-target genes. A prr5 toc1 double mutant was hyposensitive to PHA767491-induced period lengthening. Together, our results reveal posttranslational modification of transcriptional repressors in plant clock TTFL by CK1 family proteins, which also modulate nonplant circadian clocks.

DOI： 10.1073/pnas.1903357116

Controlling the Circadian Clock with High Temporal Resolution through Photodosing. 査読有り国際誌

Kolarski D, Sugiyama A, Breton G, Rakers C, Ono D, Schulte A, Tama F, Itami K, Szymanski W, Hirota T, Feringa BL

Journal of the American Chemical Society 141 巻 ( 40 ) 頁： 15784 - 15791 2019年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of the American Chemical Society

Circadian clocks, biological timekeepers that are present in almost every cell of our body, are complex systems whose disruption is connected to various diseases. Controlling cellular clock function with high temporal resolution in an inducible manner would yield an innovative approach for the circadian rhythm regulation. In the present study, we present structure-guided incorporation of photoremovable protecting groups into a circadian clock modifier, longdaysin, which inhibits casein kinase I (CKI). Using photodeprotection by UV or visible light (400 nm) as the external stimulus, we have achieved quantitative and light-inducible control over the CKI activity accompanied by an accurate regulation of circadian period in cultured human cells and mouse tissues, as well as in living zebrafish. This research paves the way for the application of photodosing in achieving precise temporal control over the biological timing and opens the door for chronophotopharmacology to deeper understand the circadian clock system.

DOI： 10.1021/jacs.9b05445

Chemical Synthesis of Atomically Tailored SUMO E2 Conjugating Enzymes for the Formation of Covalently Linked SUMO–E2–E3 Ligase Ternary Complexes 査読有り国際誌

Yinfeng Zhang, Tsuyoshi Hirota, Keiko Kuwata, Shunsuke Oishi, Subramanian, G. Gramani, Jeffrey W. Bode

Journal of the American Chemical Society 141 巻 ( 37 ) 頁： 14742 - 14751 2019年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：American Chemical Society ({ACS})

E2 conjugating enzymes are the key catalytic actors in the transfer of ubiquitin, SUMO, and other ubiquitin-like modifiers to their substrate proteins. Their high rates of transfer and promiscuous binding complicate studies of their interactions and binding partners. To access specific, covalently linked conjugates of the SUMO E2 conjugating enzyme Ubc9, we prepared synthetic variants bearing site-specific non-native modifications including the following: (1) replacement of Cys93 to 2,3-diaminopropionic acid to form the amide-linked stable E2-SUMO conjugate, which is known to have high affinity for E3 ligases; (2) a photoreactive group (diazirine) to trap E3 ligases upon UV irradiation; and (3) an N-Terminal biotin for purification and detection. To construct these Ubc9 variants in a flexible, convergent manner, we combined the three leading methods: native chemical ligation (NCL), α-ketoacid-hydroxylamine (KAHA) ligation, and serine/threonine ligation (STL). Using the synthetic proteins, we demonstrated the selective formation of Ubc9-SUMO conjugates and the trapping of an E3 ligase (RanBP2) to form the stable, covalently linked SUMO1-Ubc9-RanBP2 ternary complex. The powerful combination of ligation methods-which minimizes challenges of functional group manipulations-will enable chemical probes based on E2 conjugating enzymes to trap E3 ligases and facilitate the synthesis of other protein classes.

DOI： 10.1021/jacs.9b06820

Chemical Control of Mammalian Circadian Behavior through Dual Inhibition of Casein Kinase Iα and δ 査読有り国際誌

Lee J.W, Hirota T, Ono D, Honma S, Honma K.-I, Park K, Kay S.A

Journal of Medicinal Chemistry 62 巻 ( 4 ) 頁： 1989 - 1998 2019年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Medicinal Chemistry

Circadian rhythms are controlled by transcriptional feedback loops of clock genes and proteins. The stability of clock proteins is regulated by post-translational modification, such as phosphorylation by kinases. In particular, casein kinase I (CKI) phosphorylates the PER protein to regulate proteasomal degradation and nuclear localization. Therefore, CKI inhibition can modulate mammalian circadian rhythms. In the present study, we have developed novel CKIα and CKIδ dual inhibitors by extensive structural modification of N9 and C2 position of longdaysin. We identified NCC007 that showed stronger period effects (0.32 μM for 5 h period lengthening) in a cell-based circadian assay. The following in vitro kinase assay showed that NCC007 inhibited CKIα and CKIδ with an IC 50 of 1.8 and 3.6 μM. We further demonstrated that NCC007 lengthened the period of mouse behavioral rhythms in vivo. Thus, NCC007 is a valuable tool compound to control circadian rhythms through CKI inhibition.

DOI： 10.1021/acs.jmedchem.8b01541

Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth. 査読有り国際誌

Oshima T, Niwa Y, Kuwata K, Srivastava A, Hyoda T, Tsuchiya Y, Kumagai M, Tsuyuguchi M, Tamaru T, Sugiyama A, Ono N, Zolboot N, Aikawa Y, Oishi S, Nonami A, Arai F, Hagihara S, Yamaguchi J, Tama F, Kunisaki Y, Yagita K, Ikeda M, Kinoshita T, Kay SA, Itami K, Hirota T

Science advances 5 巻 ( 1 ) 頁： eaau9060 2019年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Science Advances

Compounds targeting the circadian clock have been identified as potential treatments for clock-related diseases, including cancer. Our cell-based phenotypic screen revealed uncharacterized clock-modulating compounds. Through affinity-based target deconvolution, we identified GO289, which strongly lengthened circadian period, as a potent and selective inhibitor of CK2. Phosphoproteomics identified multiple phosphorylation sites inhibited by GO289 on clock proteins, including PER2 S693. Furthermore, GO289 exhibited cell type–dependent inhibition of cancer cell growth that correlated with cellular clock function. The x-ray crystal structure of the CK2-GO289 complex revealed critical interactions between GO289 and CK2-specific residues and no direct interaction of GO289 with the hinge region that is highly conserved among kinases. The discovery of GO289 provides a direct link between the circadian clock and cancer regulation and reveals unique design principles underlying kinase selectivity.

