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Munteanu C, Turti S, Achim L, Muresan R, Souca M, Prifti E, Mârza SM, Papuc I. The Relationship between Circadian Rhythm and Cancer Disease. Int J Mol Sci 2024; 25:5846. [PMID: 38892035 PMCID: PMC11172077 DOI: 10.3390/ijms25115846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 05/25/2024] [Accepted: 05/26/2024] [Indexed: 06/21/2024] Open
Abstract
The circadian clock regulates biological cycles across species and is crucial for physiological activities and biochemical reactions, including cancer onset and development. The interplay between the circadian rhythm and cancer involves regulating cell division, DNA repair, immune function, hormonal balance, and the potential for chronotherapy. This highlights the importance of maintaining a healthy circadian rhythm for cancer prevention and treatment. This article investigates the complex relationship between the circadian rhythm and cancer, exploring how disruptions to the internal clock may contribute to tumorigenesis and influence cancer progression. Numerous databases are utilized to conduct searches for articles, such as NCBI, MEDLINE, and Scopus. The keywords used throughout the academic archives are "circadian rhythm", "cancer", and "circadian clock". Maintaining a healthy circadian cycle involves prioritizing healthy sleep habits and minimizing disruptions, such as consistent sleep schedules, reduced artificial light exposure, and meal timing adjustments. Dysregulation of the circadian clock gene and cell cycle can cause tumor growth, leading to the need to regulate the circadian cycle for better treatment outcomes. The circadian clock components significantly impact cellular responses to DNA damage, influencing cancer development. Understanding the circadian rhythm's role in tumor diseases and their therapeutic targets is essential for treating and preventing cancer. Disruptions to the circadian rhythm can promote abnormal cell development and tumor metastasis, potentially due to immune system imbalances and hormonal fluctuations.
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Affiliation(s)
- Camelia Munteanu
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania; (C.M.); (S.T.); (L.A.); (R.M.); (M.S.); (E.P.)
| | - Sabina Turti
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania; (C.M.); (S.T.); (L.A.); (R.M.); (M.S.); (E.P.)
| | - Larisa Achim
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania; (C.M.); (S.T.); (L.A.); (R.M.); (M.S.); (E.P.)
| | - Raluca Muresan
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania; (C.M.); (S.T.); (L.A.); (R.M.); (M.S.); (E.P.)
| | - Marius Souca
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania; (C.M.); (S.T.); (L.A.); (R.M.); (M.S.); (E.P.)
| | - Eftimia Prifti
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania; (C.M.); (S.T.); (L.A.); (R.M.); (M.S.); (E.P.)
| | - Sorin Marian Mârza
- Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania;
| | - Ionel Papuc
- Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Mănăştur 3-5, 400372 Cluj-Napoca, Romania;
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Gomatou G, Karachaliou A, Veloudiou OZ, Karvela A, Syrigos N, Kotteas E. The Role of REV-ERB Receptors in Cancer Pathogenesis. Int J Mol Sci 2023; 24:ijms24108980. [PMID: 37240325 DOI: 10.3390/ijms24108980] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/10/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
REV-ERB receptors are members of the nuclear receptor superfamily of proteins, which act as both intracellular receptors and transcription factors, therefore modulating the expression of target genes. REV-ERBs act as transcription repressors because of their unique structure. Their predominant role involves the control of peripheral circadian rhythmicity by participating in a transcription-translation feedback loop with other major clock genes. Regarding their role in cancer pathogenesis, recent studies in various cancerous tissues have revealed that their expression was downregulated in the majority of the cases. Dysregulation of their expression was also implicated in cancer-associated cachexia. The pharmacological restoration of their effects is feasible with synthetic agonists, which have been explored in preclinical studies but with scarce data. There is a need for further investigation, primarily with mechanistic studies, on the effect of the REV-ERB-induced circadian rhythm deregulation in carcinogenesis and cancer-related systemic effects, such as cachexia, in order to address the potential of relevant therapeutic implications.
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Affiliation(s)
- Georgia Gomatou
- Oncology Unit, Third Department of Medicine, "Sotiria" General Hospital for Diseases of the Chest, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - Anastasia Karachaliou
- Oncology Unit, Third Department of Medicine, "Sotiria" General Hospital for Diseases of the Chest, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - Orsalia-Zoi Veloudiou
- Oncology Unit, Third Department of Medicine, "Sotiria" General Hospital for Diseases of the Chest, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - Alexandra Karvela
- Oncology Unit, Third Department of Medicine, "Sotiria" General Hospital for Diseases of the Chest, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - Nikolaos Syrigos
- Oncology Unit, Third Department of Medicine, "Sotiria" General Hospital for Diseases of the Chest, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - Elias Kotteas
- Oncology Unit, Third Department of Medicine, "Sotiria" General Hospital for Diseases of the Chest, National and Kapodistrian University of Athens, 115 27 Athens, Greece
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Ludwig M, Basti A, Yalçin M, Schulte JH, Relógio A. Molecular characterization of the circadian clock in paediatric leukaemia patients: a prospective study protocol. BMC Pediatr 2023; 23:105. [PMID: 36870963 PMCID: PMC9985245 DOI: 10.1186/s12887-023-03921-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 02/17/2023] [Indexed: 03/06/2023] Open
Abstract
BACKGROUND In many organisms, including humans, the timing of cellular processes is regulated by the circadian clock. At the molecular level the core-clock consists of transcriptional-translational-feedback loops including several genes such as BMAL1, CLOCK, PERs and CRYs generating circa 24-h rhythms in the expression of about 40% of our genes across all tissues. Previously these core-clock genes have been shown to be differentially expressed in various cancers. Albeit a significant effect in treatment optimization of chemotherapy timing in paediatric acute lymphoblastic leukaemia has previously been reported, the mechanistic role played by the molecular circadian clock in acute paediatric leukaemia remains elusive. METHODS To characterize the circadian clock, we will recruit patients with newly diagnosed leukaemia and collect time course saliva and blood samples, as well as a single bone marrow sample. From the blood and bone marrow samples nucleated cells will be isolated and further undergo separation into CD19+ and CD19- cells. qPCR is performed on all samples targeting the core-clock genes including BMAL1, CLOCK, PER2 and CRY1. Resulting data will be analysed for circadian rhythmicity using the RAIN algorithm and harmonic regression. DISCUSSION To the best of our knowledge this is the first study aiming to characterize the circadian clock in a cohort of paediatric patients with acute leukaemia. In the future we hope to contribute to uncovering further vulnerabilities of cancers associated with the molecular circadian clock and in particular adjust chemotherapy accordingly, leading to more targeted toxicity, and hence decreased systemic toxicities.
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Affiliation(s)
- Marius Ludwig
- Department of Pediatric Hematology and Oncology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, 10117, Berlin, Germany.,Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, 10117, Berlin, Germany
| | - Alireza Basti
- Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, 10117, Berlin, Germany.,Molecular Cancer Research Center (MKFZ), Medical Department of Hematology, Oncology, and Tumour Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, 10117, Berlin, Germany.,Institute for Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, 20457, Hamburg, Germany
| | - Müge Yalçin
- Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, 10117, Berlin, Germany.,Molecular Cancer Research Center (MKFZ), Medical Department of Hematology, Oncology, and Tumour Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, 10117, Berlin, Germany
| | - Johannes H Schulte
- Department of Pediatric Hematology and Oncology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, 10117, Berlin, Germany.,German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Berlin Institute of Health, 10117, Berlin, Germany
| | - Angela Relógio
- Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, 10117, Berlin, Germany. .,Molecular Cancer Research Center (MKFZ), Medical Department of Hematology, Oncology, and Tumour Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, 10117, Berlin, Germany. .,Institute for Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, 20457, Hamburg, Germany.
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Yang J, Fu Q, Jiang H, Li Y, Liu M. Progress of phototherapy for osteosarcoma and application prospect of blue light photobiomodulation therapy. Front Oncol 2022; 12:1022973. [PMID: 36313662 PMCID: PMC9606592 DOI: 10.3389/fonc.2022.1022973] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 09/20/2022] [Indexed: 12/02/2022] Open
Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor that mainly affects the pediatric and adolescent population; limb salvage treatment has become one of the most concerned and expected outcomes of OS patients recently. Phototherapy (PT), as a novel, non-invasive, and efficient antitumor therapeutic approach including photodynamic therapy (PDT), photothermal therapy (PTT), and photobiomodulation therapy (PBMT), has been widely applied in superficial skin tumor research and clinical treatment. OS is the typical deep tumor, and its phototherapy research faces great limitations and challenges. Surprisingly, pulse mode LED light can effectively improve tissue penetration and reduce skin damage caused by high light intensity and has great application potential in deep tumor research. In this review, we discussed the research progress and related molecular mechanisms of phototherapy in the treatment of OS, mainly summarized the status quo of blue light PBMT in the scientific research and clinical applications of tumor treatment, and outlooked the application prospect of pulsed blue LED light in the treatment of OS, so as to further improve clinical survival rate and prognosis of OS treatment and explore corresponding cellular mechanisms.
