Circadian Rhythm: Biological Functions, Diseases, and Therapeutic Targets

Abstract

Circadian rhythms are intrinsic 24-h biological cycles that govern various physiological processes. In addition to the hypothalamic suprachiasmatic nucleus, the circadian system is organized in multiple peripheral tissues, such as the brain, heart, bone, liver, and lung. Emerging evidence suggests that disruptions in these rhythms, which are regulated by a network of clock genes, play pivotal roles in human health. A deeper understanding of the interplay between circadian rhythms and tissue homeostasis holds significant potential for the development of targeted therapies aimed at improving human health. This review explores the link between circadian rhythms and tissue homeostasis, delving into their biological functions, including influences on metabolic homeostasis, neuroendocrine signaling, immune and oxidative stress responses, tissue repair, and autophagy activity. It also summarizes the connections between circadian disruptions and circadian disruption-related diseases, including degenerative diseases, cardiometabolic disorders, and cancers. Furthermore, this review offers valuable perspectives on the treatment of circadian disruption-related diseases. By revealing the regulatory influence of circadian rhythms on human health and disease, this work aims to inspire the development of novel strategies for the prevention, diagnosis, and treatment of circadian disruption-related diseases.

Keywords

circadian rhythm / circadian disruption-related diseases / clock gene / therapy / tissue homeostasis

References

[1] W. Huang, K. M. Ramsey, B. Marcheva, and J. Bass, “Circadian Rhythms, Sleep, and Metabolism,” Journal of Clinical Investigation 121, no. 6 (2011): 2133-2141.

[2] A. Odriozola, A. Gonzalez, J. Alvarez-Herms, and F. Corbi, “Circadian Rhythm and Host Genetics,” Advances in Genetics 111 (2024): 451-495.

[3] J. A. Mohawk, C. B. Green, and J. S. Takahashi, “Central and Peripheral Circadian Clocks in Mammals,” Annual Review of Neuroscience 35 (2012): 445-462.

[4] A. Kalsbeek, E. Foppen, I. Schalij, et al., “Circadian Control of the Daily Plasma Glucose Rhythm: An Interplay of GABA and Glutamate,” PLoS ONE 3, no. 9 (2008): e3194.

[5] J. Mendoza, “Circadian Insights Into the Biology of Depression: Symptoms, Treatments and Animal Models,” Behavioural Brain Research 376 (2019): 112186.

[6] H. J. Burgess, J. Trinder, Y. Kim, and D. Luke, “Sleep and Circadian Influences on Cardiac Autonomic Nervous System Activity,” The American Journal of Physiology 273, no. 4 (1997): H1761-1768.

[7] W. S. Warren, T. H. Champney, and V. M. Cassone, “The Suprachiasmatic Nucleus Controls the Circadian Rhythm of Heart Rate via the Sympathetic Nervous System,” Physiology & Behavior 55, no. 6 (1994): 1091-1099.

[8] A. Balsalobre, “Clock Genes in Mammalian Peripheral Tissues,” Cell and Tissue Research 309, no. 1 (2002): 193-199.

[9] Y. Leng, E. S. Musiek, K. Hu, F. P. Cappuccio, and K. Yaffe, “Association Between Circadian Rhythms and Neurodegenerative Diseases,” Lancet Neurology 18, no. 3 (2019): 307-318.

[10] S. Crnko, C. Du Pre B, J. P. G. Sluijter, and W. Van Laake L, “Circadian Rhythms and the Molecular Clock in Cardiovascular Biology and Disease,” Nature Reviews Cardiology 16, no. 7 (2019): 437-447.

[11] A. R. Saran, S. Dave, and A. Zarrinpar, “Circadian Rhythms in the Pathogenesis and Treatment of Fatty Liver Disease,” Gastroenterology 158, no. 7 (2020): 1948-1966. e1941.

[12] T. Papagiannakopoulos, M. R. Bauer, S. M. Davidson, et al., “Circadian Rhythm Disruption Promotes Lung Tumorigenesis,” Cell Metabolism 24, no. 2 (2016): 324-331.

[13] M. J. Sherratt, L. Hopkinson, M. Naven, et al., “Circadian Rhythms in Skin and Other Elastic Tissues,” Matrix Biology 84 (2019): 97-110.

[14] C. B. Peek, D. C. Levine, J. Cedernaes, et al., “Circadian Clock Interaction With HIF1alpha Mediates Oxygenic Metabolism and Anaerobic Glycolysis in Skeletal Muscle,” Cell Metabolism 25, no. 1 (2017): 86-92.

[15] S. Yamazaki, R. Numano, M. Abe, et al., “Resetting central and Peripheral Circadian Oscillators in Transgenic Rats,” Science 288, no. 5466 (2000): 682-685.

[16] M. Gil-Lozano, P. M. Hunter, L. A. Behan, B. Gladanac, R. F. Casper, and P. L. Brubaker, “Short-term Sleep Deprivation With Nocturnal Light Exposure Alters Time-dependent Glucagon-Like Peptide-1 and Insulin Secretion in Male Volunteers,” American Journal of Physiology Endocrinology and Metabolism 310, no. 1 (2016): E41-50.

[17] B. Wilms, E. M. Leineweber, M. Molle, et al., “Sleep Loss Disrupts Morning-to-Evening Differences in Human White Adipose Tissue Transcriptome,” Journal of Clinical Endocrinology and Metabolism 104, no. 5 (2019): 1687-1696.