DOI： 10.1126/sciadv.aau9060

時計遺伝子から考える脳機能と食招待有り

羽鳥恵, 廣田毅

FOOD STYLE 21 23 巻頁： 80 - 83 2019年

Conformational dynamics of human protein kinase CK2α and its effect on function and inhibition 査読有り国際誌

Srivastava A, Hirota T, Irle S, Tama F

Proteins: Structure, Function and Bioinformatics 86 巻 ( 3 ) 頁： 344 - 353 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Proteins: Structure, Function and Bioinformatics

Protein kinase, casein kinase II (CK2), is ubiquitously expressed and highly conserved protein kinase that shows constitutive activity. It phosphorylates a diverse set of proteins and plays crucial role in several cellular processes. The catalytic subunit of this enzyme (CK2α) shows remarkable flexibility as evidenced in numerous crystal structures determined till now. Here, using analysis of multiple crystal structures and long timescale molecular dynamics simulations, we explore the conformational flexibility of CK2α. The enzyme shows considerably higher flexibility in the solution as compared to that observed in crystal structure ensemble. Multiple conformations of hinge region, located near the active site, were observed during the dynamics. We further observed that among these multiple conformations, the most populated conformational state was inadequately represented in the crystal structure ensemble. The catalytic spine, was found to be less dismantled in this state as compared to the “open” hinge/αD state crystal structures. The comparison of dynamics in unbound (Apo) state and inhibitor (CX4945) bound state exhibits inhibitor induced suppression in the overall dynamics of the enzyme. This is especially true for functionally important glycine-rich loop above the active site. Together, this work gives novel insights into the dynamics of CK2α in solution and relates it to the function. This work also explains the effect of inhibitor on the dynamics of CK2α and paves way for development of better inhibitors.

DOI： 10.1002/prot.25444

Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks. 査読有り国際誌

Qu M, Duffy T, Hirota T, Kay SA

Proceedings of the National Academy of Sciences of the United States of America 115 巻 ( 52 ) 頁： E12305 - E12312 2018年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America

Either expression level or transcriptional activity of various nuclear receptors (NRs) have been demonstrated to be under circadian control. With a few exceptions, little is known about the roles of NRs as direct regulators of the circadian circuitry. Here we show that the nuclear receptor HNF4A strongly transrepresses the transcriptional activity of the CLOCK:BMAL1 heterodimer. We define a central role for HNF4A in maintaining cell-autonomous circadian oscillations in a tissue-specific manner in liver and colon cells. Not only transcript level but also genome-wide chromosome binding of HNF4A is rhythmically regulated in the mouse liver. ChIP-seq analyses revealed cooccupancy of HNF4A and CLOCK: BMAL1 at a wide array of metabolic genes involved in lipid, glucose, and amino acid homeostasis. Taken together, we establish that HNF4A defines a feedback loop in tissue-specific mammalian oscillators and demonstrate its recruitment in the circadian regulation of metabolic pathways.

DOI： 10.1073/pnas.1816411115

Global rise of potential health hazards caused by blue light-induced circadian disruption in modern aging societies. 査読有り国際誌

Hatori M, Gronfier C, Van Gelder RN, Bernstein PS, Carreras J, Panda S, Marks F, Sliney D, Hunt CE, Hirota T, Furukawa T, Tsubota K

NPJ aging and mechanisms of disease 3 巻 ( 1 ) 頁： 9 - 9 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：npj Aging and Mechanisms of Disease

Mammals receive light information through the eyes, which perform two major functions: image forming vision to see objects and non-image forming adaptation of physiology and behavior to light. Cone and rod photoreceptors form images and send the information via retinal ganglion cells to the brain for image reconstruction. In contrast, nonimage-forming photoresponses vary widely from adjustment of pupil diameter to adaptation of the circadian clock. nonimage-forming responses are mediated by retinal ganglion cells expressing the photopigment melanopsin. Melanopsin-expressing cells constitute 1–2% of retinal ganglion cells in the adult mammalian retina, are intrinsically photosensitive, and integrate photic information from rods and cones to control nonimage-forming adaptation. Action spectra of ipRGCs and of melanopsin photopigment peak around 480 nm blue light. Understanding melanopsin function lets us recognize considerable physiological effects of blue light, which is increasingly important in our modern society that uses light-emitting diode. Misalignment of circadian rhythmicity is observed in numerous conditions, including aging, and is thought to be involved in the development of age-related disorders, such as depression, diabetes, hypertension, obesity, and cancer. The appropriate regulation of circadian rhythmicity by proper lighting is therefore essential. This perspective introduces the potential risks of excessive blue light for human health through circadian rhythm disruption and sleep deprivation. Knowing the positive and negative aspects, this study claims the importance of being exposed to light at optimal times and intensities during the day, based on the concept of the circadian clock, ultimately to improve quality of life to have a healthy and longer life.

DOI： 10.1038/s41514-017-0010-2

　前のページ - 次のページ　

1
2
3
4