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Cano LC, Navarrete E, Ochoa-Romo JP, Díaz G, Díaz-Hernández V, Montúfar-Chaveznava R, Caldelas I. Chronic Maternal Overnutrition and Nutritional Challenge in Adult Life Disrupt Metabolic Diurnal Rhythmicity and Clock Gene Expression in Central and Peripheral Circadian Oscillators. BIOLOGY 2025; 14:541. [PMID: 40427730 PMCID: PMC12108715 DOI: 10.3390/biology14050541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 11/07/2024] [Accepted: 11/25/2024] [Indexed: 05/29/2025]
Abstract
In mammals, the core molecular clock genes and the overall circadian system are established during early development; during this critical period of development, maternal metabolic condition plays a major role in programming temporal metabolic regulation. Therefore, this study aimed to evaluate the effects of the chronic maternal intake of a high-fat and high-carbohydrate diet (HFCD) before and during pregnancy, in addition to a challenge with HFCD during adulthood, on offspring diurnal metabolic profile and on clock gene expression in central and peripheral circadian oscillators. The HFCD offspring and/or those exposed to the metabolic challenge exhibited alterations in the temporal profiles of analytes associated with both the carbohydrate and lipid metabolisms, as well as markers associated with liver and kidney damage, ranging from phase changes in rhythmicity or, in some cases, to the complete loss of 24 h variations. At the molecular level, the expression of clock genes (Per1, Cry1, Bmal1, and Clock) in the central and peripheral oscillators showed differential susceptibility to undergoing changes in their abundance. Our data indicate that maternal HFCD during pregnancy, a second exposure in adulthood, or both result in the long-term misalignment of the diurnal rhythm's metabolic and damage markers; these changes are possibly associated with alterations in the core molecular circadian clockwork.
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Affiliation(s)
- Lucía Carolina Cano
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (L.C.C.); (E.N.); (J.P.O.-R.); (G.D.)
| | - Erika Navarrete
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (L.C.C.); (E.N.); (J.P.O.-R.); (G.D.)
| | - Juan Pablo Ochoa-Romo
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (L.C.C.); (E.N.); (J.P.O.-R.); (G.D.)
| | - Georgina Díaz
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (L.C.C.); (E.N.); (J.P.O.-R.); (G.D.)
| | - Verónica Díaz-Hernández
- Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico;
| | | | - Ivette Caldelas
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (L.C.C.); (E.N.); (J.P.O.-R.); (G.D.)
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Yang J, Zhao J, Chen Z, Duan L, Yang H, Cai D. BMAL1 in Ischemic Heart Disease: A Narrative Review from Molecular Clock to Myocardial Pathology. Int J Mol Sci 2025; 26:4626. [PMID: 40429770 PMCID: PMC12111104 DOI: 10.3390/ijms26104626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2025] [Revised: 04/30/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
The biological clock is crucial for controlling the circadian rhythm of the human body and maintaining the stable cyclic changes of various human life activities. Cardiovascular disease has become one of the primary problems affecting human life and health in today's society. Cardiovascular disease exhibits distinct circadian rhythms, with the core clock gene protein Brain and muscle ARNT-like protein 1 (BMAL1) playing critical roles in both physiological cardiac function and pathological processes. BMAL1 regulates myocardial gene expression, maintains normal structures, and stabilizes circadian rhythms to preserve cardiac homeostasis. In the pathological state of myocardial ischemia, BMAL1 ameliorates myocardial ischemic injury by regulating intrinsic mechanisms such as oxidative stress response, energy metabolism, immune-inflammatory response, and apoptosis and autophagy in cardiomyocytes. This review systematically examines BMAL1's involvement in myocardial ischemic injury through the circadian regulation of cardiac function. We analyze its multidimensional impacts on oxidative stress, energy metabolism, immune-inflammatory responses, apoptosis, and autophagy, highlighting the biological significance of this clock gene in ischemic pathophysiology.
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Affiliation(s)
- Jingyi Yang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (J.Y.); (J.Z.); (Z.C.); (L.D.); (H.Y.)
- Key Laboratory of Acupuncture for Senile Disease (Chengdu University of TCM), Ministry of Education/Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu 611137, China
| | - Junxin Zhao
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (J.Y.); (J.Z.); (Z.C.); (L.D.); (H.Y.)
- Key Laboratory of Acupuncture for Senile Disease (Chengdu University of TCM), Ministry of Education/Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu 611137, China
| | - Zhuoyang Chen
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (J.Y.); (J.Z.); (Z.C.); (L.D.); (H.Y.)
- Key Laboratory of Acupuncture for Senile Disease (Chengdu University of TCM), Ministry of Education/Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu 611137, China
| | - Lincheng Duan
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (J.Y.); (J.Z.); (Z.C.); (L.D.); (H.Y.)
- Key Laboratory of Acupuncture for Senile Disease (Chengdu University of TCM), Ministry of Education/Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu 611137, China
| | - Hong Yang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (J.Y.); (J.Z.); (Z.C.); (L.D.); (H.Y.)
- Key Laboratory of Acupuncture for Senile Disease (Chengdu University of TCM), Ministry of Education/Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu 611137, China
| | - Dingjun Cai
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (J.Y.); (J.Z.); (Z.C.); (L.D.); (H.Y.)
- Key Laboratory of Acupuncture for Senile Disease (Chengdu University of TCM), Ministry of Education/Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu 611137, China
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Lin Q, Du X, Ren F, Liu Y, Gong G, Ge S, Li W, Li Z, Zhou L, Duan M, Li XY, Wang GZ, Xiao R, Gui JF, Mei J. Anti-Müllerian hormone signalling sustains circadian homeostasis in zebrafish. Nat Commun 2025; 16:4359. [PMID: 40348785 PMCID: PMC12065890 DOI: 10.1038/s41467-025-59528-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 04/28/2025] [Indexed: 05/14/2025] Open
Abstract
Circadian clocks temporally orchestrate the behavioural and physiological rhythms. The core molecules establishing the circadian clock are clear; however, the critical signalling pathways that cause or favour the homeostasis are poorly understood. Here, we report that anti-Müllerian hormone (Amh)-mediated signalling plays an important role in sustaining circadian homeostasis in zebrafish. Notably, amh knockout dampens molecular clock oscillations and disrupts both behavioural and hormonal circadian rhythms, which are recapitulated in bmpr2a null mutants. Somatotropes and gonadotropes are identified as Amh-targeted pituitary cell populations. Single-cell transcriptome analysis further reveals a lineage-specific regulation of pituitary clock by Amh. Moreover, Amh-induced effect on clock gene expression can be abolished by blocking Smad1/5/9 phosphorylation and bmpr2a knockout. Mechanistically, Amh binds to its receptors, Bmpr2a/Bmpr1bb, which in turn activate Smad1/5/9 by phosphorylation and promote circadian gene expression. Our findings reveal a key hormone signalling pathway for circadian homeostasis in zebrafish with implications for rhythmic organ functions and circadian health.
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Affiliation(s)
- Qiaohong Lin
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, University of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
| | - Xian Du
- Department of Hematology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
- TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
- Department of Laboratory, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fan Ren
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, University of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- College of Fisheries, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, China
| | - Ying Liu
- College of Fisheries, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, China
| | - Gaorui Gong
- College of Fisheries, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, China
| | - Si Ge
- College of Fisheries, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, China
| | - Weiwei Li
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, University of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
| | - Zhi Li
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, University of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
| | - Li Zhou
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, University of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
| | - Ming Duan
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, University of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
| | - Xi-Yin Li
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, University of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
| | - Guang-Zhong Wang
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Rui Xiao
- Department of Hematology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
- TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
| | - Jian-Fang Gui
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, University of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
- College of Fisheries, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, China.
| | - Jie Mei
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, University of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
- College of Fisheries, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, China.
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Comai S, Manchia M, Bosia M, Miola A, Poletti S, Benedetti F, Nasini S, Ferri R, Rujescu D, Leboyer M, Licinio J, Baune BT, Serretti A. Moving toward precision and personalized treatment strategies in psychiatry. Int J Neuropsychopharmacol 2025; 28:pyaf025. [PMID: 40255203 PMCID: PMC12084835 DOI: 10.1093/ijnp/pyaf025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 04/14/2025] [Indexed: 04/22/2025] Open
Abstract
Precision psychiatry aims to improve routine clinical practice by integrating biological, clinical, and environmental data. Many studies have been performed in different areas of research on major depressive disorder, bipolar disorder, and schizophrenia. Neuroimaging and electroencephalography findings have identified potential circuit-level abnormalities predictive of treatment response. Protein biomarkers, including IL-2, S100B, and NfL, and the kynurenine pathway illustrate the role of immune and metabolic dysregulation. Circadian rhythm disturbances and the gut microbiome have also emerged as critical transdiagnostic contributors to psychiatric symptomatology and outcomes. Moreover, advances in genomic research and polygenic scores support the perspective of personalized risk stratification and medication selection. While challenges remain, such as data replication issues, prediction model accuracy, and scalability, the progress so far achieved underscores the potential of precision psychiatry in improving diagnostic accuracy and treatment effectiveness.
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Affiliation(s)
- Stefano Comai
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
- Department of Biomedical Sciences, University of Padua, Padua, Italy
- Department of Psychiatry, McGill University, Montreal, QC, Canada
- IRCSS San Raffaele Scientific Institute, Milan, Italy
| | - Mirko Manchia
- Unit of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Marta Bosia
- IRCSS San Raffaele Scientific Institute, Milan, Italy
| | | | - Sara Poletti
- IRCSS San Raffaele Scientific Institute, Milan, Italy
| | | | - Sofia Nasini
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
| | | | - Dan Rujescu
- Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria
| | - Marion Leboyer
- Université Paris-Est Créteil (UPEC), Translational Neuropsychiatry Laboratory (INSERM U955 IMRB), Département de Psychiatrie (DMU IMPACT, AP-HP, Hôpital Henri Mondor), Fondation FondaMental, ECNP Immuno-NeuroPsychiatry Network, 94010 Créteil, France
| | - Julio Licinio
- SUNY Upstate Medical University, Syracuse, NY, United States
| | - Bernhard T Baune
- Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany
- Department of Psychiatry, Melbourne Medical School, University of Melbourne, Parkville, VIC, Australia
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Alessandro Serretti
- Oasi Research Institute-IRCCS, Troina, Italy
- Department of Medicine and surgery, Kore University of Enna, Enna, Italy
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Dashti HS, Jansen EC, Zuraikat FM, Dixit S, Brown M, Laposky A, Broussard JL, Butler MP, Creasy SA, Crispim CA, Depner CM, Esser KA, Garaulet M, Hanlon EC, Makarem N, Manoogian ENC, Peterson CM, Scheer FAJL, Wright KP, Goff DC, Pratt CA, Gamble KL, St-Onge MP. Advancing Chrononutrition for Cardiometabolic Health: A 2023 National Heart, Lung, and Blood Institute Workshop Report. J Am Heart Assoc 2025; 14:e039373. [PMID: 40265587 DOI: 10.1161/jaha.124.039373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
The circadian system maintains optimal biological functions at the appropriate time of day, and the disruption of this organization can contribute to the pathogenesis of cardiometabolic disorders. The timing of eating is a prominent external time cue that influences the circadian system. "Chrononutrition" is an emerging dimension of nutrition and active area of research that examines how timing-related aspects of eating and nutrition impact circadian rhythms, biological processes, and disease pathogenesis. There is evidence to support chrononutrition as a form of chronotherapy, such that optimizing the timing of eating may serve as an actionable strategy to improve cardiometabolic health. This report summarizes key information from the National Heart, Lung, and Blood Institute's virtual workshop entitled "Chrononutrition: Elucidating the Role of Circadian Biology and Meal Timing in Cardiometabolic Health," which convened on May 2 to 3, 2023, to review current literature and identify critical knowledge gaps and research opportunities. The speakers presented evidence highlighting the impact on cardiometabolic health of earlier and shorter eating windows and more consistent day-to-day eating patterns. The multidimensionality of chrononutrition was a common theme, as it encompasses multiple facets of eating along with the timing of other behaviors including sleep and physical activity. Advancing the emerging field of chrononutrition will require: (1) standardization of terminology and metrics; (2) scalable and precise tools for real-world settings; (3) consideration of individual differences that may act as effect modifiers; and (4) deeper understanding of social, behavioral, and cultural influences. Ultimately, there is great potential for circadian-based dietary interventions to improve cardiometabolic health.
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Affiliation(s)
- Hassan S Dashti
- Department of Anesthesia, Critical Care and Pain Medicine Massachusetts General Hospital Boston MA USA
- Division of Nutrition Harvard Medical School Boston MA USA
- Division of Sleep Medicine Harvard Medical School Boston MA USA
- Broad Institute Cambridge MA USA
| | - Erica C Jansen
- Department of Nutritional Sciences University of Michigan School of Public Health Ann Arbor MI USA
- Department of Neurology University of Michigan Ann Arbor MI USA
| | - Faris M Zuraikat
- Center of Excellence for Sleep and Circadian Research, Department of Medicine Columbia University Irving Medical Center New York NY USA
- Division of General Medicine, Department of Medicine Columbia University Irving Medical Center New York NY USA
- Institute of Human Nutrition, Columbia University Irving Medical Center New York NY USA
| | - Shilpy Dixit
- National Center on Sleep Disorders Research National Heart, Lung, and Blood Institute, National Institutes of Health Bethesda MD USA
| | - Marishka Brown
- National Center on Sleep Disorders Research National Heart, Lung, and Blood Institute, National Institutes of Health Bethesda MD USA
| | - Aaron Laposky
- National Center on Sleep Disorders Research National Heart, Lung, and Blood Institute, National Institutes of Health Bethesda MD USA
| | - Josiane L Broussard
- Department of Health and Exercise Science Colorado State University Fort Collins CO USA
- Ludeman Family Center for Women's Health Research University of Colorado Anschutz Medical Campus Aurora CO USA
- Division of Endocrinology, Metabolism, and Diabetes University of Colorado Anschutz Medical Campus Aurora CO USA
- Department of Integrative Physiology University of Colorado Boulder Boulder CO USA
| | - Matthew P Butler
- Oregon Institute of Occupational Health Sciences Oregon Health and Sciences University Portland OR USA
- Department of Behavioral Neuroscience, School of Medicine Oregon Health and Sciences University Portland OR USA
| | - Seth A Creasy
- Division of Endocrinology, Metabolism, and Diabetes University of Colorado Anschutz Medical Campus Aurora CO USA
- Anschutz Health and Wellness Center University of Colorado Anschutz Medical Campus Aurora CO USA
| | - Cibele A Crispim
- Chrononutrition Research Group, School of Medicine Federal University of Uberlândia Minas Gerais Brazil
| | | | - Karyn A Esser
- Department of Physiology and Aging, College of Medicine University of Florida Gainesville FL USA
| | - Marta Garaulet
- Department of Physiology, Regional Campus of International Excellence University of Murcia Spain
- Biomedical Research Institute of Murcia, IMIB-Arrixaca-UMU, University Clinical Hospital Murcia Spain
- Division of Sleep and Circadian Disorders, Department of Medicine and Neurology Brigham and Women's Hospital Boston MA USA
| | - Erin C Hanlon
- Section of Adult and Pediatric Endocrinology, Department of Medicine University of Chicago IL USA
| | - Nour Makarem
- Department of Epidemiology, Mailman School of Public Health Columbia University Irving Medical Center New York NY USA
| | - Emily N C Manoogian
- Regulatory Biology Department Salk Institute for Biological Sciences La Jolla CA USA
| | - Courtney M Peterson
- Department of Nutrition Sciences University of Alabama at Birmingham Birmingham AL USA
| | - Frank A J L Scheer
- Division of Nutrition Harvard Medical School Boston MA USA
- Division of Sleep Medicine Harvard Medical School Boston MA USA
- Broad Institute Cambridge MA USA
- Division of Sleep and Circadian Disorders, Department of Medicine and Neurology Brigham and Women's Hospital Boston MA USA
| | - Kenneth P Wright
- Division of Endocrinology, Metabolism, and Diabetes University of Colorado Anschutz Medical Campus Aurora CO USA
- Department of Integrative Physiology University of Colorado Boulder Boulder CO USA
| | - David C Goff
- Division of Cardiovascular Sciences National Heart, Lung, and Blood Institute, National Institutes of Health Bethesda MD USA
| | - Charlotte A Pratt
- Division of Cardiovascular Sciences National Heart, Lung, and Blood Institute, National Institutes of Health Bethesda MD USA
| | - Karen L Gamble
- Department of Psychiatry and Behavioral Neurobiology, School of Medicine University of Alabama at Birmingham Birmingham AL USA
- Nutrition Obesity Research Center University of Alabama at Birmingham Birmingham AL USA
| | - Marie-Pierre St-Onge
- Center of Excellence for Sleep and Circadian Research, Department of Medicine Columbia University Irving Medical Center New York NY USA
- Division of General Medicine, Department of Medicine Columbia University Irving Medical Center New York NY USA
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Furuike Y, Onoue Y, Saito S, Mori T, Akiyama S. The priming phosphorylation of KaiC is activated by the release of its autokinase autoinhibition. PNAS NEXUS 2025; 4:pgaf136. [PMID: 40352643 PMCID: PMC12065004 DOI: 10.1093/pnasnexus/pgaf136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 03/31/2025] [Indexed: 05/14/2025]
Abstract
KaiC, a cyanobacterial circadian clock protein with autokinase activity, catalyzes the dual phosphorylation of its own S431 and T432 residues in a circadian manner in the presence of KaiA and KaiB. Priming phosphorylation at T432 is a key step that promotes secondary phosphorylation at S431. Although KaiA binding is considered essential for KaiC phosphorylation, the mechanisms underlying the activation and inactivation of priming phosphorylation remain elusive. We found that although the priming phosphorylation is autoinhibited within KaiC, it actually proceeds at a rate constant of 0.019 h-1 even in the absence of KaiA. The autoinhibition of KaiC and the mechanism underlying the release from autoinhibition by KaiA were examined by KaiC structural analysis and by classical molecular dynamics and quantum mechanics/molecular mechanics simulations. We found that the side chain of T432 adopts two rotamers in dephosphorylated KaiC, one of which places T432 in a position suitable for a nucleophilic attack on the terminal phosphate of adenosine triphosphate. However, the nucleophilicity of T432 was insufficient to overcome an energy barrier of ∼21 kcal mol-1 because the catalytic function of a nearby base, E318, was self-suppressed by hydrogen bonding to positively charged R385. Biochemical assays of KaiC mutants showed that the autoinhibition of KaiC autokinase activity is attenuated by conferring T432 high nucleophilicity through the KaiA-assisted release of R385 from E318 to E352. During the circadian cycle, R385 switches interacting partners to inactivate/activate the autokinase function and to ensure the unidirectionality of the KaiC phosphorylation cycle.