[18] K. H. Cox and J. S. Takahashi, “Circadian Clock Genes and the Transcriptional Architecture of the Clock Mechanism,” Journal of Molecular Endocrinology 63, no. 4 (2019): R93-R102.

[19] J. R. Janoski, I. Aiello, C. W. Lundberg, and C. V. Finkielstein, “Circadian Clock Gene Polymorphisms Implicated in human Pathologies,” Trends in Genetics 40, no. 10 (2024): 834-852.

[20] S. Langmesser, T. Tallone, A. Bordon, S. Rusconi, and U. Albrecht, “Interaction of Circadian Clock Proteins PER2 and CRY With BMAL1 and CLOCK,” BMC Molecular Biology 9 (2008): 41.

[21] A. G. Tamayo, H. A. Duong, M. S. Robles, M. Mann, and C. J. Weitz, “Histone Monoubiquitination by Clock-Bmal1 Complex Marks Per1 and Per2 Genes for Circadian Feedback,” Nature Structural & Molecular Biology 22, no. 10 (2015): 759-766.

[22] R. Ye, C. P. Selby, Y. Y. Chiou, I. Ozkan-Dagliyan, S. Gaddameedhi, and A. Sancar, “Dual Modes of CLOCK:BMAL1 Inhibition Mediated by Cryptochrome and Period Proteins in the Mammalian Circadian Clock,” Genes & Development 28, no. 18 (2014): 1989-1998.

[23] H. Cho, X. Zhao, M. Hatori, et al., “Regulation of Circadian Behaviour and Metabolism by REV-ERB-α and REV-ERB-β,” Nature 485, no. 7396 (2012): 123-127.

[24] N. Preitner, F. Damiola, L. Lopez-Molina, et al., “The Orphan Nuclear Receptor REV-ERBalpha Controls Circadian Transcription Within the Positive Limb of the Mammalian Circadian Oscillator,” Cell 110, no. 2 (2002): 251-260.

[25] I. Barone, N. M. Gilette, H. Hawks-Mayer, et al., “Synaptic BMAL1 Phosphorylation Controls Circadian Hippocampal Plasticity,” Science Advances 9, no. 43 (2023): eadj1010.

[26] C. Luna-Marco, D. Devos, J. Cacace, et al., “Molecular Circadian Clock Disruption in the Leukocytes of Individuals With Type 2 Diabetes and Overweight, and Its Relationship With Leukocyte-endothelial Interactions,” Diabetologia 67, no. 10 (2024): 2316-2328.

[27] J. J. Kelu and S. M. Hughes, “Muscle Peripheral Circadian Clock Drives Nocturnal Protein Degradation via Raised Ror/Rev-erb Balance and Prevents Premature Sarcopenia,” Proceedings of the National Academy of Sciences of the United States of America 122, no. 19 (2025): e2422446122.

[28] A. S. Blancas-Velazquez, T. Bering, S. Bille, and M. F. Rath, “Role and Neural Regulation of Clock Genes in the Rat Pineal Gland: Clock Modulates Amplitude of Rhythmic Expression of Aanat Encoding the Melatonin-producing Enzyme,” Journal of Pineal Research 75, no. 2 (2023): e12893.

[29] J. R. Jones, S. Chaturvedi, D. Granados-Fuentes, and E. D. Herzog, “Circadian Neurons in the Paraventricular Nucleus Entrain and Sustain Daily Rhythms in Glucocorticoids,” Nature Communications 12, no. 1 (2021): 5763.

[30] C. Zhang, S. J. Clough, E. B. Adamah-Biassi, et al., “Impact of Endogenous Melatonin on Rhythmic Behaviors, Reproduction, and Survival Revealed in Melatonin-proficient C57BL/6J Congenic Mice,” Journal of Pineal Research 71, no. 2 (2021): e12748.

[31] M. Stoiljkovic, J. E. Song, H. K. Hong, et al., “Mitofusin 2 Controls Mitochondrial and Synaptic Dynamics of Suprachiasmatic VIP Neurons and Related Circadian Rhythms,” The Journal of Clinical Investigation 135, no. 13 (2025): e185000.

[32] R. F. N. Ribeiro, D. Pereira, S. M. Lopes, et al., “Circadian Rhythms Are Disrupted in Patients and Preclinical Models of Machado-Joseph Disease,” Brain: A Journal of Neurology (2025).

[33] W. Jubiz, J. M. Canterbury, E. Reiss, and F. H. Tyler, “Circadian Rhythm in Serum Parathyroid Hormone Concentration in human Subjects: Correlation With Serum Calcium, Phosphate, Albumin, and Growth Hormone Levels,” The Journal of Clinical Investigation 51, no. 8 (1972): 2040-2046.

[34] B. Sherman, C. Wysham, and B. Pfohl, “Age-related Changes in the Circadian Rhythm of Plasma Cortisol in Man,” The Journal of Clinical Endocrinology and Metabolism 61, no. 3 (1985): 439-443.

[35] H. Trivedi, A. Szabo, S. Zhao, T. Cantor, and H. Raff, “Circadian Variation of Mineral and Bone Parameters in End-stage Renal Disease,” Journal of Nephrology 28, no. 3 (2015): 351-359.