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Affiliation(s)
- Jiali Yang
- School of Information Science and Technology, Fudan University, Shanghai, China
| | - Qiqi Fu
- School of Information Science and Technology, Fudan University, Shanghai, China
| | - Hui Jiang
- Academy for Engineering and Technology, Fudan University, Shanghai, China
| | - Yinghua Li
- Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
- *Correspondence: Yinghua Li, ; Muqing Liu,
| | - Muqing Liu
- School of Information Science and Technology, Fudan University, Shanghai, China
- Zhongshan Fudan Joint Innovation Center, Zhongshan, China
- *Correspondence: Yinghua Li, ; Muqing Liu,
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Printezi MI, Kilgallen AB, Bond MJG, Štibler U, Putker M, Teske AJ, Cramer MJ, Punt CJA, Sluijter JPG, Huitema ADR, May AM, van Laake LW. Toxicity and efficacy of chronomodulated chemotherapy: a systematic review. Lancet Oncol 2022; 23:e129-e143. [DOI: 10.1016/s1470-2045(21)00639-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/24/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022]
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Yue W, Du X, Wang X, Gui N, Zhang W, Sun J, You J, He D, Geng X, Huang Y, Hou J. Prognostic values of the core components of the mammalian circadian clock in prostate cancer. PeerJ 2021; 9:e12539. [PMID: 34966582 PMCID: PMC8667750 DOI: 10.7717/peerj.12539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 11/04/2021] [Indexed: 12/24/2022] Open
Abstract
Background Prostate cancer (PC) is one of the most common malignancies in males. Extensive and complex connections between circadian rhythm and cancer were found. Nonetheless, in PC, the potential role of the core components of the mammalian circadian clock (CCMCCs) in prognosis prediction has not been fully clarified. Methods We firstly collected 605 patients with PC from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Survival analysis was carried out for each CCMCC. Then, we investigated the prognostic ability of CCMCCs by Cox regression analysis. Independent prognostic signatures were extracted for the establishment of the circadian clock-based risk score model. We explored the predictive performance of the risk score model in the TCGA training cohort and the independent GEO dataset. Finally, the relationships between risk score and clinicopathological parameters, biological processes, and signaling pathways were evaluated. Results The expression levels of CCMCCs were widely correlated with age, tumor status, lymph node status, disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS). Nine circadian clock genes, including CSNK1D, BTRC, CLOCK, CSNK1E, FBXL3, PRKAA2, DBP, NR1D2, and RORB, were identified as vital prognostic factors in PC and were used to construct the circadian clock-based risk score model. For DFS, the area under the 3-year or 5-year receiver operating characteristic curves ranged from 0.728 to 0.821, suggesting better predictive performance. When compared with T3-4N1 stage, PC patients at T2N0 stage might be benefited more from the circadian clock-based risk score model. Furthermore, a high circadian clock-based risk score indicated shorter DFS (p < 0.0001), early progression (p < 0.0001), and higher 5-year death rate (p = 0.007) in PC. The risk score was related to tumor status (p < 0.001), lymph node status (p < 0.001), and ribosome-related biogenesis and pathways. Conclusions The vital roles of circadian clock genes in clinical outcomes were fully depicted. The circadian clock-based risk score model could reflect and predict the prognosis of patients with PC.
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Affiliation(s)
- Wenchang Yue
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiao Du
- Department of Radiation Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xuhong Wang
- Department of Urology, Tongcheng people's Hospital, Tongcheng, China
| | - Niu Gui
- General Surgery Ward 2, Fengtaixian Hospital of Chinese Medicine, Huainan, China
| | - Weijie Zhang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiale Sun
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiawei You
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Dong He
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xinyu Geng
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuhua Huang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jianquan Hou
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
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Circadian clock and cell cycle: Cancer and chronotherapy. Acta Histochem 2021; 123:151816. [PMID: 34800857 DOI: 10.1016/j.acthis.2021.151816] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 10/25/2021] [Accepted: 11/05/2021] [Indexed: 01/03/2023]
Abstract
The circadian clock is an endogenous timing system that ensures that various physiological processes have nearly 24 h circadian rhythms, including cell metabolism, division, apoptosis, and tumor production. In addition, results from animal models and molecular studies underscore emerging links between the cell cycle and the circadian clock. Mutations in the core genes of the circadian clock' can disrupt the cell cycle, which in turn increases the possibility of tumors. At present, tumor chronotherapy, which relies on a circadian clock mechanism, is developing rapidly for optimizing the time of drug administration in tumor treatment to improve drug efficacy and safety. However, the relationship between the circadian clock and the cell cycle is extremely complicated. This review summarizes the possible connection between the circadian clock and the cell cycle. In addition, the review provides evidence of the influence of the circadian clock on senescence and cancer.
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Circadian Alterations Increase with Progression in a Patient-Derived Cell Culture Model of Breast Cancer. Clocks Sleep 2021; 3:598-608. [PMID: 34842634 PMCID: PMC8628750 DOI: 10.3390/clockssleep3040042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/10/2021] [Accepted: 10/28/2021] [Indexed: 01/20/2023] Open
Abstract
Circadian rhythm disruption can elicit the development of various diseases, including breast cancer. While studies have used cell lines to study correlations between altered circadian rhythms and cancer, these models have different genetic backgrounds and do not mirror the changes that occur with disease development. Isogenic cell models can recapitulate changes across cancer progression. Hence, in this study, a patient-derived breast cancer model, the 21T series, was used to evaluate changes to circadian oscillations of core clock protein transcription as cells progress from normal to malignant states. Three cell lines were used: H16N2 (normal breast epithelium), 21PT (atypical ductal hyperplasia), and 21MT-1 (invasive metastatic carcinoma). The cancerous cells are both HER2+. We assessed the transcriptional profiles of two core clock proteins, BMAL1 and PER2, which represent a positive and negative component of the molecular oscillator. In the normal H16N2 cells, both genes possessed rhythmic mRNA oscillations with close to standard periods and phases. However, in the cancerous cells, consistent changes were observed: both genes had periods that deviated farther from normal and did not have an anti-phase relationship. In the future, mechanistic studies should be undertaken to determine the oncogenic changes responsible for the circadian alterations found.
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Hassan SA, Ali AAH, Sohn D, Flögel U, Jänicke RU, Korf H, von Gall C. Does timing matter in radiotherapy of hepatocellular carcinoma? An experimental study in mice. Cancer Med 2021; 10:7712-7725. [PMID: 34545699 PMCID: PMC8559477 DOI: 10.1002/cam4.4277] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 08/18/2021] [Accepted: 08/27/2021] [Indexed: 01/10/2023] Open
Abstract
This study investigates whether a chronotherapeutic treatment of hepatocellular carcinoma (HCC) may improve treatment efficacy and mitigate side effects on non-tumoral liver (NTL). HCC was induced in Per2::luc mice which were irradiated at four time points of the day. Proliferation and DNA-double strand breaks were analyzed in irradiated and nonirradiated animals by detection of Ki67 and γ-H2AX. Prior to whole animal experiments, organotypic slice cultures were investigated to determine the dosage to be used in whole animal experiments. Irradiation was most effective at the proliferation peaks in HCC at ZT02 (early inactivity phase) and ZT20 (late activity phase). Irradiation effects on NTL were minimal at ZT20. As compared with NTL, nonirradiated HCC revealed disruption in daily variation and downregulation of all investigated clock genes except Per1. Irradiation affected rhythmic clock gene expression in NTL and HCC at all ZTs except at ZT20 (late activity phase). Irradiation at ZT20 had no effect on total leukocyte numbers. Our results indicate ZT20 as the optimal time point for irradiation of HCC in mice at which the ratio between efficacy of tumor treatment and toxic side effects was maximal. Translational studies are now needed to evaluate whether the late activity phase is the optimal time point for irradiation of HCC in man.
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Affiliation(s)
- Soha A. Hassan
- Institute of Anatomy II, Medical FacultyHeinrich‐Heine‐UniversityDüsseldorfGermany
- Zoology DepartmentFaculty of ScienceSuez UniversitySuezEgypt
| | - Amira A. H. Ali
- Institute of Anatomy II, Medical FacultyHeinrich‐Heine‐UniversityDüsseldorfGermany
- Department of Anatomy and EmbryologyFaculty of MedicineMansoura UniversityMansouraEgypt
| | - Dennis Sohn
- Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and RadiooncologyMedical Faculty of Heinrich‐Heine‐UniversityDüsseldorfGermany
| | - Ulrich Flögel
- Department of Molecular CardiologyHeinrich‐Heine‐UniversityDüsseldorfGermany
| | - Reiner U. Jänicke
- Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and RadiooncologyMedical Faculty of Heinrich‐Heine‐UniversityDüsseldorfGermany
| | - Horst‐Werner Korf
- Institute of Anatomy IMedical FacultyHeinrich‐Heine‐UniversityDüsseldorfGermany
| | - Charlotte von Gall
- Institute of Anatomy II, Medical FacultyHeinrich‐Heine‐UniversityDüsseldorfGermany
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Ishay Y, Kolben Y, Kessler A, Ilan Y. Role of circadian rhythm and autonomic nervous system in liver function: a hypothetical basis for improving the management of hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2021; 321:G400-G412. [PMID: 34346773 DOI: 10.1152/ajpgi.00186.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatic encephalopathy (HE) is a common, incapacitating complication of cirrhosis that affects many patients with cirrhosis. Although several therapies have proven effective in the treatment and prevention of this condition, several patients continue to suffer from covert disease or episodes of relapse. The circadian rhythm has been demonstrated to be pivotal for many body functions, including those of the liver. Here, we explore the impact of circadian rhythm-dependent signaling on the liver and discuss the evidence of its impact on liver pathology and metabolism. We describe the various pathways through which circadian influences are mediated. Finally, we introduce a novel method for improving patient response to drugs aimed at treating HE by utilizing the circadian rhythm. A digital system that introduces a customization-based technique for improving the response to therapies is presented as a hypothetical approach for improving the effectiveness of current medications used for the treatment of recurrent and persistent hepatic encephalopathy.
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Affiliation(s)
- Yuval Ishay
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Yotam Kolben
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Asa Kessler
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Yaron Ilan
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
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Kireeva G, Gubareva E, Maydin M, Osetnik V, Kruglov S, Panchenko A, Dorofeeva A, Tyndyk M, Fedoros E, Anisimov V. Efficacy and Safety of Systemic and Locoregional Cisplatin Chronotherapy in Rats with Ovarian Carcinoma. Onco Targets Ther 2021; 14:3373-3381. [PMID: 34079283 PMCID: PMC8163628 DOI: 10.2147/ott.s309285] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 04/28/2021] [Indexed: 12/15/2022] Open
Abstract
Aim Alterations in circadian rhythms caused by tumor growth are thought to be clinically relevant as they affect the prognosis and treatment response. We aimed to evaluate the chronotherapeutic approach in rats with ovarian cancer receiving cisplatin intravenously (IV) or with hyperthermic intraperitoneal chemoperfusion (HIPEC) and to assess daily variations in tumor and intestinal epithelium proliferation. Methods In the pilot study, we used 12 intact rats and 12 rats with transplantable ovarian cancer, which were euthanized at ZT0 (08:00, lights on), ZT6, ZT12 and ZT18. In the main study, we used 45 rats with transplantable ovarian cancer. Animals were randomized into five groups: control, HIPEC with cisplatin at ZT0 (08:00), HIPEC with cisplatin at ZT12 (20:00), IV cisplatin at ZT0 and IV cisplatin at ZT12. We assessed the proliferation rate of tumor and small intestinal epithelium, apoptosis in small intestinal epithelium, and levels of γ-H2AX (DNA damage/repair marker) in kidneys and liver. Survival was calculated in each group. Results Ascitic ovarian cancer disrupted daily variations in intestinal epithelium proliferation and DNA damage/repair in rats. Ovarian carcinoma exhibited no daily variation in mitotic activity. In animals receiving IV cisplatin, massive cell damage in the renal medulla and cystic changes within renal tubules were observed, unlike in rats receiving HIPEC. Tumor mitotic activity was lower in morning-treated groups. The median survival of rats in the control group was 8.5 days (95% CI 6.0–22.0), in HIPEC at ZT0 40.5 days (95% CI 28.0–47.0, p<0.001) and in HIPEC at ZT12 32.0 days (95% CI 28.0–37.0, p<0.001). Conclusion In a rat model, ovarian tumor growth disrupted daily variations in intestinal epithelium proliferation and caused genotoxic stress in tumor-free tissues. HIPEC with cisplatin at ZT0 had a better efficacy/toxicity profile than HIPEC with cisplatin at ZT12 and IV administration at both time points.