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Affiliation(s)
- Yoshihiko Furuike
- Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, National Institutes of Natural Sciences, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan
- Molecular Science Program, Graduate Institute for Advanced Studies, SOKENDAI, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan
| | - Yasuhiro Onoue
- Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, National Institutes of Natural Sciences, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan
| | - Shinji Saito
- Molecular Science Program, Graduate Institute for Advanced Studies, SOKENDAI, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan
- Department of Theoretical and Computational Molecular Science, Institute for Molecular Science, National Institutes of Natural Sciences, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan
| | - Toshifumi Mori
- Division of Applied Molecular Chemistry, Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga, Fukuoka 816-8580, Japan
- Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1 Kasugakoen, Kasuga, Fukuoka 816-8580, Japan
| | - Shuji Akiyama
- Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, National Institutes of Natural Sciences, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan
- Molecular Science Program, Graduate Institute for Advanced Studies, SOKENDAI, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan
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7
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Liu L, Sun P, Lin J, Wu S. Associations of reproductive factors and circadian syndrome in middle-aged and elderly women: A nationwide cross-sectional study from China, the United Kingdom and the United States. Sleep Med 2025; 129:283-291. [PMID: 40068580 DOI: 10.1016/j.sleep.2025.02.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 02/14/2025] [Accepted: 02/19/2025] [Indexed: 04/11/2025]
Abstract
Circadian Syndrome (CircS) was recently recognized as a novel predictor of cardiovascular disease (CVD) risk, with reproductive factors playing an important role in CVD risk. Yet, studies linking reproductive factors to CircS remain sparse. Data on middle-aged and elderly women were extracted from three nationally representative surveys: the China Health and Retirement Longitudinal Study (CHARLS) and the English Longitudinal Study on Ageing (ELSA) provided the training set, and the National Health and Nutrition Examination Survey (NHANES) constituted the validation set. We employed logistic regression to evaluate the association between self-reported reproductive factors and CircS risk, with inverse probability of treatment weighting (IPTW) and subgroup analyses conducted to verify the stability. A total of 11,721 participants were analyzed. CircS prevalence differed significantly across countries, with 51.40 % in China and 20.19 % in the United Kingdom. Early menarche (age <12 years) correlated with increased CircS risk in CHARLS (OR 1.38 [95 % CI 0.99-1.92]; p = 0.061), ELSA (OR 1.64 [95 % CI 1.36-1.98]; p < 0.001), and NHANES (OR1.52 [95 % CI: 1.21-1.89]; p < 0.001). Premature menopause (age <40 years) was associated with a roughly 30 % higher CircS risk. A shorter reproductive lifespan was significantly linked to CircS, with this relationship emerging at a reproductive lifespan of ≥40 years in CHARLS (OR1.39 [95 % CI: 1.04-1.84]; p = 0.024). The aforementioned correlations retained significance following IPTW and subgroup analyses. Early menarche, premature menopause, and abbreviated reproductive lifespans may negatively affect CircS. Public health strategies should incorporate menstrual cycle-related reproductive health into primary CircS prevention.
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Affiliation(s)
- Linli Liu
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian, China; Department of Gynecology, Fuzhou First General Hospital, Affiliated to Fujian Medical University, No.190, Dadao Road, Taijiang District, Fuzhou, Fujian, China
| | - Pengming Sun
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian, China; Department of Gynecology, Fujian Clinical Research Center for Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, No. 18 Daoshan Road, Fuzhou, Fujian, China; Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, Fujian Medical University, No. 18 Daoshan Road, Fuzhou, Fujian, China.
| | - Jun Lin
- Department of Gynecology, Fuzhou First General Hospital, Affiliated to Fujian Medical University, No.190, Dadao Road, Taijiang District, Fuzhou, Fujian, China
| | - Sanshan Wu
- Department of Gynecology, Fuzhou First General Hospital, Affiliated to Fujian Medical University, No.190, Dadao Road, Taijiang District, Fuzhou, Fujian, China
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Kolarski D, Szymanski W, Feringa BL. Spatiotemporal Control Over Circadian Rhythms With Light. Med Res Rev 2025; 45:968-984. [PMID: 39757143 PMCID: PMC11976375 DOI: 10.1002/med.22099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 12/18/2024] [Accepted: 12/20/2024] [Indexed: 01/07/2025]
Abstract
Circadian rhythms are endogenous biological oscillators that synchronize internal physiological processes and behaviors with external environmental changes, sustaining homeostasis and health. Disruption of circadian rhythms leads to numerous diseases, including cardiovascular and metabolic diseases, cancer, diabetes, and neurological disorders. Despite the potential to restore healthy rhythms in the organism, pharmacological chronotherapy lacks spatial and temporal resolution. Addressing this challenge, chrono-photopharmacology, the approach that employs small molecules with light-controlled activity, enables the modulation of circadian rhythms when and where needed. Two approaches-relying on irreversible and reversible drug activation-have been proposed for this purpose. These methodologies are based on photoremovable protecting groups and photoswitches, respectively. Designing photoresponsive bioactive molecules requires meticulous structural optimization to obtain the desired chemical and photophysical properties, and the design principles, detailed guidelines and challenges are summarized here. In this review, we also analyze all the known circadian modulators responsive to light and dissect the rationale following their construction and application to control circadian biology from the protein level to living organisms. Finally, we present the strength of a reversible approach in allowing the modulation of the circadian period and the phase.
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Affiliation(s)
- Dušan Kolarski
- Max Planck Institute for Multidisciplinary SciencesNanoBioPhotonicsGöttingenGermany
| | - Wiktor Szymanski
- Centre for Systems Chemistry, Stratingh Institute for ChemistryUniversity of GroningenGroningenThe Netherlands
- Department of Radiology, Medical Imaging CenterUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
- Department of Medicinal Chemistry, Photopharmacology and Imaging, Groningen Research Institute of PharmacyUniversity of GroningenGroningenThe Netherlands
| | - Ben L. Feringa
- Centre for Systems Chemistry, Stratingh Institute for ChemistryUniversity of GroningenGroningenThe Netherlands
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Kurak K, İlbak İ, Stojanović S, Bayer R, İlbak YE, Kasicki K, Ambroży T, Rydzik Ł, Czarny W. The effect of time of day on visual reaction time performance in boxers: evaluation in terms of chronotype. Front Physiol 2025; 16:1589740. [PMID: 40308568 PMCID: PMC12040622 DOI: 10.3389/fphys.2025.1589740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Accepted: 04/04/2025] [Indexed: 05/02/2025] Open
Abstract
Introduction Considering the impact of individual differences on athletes' performance, chronotype emerges as a crucial variable in training program design. Chronotype influences an individual's ability to achieve peak physical and cognitive performance at different times of the day based on their biological rhythms. While numerous studies have explored the relationship between chronotype and physical performance, its effect on reaction time performance remains insufficiently investigated. In sports, where reaction time is a key determinant-such as in boxing-understanding this relationship could contribute to the personalization of training programs. Therefore, the aim of this cross-sectional study was to examine how the visual reaction performance of active boxers varies at different times of the day based on their chronotypes. Methods Twenty-four active boxers participated in the study. Their chronotypes were determined using the Morningness-Eveningness Questionnaire, categorizing them as either morning type (M-type) or evening type (E-type). The participants were divided into two groups: M-type (n = 12) and E-type (n = 12). Each participant completed a visual reaction time (VRT) performance test at three different times of the day: morning (09:00 h), afternoon (13:00 h), and evening (17:00 h). Results The findings revealed a statistically significant group × time interaction effect on VRT performance (p < 0.01). M-type athletes showed a significant decline in VRT performance during the evening compared to the morning and afternoon. In contrast, E-type athletes demonstrated significantly better performance in the evening compared to the morning. Conclusions Boxers' visual reaction time performance varies throughout the day depending on their chronotype. These results suggest that coaches and exercise specialists should consider athletes' chronotypes when designing training programs focused on reaction time enhancement. To optimize performance, it is recommended that M-type athletes conduct such training sessions in the morning, while E-type athletes should train in the evening, when their reaction time performance tends to peak.
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Affiliation(s)
- Kemal Kurak
- Faculty of Sport Sciences, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
| | - İsmail İlbak
- Institute of Health Sciences, İnönü University, Malatya, Türkiye
| | - Stefan Stojanović
- Faculty of Sport and Physical Education, University of Niš, Niš, Serbia
| | - Ramazan Bayer
- Department of Physical Education and Sport Teaching, Malatya Turgut Ozal University, Malatya, Türkiye
| | - Yunus Emre İlbak
- Faculty of Sport and Physical Education, İnönü University, Malatya, Türkiye
| | - Krzysztof Kasicki
- Department of Physiotherapy, Faculty of Health Sciences, Collegium Medicum, Andrzej Frycz-Modrzejewski Krakow University, Kraków, Poland
| | - Tadeusz Ambroży
- Institute of Sports Sciences, University of Physical Culture, Kraków, Poland
| | - Łukasz Rydzik
- Institute of Sports Sciences, University of Physical Culture, Kraków, Poland
| | - Wojciech Czarny
- Institute of Physical Culture Sciences, College of Medical Sciences, University of Rzeszów, Rzeszów, Poland
- Department of Sports Kinanthropology, Faculty of Sports, Universtiy of Presov, Prešov, Slovakia
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10
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Gegnaw ST, Sandu C, Bery A, ten Brink JB, Milićević N, Jongejan A, Moerland PD, Bergen AA, Felder‐Schmittbuhl M. Circadian clock disruption promotes retinal photoreceptor degeneration. FASEB J 2025; 39:e70507. [PMID: 40171795 PMCID: PMC11962828 DOI: 10.1096/fj.202401967r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 03/02/2025] [Accepted: 03/25/2025] [Indexed: 04/04/2025]
Abstract
Daily rhythms are a central hallmark of vision, in particular by adapting retinal physiology and light response to the day-night cycle. These cyclic processes are regulated by retinal circadian clocks, molecular machineries regulating gene expression across the 24-h cycle. Although hundreds of genes associated with genetic retinal disorders have been identified, no direct link has been established with the clock. Hence, we investigated the hypothesis that a poorly functioning circadian clock aggravates retinal photoreceptor disease. We performed this study in the P23H rhodopsin-mutated mouse model (P23H Rho) that mimics one major cause of human autosomal dominant retinitis pigmentosa. We also used the rod-specific knockout (rod-Bmal1KO) of Bmal1, a key clock component. More specifically, we used either heterozygous P23H Rho mice or rod-Bmal1KO alone, as well as double mutants of these strains and control mice. We showed by structural (histology, immunohistochemistry) and functional (electroretinography: ERG) analyses that the retinitis pigmentosa phenotype is exacerbated in the double mutant line compared to the P23H Rho mutation alone. Indeed, we observed marked ERG amplitude reduction and more photoreceptor cell loss in double mutants with respect to simple P23H Rho mutants. These observations were further corroborated by transcriptome analysis revealing major gene expression differences between these genotypes. In this data, we identified unique gene expression sets implicating neurogenesis, phototransduction cascade, and metabolism, associated with enhanced photoreceptor degeneration. Thus, our results establish a link between clock dysfunction and retinal degeneration and suggest underlying molecular mechanisms, together providing new concepts for understanding and managing blinding diseases.