[36] V. Hasenmajer, E. Sbardella, F. Sciarra, et al., “Circadian Clock Disruption Impairs Immune Oscillation in Chronic Endogenous Hypercortisolism: A Multi-level Analysis From a Multicentre Clinical Trial,” EBioMedicine 110 (2024): 105462.

[37] P. Z. Zhang, Y. H. Shi, Y. X. Guo, et al., “Social Jetlag Elicits Fatty Liver via Perturbed Circulating Prolactin Rhythm-mediated Circadian Remodeling of Hepatic Lipid Metabolism,” Military Medical Research 12, no. 1 (2025): 29.

[38] S. K. Halder and G. C. Melkani, “The Interplay of Genetic Predisposition, Circadian Misalignment, and Metabolic Regulation in Obesity,” Current Obesity Reports 14, no. 1 (2025): 21.

[39] J. Tamaki, M. Iki, E. Kadowaki, et al., “Biochemical Markers for Bone Turnover Predict Risk of Vertebral Fractures in Postmenopausal Women Over 10 Years: The Japanese Population-based Osteoporosis (JPOS) Cohort Study,” Osteoporosis International 24, no. 3 (2013): 887-897.

[40] E. de Papp A, H. G. Bone, M. P. Caulfield, et al., “A Cross-sectional Study of Bone Turnover Markers in Healthy Premenopausal Women,” Bone 40, no. 5 (2007): 1222-1230.

[41] C. M. Swanson, W. M. Kohrt, O. M. Buxton, et al., “The Importance of the Circadian System & Sleep for Bone Health,” Metabolism 84 (2018): 28-43.

[42] S. S. Diemar, S. S. Dahl, A. S. West, S. A. Simonsen, H. K. Iversen, and N. R. Jorgensen, “A Systematic Review of the Circadian Rhythm of Bone Markers in Blood,” Calcified Tissue International 112, no. 2 (2023): 126-147.

[43] E. Poggiogalle, H. Jamshed, and C. M. Peterson, “Circadian Regulation of Glucose, Lipid, and Energy Metabolism in Humans,” Metabolism 84 (2018): 11-27.

[44] E. M. Speksnijder, P. H. Bisschop, S. E. Siegelaar, D. J. Stenvers, and A. Kalsbeek, “Circadian Desynchrony and Glucose Metabolism,” Journal of Pineal Research 76, no. 4 (2024): e12956.

[45] D. J. Stenvers, F. Scheer, P. Schrauwen, S. E. la Fleur, and A. Kalsbeek, “Circadian Clocks and Insulin Resistance,” Nature Reviews Endocrinology 15, no. 2 (2019): 75-89.

[46] J. G. Smith, K. B. Koronowski, T. Mortimer, et al., “Liver and Muscle Circadian Clocks Cooperate to Support Glucose Tolerance in Mice,” Cell Reports 42, no. 6 (2023): 112588.

[47] K. Frazier, S. Manzoor, K. Carroll, et al., “Gut Microbes and the Liver Circadian Clock Partition Glucose and Lipid Metabolism,” Journal of Clinical Investigation 133, no. 18 (2023): e162515.

[48] C. A. Chaikin, A. V. Thakkar, A. W. T. Steffeck, et al., “Control of Circadian Muscle Glucose Metabolism Through the BMAL1-HIF Axis in Obesity,” PNAS 122, no. 13 (2025): e2424046122.

[49] J. J. Gooley, “Circadian Regulation of Lipid Metabolism,” Proceedings of the Nutrition Society 75, no. 4 (2016): 440-450.

[50] Q. Wang, M. Tikhonenko, S. N. Bozack, et al., “Changes in the Daily Rhythm of Lipid Metabolism in the Diabetic Retina,” PLoS ONE 9, no. 4 (2014): e95028.

[51] S. Li and J. D. Lin, “Transcriptional Control of Circadian Metabolic Rhythms in the Liver,” Diabetes, Obesity & Metabolism 17 (2015): 33-38. Suppl 1. 0 1.

[52] Y. Fan, J. Lu, J. Fan, and S. Guan, “1,3-dichloro-2-propanol Caused Lipid Droplets Accumulation by Suppressing Neutral Lipases via BMAL1 in Hepatocytes,” Food and Chemical Toxicology 174 (2023): 113670.

[53] M. Noshiro, T. Kawamoto, A. Nakashima, et al., “DEC1 regulates the Rhythmic Expression of PPARgamma Target Genes Involved in Lipid Metabolism in White Adipose Tissue,” Genes to Cells 25, no. 4 (2020): 232-241.

[54] A. Shostak, J. Meyer-Kovac, and H. Oster, “Circadian Regulation of Lipid Mobilization in White Adipose Tissues,” Diabetes 62, no. 7 (2013): 2195-2203.

[55] N. M. Held, J. Wefers, M. van Weeghel, et al., “Skeletal Muscle in Healthy Humans Exhibits a Day-night Rhythm in Lipid Metabolism,” Mol Metab 37 (2020): 100989.

[56] J. F. Harmsen, N. van Polanen, M. van Weeghel, et al., “Circadian Misalignment Disturbs the Skeletal Muscle Lipidome in Healthy Young Men,” Faseb Journal 35, no. 6 (2021): e21611.

[57] F. Lademann, E. Tsourdi, L. C. Hofbauer, and M. Rauner, “Thyroid Hormone Actions and Bone Remodeling—The Role of the Wnt Signaling Pathway,” Experimental and Clinical Endocrinology & Diabetes 128, no. 6-07 (2020): 450-454.