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Affiliation(s)
- Galina Kireeva
- Department of Carcinogenesis and Aging, N.N. Petrov National Medical Research Center of Oncology, Saint-Petersburg, Russia
| | - Ekaterina Gubareva
- Department of Carcinogenesis and Aging, N.N. Petrov National Medical Research Center of Oncology, Saint-Petersburg, Russia
| | - Mikhail Maydin
- Department of Carcinogenesis and Aging, N.N. Petrov National Medical Research Center of Oncology, Saint-Petersburg, Russia
| | - Vladislav Osetnik
- Surgical Department, Saint-Petersburg State University Hospital, Saint-Petersburg, Russia
| | - Stepan Kruglov
- Department of Carcinogenesis and Aging, N.N. Petrov National Medical Research Center of Oncology, Saint-Petersburg, Russia
| | - Andrey Panchenko
- Department of Carcinogenesis and Aging, N.N. Petrov National Medical Research Center of Oncology, Saint-Petersburg, Russia
| | - Anastasia Dorofeeva
- Department of Carcinogenesis and Aging, N.N. Petrov National Medical Research Center of Oncology, Saint-Petersburg, Russia
| | - Margarita Tyndyk
- Department of Carcinogenesis and Aging, N.N. Petrov National Medical Research Center of Oncology, Saint-Petersburg, Russia
| | - Elena Fedoros
- Department of Carcinogenesis and Aging, N.N. Petrov National Medical Research Center of Oncology, Saint-Petersburg, Russia
| | - Vladimir Anisimov
- Department of Carcinogenesis and Aging, N.N. Petrov National Medical Research Center of Oncology, Saint-Petersburg, Russia
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12
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Finger A, Kramer A. Mammalian circadian systems: Organization and modern life challenges. Acta Physiol (Oxf) 2021; 231:e13548. [PMID: 32846050 DOI: 10.1111/apha.13548] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/04/2020] [Accepted: 08/11/2020] [Indexed: 12/11/2022]
Abstract
Humans and other mammalian species possess an endogenous circadian clock system that has evolved in adaptation to periodically reoccurring environmental changes and drives rhythmic biological functions, as well as behavioural outputs with an approximately 24-hour period. In mammals, body clocks are hierarchically organized, encompassing a so-called pacemaker clock in the hypothalamic suprachiasmatic nucleus (SCN), non-SCN brain and peripheral clocks, as well as cell-autonomous oscillators within virtually every cell type. A functional clock machinery on the molecular level, alignment among body clocks, as well as synchronization between endogenous circadian and exogenous environmental cycles has been shown to be crucial for our health and well-being. Yet, modern life constantly poses widespread challenges to our internal clocks, for example artificial lighting, shift work and trans-meridian travel, potentially leading to circadian disruption or misalignment and the emergence of associated diseases. For instance many of us experience a mismatch between sleep timing on work and free days (social jetlag) in our everyday lives without being aware of health consequences that may arise from such chronic circadian misalignment, Hence, this review provides an overview of the organization and molecular built-up of the mammalian circadian system, its interactions with the outside world, as well as pathologies arising from circadian disruption and misalignment.
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Affiliation(s)
- Anna‐Marie Finger
- Laboratory of Chronobiology Institute for Medical immunology Charité Universitätsmedizin Berlin Berlin Germany
- Berlin Institute of Health (BIH) Berlin Germany
| | - Achim Kramer
- Laboratory of Chronobiology Institute for Medical immunology Charité Universitätsmedizin Berlin Berlin Germany
- Berlin Institute of Health (BIH) Berlin Germany
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13
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Patel SA, Kondratov RV. Clock at the Core of Cancer Development. BIOLOGY 2021; 10:150. [PMID: 33672910 PMCID: PMC7918730 DOI: 10.3390/biology10020150] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 12/29/2022]
Abstract
To synchronize various biological processes with the day and night cycle, most organisms have developed circadian clocks. This evolutionarily conserved system is important in the temporal regulation of behavior, physiology and metabolism. Multiple pathological changes associated with circadian disruption support the importance of the clocks in mammals. Emerging links have revealed interplay between circadian clocks and signaling networks in cancer. Understanding the cross-talk between the circadian clock and tumorigenesis is imperative for its prevention, management and development of effective treatment options. In this review, we summarize the role of the circadian clock in regulation of one important metabolic pathway, insulin/IGF1/PI3K/mTOR signaling, and how dysregulation of this metabolic pathway could lead to uncontrolled cancer cell proliferation and growth. Targeting the circadian clock and rhythms either with recently discovered pharmaceutical agents or through environmental cues is a new direction in cancer chronotherapy. Combining the circadian approach with traditional methods, such as radiation, chemotherapy or the recently developed, immunotherapy, may improve tumor response, while simultaneously minimizing the adverse effects commonly associated with cancer therapies.
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Affiliation(s)
- Sonal A. Patel
- Fusion Pharmaceuticals Inc., Hamilton, ON L8P 0A6, Canada;
- Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
| | - Roman V. Kondratov
- Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
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14
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Abstract
The circadian clock coordinates daily rhythmicity of biochemical, physiologic, and behavioral functions in humans. Gene expression, cell division, and DNA repair are modulated by the clock, which gives rise to the hypothesis that clock dysfunction may predispose individuals to cancer. Although the results of many epidemiologic and animal studies are consistent with there being a role for the clock in the genesis and progression of tumors, available data are insufficient to conclude that clock disruption is generally carcinogenic. Similarly, studies have suggested a circadian time-dependent efficacy of chemotherapy, but clinical trials of chronochemotherapy have not demonstrated improved outcomes compared with conventional regimens. Future hypothesis-driven and discovery-oriented research should focus on specific interactions between clock components and carcinogenic mechanisms to realize the full clinical potential of the relationship between clocks and cancer.
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Affiliation(s)
- Aziz Sancar
- Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
| | - Russell N Van Gelder
- Departments of Ophthalmology, Biological Structure, and Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98104, USA.
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15
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Astone M, Santoro MM. Time to fight: targeting the circadian clock molecular machinery in cancer therapy. Drug Discov Today 2021; 26:1164-1184. [PMID: 33549826 DOI: 10.1016/j.drudis.2021.01.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/23/2020] [Accepted: 01/22/2021] [Indexed: 02/06/2023]
Abstract
The circadian clock regulates a wide range of molecular pathways and biological processes. The expression of clock genes is often altered in cancer, fostering tumor initiation and progression. Inhibition and activation of core circadian clock genes, as well as treatments that restore circadian rhythmicity, have been successful in counteracting tumor growth in different experimental models. Here, we provide an up-to-date overview of studies that show the therapeutic effects of targeting the clock molecular machinery in cancer, both genetically and pharmacologically. We also highlight future areas for progress that offer a promising path towards innovative anticancer strategies. Substantial limitations in the current understanding of the complex interplay between the circadian clock and cancer in vivo need to be addressed in order to allow clock-targeting therapies in cancer.
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Affiliation(s)
- Matteo Astone
- Department of Biology, University of Padova, I-35131, Italy
| | - Massimo M Santoro
- Department of Biology, University of Padova, I-35131, Italy; Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.
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16
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Finger AM, Dibner C, Kramer A. Coupled network of the circadian clocks: a driving force of rhythmic physiology. FEBS Lett 2020; 594:2734-2769. [PMID: 32750151 DOI: 10.1002/1873-3468.13898] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/06/2020] [Accepted: 07/21/2020] [Indexed: 12/15/2022]
Abstract
The circadian system is composed of coupled endogenous oscillators that allow living beings, including humans, to anticipate and adapt to daily changes in their environment. In mammals, circadian clocks form a hierarchically organized network with a 'master clock' located in the suprachiasmatic nucleus of the hypothalamus, which ensures entrainment of subsidiary oscillators to environmental cycles. Robust rhythmicity of body clocks is indispensable for temporally coordinating organ functions, and the disruption or misalignment of circadian rhythms caused for instance by modern lifestyle is strongly associated with various widespread diseases. This review aims to provide a comprehensive overview of our current knowledge about the molecular architecture and system-level organization of mammalian circadian oscillators. Furthermore, we discuss the regulatory roles of peripheral clocks for cell and organ physiology and their implication in the temporal coordination of metabolism in human health and disease. Finally, we summarize methods for assessing circadian rhythmicity in humans.
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Affiliation(s)
- Anna-Marie Finger
- Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
| | - Charna Dibner
- Division of Endocrinology, Diabetes, Nutrition, and Patient Education, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland.,Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland
| | - Achim Kramer
- Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
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17
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Hassan SA, Schmithals C, von Harten M, Piiper A, Korf HW, von Gall C. Time-dependent changes in proliferation, DNA damage and clock gene expression in hepatocellular carcinoma and healthy liver of a transgenic mouse model. Int J Cancer 2020; 148:226-237. [PMID: 32700769 DOI: 10.1002/ijc.33228] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 07/03/2020] [Accepted: 07/13/2020] [Indexed: 12/16/2022]
Abstract
Hepatocellular carcinoma (HCC) is highly resistant to anticancer therapy and novel therapeutic strategies are needed. Chronotherapy may become a promising approach because it may improve the efficacy of antimitotic radiation and chemotherapy by considering timing of treatment. To date little is known about time-of-day dependent changes of proliferation and DNA damage in HCC. Using transgenic c-myc/transforming growth factor (TGFα) mice as HCC animal model, we immunohistochemically demonstrated Ki67 as marker for proliferation and γ-H2AX as marker for DNA damage in HCC and surrounding healthy liver (HL). Core clock genes (Per1, Per2, Cry1, Cry2, Bmal 1, Rev-erbα and Clock) were examined by qPCR. Data were obtained from samples collected ex vivo at four different time points and from organotypic slice cultures (OSC). Significant differences were found between HCC and HL. In HCC, the number of Ki67 immunoreactive cells showed two peaks (ex vivo: ZT06 middle of day and ZT18 middle of night; OSC: CT04 and CT16). In ex vivo samples, the number of γ-H2AX positive cells in HCC peaked at ZT18 (middle of the night), while in OSC their number remained high during subjective day and night. In both HCC and HL, clock gene expression showed a time-of-day dependent expression ex vivo but no changes in OSC. The expression of Per2 and Cry1 was significantly lower in HCC than in HL. Our data support the concept of chronotherapy of HCC. OSC may become useful to test novel cancer therapies.