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Affiliation(s)
- Shumet T. Gegnaw
- Centre National de la Recherche ScientifiqueUniversité de Strasbourg, Institut Des Neurosciences Cellulaires et IntégrativesStrasbourgFrance
- Department of Human GeneticsAmsterdam University Medical Centers, Location AMC, University of AmsterdamAmsterdamThe Netherlands
- Present address:
Department of Biotechnology, College of Natural and Computational Sciences, Debre Markos UniversityDebre MarkosEthiopia
| | - Cristina Sandu
- Centre National de la Recherche ScientifiqueUniversité de Strasbourg, Institut Des Neurosciences Cellulaires et IntégrativesStrasbourgFrance
| | - Amandine Bery
- Centre National de la Recherche ScientifiqueUniversité de Strasbourg, Institut Des Neurosciences Cellulaires et IntégrativesStrasbourgFrance
| | - Jacoline B. ten Brink
- Department of Human GeneticsAmsterdam University Medical Centers, Location AMC, University of AmsterdamAmsterdamThe Netherlands
| | - Nemanja Milićević
- Faculty of Medicine and Health TechnologyTampere UniversityTampereFinland
| | - Aldo Jongejan
- Amsterdam UMCUniversity of Amsterdam, Epidemiology and Data ScienceAmsterdamThe Netherlands
- Amsterdam Public HealthMethodology AmsterdamAmsterdamThe Netherlands
- Amsterdam Institute for Immunology and Infectious DiseasesAmsterdamThe Netherlands
| | - Perry D. Moerland
- Amsterdam UMCUniversity of Amsterdam, Epidemiology and Data ScienceAmsterdamThe Netherlands
- Amsterdam Public HealthMethodology AmsterdamAmsterdamThe Netherlands
- Amsterdam Institute for Immunology and Infectious DiseasesAmsterdamThe Netherlands
| | - Arthur A. Bergen
- Department of Human GeneticsAmsterdam University Medical Centers, Location AMC, University of AmsterdamAmsterdamThe Netherlands
- Department of OphthalmologyAmsterdam University Medical Centers, Location AMC, University of AmsterdamAmsterdamThe Netherlands
- Emma Centre for Personalized MedicineAmsterdam University Medical Centers, Location AMC, University of AmsterdamAmsterdamThe Netherlands
| | - Marie‐Paule Felder‐Schmittbuhl
- Centre National de la Recherche ScientifiqueUniversité de Strasbourg, Institut Des Neurosciences Cellulaires et IntégrativesStrasbourgFrance
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11
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Shanmugam DAS, Balaraman AD, Kar A, Franco A, Balaji BAC, Meenakumari S, Praveenkumar PK, Gayathri R, Ganesan VK, Kumar MV, Senthilkumar K, Shanthi B. Mini review: Bidirectional Regulation of Circadian Rhythm by Suprachiasmatic Nucleus and Nuclear Receptors in Female Mammals. J Circadian Rhythms 2025; 23:4. [PMID: 40225034 PMCID: PMC11987856 DOI: 10.5334/jcr.245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 03/20/2025] [Indexed: 04/15/2025] Open
Abstract
The anterior region of the hypothalamus accommodates a bilateral structure called the suprachiasmatic nucleus (SCN), which controls, modulates, and perpetuates the homeostasis of circadian rhythm and sleep hormone release. These SCN have a predominance over multitudinous peripheral tissues like the uterus, liver, intestine, pancreas, endocrine system, immune system, reproductive system, and cardiovascular system. This peripheral clock acts as a pacemaker for circadian rhythm timing, which regulates crucial metabolic pathways and organizes numerous activities in the female reproductive network of mammals. The circadian CLOCK genes are expressed in various reproductive organs. The CLOCK, BMAL1, CRY, and PER genes harmonize the balance and manifestation of nuclear receptors (NRs) expression, and the other way round, NRs regulate these circadian genes. Several NRs, in particular estrogen, progesterone, androgen, and PPARs, nurture the ovary and uterus. Bidirectional coordination between SCN and NRs maintains the circadian rhythm of the hypothalamic-pituitary-gonadal (HPG) axis of the female reproductive organs.
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Affiliation(s)
- Dharani Abirama Sundari Shanmugam
- Department of Endocrinology, Dr. ALM. PG. Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai – 600113, Tamil Nadu, India
| | - Ashwini Devi Balaraman
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur – 603202, Tamil Nadu, India
| | - Abhijit Kar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur – 603202, Tamil Nadu, India
| | - Abishek Franco
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur – 603202, Tamil Nadu, India
| | | | - S. Meenakumari
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur – 603202, Tamil Nadu, India
| | - P. K. Praveenkumar
- Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur Tk – 602117, Tamil Nadu, India
| | - R. Gayathri
- Department of Biotechnology, St Joseph’s College of Engineering, Old Mahabalipuram Road, Kamaraj Nagar, Semmancheri, Chennai – 600119, Tamil Nadu, India
| | - Vinoth Kumar Ganesan
- Department of Health Research (DHR-ICMR), Multi-Disciplinary Research Unit (MRU), Rangaraya Medical College, Kakinada – 533003, Andhra Pradesh, India
| | - Merugumolu Vijay Kumar
- Department of Pharmacology, Dayananda Sagar University, Bengaluru – 560078, Karnataka, India
| | - K. Senthilkumar
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region of China
| | - B. Shanthi
- Department of Biotechnology, JAASB Institute and Research Academia, Valasaravakkam, Chennai – 600087, Tamil Nadu, India
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Yang H, Niu L, Tian L, Hu Y, Cheng C, Li S, Le W. Circadian rhythm disturbances in Alzheimer's disease: insights from plaque-free and plaque-burdened stages in APP SWE/PS1 dE9 mice. Alzheimers Res Ther 2025; 17:76. [PMID: 40188157 PMCID: PMC11971749 DOI: 10.1186/s13195-025-01724-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 03/21/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND Disruptions in circadian rhythms are commonly observed in patients with Alzheimer's disease (AD) and could potentially accelerate the progression of the condition. However, the relationship between circadian rhythm disruptions and AD development, as well as the mechanisms involved, remain poorly understood. METHODS This study investigated the circadian behavior, rhythmic gene expression in multiple brain regions, and its correlation with sleep architecture of AD mice at two disease stages: plaque-free stage (2-month-old) and plaque-burdened stage (10-month-old) as compared to age-matched wild-type (WT) mice. RESULTS Two-month-old AD mice already displayed alteration in the activity patterns compared to WT mice, showing increased activity during the light phase and decreased activity during the dark phase, and the change in the activity pattern of 10-month-old AD mice was more significant. Further, electroencephalogram (EEG) examination showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep in 2- and 10-month-old AD mice. In addition, we documented a significant change in circadian core clock genes in the suprachiasmatic nucleus (SCN), hippocampus, and cortex of 2- and 10-month-old AD mice. Correlation analyses demonstrated the close relationship between circadian clock gene expression level and specific sleep-wake parameters, especially within the SCN and hippocampus. CONCLUSIONS These findings revealed that circadian rhythm disturbances in AD mice preceded Aβ deposition. The circadian rhythm disturbances observed in the early AD might be attributed to the abnormal expression of core clock genes in the brain regions involved in circadian rhythm regulation.
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Affiliation(s)
- Huijia Yang
- Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, 116021, China
| | - Long Niu
- Department of Neurology, Heping Hospital affiliated to Changzhi Medical College, Changzhi, China
| | - Lulu Tian
- Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, 116021, China
| | - Yiying Hu
- Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, 116021, China
| | - Cheng Cheng
- Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, 116021, China
| | - Song Li
- Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, 116021, China
| | - Weidong Le
- Center for Clinical and Translational Medicine, Shanghai University of Medicine and Health Sciences, Shanghai, China.
- Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, China.
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13
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Trukovich JJ. From reactions to reflection: A recursive framework for the evolution of cognition and complexity. Biosystems 2025; 250:105408. [PMID: 39892697 DOI: 10.1016/j.biosystems.2025.105408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/04/2025]
Abstract
This paper presents a comprehensive framework that traces the evolution of consciousness through a continuum of recursive processes spanning reaction, temporogenesis, symbiogenesis, and cognogenesis. By integrating biological cooperation, temporal structuring, and self-referential processing, our model provides a novel perspective on how complexity emerges and scales across evolutionary time. Reaction is established as the foundational mechanism that enables adaptive responses to environmental stimuli, which, through recursive refinement, transitions into temporogenesis-the synchronization of internal processes with external temporal rhythms. Symbiogenesis further enhances this process by fostering cooperative interactions at multiple biological levels, facilitating the emergence of higher-order cognitive functions. Cognogenesis represents the culmination of these recursive processes, where self-awareness and intentionality arise through iterative feedback loops. Our framework offers a biologically grounded pathway to addressing the "hard problem" of consciousness by proposing that subjective experience emerges as a result of progressively complex recursive interactions rather than as a static or isolated phenomenon. In comparing our approach with established theories such as Integrated Information Theory, Global Workspace Theory, and enactive cognition, we highlight its unique contributions in situating consciousness within a broader evolutionary and biological context. This work aims to provide a foundational model that bridges the gap between reaction and reflection, offering empirical avenues for further exploration in neuroscience, evolutionary biology, and artificial intelligence.
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14
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Ogunlusi O, Ghosh A, Sarkar M, Carter K, Davuluri H, Chakraborty M, Eckel-Mahan K, Keene A, Menet JS, Bell-Pedersen D, Sarkar TR. Rhythm is essential: Unraveling the relation between the circadian clock and cancer. Crit Rev Oncol Hematol 2025; 208:104632. [PMID: 39864535 DOI: 10.1016/j.critrevonc.2025.104632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 01/10/2025] [Accepted: 01/19/2025] [Indexed: 01/28/2025] Open
Abstract
Physiological processes such as the sleep-wake cycle, metabolism, hormone secretion, neurotransmitter release, sensory capabilities, and a variety of behaviors, including sleep, are controlled by a circadian rhythm adapted to 24-hour day-night periodicity. Disruption of circadian rhythm may lead to the risks of numerous diseases, including cancers. Several epidemiological and clinical data reveal a connection between the disruption of circadian rhythms and cancer. On the contrary, oncogenic processes may suppress the homeostatic balance imposed by the circadian clock. The integration of circadian biology into cancer research offers new options for making cancer treatment more effective, and the pharmacological modulation of core clock genes is a new approach in cancer therapy. This review highlights the role of the circadian clock in tumorigenesis, how clock disruption alters the tumor microenvironment, and discusses how pharmacological modulation of circadian clock genes can lead to new therapeutic options.
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Affiliation(s)
| | - Abantika Ghosh
- Department of Biology, Texas A&M University, College Station, TX, USA
| | - Mrinmoy Sarkar
- Department of Biology, Texas A&M University, College Station, TX, USA
| | - Kayla Carter
- Department of Biology, Texas A&M University, College Station, TX, USA
| | - Harshini Davuluri
- The Master of Biotechnology Program, Texas A&M University, College Station, TX, USA
| | - Mahul Chakraborty
- Department of Biology, Texas A&M University, College Station, TX, USA
| | - Kristin Eckel-Mahan
- Institute of Molecular Medicine, The University of Texas Health Science Centre, Houston, TX, USA
| | - Alex Keene
- Department of Biology, Texas A&M University, College Station, TX, USA; Texas A&M Center for Biological Clocks Research, USA
| | - Jerome S Menet
- Department of Biology, Texas A&M University, College Station, TX, USA; Texas A&M Center for Biological Clocks Research, USA
| | - Deborah Bell-Pedersen
- Department of Biology, Texas A&M University, College Station, TX, USA; Texas A&M Center for Biological Clocks Research, USA
| | - Tapasree Roy Sarkar
- Department of Biology, Texas A&M University, College Station, TX, USA; Texas A&M Center for Biological Clocks Research, USA.
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15
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Bafna A, Banks G, Vasilyev V, Dallmann R, Hastings MH, Nolan PM. Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus. eLife 2025; 14:RP102019. [PMID: 40117332 PMCID: PMC11928027 DOI: 10.7554/elife.102019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2025] Open
Abstract
The mammalian suprachiasmatic nucleus (SCN), situated in the ventral hypothalamus, directs daily cellular and physiological rhythms across the body. The SCN clockwork is a self-sustaining transcriptional-translational feedback loop (TTFL) that in turn coordinates the expression of clock-controlled genes (CCGs) directing circadian programmes of SCN cellular activity. In the mouse, the transcription factor, ZFHX3 (zinc finger homeobox-3), is necessary for the development of the SCN and influences circadian behaviour in the adult. The molecular mechanisms by which ZFHX3 affects the SCN at transcriptomic and genomic levels are, however, poorly defined. Here, we used chromatin immunoprecipitation sequencing to map the genomic localization of ZFHX3-binding sites in SCN chromatin. To test for function, we then conducted comprehensive RNA sequencing at six distinct times-of-day to compare the SCN transcriptional profiles of control and ZFHX3-conditional null mutants. We show that the genome-wide occupancy of ZFHX3 occurs predominantly around gene transcription start sites, co-localizing with known histone modifications, and preferentially partnering with clock transcription factors (CLOCK, BMAL1) to regulate clock gene(s) transcription. Correspondingly, we show that the conditional loss of ZFHX3 in the adult has a dramatic effect on the SCN transcriptome, including changes in the levels of transcripts encoding elements of numerous neuropeptide neurotransmitter systems while attenuating the daily oscillation of the clock TF Bmal1. Furthermore, various TTFL genes and CCGs exhibited altered circadian expression profiles, consistent with an advanced in daily behavioural rhythms under 12 h light-12 h dark conditions. Together, these findings reveal the extensive genome-wide regulation mediated by ZFHX3 in the central clock that orchestrates daily timekeeping in mammals.
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Affiliation(s)
- Akanksha Bafna
- Medical Research Council, Harwell Science CampusDidcotUnited Kingdom
- Nuffield Department of Clinical Neurosciences, University of OxfordOxfordshireUnited Kingdom
| | - Gareth Banks
- Medical Research Council, Harwell Science CampusDidcotUnited Kingdom
- Nottingham Trent UniversityNottinghamUnited Kingdom
| | - Vadim Vasilyev
- Division of Biomedical Sciences, Warwick Medical School, University of WarwickCoventryUnited Kingdom
| | - Robert Dallmann
- Division of Biomedical Sciences, Warwick Medical School, University of WarwickCoventryUnited Kingdom
- Zeeman Institute for Systems Biology and Infectious Disease Epidemiology Research, University of WarwickCoventryUnited Kingdom
| | | | - Patrick M Nolan
- Medical Research Council, Harwell Science CampusDidcotUnited Kingdom
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16
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Liu C, Liu X, Cao P, Xin H, Li X, Zhu S. Circadian rhythm related genes identified through tumorigenesis and immune infiltration-guided strategies as predictors of prognosis, immunotherapy response, and candidate drugs in skin cutaneous malignant melanoma. Front Immunol 2025; 16:1513750. [PMID: 40191195 PMCID: PMC11968383 DOI: 10.3389/fimmu.2025.1513750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 02/20/2025] [Indexed: 04/09/2025] Open
Abstract
Background Skin cutaneous malignant melanoma (SKCM) is among the most aggressive forms of skin cancer, notorious for its rapid progression and poor prognosis under late diagnosis. This study investigates the role of circadian rhythm-related genes (CRGs) in SKCM addressing a gap in understanding how CRGs affect tumor progression and patient outcomes. Methods An analysis of CRGs expression was conducted on SKCM samples derived from The Cancer Genome Atlas datasets(TCGA). Moreover, a correlation between various subtypes and their clinical features was identified. The study employed various bioinformatics methods, including differential expression analysis, consensus clustering, and survival analysis, to investigate the role of CRGs. The functional consequences of various CRG expression patterns were further investigated using immune infiltration analysis and gene set variation analysis (GSVA). A scoring system based on CRGs was developed to predict overall survival (OS) and treatment responses in SKCM patients. The predictive accuracy of this score system was then tested, and a nomogram was used to improve its clinical usefulness. Results Key findings from this study include significant genetic alterations in circadian rhythm-related genes (CRGs) in skin cutaneous melanoma (SKCM), such as mutations and CNVs. Two molecular subtypes with distinct clinical outcomes and immune profiles were identified. A prognostic model based on six CRGs (CMTM, TNPO1, CTBS, UTRN, HK2, and LIF) was developed and validated with TCGA and GEO datasets, showing high predictive accuracy for overall survival (OS). A high CRGs score correlated with poor OS, immune checkpoint expression, and reduced sensitivity to several chemotherapeutics, including AKT inhibitor VIII and Camptothecin. Conclusions This work provides valuable insights into the circadian regulation of SKCM and underscores the potential of CRGs as biomarkers for prognosis and targets for therapeutic interventions. The novel molecular subtypes and CRGs prognostic scoring model introduced in this study offer significant contributions to the understanding and management of SKCM.