[58] H. D. White, A. M. Ahmad, B. H. Durham, et al., “PTH Circadian Rhythm and PTH Target-organ Sensitivity Is Altered in Patients With Adult Growth Hormone Deficiency With Low BMD,” Journal of Bone and Mineral Research 22, no. 11 (2007): 1798-1807.

[59] W. D. Fraser, F. C. Logue, J. P. Christie, et al., “Alteration of the Circadian Rhythm of Intact Parathyroid Hormone and Serum Phosphate in Women With Established Postmenopausal Osteoporosis,” Osteoporosis International 8, no. 2 (1998): 121-126.

[60] C. J. Proctor and A. Gartland, “Simulated Interventions to Ameliorate Age-Related Bone Loss Indicate the Importance of Timing,” Front Endocrinol (Lausanne) 7 (2016): 61.

[61] L. Coppeta, L. Di Giampaolo, S. Rizza, et al., “Relationship Between the Night Shift Work and Thyroid Disorders: A Systematic Review and Meta-analysis,” Endocrine Regulations 54, no. 1 (2020): 64-70.

[62] A. van Coevorden, E. Laurent, C. Decoster, et al., “Decreased Basal and Stimulated Thyrotropin Secretion in Healthy Elderly Men,” Journal of Clinical Endocrinology and Metabolism 69, no. 1 (1989): 177-185.

[63] F. Kimura, H. Okano, and M. Kawakami, “Development of Circadian Rhythms in Serum Hormone Levels in the Immature Female Rat,” Neuroendocrinology 32, no. 1 (1981): 19-23.

[64] R. I. Versteeg, M. J. Serlie, A. Kalsbeek, and S. E. la Fleur, “Serotonin, a Possible Intermediate Between Disturbed Circadian Rhythms and Metabolic Disease,” Neuroscience 301 (2015): 155-167.

[65] A. Jagota and D. Kalyani, “Daily Serotonin Rhythms in Rat Brain During Postnatal Development and Aging,” Biogerontology 9, no. 4 (2008): 229-234.

[66] T. Matsumura, H. Nakagawa, K. Suzuki, C. Ninomiya, and T. Ishiwata, “Influence of Circadian Disruption on Neurotransmitter Levels, Physiological Indexes, and Behaviour in Rats,” Chronobiology International 32, no. 10 (2015): 1449-1457.

[67] P. Razavi, E. E. Devore, A. Bajaj, et al., “Shift Work, Chronotype, and Melatonin Rhythm in Nurses,” Cancer Epidemiology and Prevention Biomarkers 28, no. 7 (2019): 1177-1186.

[68] J. N. Zhou, R. Y. Liu, J. van Heerikhuize, M. A. Hofman, and D. F. Swaab, “Alterations in the Circadian Rhythm of Salivary Melatonin Begin During Middle-age,” Journal of Pineal Research 34, no. 1 (2003): 11-16.

[69] P. J. Snyder, D. L. Kopperdahl, A. J. Stephens-Shields, et al., “Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men with Low Testosterone: A Controlled Clinical Trial,” JAMA Internal Medicine 177, no. 4 (2017): 471-479.

[70] E. A. Rosenberg, P. Buzkova, H. A. Fink, et al., “Testosterone, Dihydrotestosterone, Bone Density, and Hip Fracture Risk Among Older Men: The Cardiovascular Health Study,” Metabolism 114 (2021): 154399.

[71] Q. Liu, H. Wang, H. Wang, N. Li, R. He, and Z. Liu, “Per1/Per2 Disruption Reduces Testosterone Synthesis and Impairs Fertility in Elderly Male Mice,” International Journal of Molecular Sciences 23, no. 13 (2022): 7399.

[72] G. Wittert, “The Relationship Between Sleep Disorders and Testosterone,” Curr Opin Endocrinol Diabetes Obes 21, no. 3 (2014): 239-243.

[73] Y. Saxena, S. Routh, and A. Mukhopadhaya, “Immunoporosis: Role of Innate Immune Cells in Osteoporosis,” Frontiers in Immunology 12 (2021): 687037.

[74] P. V. Giannoudis, D. Hak, D. Sanders, E. Donohoe, T. Tosounidis, and C. Bahney, “Inflammation, Bone Healing, and Anti-Inflammatory Drugs: An Update,” Journal of Orthopaedic Trauma 29 (2015): S6-S9. Suppl 12.

[75] F. Loi, L. A. Cordova, J. Pajarinen, T. H. Lin, Z. Yao, and S. B. Goodman, “Inflammation, Fracture and Bone Repair,” Bone 86 (2016): 119-130.

[76] N. Labrecque and N. Cermakian, “Circadian Clocks in the Immune System,” Journal of Biological Rhythms 30, no. 4 (2015): 277-290.

[77] Y. Nagasaka, Y. Nakamura, N. Q. V. Tran, Y. Kobayashi, N. Nakano, and A. Nakao, “Deficiency of BMAL1 Promotes ROS Generation and Enhances IgE-dependent Degranulation in Mast Cells,” Biochemical and Biophysical Research Communications 690 (2024): 149295.