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Affiliation(s)
- Soha A Hassan
- Institute of Anatomy II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.,Zoology Department, Faculty of Science, Suez University, Suez, Egypt
| | | | - Maike von Harten
- Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Albrecht Piiper
- Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Horst-Werner Korf
- Institute of Anatomy I, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.,Institute of Anatomy II, Goethe University, Frankfurt, Germany
| | - Charlotte von Gall
- Institute of Anatomy II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
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18
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Effects of aging and tumorigenesis on coupling between the circadian clock and cell cycle in colonic mucosa. Mech Ageing Dev 2020; 190:111317. [PMID: 32745473 DOI: 10.1016/j.mad.2020.111317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 06/21/2020] [Accepted: 07/14/2020] [Indexed: 01/20/2023]
Abstract
Aging and tumorigenesis are associated with decline and disruption of circadian rhythms in many tissues and accumulating evidence indicates molecular link between circadian clock and cell cycle. The aim of this study was to investigate the effect of aging and tumorigenesis on coupling between cell cycle and circadian clock oscillators in colon, which undergoes regular rhythmicity of cell cycle and expresses peripheral circadian clock. Using healthy 14-week-old mice and 33-week-old mice with and without colorectal tumors, we showed that the 24-h expression profiles of clock genes and clock-controlled genes were mostly unaffected by aging, whereas the genes of cell cycle and cell proliferation were rhythmic in the young colons but were silenced during aging. On the other hand, tumorigenesis completely silenced or dampened the circadian rhythmicity of the clock genes but only a few genes associated with cell cycle progression and cell proliferation. These results suggest that aging impacts the colonic circadian clock moderately but markedly suppresses the rhythms of cell cycle genes and appears to uncouple the cell cycle machinery from circadian clock control. Conversely, tumorigenesis predominantly affects the rhythms of colonic circadian clocks but is not associated with uncoupling of circadian clock and cell cycle.
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19
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Kearton TR, Doughty AK, Morton CL, Hinch GN, Godwin IR, Cowley FC. Core and peripheral site measurement of body temperature in short wool sheep. J Therm Biol 2020; 90:102606. [PMID: 32479400 DOI: 10.1016/j.jtherbio.2020.102606] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 04/07/2020] [Accepted: 04/22/2020] [Indexed: 01/20/2023]
Abstract
Understanding circadian rhythms of body temperature is important for the interpretation of single body temperature measurements and the assessment of the physiological state of an animal. The ability to measure body temperature at peripheral locations may also be important in the development of minimally invasive tools for remote temperature measurement in livestock. This study aimed to investigate how well body temperature measured at peripheral sites reflected a commonly used core measurement (vaginal temperature) and the circadian rhythmicity of the body temperature of sheep with a view to practical application in extensive sheep production systems. Eleven crossbred ewes were implanted with peripheral temperature sensing microchips (LifeChip®) which were positioned transversely in the sternocleidomastoid (neck) muscle and subcutaneously under the tail. iButton® temperature loggers were placed intravaginally to record core body temperature measurements (Tv). The body temperature measurements observed at the peripheral sites in the neck (Tn) and tail (Tt) differed significantly to those measured at the core site, Tv (P < 0.05), with Tn lower than Tv and Tt lower than both Tv and Tn. Similarities in circadian rhythm patterns were observed across the day between Tv, Tn and Tt in repeated measures analysis, with a short period of difference between Tv and Tn (from 1400 to 1600 h) and a long period of difference between Tv and Tt (from 1000 to 2100 h) (P < 0.05). These results suggest that neck muscle temperature measurements may have utility in detecting circadian rhythm patterns in core temperature in sheep, but may not accurately reflect absolute core temperatures. Peripheral measures may require adjustment or correction to more accurately reflect absolute core temperature with respect to determining accurate clinical thresholds relative to the expected normal temperature for the time of day observed. Further investigation into the utility and application of peripheral measurement of body temperature is warranted.
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Affiliation(s)
- Tellisa R Kearton
- University of New England, Armidale, New South Wales, 2351, Australia; CRC for Sheep Industry Innovation, Armidale, NSW, 2350, Australia.
| | - Amanda K Doughty
- University of New England, Armidale, New South Wales, 2351, Australia; CRC for Sheep Industry Innovation, Armidale, NSW, 2350, Australia
| | | | - Geoff N Hinch
- University of New England, Armidale, New South Wales, 2351, Australia; CRC for Sheep Industry Innovation, Armidale, NSW, 2350, Australia
| | - Ian R Godwin
- University of New England, Armidale, New South Wales, 2351, Australia
| | - Frances C Cowley
- University of New England, Armidale, New South Wales, 2351, Australia
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20
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Zhang S, Dai M, Wang X, Jiang SH, Hu LP, Zhang XL, Zhang ZG. Signalling entrains the peripheral circadian clock. Cell Signal 2020; 69:109433. [PMID: 31982551 DOI: 10.1016/j.cellsig.2019.109433] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/29/2019] [Accepted: 09/29/2019] [Indexed: 12/18/2022]
Abstract
In mammals, 24-h rhythms of behaviour and physiology are regulated by the circadian clock. The circadian clock is controlled by a central clock in the brain's suprachiasmatic nucleus (SCN) that synchronizes peripheral clocks in peripheral tissues. Clock genes in the SCN are primarily entrained by light. Increasing evidence has shown that peripheral clocks are also regulated by light and hormones independent of the SCN. How the peripheral clocks deal with internal signals is dependent on the relevance of a specific cue to a specific tissue. In different tissues, most genes that are under circadian control are not overlapping, revealing the tissue-specific control of peripheral clocks. We will discuss how different signals control the peripheral clocks in different peripheral tissues, such as the liver, gastrointestinal tract, and pancreas, and discuss the organ-to-organ communication between the peripheral clocks at the molecular level.
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Affiliation(s)
- Shan Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Miao Dai
- Department of Gynecologic Oncology, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Xu Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shu-Heng Jiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Li-Peng Hu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xue-Li Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Zhi-Gang Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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21
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Lellupitiyage Don SS, Lin HH, Furtado JJ, Qraitem M, Taylor SR, Farkas ME. Circadian oscillations persist in low malignancy breast cancer cells. Cell Cycle 2019; 18:2447-2453. [PMID: 31357909 PMCID: PMC6739049 DOI: 10.1080/15384101.2019.1648957] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 07/15/2019] [Accepted: 07/19/2019] [Indexed: 01/20/2023] Open
Abstract
Epidemiological studies have shown that humans with altered circadian rhythms have higher cancer incidence, with breast cancer being one of the most cited examples. To uncover how circadian disruptions may be correlated with breast cancer and its development, prior studies have assessed the expression of BMAL1 and PER2 core clock genes via RT-qPCR and western blot analyses. These and our own low-resolution data show that BMAL1 and PER2 expression are suppressed and arrhythmic. We hypothesized that oscillations persist in breast cancer cells, but due to limitations of protocols utilized, cannot be observed. This is especially true where dynamic changes may be subtle. In the present work, we generated luciferase reporter cell lines representing high- and low-grade breast cancers to assess circadian rhythms. We tracked signals for BMAL1 and PER2 to determine whether and to what extent oscillations exist and provide initial correlations of circadian rhythm alterations with breast cancer aggression. In contrast to previous studies, where no oscillations were apparent in any breast cancer cell line, our luminometry data reveal that circadian oscillations of BMAL1 and PER2 in fact exist in the low-grade, luminal A MCF7 cells but are not present in high-grade, basal MDA-MB-231 cells. To our knowledge, this is the first evidence of core circadian clock oscillations in breast cancer cells. This work also suggests that circadian rhythms are further disrupted in more aggressive/high tumor grades of breast cancer, and that use of real time luminometry to study additional representatives of breast and other cancer subtypes is merited.
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Affiliation(s)
| | - Hui-Hsien Lin
- Department of Chemistry, University of Massachusetts, Amherst, MA, USA
| | - Jessica J. Furtado
- Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA, USA
| | - Maan Qraitem
- Department of Computer Science, Colby College, Waterville, ME, USA
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22
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Inhibition of activin-like kinase 4/5 attenuates cancer cachexia associated muscle wasting. Sci Rep 2019; 9:9826. [PMID: 31285507 PMCID: PMC6614551 DOI: 10.1038/s41598-019-46178-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 06/12/2019] [Indexed: 12/28/2022] Open
Abstract
Cancer mediated activation of the ActRIIB-ALK4/5 heterodimer by myostatin is strongly associated with muscle wasting. We investigated in vitro and in vivo the efficacy of ALK4/5 receptor blockers SB431542 and GW788388 in preventing muscle wasting, and explored synergy with IGF-I analogue LONG R3 (LR3) IGF-I. In vitro, C2C12 skeletal muscle cells were treated with vehicle, SB431542, GW788388 and LR3 IGF-I. A C26-CD2F1 cachexia model was used to induce cachexia in vivo. Mice were allocated as non-tumour bearing (NTB) or C26 tumour-bearing (C26 TB) vehicle control, treated with SB431542, LR3 IGF-I, SB431542 and LR3 IGF-I, or GW788388 (intraperitoneally or orally). In vitro, differentiation index and mean nuclei count increased using SB431542, GW788388, LR3 IGF-I. In vivo, GW788388 was superior to SB431542 in limiting loss of bodyweight, grip-strength and gastrocnemius weight. and downregulated Atrogin-1 expression comparable to NTB mice. LR3 IGF-I treatment limited loss of muscle mass, but at the expense of accelerated tumour growth. In conclusion, treatment with GW788388 prevented cancer cachexia, and downregulated associated ubiquitin ligase Atrogin-1.