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Affiliation(s)
- Chengling Liu
- Center of Burns and Plastic Surgery and Dermatology, The 924th Hospital of Joint Logistics Support Force of the Chinese People's Liberation Army (PLA), Guilin, China
| | - Xingchen Liu
- Department of Pathology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Pengjuan Cao
- Department of Endocrinology and Traditional Chinese Medicine, The 924th Hospital of Joint Logistics Support Force of the Chinese People's Liberation Army (PLA), Guilin, China
| | - Haiming Xin
- Center of Burns and Plastic Surgery and Dermatology, The 924th Hospital of Joint Logistics Support Force of the Chinese People's Liberation Army (PLA), Guilin, China
| | - Xin Li
- Center of Burns and Plastic Surgery and Dermatology, The 924th Hospital of Joint Logistics Support Force of the Chinese People's Liberation Army (PLA), Guilin, China
| | - Sailing Zhu
- Center of Burns and Plastic Surgery and Dermatology, The 924th Hospital of Joint Logistics Support Force of the Chinese People's Liberation Army (PLA), Guilin, China
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17
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Ning G, Li BN, Wu H, Shi RB, Peng AJ, Wang HY, Zhou X. Regulation of testosterone synthesis by circadian clock genes and its research progress in male diseases. Asian J Androl 2025:00129336-990000000-00298. [PMID: 40101130 DOI: 10.4103/aja20258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 01/20/2025] [Indexed: 03/20/2025] Open
Abstract
ABSTRACT The circadian clock is an important internal time regulatory system for a range of physiological and behavioral rhythms within living organisms. Testosterone, as one of the most critical sex hormones, is essential for the development of the reproductive system, maintenance of reproductive function, and the overall health of males. The secretion of testosterone in mammals is characterized by distinct circadian rhythms and is closely associated with the regulation of circadian clock genes. Here we review the central and peripheral regulatory mechanisms underlying the influence of circadian clock genes upon testosterone synthesis. We also examined the specific effects of these genes on the occurrence, development, and treatment of common male diseases, including late-onset hypogonadism, erectile dysfunction, male infertility, and prostate cancer.
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Affiliation(s)
- Gang Ning
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
- Department of Andrology, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, China
| | - Bo-Nan Li
- Affiliated Changsha Hospital of Hunan Normal University, Changsha 410023, China
| | - Hui Wu
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Ruo-Bing Shi
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - A-Jian Peng
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Hao-Yu Wang
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Xing Zhou
- Department of Andrology, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, China
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Jamadar A, Ward CJ, Remadevi V, Varghese MM, Pabla NS, Gumz ML, Rao R. Circadian Clock Disruption and Growth of Kidney Cysts in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol 2025; 36:378-392. [PMID: 39401086 PMCID: PMC11888963 DOI: 10.1681/asn.0000000528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 10/04/2024] [Indexed: 10/23/2024] Open
Abstract
Key Points Lack of Bmal1 , a circadian clock protein in renal collecting ducts disrupted the clock and increased cyst growth and fibrosis in an autosomal dominant polycystic kidney disease mouse model. Bmal1 gene deletion increased cell proliferation by increasing lipogenesis in kidney cells. Thus, circadian clock disruption could be a risk factor for accelerated disease progression in patients with autosomal dominant polycystic kidney disease. Background Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the PKD1 and PKD2 genes and often progresses to kidney failure. ADPKD progression is not uniform among patients, suggesting that factors secondary to the PKD1/2 gene mutation could regulate the rate of disease progression. Here, we tested the effect of circadian clock disruption on ADPKD progression. Circadian rhythms are regulated by cell-autonomous circadian clocks composed of clock proteins. BMAL1 is a core constituent of the circadian clock. Methods To disrupt the circadian clock, we deleted Bmal1 gene in the renal collecting ducts of the Pkd1 RC/RC (RC/RC) mouse model of ADPKD (RC/RC;Bmal1 f/f;Pkhd1 cre, called double knockout [DKO] mice) and in Pkd1 knockout mouse inner medullary collecting duct cells (Pkd1Bmal1 KO mouse renal inner medullary collecting duct cells). Only male mice were used. Results Human nephrectomy ADPKD kidneys showed altered clock gene expression when compared with normal control human kidneys. When compared with RC/RC kidneys, DKO kidneys showed significantly altered clock gene expression, increased cyst growth, cell proliferation, apoptosis, and fibrosis. DKO kidneys also showed increased lipogenesis and cholesterol synthesis–related gene expression and increased tissue triglyceride levels compared with RC/RC kidneys. Similarly, in vitro , Pkd1Bmal1 KO cells showed altered clock genes, increased lipogenesis and cholesterol synthesis–related genes, and reduced fatty acid oxidation–related gene expression compared with Pkd1KO cells. The Pkd1Bmal1 KO cells showed increased cell proliferation compared with Pkd1KO cells, which was rescued by pharmacological inhibition of lipogenesis. Conclusions Renal collecting duct–specific Bmal1 gene deletion disrupted the circadian clock and triggered accelerated ADPKD progression by altering lipid metabolism–related gene expression.
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Affiliation(s)
- Abeda Jamadar
- Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
- Department of Medicine, Division of Nephrology, University of Kansas Medical Center, Kansas City, Kansas
| | - Christopher J. Ward
- Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
- Department of Medicine, Division of Nephrology, University of Kansas Medical Center, Kansas City, Kansas
| | - Viji Remadevi
- Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
- Department of Medicine, Division of Nephrology, University of Kansas Medical Center, Kansas City, Kansas
| | - Meekha M. Varghese
- Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
- Department of Medicine, Division of Nephrology, University of Kansas Medical Center, Kansas City, Kansas
| | - Navjot S. Pabla
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Michelle L. Gumz
- Division of Nephrology, Hypertension, and Renal Transplantation, Department of Physiology and Aging, Department of Medicine, University of Florida, Gainesville, Florida
| | - Reena Rao
- Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
- Department of Medicine, Division of Nephrology, University of Kansas Medical Center, Kansas City, Kansas
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Moescheid MF, Lu Z, Soria CD, Quack T, Puckelwaldt O, Holroyd N, Holzaepfel P, Haeberlein S, Rinaldi G, Berriman M, Grevelding CG. The retinoic acid family-like nuclear receptor SmRAR identified by single-cell transcriptomics of ovarian cells controls oocyte differentiation in Schistosoma mansoni. Nucleic Acids Res 2025; 53:gkae1228. [PMID: 39676663 PMCID: PMC11879061 DOI: 10.1093/nar/gkae1228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 10/30/2024] [Accepted: 11/28/2024] [Indexed: 12/17/2024] Open
Abstract
Studies on transcription regulation in platyhelminth development are scarce, especially for parasitic flatworms. Here, we employed single-cell transcriptomics to identify genes involved in reproductive development in the trematode model Schistosoma mansoni. This parasite causes schistosomiasis, a major neglected infectious disease affecting >240 million people worldwide. The pathology of schistosomiasis is closely associated with schistosome eggs deposited in host organs including the liver. Unlike other trematodes, schistosomes exhibit distinct sexes, with egg production reliant on the pairing-dependent maturation of female reproductive organs. Despite this significance, the molecular mechanisms underlying ovary development and oocyte differentiation remain largely unexplored. Utilizing an organ isolation approach for S. mansoni, we extracted ovaries of paired females followed by single-cell RNA sequencing (RNA-seq) with disassociated oocytes. A total of 1967 oocytes expressing 7872 genes passed quality control (QC) filtering. Unsupervised clustering revealed four distinct cell clusters: somatic, germ cells and progeny, intermediate and late germ cells. Among distinct marker genes for each cluster, we identified a hitherto uncharacterized transcription factor of the retinoic acid receptor family, SmRAR. Functional analyses of SmRAR and associated genes like Smmeiob (meiosis-specific, oligonucleotide/oligosaccharide binding motif (OB) domain-containing) demonstrated their pairing-dependent and ovary-preferential expression and their decisive roles in oocyte differentiation of S. mansoni.
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Affiliation(s)
- Max F Moescheid
- Institute of Parasitology, Justus Liebig University, Schubertstrasse 81, 35392 Giessen, Germany
| | - Zhigang Lu
- Institute of Parasitology, Justus Liebig University, Schubertstrasse 81, 35392 Giessen, Germany
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10, 1SA, UK
| | - Carmen Diaz Soria
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10, 1SA, UK
| | - Thomas Quack
- Institute of Parasitology, Justus Liebig University, Schubertstrasse 81, 35392 Giessen, Germany
| | - Oliver Puckelwaldt
- Institute of Parasitology, Justus Liebig University, Schubertstrasse 81, 35392 Giessen, Germany
| | - Nancy Holroyd
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10, 1SA, UK
| | - Pauline Holzaepfel
- Institute of Parasitology, Justus Liebig University, Schubertstrasse 81, 35392 Giessen, Germany
| | - Simone Haeberlein
- Institute of Parasitology, Justus Liebig University, Schubertstrasse 81, 35392 Giessen, Germany
| | - Gabriel Rinaldi
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10, 1SA, UK
- Department of Life Sciences, Aberystwyth University, Penglais, Aberystwyth, Ceredigion, SY23 3DA, UK
| | - Matthew Berriman
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10, 1SA, UK
- School of Infection and Immunity, College of Medicine, Veterinary and Life Sciences, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK
| | - Christoph G Grevelding
- Institute of Parasitology, Justus Liebig University, Schubertstrasse 81, 35392 Giessen, Germany
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Vriend J, Glogowska A. Transcription of Clock Genes in Medulloblastoma. Cancers (Basel) 2025; 17:575. [PMID: 40002179 PMCID: PMC11852889 DOI: 10.3390/cancers17040575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/25/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
We investigated the transcription of circadian clock genes in publicly available datasets of gene expression in medulloblastoma (MB) tissues using the R2 Genomics Analysis and Visualization Platform. Differential expression of the core clock genes among the four consensus subgroups of MB (defined in 2012 as Group 3, Group 4, the SHH group, and the WNT group) included the core clock genes (CLOCK, NPAS2, PER1, PER2, CRY1, CRY2, BMAL1, BMAL2, NR1D1, and TIMELESS) and genes which encode proteins that regulate the transcription of clock genes (CIPC, FBXL21, and USP2). The over-expression of several clock genes, including CIPC, was found in individuals with the isochromosome 17q chromosomal aberration in MB Group 3 and Group 4. The most significant biological pathways associated with clock gene expression were ribosome subunits, phototransduction, GABAergic synapse, WNT signaling pathway, and the Fanconi anemia pathway. Survival analysis of clock genes was examined using the Kaplan-Meier method and the Cox proportional hazards regression model through the R2 Genomics Platform. Two clock genes most significantly related to survival were CRY1 and USP2. The data suggest that several clock proteins, including CRY1 and USP2, be investigated as potential therapeutic targets in MB.
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Affiliation(s)
- Jerry Vriend
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
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Pferdehirt L, Damato AR, Lenz KL, Gonzalez-Aponte MF, Palmer D, Meng QJ, Herzog ED, Guilak F. A synthetic chronogenetic gene circuit for programmed circadian drug delivery. Nat Commun 2025; 16:1457. [PMID: 39920119 PMCID: PMC11806060 DOI: 10.1038/s41467-025-56584-5] [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: 12/07/2022] [Accepted: 01/20/2025] [Indexed: 02/09/2025] Open
Abstract
Circadian medicine, the delivery of therapeutic interventions based on an individual's daily rhythms, has shown improved efficacy and reduced side-effects for various treatments. Rheumatoid arthritis and other inflammatory diseases are characterized by diurnal changes in cytokines, leading to inflammatory flares, with peak disease activity in the early morning. Using a combination of synthetic biology and tissue engineering, we developed circadian-based gene circuits, termed "chronogenetics", that express a prescribed transgene downstream of the core clock gene promoter, Period2 (Per2). Gene circuits were transduced into induced pluripotent stem cells that were tissue-engineered into cartilage constructs. Our anti-inflammatory chronogenetic constructs produced therapeutic concentrations of interleukin-1 receptor antagonist in vitro. Once implanted in vivo, the constructs expressed circadian rhythms and entrained to daily light cycles, producing daily increases in biologic drug at the peak of Per2 expression. This approach represents the development of a cell-based chronogenetic therapy for various applications in circadian medicine.
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Affiliation(s)
- Lara Pferdehirt
- Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
- Shriners Hospitals for Children - Saint Louis, St. Louis, MO, USA
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Department of Biomedical Engineering, Washington University, St. Louis, MO, USA
| | - Anna R Damato
- Department of Biology, Washington University, St. Louis, MO, USA
| | - Kristin L Lenz
- Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
- Shriners Hospitals for Children - Saint Louis, St. Louis, MO, USA
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | | | - Daniel Palmer
- Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
- Shriners Hospitals for Children - Saint Louis, St. Louis, MO, USA
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Department of Biomedical Engineering, Washington University, St. Louis, MO, USA
| | - Qing-Jun Meng
- Wellcome Centre for Cell Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Erik D Herzog
- Department of Biology, Washington University, St. Louis, MO, USA
| | - Farshid Guilak
- Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, USA.
- Shriners Hospitals for Children - Saint Louis, St. Louis, MO, USA.
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Biomedical Engineering, Washington University, St. Louis, MO, USA.
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22
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Xu YX, Li J, Wan YH, Su PY, Tao FB, Sun Y. Association between behavioral jet lag with subjective and objective circadian rhythm among Chinese young adults. Soc Sci Med 2025; 366:117689. [PMID: 39799931 DOI: 10.1016/j.socscimed.2025.117689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 12/17/2024] [Accepted: 01/07/2025] [Indexed: 01/15/2025]
Abstract
BACKGROUND Behavioral jet lags (social and eating jet lag), the difference in sleep and eating time between weekdays and weekends, are ubiquitous in modern society. However, evidence on the effects of behavioral jet lags on circadian rhythm is limited. METHODS Social jet lag was assessed using wrist-worn accelerometers. Eating jet lag was measured through Tencent online form with the method of ecological momentary assessment. Total jet lag was calculated as social jet lag plus eating jet lag. Participants were divided into 3 behavioral jet lag patterns: low (both social and eating jet lag < 1h), medium (social or eating jet lag ≥ 1h), and high (both social and eating jet lag ≥ 1h). Subjective and objective circadian rhythm were assessed by reduced Morningness-Eveningness Questionnaire (rMEQ)-based chronotype and the dim light melatonin onset (DLMO) time in 7 saliva samples, respectively. RESULTS The mean age of the sample (n = 140) was 20.7 ± 0.8 years, and 60% were women. Compared to low behavioral jet lag group, medium and high behavioral jet lag group exhibited lower rMEQ score and later DLMO time. Each hour increase in social jet lag was associated with 2.27 point-decrease of rMEQ score, and 24 min-delay of DLMO time; each hour increase in eating jet lag was associated with 1.71 point-decrease of rMEQ score, and 28 min-delay of DLMO time; each hour increase in total jet lag was associated with 1.08 point-decrease of rMEQ score, and 17 min-delay of DLMO time (all P-values <0.05). Additionally, social jet lag explained 6.7% of the variance in the timing of DLMO, which was higher than eating jet lag (4.2%). CONCLUSION Higher behavioral jet lags were significantly associated with increased risk of circadian disruption among young adults. Maintaining consistency in daily behavioral cycles may be an effective intervention for the prevention of circadian disruption.