[78] H. Nam, B. Kim, Y. Lee, H. K. Choe, and S. W. Yu, “Presenilin 2 N141I Mutation Induces Hyperimmunity by Immune Cell-specific Suppression of REV-ERBalpha Without Altering Central Circadian Rhythm,” Exp Neurobiol 32, no. 4 (2023): 259-270.

[79] P. Honzlova and A. Sumova, “Metabolic Regulation of the Circadian Clock in Classically and Alternatively Activated Macrophages,” Immunology and Cell Biology 101, no. 5 (2023): 428-443.

[80] H. Hong, Y. M. Cheung, X. Cao, Y. Wu, C. Li, and X. Y. Tian, “REV-ERBalpha Agonist SR9009 Suppresses IL-1beta Production in Macrophages Through BMAL1-dependent Inhibition of Inflammasome,” Biochemical Pharmacology 192 (2021): 114701.

[81] Z. Zhou, Y. Lin, L. Gao, Z. Yang, S. Wang, and B. Wu, “Circadian Pharmacological Effects of berberine on Chronic Colitis in Mice: Role of the Clock Component Rev-erbalpha,” Biochemical Pharmacology 172 (2020): 113773.

[82] L. Chen, C. Yu, W. Xu, et al., “Dual-Targeted Nanodiscs Revealing the Cross-Talk Between Osteogenic Differentiation of Mesenchymal Stem Cells and Macrophages,” ACS Nano 17, no. 3 (2023): 3153-3167.

[83] W. S. Guo, X. Deng, M. X. Yang, T. Hu, and X. H. Li, “A Pilot Study on the Expression of Circadian Clock Genes in the Alveolar Bone of Mice With Periodontitis,” Chronobiology International 41, no. 2 (2024): 193-200.

[84] X. Ma, X. Chen, Z. Duan, et al., “Circadian Rhythm Disruption Exacerbates the Progression of Macrophage Dysfunction and Alveolar Bone Loss in Periodontitis,” International Immunopharmacology 116 (2023): 109796.

[85] L. Ye, G. Mei, H. Liu, R. Zhong, Q. Tang, and Z. Yuan, “Circadian Rhythm Disruption Aggravates Alveolar Bone Loss in Rat Apical Periodontitis,” International Endodontic Journal (2025).

[86] D. P. Cardinali, A. I. Esquifino, V. Srinivasan, and S. R. Pandi-Perumal, “Melatonin and the Immune System in Aging,” Neuroimmunomodulation 15, no. 4-6 (2008): 272-278.

[87] X. Liao, N. Sharma, F. Kapadia, et al., “Kruppel-Like Factor 4 Regulates Macrophage Polarization,” Journal of Clinical Investigation 121, no. 7 (2011): 2736-2749.

[88] E. Blacher, C. Tsai, L. Litichevskiy, et al., “Aging Disrupts Circadian Gene Regulation and Function in Macrophages,” Nature Immunology (2021).

[89] Z. Zhu, G. Chen, S. Yu, et al., “Circadian Clock Disruption Stimulates Bone Loss via Regulatory T Cell-Mediated Regulation of IL-10 Expression,” International Immunopharmacology 139 (2024): 112589.

[90] M. Budkowska, E. Cecerska-Heryc, Z. Marcinowska, A. Siennicka, and B. Dolegowska, “The Influence of Circadian Rhythm on the Activity of Oxidative Stress Enzymes,” International Journal of Molecular Sciences 23, no. 22 (2022): 14275.

[91] J. Shi, W. Li, X. Ding, et al., “The Role of the SIRT1-BMAL1 Pathway in Regulating Oxidative Stress in the Early Development of Ischaemic Stroke,” Scientific Reports 14, no. 1 (2024): 1773.

[92] Q. Sun, Y. Yang, Z. Wang, et al., “PER1 interaction With GPX1 Regulates Metabolic Homeostasis Under Oxidative Stress,” Redox Biology 37 (2020): 101694.

[93] A. Giri, Q. Wang, I. Rahman, and I. K. Sundar, “Circadian Molecular Clock Disruption in Chronic Pulmonary Diseases,” Trends in Molecular Medicine 28, no. 6 (2022): 513-527.

[94] A. W. C. Man, H. Li, and N. Xia, “Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis,” International Journal of Molecular Sciences 22, no. 2 (2021): 676.

[95] A. Arthur and S. Gronthos, “Clinical Application of Bone Marrow Mesenchymal Stem/Stromal Cells to Repair Skeletal Tissue,” International Journal of Molecular Sciences 21, no. 24 (2020): 9759.

[96] X. Wang, S. P. Reece, R. Van Scott M, and J. M. Brown, “A Circadian Clock in Murine Bone Marrow-derived Mast Cells Modulates IgE-dependent Activation in Vitro,” Brain, Behavior, and Immunity 25, no. 1 (2011): 127-134.

[97] X. Wu, G. Yu, H. Parks, et al., “Circadian Mechanisms in Murine and human Bone Marrow Mesenchymal Stem Cells Following Dexamethasone Exposure,” Bone 42, no. 5 (2008): 861-870.

[98] M. L. Erickson, D. Dobias, M. R. Keleher, et al., “In Vitro Circadian Clock Gene Expression Assessments in Mesenchymal Stem Cells From Human Infants: A Pilot Study,” Nutrients 16, no. 1 (2023): 52.

[99] W. Gao, R. Li, M. Ye, et al., “The Circadian Clock Has Roles in Mesenchymal Stem Cell Fate Decision,” Stem Cell Res Ther 13, no. 1 (2022): 200.