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23
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Burgermeister E, Battaglin F, Eladly F, Wu W, Herweck F, Schulte N, Betge J, Härtel N, Kather JN, Weis CA, Gaiser T, Marx A, Weiss C, Hofheinz R, Miller IS, Loupakis F, Lenz HJ, Byrne AT, Ebert MP. Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor A. EBioMedicine 2019; 45:139-154. [PMID: 31300350 PMCID: PMC6642438 DOI: 10.1016/j.ebiom.2019.07.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/26/2019] [Accepted: 07/02/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The identification of new biomarkers and the development of novel, targetable contexts of vulnerability are of urgent clinical need in drug-resistant metastatic colorectal cancer (mCRC). Aryl-Hydrocarbon-Receptor-Nuclear-Translocator-Like (ARNTL/BMAL1) is a circadian clock-regulated transcription factor promoting expression of genes involved in angiogenesis and tumour progression. We hypothesised that BMAL1 increases expression of the vascular endothelial growth factor A VEGFA gene and, thereby, confers resistance to anti-angiogenic therapy with bevacizumab (Beva), a clinically used antibody for neutralization of VEGFA. METHODS PCR and immunohistochemistry were employed to assess BMAL1 expression in mice (C57BL/6 J Apcmin/+; BALB/c nu/nu xenografts) and CRC patients under combination chemotherapy with Beva. BMAL1 single nucleotide gene polymorphisms (SNPs) were analysed by DNA-microarray in clinical samples. BMAL1 functions were studied in human CRC cell lines using colorimetric growth, DNA-binding and reporter assays. FINDINGS In murine CRCs, high BMAL1 expression correlated with poor preclinical response to Beva treatment. In CRC patients' tumours (n = 74), high BMAL1 expression was associated with clinical non-response to combination chemotherapy with Beva (*p = .0061) and reduced progression-free survival (PFS) [*p = .0223, Hazard Ratio (HR) = 1.69]. BMAL1 SNPs also correlated with shorter PFS (rs7396943, rs7938307, rs2279287) and overall survival (OS) [rs11022780, *p = .014, HR = 1.61]. Mechanistically, Nuclear-Receptor-Subfamily-1-Group-D-Member-1 (NR1D1/REVERBA) bound a - 672 bp Retinoic-Acid-Receptor-Related-Orphan-Receptor-Alpha-responsive-element (RORE) adjacent to a BMAL1 DNA-binding motif (E-box) in the VEGFA gene promoter, resulting in increased VEGFA synthesis and proliferation of human CRC cell lines. INTERPRETATION BMAL1 was associated with Beva resistance in CRC. Inhibition of REVERBA-BMAL1 signalling may prevent resistance to anti-angiogenic therapy. FUND: This work was in part supported by the European Commission Seventh Framework Programme (Contract No. 278981 [ANGIOPREDICT]).
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Affiliation(s)
- Elke Burgermeister
- Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, CA, United States; Unit of Medical Oncology 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Fagr Eladly
- Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Wen Wu
- Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Frank Herweck
- Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Nadine Schulte
- Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Johannes Betge
- Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Nicolai Härtel
- Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Jakob N Kather
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany
| | - Cleo-Aron Weis
- Institute of Pathology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Timo Gaiser
- Institute of Pathology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Alexander Marx
- Institute of Pathology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Christel Weiss
- Department of Medical Statistics, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Ralf Hofheinz
- Department of Medicine III, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Ian S Miller
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Fotios Loupakis
- Unit of Medical Oncology 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, CA, United States
| | - Annette T Byrne
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland; UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Matthias P Ebert
- Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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24
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Gnocchi D, Custodero C, Sabbà C, Mazzocca A. Circadian rhythms: a possible new player in non-alcoholic fatty liver disease pathophysiology. J Mol Med (Berl) 2019; 97:741-759. [PMID: 30953079 DOI: 10.1007/s00109-019-01780-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 03/10/2019] [Accepted: 03/13/2019] [Indexed: 12/16/2022]
Abstract
Over the last decades, a better knowledge of the molecular machinery supervising the regulation of circadian clocks has been achieved, and numerous findings have helped in unravelling the outstanding significance of the molecular clock for the proper regulation of our physiologic and metabolic homeostasis. Non-alcoholic fatty liver disease (NAFLD) is currently considered as one of the emerging liver pathologies in the Western countries due to the modification of eating habits and lifestyle. Although NAFLD is considered a pretty benign condition, it can progress towards non-alcoholic steatohepatitis (NASH) and eventually hepatocellular carcinoma (HCC). The pathogenic mechanisms involved in NAFLD development are complex, since this disease is a multifactorial condition. Major metabolic deregulations along with a genetic background are believed to take part in this process. In this light, the aim of this review is to give a comprehensive description of how our circadian machinery is regulated and to describe to what extent our internal clock is involved in the regulation of hormonal and metabolic homeostasis, and by extension in the development and progression of NAFLD/NASH and eventually in the onset of HCC.
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Affiliation(s)
- Davide Gnocchi
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124, Bari, Italy
| | - Carlo Custodero
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124, Bari, Italy
| | - Carlo Sabbà
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124, Bari, Italy
| | - Antonio Mazzocca
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124, Bari, Italy.
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Gil-Martín E, Egea J, Reiter RJ, Romero A. The emergence of melatonin in oncology: Focus on colorectal cancer. Med Res Rev 2019; 39:2239-2285. [PMID: 30950095 DOI: 10.1002/med.21582] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/04/2019] [Accepted: 03/16/2019] [Indexed: 12/17/2022]
Abstract
Within the last few decades, melatonin has increasingly emerged in clinical oncology as a naturally occurring bioactive molecule with substantial anticancer properties and a pharmacological profile optimal for joining the currently available pharmacopeia. In addition, extensive experimental data shows that this chronobiotic agent exerts oncostatic effects throughout all stages of tumor growth, from initial cell transformation to mitigation of malignant progression and metastasis; additionally, melatonin alleviates the side effects and improves the welfare of radio/chemotherapy-treated patients. Thus, the support of clinicians and oncologists for the use of melatonin in both the treatment and proactive prevention of cancer is gaining strength. Because of its epidemiological importance and symptomatic debut in advanced stages of difficult clinical management, colorectal cancer (CRC) is a preferential target for testing new therapies. In this regard, the development of effective forms of clinical intervention for the improvement of CRC outcome, specifically metastatic CRC, is urgent. At the same time, the need to reduce the costs of conventional anti-CRC therapy results is also imperative. In light of this status quo, the therapeutic potential of melatonin, and the direct and indirect critical processes of CRC malignancy it modulates, have aroused much interest. To illuminate the imminent future on CRC research, we focused our attention on the molecular mechanisms underlying the multiple oncostatic actions displayed by melatonin in the onset and evolution of CRC and summarized epidemiological evidence, as well as in vitro, in vivo and clinical findings that support the broadly protective potential demonstrated by melatonin.
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Affiliation(s)
- Emilio Gil-Martín
- Department of Biochemistry, Genetics and Immunology, Biomedical Research Center (CINBIO, 'Centro Singular de Investigación de Galicia'), University of Vigo, Vigo, Spain
| | - Javier Egea
- Molecular Neuroinflammation and Neuronal Plasticity Laboratory, Research Unit, Hospital Universitario Santa Cristina, Madrid, Spain.,Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain.,Departamento de Farmacología y Terapéutica, Instituto-Fundación Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, Texas, USA
| | - Alejandro Romero
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain
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Liu Z, Yu K, Zheng J, Lin H, Zhao Q, Zhang X, Feng W, Wang L, Xu J, Xie D, Zuo Z, Liu Z, Zheng Q. Dysregulation, functional implications, and prognostic ability of the circadian clock across cancers. Cancer Med 2019; 8:1710-1720. [PMID: 30791227 PMCID: PMC6488113 DOI: 10.1002/cam4.2035] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 01/15/2019] [Accepted: 01/29/2019] [Indexed: 12/21/2022] Open
Abstract
It has been proposed that the circadian rhythm generally plays important roles in tumor suppression, but there is also evidence that disruption of the canonical circadian pathway has anticancer effects. In this study, we systematically analyzed the aberrances of circadian clock genes across cancers based on data from The Cancer Genome Atlas (TCGA). These data showed that the frequencies of mutations and copy number alterations in core clock genes (PER1/2/3, CLOCK, CRY1/2, and ARNTL) were low, but that the expression levels of core clock genes were downregulated by the higher levels of DNA methylation in most tumors. The circadian clock index (CCI) was established through a principal component analysis, and this measure well represents the overall expression of the core clock genes. In fact, the CCI was significantly lower in hepatocellular carcinoma with HBV infection than in other cancers. Furthermore, pathways such as the MAPK, JAK-STAT, and immune-related signaling pathways were enriched in tumors with high CCI values. Interestingly, the CCI was generally positively related to the immunophenoscores and immunophenotypes of tumors. Additionally, the expression levels of core clock genes and the CCI were also generally positively related to survival across cancers. Taken together, the results of this study provide a comprehensive analysis of circadian clock aberrances in cancer, and the results should aid further investigations of the molecular mechanisms of cancer and the development of therapeutic strategies.
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Affiliation(s)
- Zekun Liu
- Department of Hepatobiliary SurgeryUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouChina
| | - Kai Yu
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouChina
| | - Jian Zheng
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouChina
| | - Huan Lin
- The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhouChina
| | - Qi Zhao
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouChina
| | - Xiaolong Zhang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouChina
| | - Weiyi Feng
- Big Data Research Center, School of Computer Science and EngineeringUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Liyu Wang
- Department of Hepatobiliary SurgeryUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Jianjun Xu
- Department of Hepatobiliary SurgeryUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Dawei Xie
- Department of Hepatobiliary SurgeryUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Zhi‐Xiang Zuo
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouChina
| | - Ze‐Xian Liu
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouChina
| | - Qichang Zheng
- Department of Hepatobiliary SurgeryUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
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Davis K, Roden LC, Leaner VD, van der Watt PJ. The tumour suppressing role of the circadian clock. IUBMB Life 2019; 71:771-780. [DOI: 10.1002/iub.2005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 12/10/2018] [Accepted: 12/17/2018] [Indexed: 12/12/2022]
Affiliation(s)
- Kate Davis
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences; University of Cape Town; Cape Town South Africa
| | - Laura C. Roden
- School of Life Sciences; Coventry University, Alison Gingell Building Room 2.24; Coventry, CV1 5FB UK
| | - Virna D. Leaner
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences; University of Cape Town; Cape Town South Africa
- SAMRC/UCT Gynaecological Cancer Research Centre; Institute of Infectious Disease and Molecular Medicine, University of Cape Town; Cape Town South Africa
| | - Pauline J. van der Watt
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences; University of Cape Town; Cape Town South Africa
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28
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Codoñer-Franch P, Gombert M. Circadian rhythms in the pathogenesis of gastrointestinal diseases. World J Gastroenterol 2018; 24:4297-4303. [PMID: 30344415 PMCID: PMC6189841 DOI: 10.3748/wjg.v24.i38.4297] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 08/31/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
The etiology of digestive pathologies such as irritable bowel syndrome (IBS), inflammatory bowel diseases (IBD) and cancer is not yet fully understood. In recent years, several studies have evidenced circadian variations in mechanisms involved in digestive health. In situations of disturbed circadian rhythms (chronodisruption) where the central clock and the peripheral clocks receive incoherent signals, the synchronicity is lost producing implications for health. This lack of coordination could alter the tissue function and cause long term damage to the organs. Life habits such as sleep, physical exercise, social interaction, and feeding times are determinants for stability and integrity of circadian rhythms. In recent years, experimental and clinical studies have consistently evidenced that the alteration of circadian rhythms is associated with the development of digestive pathologies mainly linked to dismotility or changes in microbiota composition. Likewise, it seems reasonable to deep into the importance of chronodisruption as a factor that may participate in the development of pathologies such as IBS, IBD and digestive cancers. Moreover, life habits respecting circadian rhythms should be promoted for the prevention of these diseases. Further studies will allow us a better understanding of the mechanisms acting at molecular level, and the development of new therapeutic targets.