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Affiliation(s)
- Yu-Xiang Xu
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China; MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China; Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei, China
| | - Jing Li
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China; MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China; Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei, China
| | - Yu-Hui Wan
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China; MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China; Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Hefei, China; Anhui Provincial Key Laboratory of Environment and Population Health Across the Life Course, Anhui Medical University, Hefei, China
| | - Pu-Yu Su
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China; MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China; Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Hefei, China; Anhui Provincial Key Laboratory of Environment and Population Health Across the Life Course, Anhui Medical University, Hefei, China
| | - Fang-Biao Tao
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China; MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China; Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Hefei, China; Anhui Provincial Key Laboratory of Environment and Population Health Across the Life Course, Anhui Medical University, Hefei, China
| | - Ying Sun
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China; MOE Key Laboratory of Population Health Across Life Cycle, Hefei, China; Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Hefei, China; Anhui Provincial Key Laboratory of Environment and Population Health Across the Life Course, Anhui Medical University, Hefei, China.
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23
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Rahim AR, Will V, Myung J. Mood variation under dual regulation of circadian clock and light. Chronobiol Int 2025; 42:162-184. [PMID: 39840618 DOI: 10.1080/07420528.2025.2455144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 12/16/2024] [Accepted: 01/09/2025] [Indexed: 01/23/2025]
Abstract
The intricate relationship between circadian rhythms and mood is well-established. Disturbances in circadian rhythms and sleep often precede the development of mood disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and seasonal affective disorder (SAD). Two primary factors, intrinsic circadian clocks and light, drive the natural fluctuations in mood throughout the day, mirroring the patterns of sleepiness and wakefulness. Nearly all organisms possess intrinsic circadian clocks that coordinate daily rhythms, with light serving as the primary environmental cue to synchronize these internal timekeepers with the 24-hour cycle. Additionally, light directly influences mood states. Disruptions to circadian rhythms, such as those caused by jet lag, shift work, or reduced daylight hours, can trigger or exacerbate mood symptoms. The complex and often subtle connections between circadian disruptions and mood dysregulation suggest that focusing solely on individual clock genes is insufficient to fully understand their etiology and progression. Instead, mood instability may arise from systemic misalignments between external cycles and the internal synchronization of circadian clocks. Here, we synthesize past research on the independent contributions of circadian clocks and light to mood regulation, drawing particularly on insights from animal studies that illuminate fundamental mechanisms relevant to human health.
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Affiliation(s)
- Amalia Ridla Rahim
- Laboratory of Braintime, Graduate Institute of Mind, Brain and Consciousness (GIMBC), Taipei Medical University, Taipei, Taiwan
| | - Veronica Will
- Laboratory of Braintime, Graduate Institute of Mind, Brain and Consciousness (GIMBC), Taipei Medical University, Taipei, Taiwan
| | - Jihwan Myung
- Laboratory of Braintime, Graduate Institute of Mind, Brain and Consciousness (GIMBC), Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Medical Sciences (GIMS), Taipei Medical University, Taipei, Taiwan
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24
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Ze Y, Wu Y, Tan Z, Li R, Li R, Gao W, Zhao Q. Signaling pathway mechanisms of circadian clock gene Bmal1 regulating bone and cartilage metabolism: a review. Bone Res 2025; 13:19. [PMID: 39870641 PMCID: PMC11772753 DOI: 10.1038/s41413-025-00403-6] [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: 08/02/2024] [Revised: 12/17/2024] [Accepted: 12/31/2024] [Indexed: 01/29/2025] Open
Abstract
Circadian rhythm is ubiquitous in nature. Circadian clock genes such as Bmal1 and Clock form a multi-level transcription-translation feedback network, and regulate a variety of physiological and pathological processes, including bone and cartilage metabolism. Deletion of the core clock gene Bmal1 leads to pathological bone alterations, while the phenotypes are not consistent. Studies have shown that multiple signaling pathways are involved in the process of Bmal1 regulating bone and cartilage metabolism, but the exact regulatory mechanisms remain unclear. This paper reviews the signaling pathways by which Bmal1 regulates bone/cartilage metabolism, the upstream regulatory factors that control Bmal1, and the current Bmal1 knockout mouse models for research. We hope to provide new insights for the prevention and treatment of bone/cartilage diseases related to circadian rhythms.
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Affiliation(s)
- Yiting Ze
- Department of Orthodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yongyao Wu
- Department of Orthodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Zhen Tan
- Department of Implant Dentistry, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Rui Li
- Department of Orthodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Rong Li
- Department of Orthodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Wenzhen Gao
- Department of Orthodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Qing Zhao
- Department of Orthodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
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Zhao B, Nepovimova E, Wu Q. The role of circadian rhythm regulator PERs in oxidative stress, immunity, and cancer development. Cell Commun Signal 2025; 23:30. [PMID: 39825442 PMCID: PMC11740368 DOI: 10.1186/s12964-025-02040-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 01/11/2025] [Indexed: 01/20/2025] Open
Abstract
The complex interaction between circadian rhythms and physiological functions is essential for maintaining human health. At the heart of this interaction lies the PERIOD proteins (PERs), pivotal to the circadian clock, influencing the timing of physiological and behavioral processes and impacting oxidative stress, immune functionality, and tumorigenesis. PER1 orchestrates the cooperation of the enzyme GPX1, modulating mitochondrial dynamics in sync with daily rhythms and oxidative stress, thus regulating the mechanisms managing energy substrates. PERs in innate immune cells modulate the temporal patterns of NF-κB and TNF-α activities, as well as the response to LPS-induced toxic shock, initiating inflammatory responses that escalate into chronic inflammatory conditions. Crucially, PERs modulate cancer cell behaviors including proliferation, apoptosis, and migration by influencing the levels of cell cycle proteins and stimulating the expression of oncogenes c-Myc and MDM2. PER2/3, as antagonists in cancer stem cell biology, play important roles in differentiating cancer stem cells and in maintaining their stemness. Importantly, the expression of Pers serve as a significant factor for early cancer diagnosis and prognosis. This review delves into the link between circadian rhythm regulator PERs, disruptions in circadian rhythm, and oncogenesis. We examine the evidence that highlights how dysfunctions in PERs activities initiate cancer development, aid tumor growth, and modify cancer cell metabolism through pathways involved in oxidative stress and immune system. Comprehending these connections opens new pathways for the development of circadian rhythm-based therapeutic strategies, with the aims of boosting immune responses and enhancing cancer treatments.
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Affiliation(s)
- Baimei Zhao
- College of Life Science, Yangtze University, Jingzhou, 434025, China
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové , 500 03, Czech Republic
| | - Qinghua Wu
- College of Life Science, Yangtze University, Jingzhou, 434025, China.
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Quan Y, Wang Z, Zhang T, Sui Y, Zhang X, Ji X, Liu AF, Jiang W. Evaluation of circadian rhythm and prognostic variability pre-and post-CEA or CAS treatment in patients with carotid artery stenosis. Front Neurol 2025; 15:1501316. [PMID: 39835159 PMCID: PMC11743175 DOI: 10.3389/fneur.2024.1501316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 12/02/2024] [Indexed: 01/22/2025] Open
Abstract
Objective Carotid artery stenosis, primarily caused by atherosclerosis, is a major risk factor for ischemic stroke. Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are established interventions to reduce stroke risk and restore cerebral blood flow. However, the effect of these treatments on circadian rhythms, and their influence on stroke recovery, remains underexplored. This study aims to assess how disruptions in circadian rhythms-specifically sleep quality and blood pressure variability-impact recovery in patients undergoing CEA or CAS. Methods We conducted a prospective study involving 177 patients with carotid artery stenosis, all treated with either CEA or CAS. Patients were followed for 90 days post-treatment, with neurological outcomes evaluated using the NIHSS Stroke Scale (NIHSS). Circadian rhythm-related factors, including sleep quality (Pittsburgh Sleep Quality Index [PSQI]) and blood pressure variability (daytime systolic and nighttime diastolic BP), were assessed pre-and post-treatment. Stepwise regression was used to identify predictors of stroke recovery. Results In a cohort of 177 patients with symptomatic carotid atherosclerotic stenosis, stepwise regression identified post-treatment changes in PSQI, nighttime diastolic blood pressure, and the presence of coronary heart disease as significant independent predictors of poor neurological outcomes (p < 0.001). Both CEA and CAS significantly improved daytime systolic (p < 0.01) and nighttime diastolic blood pressure (p < 0.01). Patients with poorer prognosis had higher post-treatment PSQI scores (p < 0.001). Additionally, increased physical activity after treatment was linked to improved neurological recovery. Conclusion This study highlights the critical role of circadian rhythm regulation and cardiovascular health in stroke recovery following CEA or CAS. Stepwise regression analysis revealed that sleep quality, blood pressure stability, and coronary heart disease were key predictors of neurological outcomes, underscoring the importance of integrating circadian rhythm management into rehabilitation strategies. These results provide a robust scientific foundation for further investigation into the role of circadian rhythms in clinical practice.
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Affiliation(s)
- Yi Quan
- Department of Neurosurgery, Peking University People’s Hospital, Beijing, China
| | - Zhongzhu Wang
- Qingdao Women and Children’s Hospital, Qingdao, Shandong, China
| | - Tao Zhang
- Qingdao Women and Children’s Hospital, Qingdao, Shandong, China
| | - Yanyong Sui
- Qingdao Women and Children’s Hospital, Qingdao, Shandong, China
| | - Xin Zhang
- Qingdao Women and Children’s Hospital, Qingdao, Shandong, China
| | - Xueliang Ji
- Qingdao Women and Children’s Hospital, Qingdao, Shandong, China
| | - Ao-fei Liu
- Department of Vascular Neurosurgery, New Era Stroke Care and Research Institute, The PLA Rocket Force Characteristic Medical Center, Beijing, China
| | - Weijian Jiang
- Department of Vascular Neurosurgery, New Era Stroke Care and Research Institute, The PLA Rocket Force Characteristic Medical Center, Beijing, China
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Zou S, Chen Q, Shen Z, Qin B, Zhu X, Lan Y. Update on the roles of regular daily rhythms in combating brain tumors. Eur J Pharmacol 2025; 986:177144. [PMID: 39571672 DOI: 10.1016/j.ejphar.2024.177144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 11/08/2024] [Accepted: 11/17/2024] [Indexed: 11/25/2024]
Abstract
An endogenous time-keeping system found in all kingdoms of life, the endogenous circadian clock, is the source of the essential cyclic change mechanism known as the circadian rhythm. The primary circadian clock that synchronizes peripheral circadian clocks to the proper phase is housed in the anterior hypothalamus's suprachiasmatic nuclei (SCN), which functions as a central pacemaker. According to many epidemiological studies, many cancer types, especially brain tumors, have shown evidence of dysregulated clock gene expression, and the connection between clock and brain tumors is highly specific. In some studies, it is reported that the treatment administered in the morning has been linked to prolonged survival for brain cancer patients, and drug sensitivity and gene expression in gliomas follow daily rhythms. These results suggest a relationship between the circadian rhythm and the onset and spread of brain tumors, while further accumulation of research evidence will be needed to establish definitely these positive outcomes as well as to determine the mechanism underlying them. Chronotherapy provides a means of harnessing current medicines to prolong patients' lifespans and improve their quality of life, indicating the significance of circadian rhythm in enhancing the design of future patient care and clinical trials. Moreover, it is implicated that chronobiological therapy target may provide a significant challenge that warrants extensive effort to achieve. This review examines evidence of the relationship of circadian rhythm with glioma molecular pathogenesis and summarizes the mechanisms and drugs implicated in this disease.
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Affiliation(s)
- Shuang Zou
- Department of Neurosurgery and Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qi Chen
- Interdisciplinary Institute for Medical Engineering, Fuzhou University, Fuzhou, China
| | - Zhiwei Shen
- Department of Neurosurgery and Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bing Qin
- Department of Neurosurgery and Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiangdong Zhu
- Department of Neurosurgery and Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
| | - Yulong Lan
- Department of Neurosurgery and Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
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Dai X, Williams GJ, Groeger JA, Jones G, Brookes K, Zhou W, Hua J, Du W. The role of circadian rhythms and sleep in the aetiology of autism spectrum disorder and attention-deficit/hyperactivity disorder: New evidence from bidirectional two-sample Mendelian randomization analysis. AUTISM : THE INTERNATIONAL JOURNAL OF RESEARCH AND PRACTICE 2025; 29:76-86. [PMID: 38869021 PMCID: PMC11656626 DOI: 10.1177/13623613241258546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2024]
Abstract
LAY ABSTRACT Research shows that people with autism spectrum disorder and attention-deficit/hyperactivity disorder often have sleep issues and problems with the body's natural daily rhythms, known as circadian rhythms. By exploring the genetic variants associated with these rhythms and the conditions, this study reveals that these rhythm changes and sleep patterns are directly linked to autism spectrum disorder and attention-deficit/hyperactivity disorder. It found that the timing of one's most active hours can increase the likelihood of having both autism spectrum disorder and attention-deficit/hyperactivity disorder. Importantly, it also shows that good sleep quality might protect against autism spectrum disorder, while disturbed sleep in people with attention-deficit/hyperactivity disorder seems to be a result rather than the cause of the condition. This understanding can help doctors and researchers develop better treatment approaches that focus on the specific ways sleep and body rhythms affect those with autism spectrum disorder and attention-deficit/hyperactivity disorder, considering their unique associations with circadian rhythms and sleep patterns. Understanding these unique links can lead to more effective, personalized care for those affected by these conditions.
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Affiliation(s)
| | | | | | | | | | - Wei Zhou
- Shanghai Jiao Tong University School of Medicine, China
| | - Jing Hua
- Tongji University, Shanghai, China
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Selman A, Dai J, Driskill J, Reddy AP, Reddy PH. Depression and obesity: Focus on factors and mechanistic links. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167561. [PMID: 39505048 DOI: 10.1016/j.bbadis.2024.167561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/30/2024] [Accepted: 11/01/2024] [Indexed: 11/08/2024]
Abstract
Major depressive disorder (MDD) is defined as mood disorder causing a persistent loss of interest and despair for two weeks or greater, with related symptoms. Depression can interfere with daily life and can cause those affected to not work, study, eat, sleep, and enjoy previously enjoyed hobbies and life events as they did previously. If untreated, it can become a serious health condition. Depression is multifactorial with a variety of factors influencing the condition. These factors include: (1) poor diet and exercise, (2) socioeconomic status, (3) gender, (4) biological clocks, (5) genetics and epigenetics, and (6) personal stressors. Treatment of depressive disorders is thus also multifactorial and utilizes the following therapies: (1) diet and exercise, (2) bright light therapy, (3) cognitive behavioral therapy, and (4) pharmaceutical therapy. Obesity is defined as body mass index over 30 and above, is believed to be causally linked to MDD through both psychological and molecular means. Atypical depression, a common form of MDD, is most strongly correlated with a high proclivity for obesity. Obesity and depression have a bidirectional relationship, a patient experiencing either condition singularly is more likely to develop the other due to the neural links between the two, including emotional lability, physical health of the brain, hormones, cytokine secretion, appetite, diet and feeding habits, inflammatory state. In individuals consuming a high fat diet (HFD) commonly ingested by those with obesity, the gut-microbiome is altered leading to systemic inflammation and the dysregulation of mood and the HPA axis impacting their neural health. The purpose of this paper is to examine the interplay of potential molecular, psychological, societal, and environmental causal factors of depressive disorders and how obesity perpetuates depression. A secondary aim of this paper is to examine current interventions that may help improve those affected by both conditions.