[100] Y. Chen, X. Xu, Z. Tan, C. Ye, Q. Zhao, and Y. Chen, “Age-related BMAL1 Change Affects Mouse Bone Marrow Stromal Cell Proliferation and Osteo-differentiation Potential,” Arch Med Sci 8, no. 1 (2012): 30-38.

[101] S. Miyamoto, L. Cooper, K. Watanabe, et al., “Role of Retinoic Acid-related Orphan Receptor-alpha in Differentiation of human Mesenchymal Stem Cells Along With Osteoblastic Lineage,” Pathobiology 77, no. 1 (2010): 28-37.

[102] W. E. Samsa, A. Vasanji, R. J. Midura, and R. V. Kondratov, “Deficiency of Circadian Clock Protein BMAL1 in Mice Results in a Low Bone Mass Phenotype,” Bone 84 (2016): 194-203.

[103] H. Zhuo, Y. Wang, and Q. Zhao, “The Interaction Between Bmal1 and Per2 in Mouse BMSC Osteogenic Differentiation,” Stem Cells Int 2018 (2018): 3407821.

[104] U. H. Langen, M. E. Pitulescu, J. M. Kim, et al., “Cell-matrix Signals Specify Bone Endothelial Cells During Developmental Osteogenesis,” Nature Cell Biology 19, no. 3 (2017): 189-201.

[105] A. D. Bhatwadekar, E. Beli, Y. Diao, et al., “Conditional Deletion of Bmal1 Accentuates Microvascular and Macrovascular Injury,” American Journal of Pathology 187, no. 6 (2017): 1426-1435.

[106] K. Tsuzuki, Y. Shimizu, J. Suzuki, et al., “Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia,” Journal of the American Heart Association 10, no. 16 (2021): e020896.

[107] L. Xu, Y. Liu, Q. Cheng, et al., “Bmal1 Downregulation Worsens Critical Limb Ischemia by Promoting Inflammation and Impairing Angiogenesis,” Frontiers in Cardiovascular Medicine 8 (2021): 712903.

[108] Y. Xiao, Y. Li, J. Gu, S. Lu, S. Yu, and C. Song, “Circadian Rhythm Gene Cryptochrome 2 (Cry2) Interacts With Lipid Metabolism to Promote Vascular Aging,” Archives of Gerontology and Geriatrics 131 (2025): 105761.

[109] C. Y. Wang, M. S. Wen, H. W. Wang, et al., “Increased Vascular Senescence and Impaired Endothelial Progenitor Cell Function Mediated by Mutation of Circadian Gene Per2,” Circulation 118, no. 21 (2008): 2166-2173.

[110] V. Mastrullo, R. van der Veen D, P. Gupta, et al., “Pericytes' Circadian Clock Affects Endothelial Cells' Synchronization and Angiogenesis in a 3D Tissue Engineered Scaffold,” Frontiers in Pharmacology 13 (2022): 867070.

[111] M. Siragusa, J. Thole, S. I. Bibli, et al., “Nitric Oxide Maintains Endothelial Redox Homeostasis Through PKM2 Inhibition,” Embo Journal 38, no. 17 (2019): e100938.

[112] D. M. Meesters, S. Neubert, K. A. P. Wijnands, et al., “Deficiency of Inducible and Endothelial Nitric Oxide Synthase Results in Diminished Bone Formation and Delayed Union and Nonunion Development,” Bone 83 (2016): 111-118.

[113] K. Zaichko, M. Stanislavchuk, and N. Zaichko, “Circadian Fluctuations of Endothelial Nitric Oxide Synthase Activity in Females With Rheumatoid Arthritis: A Pilot Study,” Rheumatology International 40, no. 4 (2020): 549-554.

[114] I. Dikic and Z. Elazar, “Mechanism and Medical Implications of Mammalian Autophagy,” Nature Reviews Molecular Cell Biology 19, no. 6 (2018): 349-364.

[115] B. Levine and G. Kroemer, “Biological Functions of Autophagy Genes: A Disease Perspective,” Cell 176, no. 1-2 (2019): 11-42.

[116] Y. Ma, M. Qi, Y. An, et al., “Autophagy Controls Mesenchymal Stem Cell Properties and Senescence During Bone Aging,” Aging Cell 17, no. 1 (2018): e12709.

[117] T. W. Zhang, Z. F. Li, J. Dong, and L. B. Jiang, “The Circadian Rhythm in Intervertebral Disc Degeneration: An Autophagy Connection,” Experimental & Molecular Medicine 52, no. 1 (2020): 31-40.

[118] Y. R. Juste, S. Kaushik, M. Bourdenx, et al., “Reciprocal Regulation of Chaperone-mediated Autophagy and the Circadian Clock,” Nature Cell Biology 23, no. 12 (2021): 1255-1270.

[119] S. M. Yoo and Y. K. Jung, “A Molecular Approach to Mitophagy and Mitochondrial Dynamics,” Molecules and Cells 41, no. 1 (2018): 18-26.

[120] K. Sun, X. Jing, J. Guo, X. Yao, and F. Guo, “Mitophagy in Degenerative Joint Diseases,” Autophagy 17, no. 9 (2021): 2082-2092.