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Affiliation(s)
- Pilar Codoñer-Franch
- Department of Pediatrics, Obstetrics and Ginecology, University of Valencia, Valencia 46010, Spain
- Department of Pediatrics, Dr. Peset University Hospital, Valencia 46017, Spain
| | - Marie Gombert
- Department of Pediatrics, Obstetrics and Ginecology, University of Valencia, Valencia 46010, Spain
- Department of Biotechnology, University of La Rochelle, La Rochelle 17000, France
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29
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Gómez-Sierra T, Eugenio-Pérez D, Sánchez-Chinchillas A, Pedraza-Chaverri J. Role of food-derived antioxidants against cisplatin induced-nephrotoxicity. Food Chem Toxicol 2018; 120:230-242. [DOI: 10.1016/j.fct.2018.07.018] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 06/22/2018] [Accepted: 07/06/2018] [Indexed: 12/21/2022]
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Alasadi A, Chen M, Swapna GVT, Tao H, Guo J, Collantes J, Fadhil N, Montelione GT, Jin S. Effect of mitochondrial uncouplers niclosamide ethanolamine (NEN) and oxyclozanide on hepatic metastasis of colon cancer. Cell Death Dis 2018; 9:215. [PMID: 29440715 PMCID: PMC5833462 DOI: 10.1038/s41419-017-0092-6] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 08/25/2017] [Accepted: 09/20/2017] [Indexed: 02/06/2023]
Abstract
Metabolism of cancer cells is characterized by aerobic glycolysis, or the Warburg effect. Aerobic glycolysis reduces pyruvate flux into mitochondria, preventing a complete oxidation of glucose and shunting glucose to anabolic pathways essential for cell proliferation. Here we tested a new strategy, mitochondrial uncoupling, for its potential of antagonizing the anabolic effect of aerobic glycolysis and for its potential anticancer activities. Mitochondrial uncoupling is a process that facilitates proton influx across the mitochondrial inner membrane without generating ATP, stimulating a futile cycle of acetyl- CoA oxidation. We tested two safe mitochondrial uncouplers, NEN (niclosamide ethanolamine) and oxyclozanide, on their metabolic effects and anti-cancer activities. We used metabolomic NMR to examine the effect of mitochondrial uncoupling on glucose metabolism in colon cancer MC38 cells. We further tested the anti-cancer effect of NEN and oxyclozanide in cultured cell models, APCmin/+ mouse model, and a metastatic colon cancer mouse model. Using a metabolomic NMR approach, we demonstrated that mitochondrial uncoupling promotes pyruvate influx to mitochondria and reduces various anabolic pathway activities. Moreover, mitochondrial uncoupling inhibits cell proliferation and reduces clonogenicity of cultured colon cancer cells. Furthermore, oral treatment with mitochondrial uncouplers reduces intestinal polyp formation in APCmin/+ mice, and diminishes hepatic metastasis of colon cancer cells transplanted intrasplenically. Our data highlight a unique approach for targeting cancer cell metabolism for cancer prevention and treatment, identified two prototype compounds, and shed light on the anti-cancer mechanism of niclosamide.
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Affiliation(s)
- Amer Alasadi
- Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers - The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ, 08854, USA
- Graduate Program of Physiology and Integrative Biology, Robert Wood Johnson Medical School, Rutgers - The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ, 08854, USA
| | - Michael Chen
- Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers - The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ, 08854, USA
| | - G V T Swapna
- Center for Advanced Biotechnology and Medicine, and Department of Molecular Biology and Biochemistry, Rutgers - The State University of New Jersey, 679 Hoes Lane West, Piscataway, NJ, 08854, USA
| | - Hanlin Tao
- Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers - The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ, 08854, USA
| | - Jingjing Guo
- Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers - The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ, 08854, USA
| | - Juan Collantes
- Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers - The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ, 08854, USA
| | - Noor Fadhil
- Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers - The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ, 08854, USA
- Clinical and Translational Science Program, Robert Wood Johnson Medical School, Rutgers - The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ, 08854, USA
| | - Gaetano T Montelione
- Center for Advanced Biotechnology and Medicine, and Department of Molecular Biology and Biochemistry, Rutgers - The State University of New Jersey, 679 Hoes Lane West, Piscataway, NJ, 08854, USA
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers - The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ, 08854, USA
| | - Shengkan Jin
- Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers - The State University of New Jersey, 675 Hoes Lane West, Piscataway, NJ, 08854, USA.
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Abstract
Epidemiological studies provided the first evidence suggesting a connection between the circadian clock and human health. Mutant mice convincingly demonstrate the principle that dysregulation of the circadian system leads to a multitude of pathologies. Chrono-medicine is one of the most important upcoming themes in the field of circadian biology. Although treatments counteracting circadian dysregulation are already being applied (e.g., prescribing strong and regular zeitgebers), we need to comprehend entrainment throughout the body's entire circadian network before understanding the mechanisms that tie circadian dysregulation to pathology. Here, we attempt to provide a systematic approach to understanding the connection between the circadian clock and health. This taxonomy of (mis)alignments on one hand exposes how little we know about entrainment within any organism and which 'eigen-zeitgeber' signals are used for entrainment by the different cells and tissues. On the other hand, it provides focus for experimental approaches and tools that will logically map out how circadian systems contribute to disease as well as how we can treat and prevent them.
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32
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Royse KE, El-Serag HB, Chen L, White DL, Hale L, Sangi-Haghpeykar H, Jiao L. Sleep Duration and Risk of Liver Cancer in Postmenopausal Women: The Women's Health Initiative Study. J Womens Health (Larchmt) 2017; 26:1270-1277. [PMID: 28933583 PMCID: PMC6037184 DOI: 10.1089/jwh.2017.6412] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Sleep duration has been associated with nonalcoholic fatty liver disease, but its association with liver cancer remains unknown. MATERIAL AND METHODS In the prospective Women's Health Initiative Study, 139,368 postmenopausal women reported sleep habits at baseline (1993-1998). We ascertained 175 incident liver cancer cases during an average 13.8 years of follow-up through August 2014. We used multivariable Cox proportional hazard regression models to estimate a hazard ratio (HR) and its 95% confidence interval (95% CI) for risk of liver cancer in association with nocturnal sleep duration. RESULTS Compared to women reporting 6-8 hours of sleep, the HR for liver cancer was 1.94 (95% CI 1.07-3.53) for women reporting ≥9 hours of sleep. Among the obese women, the HR associated with ≥9 hours of sleep was 3.18 (95% CI 1.84-8.60). The HR was 0.93 (95% CI 0.34-2.53) among nonobese women (p value for interaction = 0.18). Short sleep duration (≤5 hours) was not associated with liver cancer risk. CONCLUSION Long sleep duration was associated with a moderate increase in liver cancer risk in obese postmenopausal women in the United States. Larger study is needed to confirm our observation on effect modification by adiposity status.
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Affiliation(s)
- Kathryn E. Royse
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
- Center for Innovations in Quality, Effectiveness and Safety (iQuEST), Michael E. DeBakey VA Medical Center, Houston, Texas
| | - Hashem B. El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
- Center for Innovations in Quality, Effectiveness and Safety (iQuEST), Michael E. DeBakey VA Medical Center, Houston, Texas
- Texas Medical Center Digestive Disease Center, Houston, Texas
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Liang Chen
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
- Center for Innovations in Quality, Effectiveness and Safety (iQuEST), Michael E. DeBakey VA Medical Center, Houston, Texas
| | - Donna L. White
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
- Center for Innovations in Quality, Effectiveness and Safety (iQuEST), Michael E. DeBakey VA Medical Center, Houston, Texas
- Texas Medical Center Digestive Disease Center, Houston, Texas
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, Texas
| | - Lauren Hale
- Program in Public Health, School of Medicine, Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, New York
| | | | - Li Jiao
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
- Center for Innovations in Quality, Effectiveness and Safety (iQuEST), Michael E. DeBakey VA Medical Center, Houston, Texas
- Texas Medical Center Digestive Disease Center, Houston, Texas
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, Texas
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Momma T, Okayama H, Saitou M, Sugeno H, Yoshimoto N, Takebayashi Y, Ohki S, Takenoshita S. Expression of circadian clock genes in human colorectal adenoma and carcinoma. Oncol Lett 2017; 14:5319-5325. [PMID: 29113166 PMCID: PMC5661361 DOI: 10.3892/ol.2017.6876] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 10/05/2016] [Indexed: 12/11/2022] Open
Abstract
Circadian rhythms are fundamental biological systems in most organisms. Epidemiological and animal studies have demonstrated that disruption of circadian rhythms is linked to tumor progression and mammalian tumorigenesis. However, the clinical significance of in situ clock gene expression in precancerous and cancerous colorectal lesions remains unknown. The present study aimed to investigate mRNA transcript levels of circadian clock genes within human colorectal cancer and adenoma tissue sections. Using in situ hybridization, the expression of key clock genes, including period circadian protein homolog (Per) 1 and 2, cryptochrome 1 (Cry1), circadian locomoter output cycles protein kaput (Clock), brain and muscle ARNT-like protein 1 (Bmal1) and casein kinase 1ε (CK1ε) were retrospectively examined in 51 cases of colorectal carcinoma and 10 cases of adenoma. The expression of clock genes was almost undetectable in the majority of adenomas, whereas positive expression of clock genes was observed in 27–47% of carcinomas. Notably, positive Per1, Per2 and Clock staining in colorectal carcinomas were each significantly associated with a larger tumor size (P=0.012, P=0.011 and P=0.009, respectively). Tumors with positive Per2 and Clock expression tended to exhibit deeper depth of invasion and were generally more advanced than tumors that did not express these genes (P=0.052 and P=0.064, respectively). However, no statistically significant association was observed between clock gene expression and clinicopathological variables, including histopathological differentiation, lymph node metastasis, depth of invasion or disease stage, although Per2-positive tumors tended to be associated with poorer overall survival (P=0.060). The results of the current study suggest that dysregulated expression of clock genes may be important in human colorectal tumorigenesis.