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Affiliation(s)
- Ashley Selman
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Jean Dai
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Jackson Driskill
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Arubala P Reddy
- Nutritional Sciences Department, College Human Sciences, Texas Tech University, Lubbock, TX 79409, USA
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Nutritional Sciences Department, College Human Sciences, Texas Tech University, Lubbock, TX 79409, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
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Xue Q, Wang R, Zhu-Ge R, Guo L. Research progresses on the effects of heavy metals on the circadian clock system. REVIEWS ON ENVIRONMENTAL HEALTH 2024; 39:721-727. [PMID: 37572029 DOI: 10.1515/reveh-2022-0104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 06/12/2023] [Indexed: 08/14/2023]
Abstract
Environmental pollution with heavy metals is widespread, thus increasing attention has been paid to their toxic effects. Recent studies have suggested that heavy metals may influence the expression of circadian clock genes. Almost all organs and tissues exhibit circadian rhythms. The normal circadian rhythm of an organism is maintained by the central and peripheral circadian clock. Thus, circadian rhythm disorders perturb normal physiological processes. Here, we review the effects of heavy metals, including manganese, copper, cadmium, and lead, on four core circadian clock genes, i.e., ARNTL, CLOCK, PER, and CRY genes.
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Affiliation(s)
- Qian Xue
- Department of Toxicology, School of Public Health, Jilin University, Changchun, Jilin Province, China
| | - Rui Wang
- Department of Toxicology, School of Public Health, Jilin University, Changchun, Jilin Province, China
| | - Ruijian Zhu-Ge
- Department of Toxicology, School of Public Health, Jilin University, Changchun, Jilin Province, China
| | - Li Guo
- Department of Toxicology, School of Public Health, Jilin University, Changchun, Jilin Province, China
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Halabian A, Radahmadi M. The neurobiological mechanisms of photoperiod impact on brain functions: a comprehensive review. Rev Neurosci 2024; 35:933-958. [PMID: 39520288 DOI: 10.1515/revneuro-2024-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 06/19/2024] [Indexed: 11/16/2024]
Abstract
Variations in day length, or photoperiodism, whether natural or artificial light, significantly impact biological, physiological, and behavioral processes within the brain. Both natural and artificial light sources are environmental factors that significantly influence brain functions and mental well-being. Photoperiodism is a phenomenon, occurring either over a 24 h cycle or seasonally and denotes all biological responses of humans and animals to these fluctuations in day and night length. Conversely, artificial light occurrence refers to the presence of light during nighttime hours and/or its absence during the daytime (unnaturally long and short days, respectively). Light at night, which is a form of light pollution, is prevalent in many societies, especially common in certain emergency occupations. Moreover, individuals with certain mental disorders, such as depression, often exhibit a preference for darkness over daytime light. Nevertheless, disturbances in light patterns can have negative consequences, impacting brain performance through similar mechanisms albeit with varying degrees of severity. Furthermore, changes in day length lead to alterations in the activity of receptors, proteins, ion channels, and molecular signaling pathways, all of which can impact brain health. This review aims to summarize the mechanisms by which day length influences brain functions through neural circuits, hormonal systems, neurochemical processes, cellular activity, and even molecular signaling pathways.
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Affiliation(s)
- Alireza Halabian
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western, Ontario, N6A 3K7 London, ON, Canada
| | - Maryam Radahmadi
- Department of Physiology, School of Medicine, 48455 Isfahan University of Medical Sciences , 81746-73461 Isfahan, Iran
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Nikhil K, Singhal B, Granados-Fuentes D, Li JS, Kiss IZ, Herzog ED. The Functional Connectome Mediating Circadian Synchrony in the Suprachiasmatic Nucleus. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.06.627294. [PMID: 39713450 PMCID: PMC11661124 DOI: 10.1101/2024.12.06.627294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Circadian rhythms in mammals arise from the spatiotemporal synchronization of ~20,000 neuronal clocks in the Suprachiasmatic Nucleus (SCN). While anatomical, molecular, and genetic approaches have revealed diverse cell types and signaling mechanisms, the network wiring that enables SCN cells to communicate and synchronize remains unclear. To overcome the challenges of revealing functional connectivity from fixed tissue, we developed MITE (Mutual Information & Transfer Entropy), an information theory approach that infers directed cell-cell connections with high fidelity. By analyzing 3447 hours of continuously recorded clock gene expression from 9011 cells in 17 mice, we found that the functional connectome of SCN was highly conserved bilaterally and across mice, sparse, and organized into a dorsomedial and a ventrolateral module. While most connections were local, we discovered long-range connections from ventral cells to cells in both the ventral and dorsal SCN. Based on their functional connectivity, SCN cells can be characterized as circadian signal generators, broadcasters, sinks, or bridges. For example, a subset of VIP neurons acts as hubs that generate circadian signals critical to synchronize daily rhythms across the SCN neural network. Simulations of the experimentally inferred SCN networks recapitulated the stereotypical dorsal-to-ventral wave of daily PER2 expression and ability to spontaneously synchronize, revealing that SCN emergent dynamics are sculpted by cell-cell connectivity. We conclude that MITE provides a powerful method to infer functional connectomes, and that the conserved architecture of cell-cell connections mediates circadian synchrony across space and time in the mammalian SCN.
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Affiliation(s)
- K.L. Nikhil
- Department of Biology, Washington University in Saint Louis, USA
| | - Bharat Singhal
- Department of Electrical and Systems Engineering, Washington University in Saint Louis, USA
| | | | - Jr-Shin Li
- Department of Electrical and Systems Engineering, Washington University in Saint Louis, USA
| | | | - Erik D. Herzog
- Department of Biology, Washington University in Saint Louis, USA
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Mansingh S, Maier G, Delezie J, Westermark PO, Ritz D, Duchemin W, Santos G, Karrer‐Cardel B, Steurer SA, Albrecht U, Handschin C. More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORα. J Physiol 2024; 602:6373-6402. [PMID: 38850551 PMCID: PMC11607892 DOI: 10.1113/jp285585] [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: 08/28/2023] [Accepted: 05/20/2024] [Indexed: 06/10/2024] Open
Abstract
Circadian rhythms, governed by the dominant central clock, in addition to various peripheral clocks, regulate almost all biological processes, including sleep-wake cycles, hormone secretion and metabolism. In certain contexts, the regulation and function of the peripheral oscillations can be decoupled from the central clock. However, the specific mechanisms underlying muscle-intrinsic clock-dependent modulation of muscle function and metabolism remain unclear. We investigated the outcome of perturbations of the primary and secondary feedback loops of the molecular clock in skeletal muscle by specific gene ablation of Period circadian regulator 2 (Per2) and RAR-related orphan receptor alpha (Rorα), respectively. In both models, a dampening of core clock gene oscillation was observed, while the phase was preserved. Moreover, both loops seem to be involved in the homeostasis of amine groups. Highly divergent outcomes were seen for overall muscle gene expression, primarily affecting circadian rhythmicity in the PER2 knockouts and non-oscillating genes in the RORα knockouts, leading to distinct outcomes in terms of metabolome and phenotype. These results highlight the entanglement of the molecular clock and muscle plasticity and allude to specific functions of different clock components, i.e. the primary and secondary feedback loops, in this context. The reciprocal interaction between muscle contractility and circadian clocks might therefore be instrumental to determining a finely tuned adaptation of muscle tissue to perturbations in health and disease. KEY POINTS: Specific perturbations of the primary and secondary feedback loop of the molecular clock result in specific outcomes on muscle metabolism and function. Ablation of Per2 (primary loop) or Rorα (secondary loop) blunts the amplitude of core clock genes, in absence of a shift in phase. Perturbation of the primary feedback loop by deletion of PER2 primarily affects muscle gene oscillation. Knockout of RORα and the ensuing modulation of the secondary loop results in the aberrant expression of a large number of non-clock genes and proteins. The deletion of PER2 and RORα affects muscle metabolism and contractile function in a circadian manner, highlighting the central role of the molecular clock in modulating muscle plasticity.
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Affiliation(s)
| | | | | | - Pål O. Westermark
- Leibniz‐Institut für NutztierbiologieInstitut für Genetik und BiometrieDummerstorfGermany
| | - Danilo Ritz
- Biozentrum, University of BaselBaselSwitzerland
| | - Wandrille Duchemin
- sciCORE Center for Scientific ComputingUniversity of BaselBaselSwitzerland
| | - Gesa Santos
- Biozentrum, University of BaselBaselSwitzerland
| | | | | | - Urs Albrecht
- Department of BiologyUniversity of FribourgFribourgSwitzerland
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Lian JW, Li SY, Clarke RB, Howell SJ, Meng QJ. Can we utilise the circadian clock to target cancer stem cells? Cancer Lett 2024; 611:217360. [PMID: 39608441 DOI: 10.1016/j.canlet.2024.217360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 11/03/2024] [Accepted: 11/25/2024] [Indexed: 11/30/2024]
Abstract
The 24-hourly circadian clock has been implicated in the regulation of multiple cancer hallmarks and characteristics. Cancer stem cells (CSCs) are a small but significant population of cells within many cancers, characterised by their self-renewal and clonogenic capacities. Increasing evidence points to CSCs having prominent roles in metastasis and drug resistance. However, it remains largely unknown how circadian clocks are involved with CSCs and what implications these interactions have for cancer progression and therapeutics. In this review, we examine the growing evidence on the role of circadian clocks in CSCs and discuss the potential therapeutic implications. This opens up new opportunities to target CSCs through various chronotherapeutic approaches, potentially improving clinical cancer outcomes. We propose different scenarios in which targeting circadian clocks in CSCs or their surrounding microenvironment could be developed into effective therapeutic strategies, including: (1) direct pharmacological targeting of core clock molecules, (2) optimising the timing of systemic anticancer therapies, and (3) targeting the neighbouring cells or systemic factors that influence tumour cells in a circadian-dependent manner.
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Affiliation(s)
- Jia-Wen Lian
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Shi-Yang Li
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Robert B Clarke
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Sacha J Howell
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Qing-Jun Meng
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
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Tchio C, Williams J, Taylor H, Ollila H, Saxena R. An integrative approach prioritizes the orphan GPR61 genomic region in tissue-specific regulation of chronotype. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.22.624721. [PMID: 39651283 PMCID: PMC11623522 DOI: 10.1101/2024.11.22.624721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Objectives Chronotype, a manifestation of circadian rhythms, affects morning or evening preferences and ease of getting-up. This study explores the genetic basis of morning chronotype and ease of getting-up, focusing on the G protein-coupled receptor locus, GPR61. Methods We analyzed the genetic correlation between chronotype and ease of getting-up using linkage disequilibrium score regression with summary statistics from the UK Biobank (n=453,379). We prioritized shared signals between chronotype and ease of getting-up using the Human Genetic Evidence (HuGE) score. We assessed the significance of GPR61 and the lead variant rs12044778 through colocalization and in-silico analyses from ENCODE, Genotype-Tissue Expression, Hi-C, and Knockout Mouse Project databases to explore potential regulatory roles of causal genes. Results We identified a strong genetic correlation (Rg=0.80, P=4.9 x10 324 ) between chronotype and ease of getting-up. Twenty-three genes, including three circadian core clock components, had high HuGE scores for both traits. Lead variant rs12044778 in GPR61 was prioritized for its high HuGE score (45) and causal pleiotropy (posterior probability=0.98). This morningness variant influenced gene expression in key tissues: decreasing GPR61 in tibial nerve, increasing AMIGO1 in subcutaneous adipose, and increasing ATXN7L2 in the cerebellum. Functional knockout models showed GPR61 knockout increased fat mass and activity, AMIGO1 knockout increased activity, and ATXN7L2 knockout reduced body weight without affecting activity. Conclusions Our findings reveal pleiotropic genetic factors influencing chronotype and ease of getting-up, emphasizing GPR61 's rs12044778 and nearby genes like AMIGO1 and ATXN7L2 . These insights advance understanding of circadian preferences and suggest potential therapeutic interventions. SIGNIFICANCE This study investigates the genetic underpinnings of chronotype preferences and ease of getting up, with a focus on the orphan G protein-coupled receptor GPR61 and the locus lead variant rs12044778. By combining genomic data with in silico functional analysis, we provide mechanistic insight into a locus for morning chronotype and ease of getting in the morning. We identified the variant rs12044778 as a key regulator of GPR61 and nearby genes AMIGO1 and ATXN7L2 influencing circadian and metabolic traits. Our findings shed light on the intricate genetic networks governing circadian rhythms, suggesting potential therapeutic targets for disorders of the circadian rhythm.
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Jiang Y, Shi J, Tai J, Yan L. Circadian Regulation in Diurnal Mammals: Neural Mechanisms and Implications in Translational Research. BIOLOGY 2024; 13:958. [PMID: 39765625 PMCID: PMC11727363 DOI: 10.3390/biology13120958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/16/2024] [Accepted: 11/19/2024] [Indexed: 01/15/2025]
Abstract
Diurnal and nocturnal mammals have evolved unique behavioral and physiological adaptations to optimize survival for their day- or night-active lifestyle. The mechanisms underlying the opposite activity patterns are not fully understood but likely involve the interplay between the circadian time-keeping system and various arousal- or sleep-promoting factors, e.g., light or melatonin. Although the circadian systems between the two chronotypes share considerable similarities, the phase relationships between the principal and subordinate oscillators are chronotype-specific. While light promotes arousal and wakefulness in diurnal species like us, it induces sleep in nocturnal ones. Similarly, melatonin, the hormone of darkness, is commonly used as a hypnotic in humans but is secreted in the active phase of nocturnal animals. Thus, the difference between the two chronotypes is more complex than a simple reversal, as the physiological and neurological processes in diurnal mammals during the day are not equivalent to that of nocturnal ones at night. Such chronotype differences could present a significant translational gap when applying research findings obtained from nocturnal rodents to diurnal humans. The potential advantages of diurnal models are being discussed in a few sleep-related conditions including familial natural short sleep (FNSS), obstructive sleep apnea (OSA), and Smith-Magenis syndrome (SMS). Considering the difference in chronotype, a diurnal model will be more adequate for revealing the physiology and physiopathology pertaining to human health and disease, especially in conditions in which circadian rhythm disruption, altered photic response, or melatonin secretion is involved. We hope the recent advances in gene editing in diurnal rodents will promote greater utility of the diurnal models in basic and translational research.
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Affiliation(s)
- Yirun Jiang
- Department of Otolaryngology, Head and Neck Surgery, Capital Institute of Pediatrics, Beijing 100020, China; (Y.J.); (J.T.)
| | - Jiaming Shi
- Department of Psychology, Michigan State University, East Lansing, MI 48824, USA;
| | - Jun Tai
- Department of Otolaryngology, Head and Neck Surgery, Capital Institute of Pediatrics, Beijing 100020, China; (Y.J.); (J.T.)
| | - Lily Yan
- Department of Psychology, Michigan State University, East Lansing, MI 48824, USA;
- Neuroscience Program, Interdisciplinary Science & Technology Building (ISTB), Michigan State University, East Lansing, MI 48824, USA
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Men S, Xu J, Yang Z, Yan Z. DEHP-Induced Glioblastoma in Zebrafish Is Associated with Circadian Dysregulation of PER3. TOXICS 2024; 12:835. [PMID: 39771050 PMCID: PMC11679192 DOI: 10.3390/toxics12120835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 11/19/2024] [Accepted: 11/19/2024] [Indexed: 01/11/2025]
Abstract
DEHP is a plasticizer that is widely found in our water environment and poses a significant risk to the environment and human health. Long-term exposure to DEHP can cause endocrine disruption and interfere with the organism's normal functioning. In order to explore the potential effects of DEHP on the development of biological brain tissues, this study used bioinformatics analysis to confirm the diagnostic and prognostic value of PER3 in gliomas and further validated the neurotoxicity of DEHP using methods such as behavioral experiments and molecular biology in zebrafish. The experimental findings revealed that the expression level of PER3 in diseased tissues was significantly lower than that in the control group. In addition, the expression level of PER3 was significantly correlated with immune cell infiltration, immune checkpoint genes, and oncogenes. Moreover, the ROC curve analysis showed that PER3 could accurately differentiate between GBM tissues and adjacent normal tissues. To further validate the neurotoxicity of DEHP, we analyzed the effects of DEHP exposure on zebrafish development and PER3 expression by behavioral experiments and molecular biology. The results showed that exposure to DEHP substantially altered both the behavioral responses and the gene expression profiles within the brain tissues of zebrafish. PCR results indicate that the expression of circadian rhythm factor PER3 was significantly reduced in the brains of zebrafish in the exposed group, and circadian dysregulation had a certain promoting effect on the development of glioma. The aim of this work was to investigate the potential effects of DEHP contamination in a water environment on organism brain development. It was demonstrated that PER3 is an effective early diagnostic marker, which is of great significance in the diagnosis and clinical prognosis of glioma, and that DEHP exposure can lead to a significant reduction in PER3 expression in zebrafish brain tissue. This study further proved that DEHP has a potential carcinogenic effect, which adds scientific evidence to the carcinogenicity study of DEHP.