[121] Z. Qiu, H. Ming, S. Lei, et al., “Roles of HDAC3-orchestrated Circadian Clock Gene Oscillations in Diabetic Rats Following Myocardial Ischaemia/Reperfusion Injury,” Cell Death & Disease 12, no. 1 (2021): 43.

[122] E. Li, X. Li, J. Huang, et al., “BMAL1 regulates Mitochondrial Fission and Mitophagy Through Mitochondrial Protein BNIP3 and Is Critical in the Development of Dilated Cardiomyopathy,” Protein Cell 11, no. 9 (2020): 661-679.

[123] N. van Gastel and G. Carmeliet, “Metabolic Regulation of Skeletal Cell Fate and Function in Physiology and Disease,” Nat Metab 3, no. 1 (2021): 11-20.

[124] N. Ansari and N. A. Sims, “The Cells of Bone and Their Interactions,” Handb Exp Pharmacol 262 (2020): 1-25.

[125] J. M. Lane, L. Russell, and S. N. Khan, “Osteoporosis,” Clinical Orthopaedics and Related Research no. 372 (2000): 139-150.

[126] H. Wang, T. Yuan, Y. Wang, et al., “Osteoclasts and Osteoarthritis: Novel Intervention Targets and Therapeutic Potentials During Aging,” Aging Cell 23, no. 4 (2024): e14092.

[127] T. J. Aspray and T. R. Hill, “Osteoporosis and the Ageing Skeleton,” Sub-Cellular Biochemistry 91 (2019): 453-476.

[128] A. Anthamatten and A. Parish, “Clinical Update on Osteoporosis,” Journal of Midwifery & Womens Health 64, no. 3 (2019): 265-275.

[129] L. A. Armas and R. R. Recker, “Pathophysiology of Osteoporosis: New Mechanistic Insights,” Endocrinology and Metabolism Clinics of North America 41, no. 3 (2012): 475-486.

[130] E. A. Lucassen, R. de Mutsert, S. le Cessie, et al., “Poor Sleep Quality and Later Sleep Timing Are Risk Factors for Osteopenia and Sarcopenia in Middle-aged Men and Women: The NEO Study,” PLoS ONE 12, no. 5 (2017): e0176685.

[131] M. G. Lima, M. Bergamo Francisco P, B. de Azevedo, and Barros M, “Sleep Duration Pattern and Chronic Diseases in Brazilian Adults (ISACAMP, 2008/09),” Sleep Medicine 13, no. 2 (2012): 139-144.

[132] A. Bukowska-Damska, E. Skowronska-Jozwiak, P. Kaluzny, and A. Lewinski, “Night Shift Work and Osteoporosis—bone Turnover Markers Among Female Blue-collar Workers in Poland,” Chronobiology International (2022): 1-8.

[133] M. Martelli, G. Salvio, R. Lazzarini, et al., “Night Shift Work and Serum Markers of Bone Turnover in Male Shift Workers,” Chronobiology International 40, no. 9 (2023): 1270-1278.

[134] B. K. Kim, Y. J. Choi, and Y. S. Chung, “Other Than Daytime Working Is Associated With Lower Bone Mineral Density: The Korea National Health and Nutrition Examination Survey 2009,” Calcified Tissue International 93, no. 6 (2013): 495-501.

[135] X. Xu, L. Wang, L. Chen, et al., “Effects of Chronic Sleep Deprivation on Bone Mass and Bone Metabolism in Rats,” J Orthop Surg Res 11, no. 1 (2016): 87.

[136] M. Schilperoort, N. Bravenboer, J. Lim, et al., “Circadian Disruption by Shifting the Light-dark Cycle Negatively Affects Bone Health in Mice,” Faseb Journal 34, no. 1 (2020): 1052-1064.

[137] C. M. Swanson, S. A. Shea, P. Wolfe, et al., “Bone Turnover Markers after Sleep Restriction and Circadian Disruption: A Mechanism for Sleep-Related Bone Loss in Humans,” Journal of Clinical Endocrinology and Metabolism 102, no. 10 (2017): 3722-3730.

[138] S. Shi, L. Zhang, Q. Wang, et al., “Targeting Cartilage miR-195/497 Cluster for Osteoarthritis Treatment Regulates the Circadian Clock,” Gerontology, 70 no. 1 (2023): 59-75, https://doi.org/10.1159/000534292.

[139] M. A. Naven, L. A. H. Zeef, S. Li, et al., “Development of human Cartilage Circadian Rhythm in a Stem Cell-chondrogenesis Model,” Theranostics 12, no. 8 (2022): 3963-3976.

[140] N. Gossan, R. Boot-Handford, and Q. J. Meng, “Ageing and Osteoarthritis: A Circadian Rhythm Connection,” Biogerontology 16, no. 2 (2015): 209-219.

[141] X. Song, T. Ma, H. Hu, et al., “Chronic Circadian Rhythm Disturbance Accelerates Knee Cartilage Degeneration in Rats Accompanied by the Activation of the Canonical Wnt/Beta-Catenin Signaling Pathway,” Frontiers in Pharmacology 12 (2021): 760988.

[142] X. Song, M. Zhao, J. Tang, et al., “Dark-light Cycle Disrupts Bone Metabolism and Suppresses Joint Deterioration in Osteoarthritic Rats,” Arthritis Research & Therapy 24, no. 1 (2022): 158.