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Affiliation(s)
- Tomoyuki Momma
- Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Hirokazu Okayama
- Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Masaru Saitou
- Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Hidekazu Sugeno
- Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Nobuhiro Yoshimoto
- Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Yuji Takebayashi
- Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Shinji Ohki
- Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Seiichi Takenoshita
- Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
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Shimizu T, Watanabe K, Anayama N, Miyazaki K. Effect of lipopolysaccharide on circadian clock genes Per2 and Bmal1 in mouse ovary. J Physiol Sci 2017; 67:623-628. [PMID: 28213822 PMCID: PMC10717690 DOI: 10.1007/s12576-017-0532-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 02/12/2017] [Indexed: 12/12/2022]
Abstract
In mammals, circadian rhythms are associated with multiple physiological events. The aim of the present study was to examine the effect of lipopolysaccharide (LPS) on circadian systems in the ovary. Immature female mice were received an intra-peritoneal injection of equine chorionic gonadotropin (eCG) and LPS. Total RNA was collected from the ovary at 6-h intervals throughout a 48 h of experimental period. The expression of the circadian genes period 2 (Per2) and brain and muscle ARNT-like 1 (Bmal1) such as circadian genes was measured by quantitative PCR. Although expression of Per2 and Bmal1 in the ovary did not display clear diurnal oscillation, LPS suppressed the amplitude of Per2 expression. Additionally, LPS inhibited the expression of cytochrome P450 aromatase (CYP19) and luteinizing hormone receptor (LHr) genes in the ovary of eCG-treated mice. Our data suggest that Per2 may be associated with the inhibition of CYP19 and LHr expression by LPS in the ovaries of immature mice.
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Affiliation(s)
- Takashi Shimizu
- Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, 0808555, Japan.
| | - Kaya Watanabe
- Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, 0808555, Japan
| | - Nozomi Anayama
- Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, 0808555, Japan
| | - Koyomi Miyazaki
- Biomedical Research Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, 3058568, Japan
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Entrainment of Breast Cell Lines Results in Rhythmic Fluctuations of MicroRNAs. Int J Mol Sci 2017; 18:ijms18071499. [PMID: 28704935 PMCID: PMC5535989 DOI: 10.3390/ijms18071499] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 06/12/2017] [Accepted: 07/05/2017] [Indexed: 12/13/2022] Open
Abstract
Circadian rhythms are essential for temporal (~24 h) regulation of molecular processes in diverse species. Dysregulation of circadian gene expression has been implicated in the pathogenesis of various disorders, including hypertension, diabetes, depression, and cancer. Recently, microRNAs (miRNAs) have been identified as critical modulators of gene expression post-transcriptionally, and perhaps involved in circadian clock architecture or their output functions. The aim of the present study is to explore the temporal expression of miRNAs among entrained breast cell lines. For this purpose, we evaluated the temporal (28 h) expression of 2006 miRNAs in MCF-10A, MCF-7, and MDA-MB-231 cells using microarrays after serum shock entrainment. We noted hundreds of miRNAs that exhibit rhythmic fluctuations in each breast cell line, and some of them across two or three cell lines. Afterwards, we validated the rhythmic profiles exhibited by miR-141-5p, miR-1225-5p, miR-17-5p, miR-222-5p, miR-769-3p, and miR-548ay-3p in the above cell lines, as well as in ZR-7530 and HCC-1954 using RT-qPCR. Our results show that serum shock entrainment in breast cells lines induces rhythmic fluctuations of distinct sets of miRNAs, which have the potential to be related to endogenous circadian clock, but extensive investigation is required to elucidate that connection.
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Shostak A. Circadian Clock, Cell Division, and Cancer: From Molecules to Organism. Int J Mol Sci 2017; 18:E873. [PMID: 28425940 PMCID: PMC5412454 DOI: 10.3390/ijms18040873] [Citation(s) in RCA: 117] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 04/12/2017] [Accepted: 04/14/2017] [Indexed: 12/21/2022] Open
Abstract
As a response to environmental changes driven by the Earth's axial rotation, most organisms evolved an internal biological timer-the so called circadian clock-which regulates physiology and behavior in a rhythmic fashion. Emerging evidence suggests an intimate interplay between the circadian clock and another fundamental rhythmic process, the cell cycle. However, the precise mechanisms of this connection are not fully understood. Disruption of circadian rhythms has a profound impact on cell division and cancer development and, vice versa, malignant transformation causes disturbances of the circadian clock. Conventional knowledge attributes tumor suppressor properties to the circadian clock. However, this implication might be context-dependent, since, under certain conditions, the clock can also promote tumorigenesis. Therefore, a better understanding of the molecular links regulating the physiological balance between the two cycles will have potential significance for the treatment of cancer and associated disorders.
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Affiliation(s)
- Anton Shostak
- Circadian Rhythms and Molecular Clocks Group, Heidelberg University Biochemistry Center, 69120 Heidelberg, Germany.
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37
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Ge XC, Wu F, Li WT, Zhu XJ, Liu JW, Wang BL. Upregulation of WEE1 is a potential prognostic biomarker for patients with colorectal cancer. Oncol Lett 2017; 13:4341-4348. [PMID: 28599436 DOI: 10.3892/ol.2017.5984] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 02/07/2017] [Indexed: 12/24/2022] Open
Abstract
WEE1 is a serine/threonine protein kinase that inactivates cell division cycle 2 and is therefore a critical cell cycle regulator. Increased WEE1 expression has been observed in numerous types of human malignancies, including hepatocellular carcinoma and melanoma. WEE1 inhibition also results in evident anti-tumor effects in several human tumor cells including colon cancer cells, suggesting WEE1 as a potential therapeutic target for the treatment of cancer. However, the expression pattern of WEE1 in colorectal cancer (CRC) remains unclear. In the present study, WEE1 mRNA expression in 43 cases of CRC tissues matched with adjacent normal tissues was determined by reverse-transcription quantitative polymerase chain reaction. The results demonstrated that WEE1 mRNA expression was significantly increased in CRC tissues and that this upregulation correlated significantly with hepatic metastasis, distant metastasis and high tumor node metastasis (TNM) stage of CRC. Additionally, WEE1 protein in 102 CRC tissue samples was detected by immunohistochemistry, and positive staining of WEE1 was identified in more than half of patients with CRC. WEE1 staining scores were also observed to be associated with distant metastasis and high TNM stage of CRC. In addition, patients with CRC with high WEE1 staining score (2+ or 3+) exhibited either poorer overall survival or poorer disease-free survival compared with those with low WEE1 staining score (0 or 1+). The multivariable Cox model also identified a high WEE1 staining score as well as high TNM stage to be independent prognostic factors for CRC. In conclusion, WEE1 upregulation is associated with a high degree of malignancy and poor prognosis of CRC, suggesting WEE1 as a potential prognostic biomarker for CRC.
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Affiliation(s)
- Xiao-Chuan Ge
- Department of General Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Fan Wu
- Department of General Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Wei-Tao Li
- Department of General Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Xuan-Jin Zhu
- Department of General Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Jian-Wei Liu
- Department of General Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Bai-Lin Wang
- Department of General Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, Guangdong 510220, P.R. China
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Huisman SA, Ahmadi AR, IJzermans JNM, Verhoef C, van der Horst GTJ, de Bruin RWF. Disruption of clock gene expression in human colorectal liver metastases. Tumour Biol 2016; 37:13973-13981. [PMID: 27492458 PMCID: PMC5097083 DOI: 10.1007/s13277-016-5231-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 07/15/2016] [Indexed: 12/20/2022] Open
Abstract
The circadian timing system controls about 40 % of the transcriptome and is important in the regulation of a wide variety of biological processes including metabolic and proliferative functions. Disruption of the circadian clock could have significant effect on human health and has an important role in the development of cancer. Here, we compared the expression levels of core clock genes in primary colorectal cancer (CRC), colorectal liver metastases (CRLM), and liver tissue within the same patient. Surgical specimens of 15 untreated patients with primary CRC and metachronous CRLM were studied. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of 10 clock genes: CLOCK, BMAL1, PER1, PER2, PER3, CRY1, CRY2, CSNK1E, TIM, TIPIN, and 2 clock-controlled genes: Cyclin-D1, and WEE1. Expression levels of 7 core clock genes were downregulated in CRLM: CLOCK (p = 0.006), BMAL1 (p = 0.003), PER1 (p = 0.003), PER2 (p = 0.002), PER3 (p < 0.001), CRY1 (p = 0.002), and CRY2 (p < 0.001). In CRC, 5 genes were downregulated: BMAL1 (p = 0.02), PER1 (p = 0.004), PER2 (p = 0.008), PER3 (p < 0.001), and CRY2 (p < 0.001). CSNK1E was upregulated in CRC (p = 0.02). Cyclin-D1 and WEE1 were both downregulated in CRLM and CRC. Related to clinicopathological factors, a significant correlation was found between low expression of CRY1 and female gender, and low PER3 expression and the number of CRLM. Our data demonstrate that the core clock is disrupted in CRLM and CRC tissue from the same patient. This disruption may be linked to altered cell-cycle dynamics and carcinogenesis.
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Affiliation(s)
- Sander A Huisman
- Department of Surgery, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands
| | - Ali R Ahmadi
- Department of Surgery, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands
| | - Jan N M IJzermans
- Department of Surgery, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands
| | - Cees Verhoef
- Department of Surgery, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands
| | - Gijsbertus T J van der Horst
- Department of Molecular Genetics, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands
| | - Ron W F de Bruin
- Department of Surgery, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands.