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Affiliation(s)
- Shuhui Men
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China;
| | - Jiayun Xu
- Ningbo Clinical Pathology Diagnosis Center, Ningbo 315021, China;
| | - Zhanhong Yang
- Environmental Standards Institute of Ministry of Ecology and Environment of the People’s Republic of China, Beijing 100012, China
| | - Zhenguang Yan
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China;
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de la Puente-Aldea J, Lopez-Llanos O, Horrillo D, Marcos-Sanchez H, Sanz-Ballesteros S, Franco R, Jaisser F, Senovilla L, Palacios-Ramirez R. Mineralocorticoid Receptor and Sleep Quality in Chronic Kidney Disease. Int J Mol Sci 2024; 25:12320. [PMID: 39596384 PMCID: PMC11594958 DOI: 10.3390/ijms252212320] [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: 09/09/2024] [Revised: 11/06/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
The classical function of the mineralocorticoid receptor (MR) is to maintain electrolytic homeostasis and control extracellular volume and blood pressure. The MR is expressed in the central nervous system (CNS) and is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis as well as sleep physiology, playing a role in the non-rapid eye movement (NREM) phase of sleep. Some patients with psychiatric disorders have very poor sleep quality, and a relationship between MR dysregulation and this disorder has been found in them. In addition, the MR is involved in the regulation of the renal peripheral clock. One of the most common comorbidities observed in patients with chronic kidney disease (CKD) is poor sleep quality. Patients with CKD experience sleep disturbances, including reduced sleep duration, sleep fragmentation, and insomnia. To date, no studies have specifically investigated the relationship between MR activation and CKD-associated sleep disturbances. However, in this review, we analyzed the environment that occurs in CKD and proposed two MR-related mechanisms that may be responsible for these sleep disturbances: the circadian clock disruption and the high levels of MR agonist observed in CKD.
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Affiliation(s)
- Juan de la Puente-Aldea
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain; (J.d.l.P.-A.); (O.L.-L.); (L.S.)
| | - Oscar Lopez-Llanos
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain; (J.d.l.P.-A.); (O.L.-L.); (L.S.)
| | - Daniel Horrillo
- Facultad de ciencias de la Salud, Universidad Rey Juan Carlos, 28922 Alcorcon, Spain; (D.H.); (R.F.)
| | | | | | - Raquel Franco
- Facultad de ciencias de la Salud, Universidad Rey Juan Carlos, 28922 Alcorcon, Spain; (D.H.); (R.F.)
| | - Frederic Jaisser
- INSERM U1166, Team Diabetes, Metabolic Diseases and Comorbidities, Sorbonne Université, 75013 Paris, France;
- INSERM UMR 1116, Centre d’Investigations Cliniques-Plurithématique 1433, Université de Lorraine, CHRU de Nancy, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, 54500 Nancy, France
| | - Laura Senovilla
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain; (J.d.l.P.-A.); (O.L.-L.); (L.S.)
- INSERM U1138, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Sorbonne Université, Institut Universitaire de France, 75006 Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Roberto Palacios-Ramirez
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain; (J.d.l.P.-A.); (O.L.-L.); (L.S.)
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Gálvez D, Romero E, Murcia-Moreno D, Bonilla B, Valdés R. Daily activity patterns in agoutis ( Dasyprocta spp) in response to relaxed predation. Heliyon 2024; 10:e39986. [PMID: 39553657 PMCID: PMC11566868 DOI: 10.1016/j.heliyon.2024.e39986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 10/16/2024] [Accepted: 10/16/2024] [Indexed: 11/19/2024] Open
Abstract
Animals' fitness is determined in a large proportion by the balance in energetic requirements maintained during daily activities, in response to environmental factors. Predation is a major environmental factor influencing the activity patterns of prey, and the deployment of adaptive responses to predation represents a significant cost to prey populations and communities. Experimental removal of predators to study the effect on activity patterns of prey is impractical for vertebrate species. However, islands are often deprived of predators and provide an excellent arena to study prey's responses in the absence of any cue related to predation risk. Here, we investigated whether natural absence of predators in islands has influenced the activity patterns of diurnal agoutis in Panama, by monitoring activity in three sites in each habitat type (predator-free vs predator). We predicted that agoutis in predator-free sites can expand their activity patterns towards the night, which is the period of highest predation risk, in sites with predators. One of our predator-free sites showed relative high activity at night, with no evidence of nocturnality in sites with predators. A clear pattern across our three predator-free sites was that agoutis started their daily activity earlier, before sunrise, which is a period with significant predation risk as well. Our study highlights the role that felids play in regulating agoutis' daily activity patterns and we discuss the implications of our finding. Finally, we also offer a review on agoutis' activity pattern in the Neotropics.
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Affiliation(s)
- Dumas Gálvez
- Coiba Scientific Station, City of Knowledge, Calle Gustavo Lara, Bld. 145B, Clayton, 0843-01853, Panama
- Programa Centroamericano de Maestría en Entomología, Universidad de Panamá, Ciudad de Panamá, Estafeta universitaria, Avenida Simón Bolívar, 0824, Panama
- Smithsonian Tropical Research Institute, Ciudad de Panamá, P.O. Box 0843-03092, Panama
| | - Emilio Romero
- Laboratories of Integrative Neuroscience and Endocrinology, Bristol Medical School, University of Bristol, Bristol, UK
- Escuela de Biología, Departamento de Fisiología y Comportamiento Animal., Universidad de Panamá, Panama
| | - Daniel Murcia-Moreno
- Coiba Scientific Station, City of Knowledge, Calle Gustavo Lara, Bld. 145B, Clayton, 0843-01853, Panama
- Smithsonian Tropical Research Institute, Ciudad de Panamá, P.O. Box 0843-03092, Panama
| | - Braulio Bonilla
- Escuela de Biología, Departamento de Zoología, Universidad de Panamá, Panama
| | - Roderick Valdés
- Coiba Scientific Station, City of Knowledge, Calle Gustavo Lara, Bld. 145B, Clayton, 0843-01853, Panama
- Universidad Autónoma de Chiriquí, Panama
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Ren J, Zhang X, Gao YX. Influencing factors of work engagement among ophthalmic specialized nurses in China: a cross-sectional study. BMC Nurs 2024; 23:795. [PMID: 39478542 PMCID: PMC11523766 DOI: 10.1186/s12912-024-02452-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 10/18/2024] [Indexed: 11/03/2024] Open
Abstract
AIM This study aims to investigate the current status of work engagement among ophthalmic specialized nurses in China and explore the multifaceted factors influencing work engagement from the physical, psychological, and social perspectives. METHODS This study adopts a cross-sectional survey design, distributed electronic questionnaires through WeChat software, and 261 valid questionnaires were received from ophthalmic specialized nurses. The survey includes demographic information about ophthalmic specialized nurses, as well as work engagement, sleep quality and social support. A generalized linear model was used to investigate the factors influencing the work engagement of ophthalmic specialized nurses. RESULTS The overall work engagement score among ophthalmic specialized nurses in our study was 143.70 ± 13.66. Multivariate analysis showed that participation in teaching, professional title, sleep quality and perceived social support were the influencing factors of work engagement of ophthalmic specialized nurses. DISCUSSION The results showed that ophthalmic specialized nurses with the title of "senior nurse", participating in teaching had higher work engagement. According to the Two-Factor Theory, incentive factors can stimulate the work enthusiasm of specialized nurses. The worse the sleep quality of ophthalmic specialized nurses, the lower the work engagement. It is suggested that nursing managers should pay attention to the sleep problems of specialized nurses and reduce work burnout. The nurses who perceived higher levels of social support exhibited higher work engagement. Because social support can mitigate nurses' work burnout and work-related stress. CONCLUSION Ophthalmic specialized nurses in China demonstrate a relatively high level of work engagement. Those with the title of senior nurse, involvement in teaching, better sleep quality, and higher perceived social support exhibit higher work engagement.
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Affiliation(s)
- Jie Ren
- Department of Ophthalmology, West China Hospital/ West China School of Nursing, Sichuan University, Chengdu, 610041, China
| | - Xin Zhang
- Department of Ophthalmology, West China Hospital/ West China School of Nursing, Sichuan University, Chengdu, 610041, China
| | - Yun-Xia Gao
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Bale R, Doshi G. Deciphering the role of siRNA in anxiety and depression. Eur J Pharmacol 2024; 981:176868. [PMID: 39128805 DOI: 10.1016/j.ejphar.2024.176868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 07/02/2024] [Accepted: 08/05/2024] [Indexed: 08/13/2024]
Abstract
Anxiety and depression are central nervous system illnesses that are among the most prevalent medical concerns of the twenty-first century. Patients with this condition and their families bear psychological, financial, and societal hardship. There are currently restrictions when utilizing the conventional course of treatment. RNA interference is expected to become an essential approach in anxiety and depression due to its potent and targeted gene silencing. Silencing of genes by post-transcriptional modification is the mechanism of action of small interfering RNA (siRNA). The suppression of genes linked to disease is typically accomplished by siRNA molecules in an efficient and targeted manner. Unfavourable immune responses, off-target effects, naked siRNA instability, nuclease vulnerability, and the requirement to create an appropriate delivery method are some of the challenges facing the clinical application of siRNA. This review focuses on the use of siRNA in the treatment of anxiety and depression.
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Affiliation(s)
- Rajeshwari Bale
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V L M Road, Vile Parle (w), Mumbai, 400056, India
| | - Gaurav Doshi
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V L M Road, Vile Parle (w), Mumbai, 400056, India.
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Li Y, Li W, Deng J, Yin M. PER3 promoter hypermethylation correlates to the progression of pan-cancer. Clin Epigenetics 2024; 16:140. [PMID: 39402618 PMCID: PMC11476066 DOI: 10.1186/s13148-024-01760-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Malignant cells exhibit reduced period circadian regulator 3 (PER3) expression. However, the underlying mechanisms of variations in PER3 expression in cancers and the specific function of PER3 in tumor progression remain poorly understood. RESULTS We explored multiple public databases, conducted bioinformatics analyses, and performed in vitro and in vivo experiments for validation. We found PER3 expression was decreased in most types of cancers, and PER3 downregulation was associated with a poor prognosis in 8 types of cancer. PER3 promoter methylation levels were increased in 11 types of cancer. Promoter hypermethylation (CpG islands [CGIs] cg12258811 and cg14204433) correlated with decreased PER3 expression in six cancers (breast invasive carcinoma, colon adenocarcinoma, head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma [KIRP], lung adenocarcinoma [LUAD], and uterine corpus endometrial carcinoma). CGI cg12258811 hypermethylation was associated with reduced survival time and advanced cancer stages. Moreover, the bisulfite pyrosequencing assay confirmed CGI cg12258811 hypermethylation and its negative correlation with PER3 expression. In vitro and in vivo experiments demonstrated that PER3 inhibited KIRP and LUAD progression. Decitabine enhanced PER3 expression and inhibited KIRP cell functions by reducing promoter (cg12258811) methylation level. CONCLUSIONS Our findings advanced the mechanistic understanding of variations in PER3 expression in cancers and confirmed the tumor-associated function of PER3 hypermethylation and downregulation.
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Affiliation(s)
- Yaoxu Li
- Department of Stomatology, Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Wanzhou District, Chongqing, 404100, China
- Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Wanzhou District, Chongqing, 404100, China
| | - Wenjuan Li
- Department of Emergency and Critical Care Medicine, The First Afliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Jinhai Deng
- Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Wanzhou District, Chongqing, 404100, China
| | - Mingzhu Yin
- Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Wanzhou District, Chongqing, 404100, China.
- Chongqing Technical Innovation Center for Quality Evaluation and Identification of Authentic Medicinal Herbs, Wanzhou District, Chongqing, 404100, China.
- Three Gorges Hospital & Academy for Advanced Interdisciplinary Technology, CQU-Ferenc Krausz Nobel Laureate Scientific Workstation, Chongqing University, Chongqing, China.
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Dashti HS. Sleep and home parenteral nutrition in adults: A narrative review. Nutr Clin Pract 2024; 39:1081-1093. [PMID: 38934221 DOI: 10.1002/ncp.11181] [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: 02/01/2024] [Revised: 04/24/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
Infusions of home parenteral nutrition (HPN) are often cycled at night coinciding with sleep episodes. Adult consumers of HPN are known to experience poor sleep attributed to frequent awakenings and long durations of wakefulness after falling asleep. Consequently, most consumers do not meet recommendations for sleep duration and quality or daytime napping. The primary underlying pathophysiology resulting in sleep problems is nocturia; however, other factors also exist, including disruptions caused by medical equipment (ie, pump alarms), comorbid conditions, dysglycemia, and medication use. Early guidance on sleep is imperative because of the central role of sleep in physical health and wellbeing, including mitigating complications, such as infection risk, gastrointestinal problems, pain sensitivity, and fatigue. Clinicians should routinely inquire about the sleep of their patients and address factors known to perturb sleep. Nonpharmacologic opportunities to mitigate sleep problems include education on healthy sleep practices (ie, sleep hygiene); changes in infusion schedules, volumes, rates, and equipment; and, possibly, behavioral interventions, which have yet to be examined in this population. Addressing comorbid conditions, such as mood disorders, and nutrition deficiencies may also help. Pharmacologic interventions and technological advancement in HPN delivery are also needed. Research on sleep in this population is considered a priority, yet it remains limited at this time.
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Affiliation(s)
- Hassan S Dashti
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts, USA
- Division of Nutrition, Harvard Medical School, Boston, Massachusetts, USA
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Onuma S, Kawai M. Circadian Regulatory Networks of Glucose Homeostasis and Its Disruption as a Potential Cause of Undernutrition. Endocrinology 2024; 165:bqae126. [PMID: 39276035 DOI: 10.1210/endocr/bqae126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 08/09/2024] [Accepted: 09/12/2024] [Indexed: 09/16/2024]
Abstract
The circadian clock system, an evolutionarily conserved mechanism, orchestrates diurnal rhythms in biological activities such as behavior and metabolism, aligning them with the earth's 24-hour light/dark cycle. This synchronization enables organisms to anticipate and adapt to predictable environmental changes, including nutrient availability. However, modern lifestyles characterized by irregular eating and sleeping habits disrupt this synchrony, leading to metabolic disorders such as obesity and metabolic syndrome, evidenced by higher obesity rates among shift workers. Conversely, circadian disturbances are also associated with reduced nutrient absorption and an increased risk of malnutrition in populations such as the critically ill or the elderly. The precise mechanisms of these disturbances in leading to either overnutrition or undernutrition is complex and not yet fully understood. Glucose, a crucial energy source, is closely linked to obesity when consumed excessively and to weight loss when intake is reduced, which suggests that circadian regulation of glucose metabolism is a key factor connecting circadian disturbances with nutritional outcomes. In this review, we describe how the biological clock in various tissues regulates glucose metabolism, with a primary focus on studies utilizing animal models. Additionally, we highlight current clinical evidence supporting the association between circadian disturbance and glucose metabolism, arguing that such disruption could predominantly contribute to undernutrition due to impaired efficient utilization of nutrients.