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Egeland EV, Flatmark K, Nesland JM, Flørenes VA, Mælandsmo GM, Boye K. Expression and clinical significance of Wee1 in colorectal cancer. Tumour Biol 2016; 37:12133-12140. [PMID: 27220319 DOI: 10.1007/s13277-016-5081-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 05/15/2016] [Indexed: 12/22/2022] Open
Abstract
Wee1 is a nuclear kinase regulating cell cycle progression, and has emerged as a promising therapeutic target in cancer. Expression of Wee1 has been associated with poor outcome in certain tumor types, but the prognostic impact and clinical significance in colorectal cancer is unknown. The expression of Wee1 was examined by immunohistochemistry in primary colorectal carcinomas from a prospectively collected patient cohort, and associations with clinicopathological parameters and outcome were investigated. Cell culture experiments were performed using the cell lines RKO and SW620, and the relationship with the metastasis-promoting protein S100A4 was investigated. Nuclear expression was detected in 229 of the 258 tumors analyzed (89 %). Wee1 staining was associated with low pT stage, but no other significant associations with demographic or histopathological variables were found. Moderate Wee1 staining intensity was a predictor of favorable metastasis-free and overall survival compared to strong intensity and no or weak staining. The fraction of positive cells was not a prognostic factor in the present cohort. Inhibition of Wee1 expression using siRNA or treatment with the Wee1 inhibitor MK-1775 reduced expression of the metastasis-promoting protein S100A4, but no relationship between Wee1 and S100A4 was found in the patient samples. In conclusion, Wee1 is highly expressed in primary colorectal carcinomas, but few relevant associations with clinicopathological parameters or outcome were found. The lack of clinical significance of Wee1 expression could indicate that other tumor types might be better suited for further development of Wee1 inhibitors.
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Affiliation(s)
- Eivind Valen Egeland
- Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, PO Box 4953, Nydalen, NO-0424, Oslo, Norway
| | - Kjersti Flatmark
- Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, PO Box 4953, Nydalen, NO-0424, Oslo, Norway.,Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Medical Faculty, University of Oslo, Oslo, Norway
| | - Jahn M Nesland
- Medical Faculty, University of Oslo, Oslo, Norway.,Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Vivi Ann Flørenes
- Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Gunhild M Mælandsmo
- Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, PO Box 4953, Nydalen, NO-0424, Oslo, Norway.,Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
| | - Kjetil Boye
- Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, PO Box 4953, Nydalen, NO-0424, Oslo, Norway. .,Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
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Tahara Y, Shibata S. Circadian rhythms of liver physiology and disease: experimental and clinical evidence. Nat Rev Gastroenterol Hepatol 2016; 13:217-26. [PMID: 26907879 DOI: 10.1038/nrgastro.2016.8] [Citation(s) in RCA: 157] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The circadian clock system consists of a central clock located in the suprachiasmatic nucleus in the hypothalamus and peripheral clocks in peripheral tissues. Peripheral clocks in the liver have fundamental roles in maintaining liver homeostasis, including the regulation of energy metabolism and the expression of enzymes controlling the absorption and metabolism of xenobiotics. Over the past two decades, research has investigated the molecular mechanisms linking circadian clock genes with the regulation of hepatic physiological functions, using global clock-gene-knockout mice, or mice with liver-specific knockout of clock genes or clock-controlled genes. Clock dysfunction accelerates the development of liver diseases such as fatty liver diseases, cirrhosis, hepatitis and liver cancer, and these disorders also disrupt clock function. Food is an important regulator of circadian clocks in peripheral tissues. Thus, controlling the timing of food consumption and food composition, a concept known as chrononutrition, is one area of active research to aid recovery from many physiological dysfunctions. In this Review, we focus on the molecular mechanisms of hepatic circadian gene regulation and the relationships between hepatic circadian clock systems and liver physiology and disease. We concentrate on experimental data obtained from cell or mice and rat models and discuss how these findings translate into clinical research, and we highlight the latest developments in chrononutritional studies.
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Affiliation(s)
- Yu Tahara
- Waseda Institute for Advanced Study, Waseda University, Shinjuku-ku, Tokyo, 162-8480, Japan
| | - Shigenobu Shibata
- Laboratory of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Wakamatsu-cho 2-2, Shinjuku-ku, Tokyo, 162-8480, Japan
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Zhou D, Wang Y, Chen L, Jia L, Yuan J, Sun M, Zhang W, Wang P, Zuo J, Xu Z, Luan J. Evolving roles of circadian rhythms in liver homeostasis and pathology. Oncotarget 2016; 7:8625-39. [PMID: 26843619 PMCID: PMC4890992 DOI: 10.18632/oncotarget.7065] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 01/18/2016] [Indexed: 02/06/2023] Open
Abstract
Circadian clock in mammals is determined by a core oscillator in the suprachiasmatic nucleus (SCN) of the hypothalamus and synchronized peripheral clocks in other tissues. The coherent timing systems could sustain robust output of circadian rhythms in response to the entrainment controlled environmentally. Disparate approaches have discovered that clock genes and clock-controlled genes (CCGs) exist in nearly all mammalian cell types and are essential for establishing the mechanisms and complexity of internal time-keeping systems. Accumulating evidence demonstrates that the control of homeostasis and pathology in the liver involves intricate loops of transcriptional and post-translational regulation of clock genes expression. This review will focus on the recent advances with great importance concerning clock rhythms linking liver homeostasis and diseases. We particularly highlight what is currently known of the evolving insights into the mechanisms underlying circadian clock . Eventually , findings during recent years in the field might prompt new circadian-related chronotherapeutic strategies for the diagnosis and treatment of liver diseases by coupling these processes.
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Affiliation(s)
- Dexi Zhou
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Yaqin Wang
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Lu Chen
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Leijuan Jia
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Jie Yuan
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Mei Sun
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Wen Zhang
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Peipei Wang
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Jian Zuo
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Zhenyu Xu
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Jiajie Luan
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
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Modulation of E-cadherin expression promotes migration ability of esophageal cancer cells. Sci Rep 2016; 6:21713. [PMID: 26898709 PMCID: PMC4761978 DOI: 10.1038/srep21713] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 01/22/2016] [Indexed: 12/22/2022] Open
Abstract
Losing the E-cadherin plays an important role in the metastasis of cancer. The regulation of the expression of E-cadherin is unclear. Circadian rhythm alteration is associated with the pathogenesis of a number of cancers. This study aims to investigate the role of one of the circadian proteins, period-2 (Per2) in repressing the expression of E-cadherin in esophageal cancer (esophageal cancer). We observed that the levels of circadian protein Per2 were significantly increased and E-cadherin was significantly decreased in the tissue of human esophageal cancer with metastasis as compared with non-metastatic esophageal cancer. Overexpression of Per2 in the esophageal cancer cells markedly repressed the expression of E-cadherin. The pHDAC1 was detected in human esophageal cancer with metastasis, which was much less in the esophageal cancer tissue without metastasis. Overexpression of Per2 increased the levels of pHDAC1 as well as the E-cadherin repressors at the E-cadherin promoter locus. Overexpression of Per2 markedly increased the migratory capacity of esophageal cancer cells, which was abolished by the inhibition of HDAC1. We conclude that Per-2 plays an important role in the esophageal cancer cell metastasis, which may be a novel therapeutic target for the treatment of esophageal cancer.
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Valenzuela FJ, Vera J, Venegas C, Muñoz S, Oyarce S, Muñoz K, Lagunas C. Evidences of Polymorphism Associated with Circadian System and Risk of Pathologies: A Review of the Literature. Int J Endocrinol 2016; 2016:2746909. [PMID: 27313610 PMCID: PMC4893437 DOI: 10.1155/2016/2746909] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 04/14/2016] [Accepted: 04/19/2016] [Indexed: 12/15/2022] Open
Abstract
The circadian system is a supraphysiological system that modulates different biological functions such as metabolism, sleep-wake, cellular proliferation, and body temperature. Different chronodisruptors have been identified, such as shift work, feeding time, long days, and stress. The environmental changes and our modern lifestyle can alter the circadian system and increase the risk of developing pathologies such as cancer, preeclampsia, diabetes, and mood disorder. This system is organized by transcriptional/tranductional feedback loops of clock genes Clock, Bmal1, Per1-3, and Cry1-2. How molecular components of the clock are able to influence the development of diseases and their risk relation with genetic components of polymorphism of clock genes is unknown. This research describes different genetic variations in the population and how these are associated with risk of cancer, metabolic diseases such as diabetes, obesity, and dyslipidemias, and also mood disorders such as depression, bipolar disease, excessive alcohol intake, and infertility. Finally, these findings will need to be implemented and evaluated at the level of genetic interaction and how the environment factors trigger the expression of these pathologies will be examined.
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Affiliation(s)
- F. J. Valenzuela
- Department of Basic Sciences, Universidad del Bío-Bío, Campus Fernando May, 378000 Chillán, Chile
- Group of Biotechnological Sciences, Department of Basic Sciences, Universidad del Bío-Bío, Campus Fernando May, 378000 Chillán, Chile
- *F. J. Valenzuela:
| | - J. Vera
- Department of Basic Sciences, Universidad del Bío-Bío, Campus Fernando May, 378000 Chillán, Chile
- Group of Biotechnological Sciences, Department of Basic Sciences, Universidad del Bío-Bío, Campus Fernando May, 378000 Chillán, Chile
| | - C. Venegas
- Department of Basic Sciences, Universidad del Bío-Bío, Campus Fernando May, 378000 Chillán, Chile
| | - S. Muñoz
- Department of Basic Sciences, Universidad del Bío-Bío, Campus Fernando May, 378000 Chillán, Chile
| | - S. Oyarce
- Department of Basic Sciences, Universidad del Bío-Bío, Campus Fernando May, 378000 Chillán, Chile
| | - K. Muñoz
- Department of Basic Sciences, Universidad del Bío-Bío, Campus Fernando May, 378000 Chillán, Chile
| | - C. Lagunas
- Department of Basic Sciences, Universidad del Bío-Bío, Campus Fernando May, 378000 Chillán, Chile
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Sakakibara H, Torii Yasuda M, Shimoi K. Effects of environmental and social stressors on biological rhythms. THE JOURNAL OF PHYSICAL FITNESS AND SPORTS MEDICINE 2016. [DOI: 10.7600/jpfsm.5.143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
| | | | - Kayoko Shimoi
- School of Food and Nutritional Sciences, University of Shizuoka
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Kobuchi S, Ito Y, Nakano Y, Sakaeda T. Population pharmacokinetic modelling and simulation of 5-fluorouracil incorporating a circadian rhythm in rats. Xenobiotica 2015; 46:597-604. [DOI: 10.3109/00498254.2015.1100767] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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