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Affiliation(s)
- Shinsuke Onuma
- Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, 594-1101, Osaka, Japan
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Masanobu Kawai
- Department of Molecular Genetics and Endocrinology, Research Institute, Osaka Women's and Children's Hospital, 594-1101, Osaka, Japan
- Department of Gastroenterology, Nutrition and Endocrinology, Osaka Women's and Children's Hospital, 594-1101, Osaka, Japan
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Chanel PNC, Bennett NC, Oosthuizen MK. Light sensitivity of the circadian system in the social Highveld mole-rat Cryptomys hottentotus pretoriae. J Exp Biol 2024; 227:jeb247793. [PMID: 39207238 PMCID: PMC11449439 DOI: 10.1242/jeb.247793] [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: 03/27/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024]
Abstract
Highveld mole-rats (Cryptomys hottentotus pretoriae) are social rodents that inhabit networks of subterranean tunnels. In their natural environment, they are rarely exposed to light, and consequently their visual systems have regressed over evolutionary time. However, in the laboratory they display nocturnal activity, suggesting that they are sensitive to changes in ambient illumination. We examined the robustness of the Highveld mole-rat circadian system by assessing its locomotor activity under decreasing light intensities. Mole-rats were subjected to seven consecutive light cycles commencing with a control cycle (overhead fluorescent lighting at 150 lx), followed by decreasing LED lighting (500, 300, 100, 10 and 1 lx) on a 12 h light:12 h dark (L:D) photoperiod and finally a constant darkness (DD) cycle. Mole-rats displayed nocturnal activity under the whole range of experimental lighting conditions, with a distinct spike in activity at the end of the dark phase in all cycles. The mole-rats were least active during the control cycle under fluorescent light, locomotor activity increased steadily with decreasing LED light intensities, and the highest activity was exhibited when the light was completely removed. In constant darkness, mole-rats displayed free-running rhythms with periods (τ) ranging from 23.77 to 24.38 h, but was overall very close to 24 h at 24.07 h. Our findings confirm that the Highveld mole-rat has a higher threshold for light compared with aboveground dwelling rodents, which is congruent with previous neurological findings, and has implications for behavioural rhythms.
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Affiliation(s)
- Pauline N. C. Chanel
- Department of Zoology and Entomology, University of Pretoria, Private Bag X20, Pretoria 0028, South Africa
| | - Nigel C. Bennett
- Department of Zoology and Entomology, University of Pretoria, Private Bag X20, Pretoria 0028, South Africa
- Mammal Research Institute, Department of Zoology and Entomology, University of Pretoria, Pretoria 0002, South Africa
| | - Maria K. Oosthuizen
- Department of Zoology and Entomology, University of Pretoria, Private Bag X20, Pretoria 0028, South Africa
- Mammal Research Institute, Department of Zoology and Entomology, University of Pretoria, Pretoria 0002, South Africa
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Le MK, Tran NQV, Nguyen PT, Nguyen TA, Nakao A, Kondo T. Comprehensive analysis of distinct circadian clock subtypes of adult diffuse glioma and their associations with clinicopathological, genetic, and epigenetic profiles. J Neuropathol Exp Neurol 2024; 83:736-744. [PMID: 38964366 DOI: 10.1093/jnen/nlae055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/06/2024] Open
Abstract
The circadian clock (CC) has biological and clinical implications in gliomas. Most studies focused on CC effects on the tumor microenvironment and the application of chronotherapy. The present study focused on CC gene expression patterns and intracellular oncogenic activities. Glioma gene expression data were collected from The Human Cancer Genome Atlas (TCGA) project. After applying inclusion and exclusion criteria, we selected 666 patients from TCGA-GBM and TCGA-LGG projects and included important clinicopathological variables. The entire cohort was subjected to clustering analysis and divided into CC1 and CC2 subtypes based on statistical, biological, and clinical criteria. CC2 gliomas showed higher expression of BMAL1 and CRY1 and lower expression of CRY2 and PER2 (adjusted P < .001). CC2 gliomas had q higher activity of cell proliferation, metabolic reprogramming, angiogenesis, hypoxia, and many oncogenic signals (P < .001). The CC2 subtype contained a higher proportion of glioblastomas (P < .001) and had a worse prognosis (P < .001). Stratified Kaplan-Meier and multivariable Cox analyses illustrated that the CC subtype is an independent prognostic factor to clinicopathological characteristics (P < .001), genetic aberrations (P = .006), and biological processes (P < .001). Thus, this study shows statistical evidence of CC subtypes and their biological, and clinicopathological significance in adult gliomas.
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Affiliation(s)
- Minh-Khang Le
- Department of Human Pathology, University of Yamanashi, Yamanashi, Japan
| | | | - Phuc-Tan Nguyen
- Department of Immunology, University of Yamanashi, Yamanashi, Japan
| | - Thuy-An Nguyen
- Department of Immunology, University of Yamanashi, Yamanashi, Japan
| | - Atsuhito Nakao
- Department of Immunology, University of Yamanashi, Yamanashi, Japan
| | - Tetsuo Kondo
- Department of Human Pathology, University of Yamanashi, Yamanashi, Japan
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Jamadar A, Ward CJ, Remadevi V, Varghese MM, Pabla NS, Gumz ML, Rao R. Circadian clock disruption and growth of kidney cysts in autosomal dominant polycystic kidney disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.05.606676. [PMID: 39211074 PMCID: PMC11361200 DOI: 10.1101/2024.08.05.606676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Background Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the PKD1 and PKD2 genes, and often progresses to kidney failure. ADPKD progression is not uniform among patients, suggesting that factors secondary to the PKD1/2 gene mutation could regulate the rate of disease progression. Here we tested the effect of circadian clock disruption on ADPKD progression. Circadian rhythms are regulated by cell-autonomous circadian clocks composed of clock proteins. BMAL1 is a core constituent of the circadian clock. Methods To disrupt the circadian clock, we deleted Bmal1 gene in the renal collecting ducts of the Pkd1 RC/RC (RC/RC) mouse model of ADPKD (RC/RC; Bmal1 f/f ; Pkhd1 cre , called DKO mice), and in Pkd1 knockout mouse inner medullary collecting duct cells ( Pkd1Bmal1 KO mIMCD3 cells). Only male mice were used. Results Human nephrectomy ADPKD kidneys and Pkd1 KO mIMCD3 cells showed reduced Bmal1 gene expression compared to normal controls. When compared to RC/RC kidneys, DKO kidneys showed significantly altered clock gene expression, increased cyst growth, cell proliferation, apoptosis and fibrosis. DKO kidneys also showed increased lipogenesis and cholesterol synthesis-related gene expression, and increased tissue triglyceride levels compared to RC/RC kidneys. Similarly, in vitro, Pkd1Bmal1 KO cells showed altered clock genes, increased lipogenesis and cholesterol synthesis-related genes, and reduced fatty-acid oxidation-related gene expression compared to Pkd1KO cells. The Pkd1Bmal1 KO cells showed increased cell proliferation compared to Pkd1KO cells, which was rescued by pharmacological inhibition of lipogenesis. Conclusion Renal collecting duct specific Bmal1 gene deletion disrupts the circadian clock and triggers accelerated ADPKD progression by altering lipid metabolism-related gene expression. Key points Lack of BMAL1, a circadian clock protein in renal collecting ducts disrupted the clock and increased cyst growth and fibrosis in an ADPKD mouse model.BMAL1 gene deletion increased cell proliferation by increasing lipogenesis in kidney cells.Thus, circadian clock disruption could be a risk factor for accelerated disease progression in patients with ADPKD.
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48
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Xie X, Zhang M, Luo H. Regulation of metabolism by circadian rhythms: Support from time-restricted eating, intestinal microbiota & omics analysis. Life Sci 2024; 351:122814. [PMID: 38857654 DOI: 10.1016/j.lfs.2024.122814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 05/05/2024] [Accepted: 06/04/2024] [Indexed: 06/12/2024]
Abstract
Circadian oscillatory system plays a key role in coordinating the metabolism of most organisms. Perturbation of genetic effects and misalignment of circadian rhythms result in circadian dysfunction and signs of metabolic disorders. The eating-fasting cycle can act on the peripheral circadian clocks, bypassing the photoperiod. Therefore, time-restricted eating (TRE) can improve metabolic health by adjusting eating rhythms, a process achieved through reprogramming of circadian genomes and metabolic programs at different tissue levels or remodeling of the intestinal microbiota, with omics technology allowing visualization of the regulatory processes. Here, we review recent advances in circadian regulation of metabolism, focus on the potential application of TRE for rescuing circadian dysfunction and metabolic disorders with the contribution of intestinal microbiota in between, and summarize the significance of omics technology.
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Affiliation(s)
- Ximei Xie
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, PR China
| | - Mengjie Zhang
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, PR China
| | - Hailing Luo
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, PR China.
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Pereira AC, Serrano-Cuñarro L, Cruz MT, Cavadas C, Pereira CMF. The link between alterations in circadian rhythms and lipid metabolism in bipolar disorder: the hypothesis of lipid droplets. REVISTA BRASILEIRA DE PSIQUIATRIA (SAO PAULO, BRAZIL : 1999) 2024; 46:e20243670. [PMID: 39102528 PMCID: PMC11744263 DOI: 10.47626/1516-4446-2024-3670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 07/19/2024] [Indexed: 08/07/2024]
Abstract
Bipolar disorder (BD) is a neuropsychiatric illness characterized by recurrent episodes of mania and depression, leading to significant cognitive and functional impairments, psychiatric and metabolic comorbidities, and substantial healthcare costs. The complex nature and lack of specific biomarkers for BD make it a daily challenge for clinicians. Therefore, advancing our understanding of BD pathophysiology is essential to identify novel diagnostic biomarkers and potential therapeutic targets. Although its neurobiology remains unclear, circadian disruption and lipid alterations have emerged as key hallmarks of BD. Lipids are essential components of the brain and play a critical role in regulating synaptic activity and neuronal development. Consequently, alterations in brain lipids may contribute to the neuroanatomical changes and reduced neuroplasticity observed in BD. Lipid droplets, which regulate the storage of neutral lipids, buffer the levels of toxic lipids within cells. These dynamic organelles adapt to cellular needs, and their dysregulated accumulation has been implicated in several pathological conditions. Notably, lipid droplets and different classes of lipids exhibit rhythmic oscillations throughout the 24-hour cycle, suggesting a link between lipid metabolism, circadian rhythms, and lipid droplets. In this review, we explore the impairment of circadian rhythms and lipid metabolism in BD and present evidence that circadian clocks regulate lipid droplet accumulation. Importantly, we propose the "hypothesis of lipid droplets for BD," which posits that impaired lipid metabolism in BD is closely linked to alterations in lipid droplet homeostasis driven by circadian clock disruption.
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Affiliation(s)
- Ana Catarina Pereira
- Centro de Neurociências e Biologia Celular, Universidade de Coimbra (UC), Coimbra, Portugal
- Centro de Inovação em Biotecnologia e Biomedicina (CIBB), UC, Coimbra, Portugal
- Faculdade de Medicina, UC, Coimbra, Portugal
- Centro Académico Clínico de Coimbra, Coimbra, Portugal
| | - Laura Serrano-Cuñarro
- Centro de Neurociências e Biologia Celular, Universidade de Coimbra (UC), Coimbra, Portugal
- Centro de Inovação em Biotecnologia e Biomedicina (CIBB), UC, Coimbra, Portugal
| | - Maria Teresa Cruz
- Centro de Neurociências e Biologia Celular, Universidade de Coimbra (UC), Coimbra, Portugal
- Centro de Inovação em Biotecnologia e Biomedicina (CIBB), UC, Coimbra, Portugal
- Centro Académico Clínico de Coimbra, Coimbra, Portugal
- Faculdade de Farmácia, UC, Coimbra, Portugal
| | - Cláudia Cavadas
- Centro de Neurociências e Biologia Celular, Universidade de Coimbra (UC), Coimbra, Portugal
- Centro de Inovação em Biotecnologia e Biomedicina (CIBB), UC, Coimbra, Portugal
- Faculdade de Farmácia, UC, Coimbra, Portugal
| | - Cláudia Maria Fragão Pereira
- Centro de Neurociências e Biologia Celular, Universidade de Coimbra (UC), Coimbra, Portugal
- Centro de Inovação em Biotecnologia e Biomedicina (CIBB), UC, Coimbra, Portugal
- Faculdade de Medicina, UC, Coimbra, Portugal
- Centro Académico Clínico de Coimbra, Coimbra, Portugal
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Chau PK, Ryan E, Dalen KT, Haugen F. Timing of acute cold exposure determines UCP1 and FGF21 expression - Possible interactions between the thermal environment, thermoregulatory responses, and peripheral clocks. J Therm Biol 2024; 124:103938. [PMID: 39142264 DOI: 10.1016/j.jtherbio.2024.103938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 06/26/2024] [Accepted: 07/15/2024] [Indexed: 08/16/2024]
Abstract
Thermoregulation is synchronized across the circadian cycle to uphold thermal homeostasis. To test if time-of-day matters for the response to environmental cold exposure, mice were acclimated to thermoneutrality (27 °C) for 2 months were subjected acutely (8 h) to cold ambient conditions (15 °C), whereas controls were maintained at thermoneutral conditions. The thermal exposure was tested in separate groups (N = 8) at three distinct time-of-day periods: in the LIGHT phase (L); the DARK phase (D); and a mix of the two (D + L). The magnitude of UCP1 protein and mRNA induction in brown adipose tissue (BAT) in response to acute cold exposure was time-of-day sensitive, peaking in LIGHT, whereas lower induction levels were observed in D + L, and DARK. Plasma levels of FGF21 were induced 3-fold by acute cold exposure at LIGHT and D + L, compared to the time-matched thermoneutral controls, whereas cold in DARK did not cause a significant increase of FGF21 plasma levels. Cold exposure affected, in BAT, the temporal mRNA expression patterns of core circadian clock components: Bmal1, Clock, Per1, Per3, Cry1, Cry2 Nr1d1, and Nr1d2, but in the liver, none of the transcripts were modified. Behavioral assessment using the Thermal Gradient Test (TGT) showed that acute cold exposure reduced cold sensitivity in D + L, but not in DARK. RNA-seq analyses of somatosensory neurons in DRG highlighted the role of the core circadian components in these cells, as well as transcriptional changes due to acute cold exposure. This elucidates the sensory system as a gauge and potential regulator of thermoregulatory responses based on circadian physiology. In conclusion, acute cold exposure elicits time-of-day specific effects on thermoregulatory pathways, which may involve underlying changes in thermal perception. These results have implications for efforts aimed at reducing risks associated with the organization of shift work in cold environments.
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Affiliation(s)
- Phong Kt Chau
- Division of Work Psychology and Physiology, National Institute of Occupational Health (STAMI), Oslo, Norway
| | - Elin Ryan
- Division of Work Psychology and Physiology, National Institute of Occupational Health (STAMI), Oslo, Norway
| | - Knut Tomas Dalen
- Department of Nutrition and Norwegian Transgenic Center, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Fred Haugen
- Division of Work Psychology and Physiology, National Institute of Occupational Health (STAMI), Oslo, Norway.
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