[143] G. Chen, H. Zhao, S. Ma, et al., “Circadian Rhythm Protein Bmal1 Modulates Cartilage Gene Expression in Temporomandibular Joint Osteoarthritis via the MAPK/ERK Pathway,” Frontiers in Pharmacology 11 (2020): 527744.

[144] H. Bekki, T. Duffy, N. Okubo, et al., “Suppression of Circadian Clock Protein Cryptochrome 2 Promotes Osteoarthritis,” Osteoarthritis and Cartilage 28, no. 7 (2020): 966-976.

[145] J. Wei, Y. Wang, S. Tu, et al., “Circadian Rhythm Disruption Upregulating Per1 in Mandibular Condylar Chondrocytes Mediating Temporomandibular Joint Osteoarthritis via GSK3beta/Beta-CATENIN Pathway,” Journal of Translational Medicine 22, no. 1 (2024): 662.

[146] D. M. Sumsuzzman, J. Choi, Z. A. Khan, G. Kamenos, and Y. Hong, “Melatonin Maintains Anabolic-Catabolic Equilibrium and Regulates Circadian Rhythm during Osteoarthritis Development in Animal Models: A Systematic Review and Meta-analysis,” Frontiers in Pharmacology 12 (2021): 714974.

[147] J. H. Badhiwala, C. S. Ahuja, M. A. Akbar, et al., “Degenerative Cervical Myelopathy—update and Future Directions,” Nature Reviews Neurology 16, no. 2 (2020): 108-124.

[148] J. Jiong Guo, J. Du, Y. Xu, A. Liu, and H. L. Yang, “Catching the Circadian Rhythm of Intervertebral Disc and Association With Clinical Outcomes by twice-a-day Magnetic Resonance Imaging,” European Journal of Radiology 147 (2022): 110130.

[149] S. L. Ding, T. W. Zhang, Q. C. Zhang, et al., “Excessive Mechanical Strain Accelerates Intervertebral Disc Degeneration by Disrupting Intrinsic Circadian Rhythm,” Experimental & Molecular Medicine 53, no. 12 (2021): 1911-1923.

[150] H. Morris, C. F. Goncalves, M. Dudek, J. Hoyland, and Q. J. Meng, “Tissue Physiology Revolving Around the Clock: Circadian Rhythms as Exemplified by the Intervertebral Disc,” Annals of the Rheumatic Diseases 80, no. 7 (2021): 828-839.

[151] M. Dudek, N. Yang, J. P. Ruckshanthi, et al., “The Intervertebral Disc Contains Intrinsic Circadian Clocks That Are Regulated by Age and Cytokines and Linked to Degeneration,” Annals of the Rheumatic Diseases 76, no. 3 (2017): 576-584.

[152] P. Peng, D. Wang, X. Xu, et al., “Targeting Clock-controlled Gene Nrf2 Ameliorates Inflammation-induced Intervertebral Disc Degeneration,” Arthritis Research & Therapy 24, no. 1 (2022): 181.

[153] D. Wang, P. Peng, M. Dudek, et al., “Restoring the Dampened Expression of the Core Clock Molecule BMAL1 Protects Against Compression-induced Intervertebral Disc Degeneration,” Bone Res 10, no. 1 (2022): 20.

[154] Q. Zheng and X. Wang, “Alzheimer's Disease: Insights Into Pathology, Molecular Mechanisms, and Therapy,” Protein Cell 16, no. 2 (2025): 83-120.

[155] Z. Ungvari, M. Fekete, A. Lehoczki, et al., “Sleep Disorders Increase the Risk of Dementia, Alzheimer's Disease, and Cognitive Decline: A Meta-analysis,” Geroscience 47, no. 3 (2025): 4899-4920.

[156] J. Chen, G. Peng, and B. Sun, “Alzheimer's Disease and Sleep Disorders: A Bidirectional Relationship,” Neuroscience 557 (2024): 12-23.

[157] H. Wu, S. Dunnett, Y. S. Ho, and R. C. Chang, “The Role of Sleep Deprivation and Circadian Rhythm Disruption as Risk Factors of Alzheimer's Disease,” Frontiers in Neuroendocrinology 54 (2019): 100764.

[158] L. C. Duret and E. Nagoshi, “The Intertwined Relationship Between Circadian Dysfunction and Parkinson's Disease,” Trends in Neuroscience (Tins) 48, no. 1 (2025): 62-76.

[159] S. Li, Y. Wang, F. Wang, L. F. Hu, and C. F. Liu, “A New Perspective for Parkinson's Disease: Circadian Rhythm,” Neurosci Bull 33, no. 1 (2017): 62-72.

[160] L. Wang, Y. Bao, X. Duan, et al., “A Diagnostic Model for Parkinson's Disease Based on Circadian Rhythm-related Genes,” Journal of Translational Medicine 22, no. 1 (2024): 635.

[161] J. R. P. Zuzuarregui and E. H. During, “Sleep Issues in Parkinson's Disease and Their Management,” Neurotherapeutics 17, no. 4 (2020): 1480-1494.

[162] J.-Y. Liu, J. Xue, F. Wang, Y.-L. Wang, and W.-L. Dong, “α-Synuclein-Induced Destabilized BMAL1 mRNA Leads to Circadian Rhythm Disruption in Parkinson's Disease,” Neurotoxicity Research, 41 no. 2, (2023): 177-186, https://doi.org/10.1007/s12640-022-00633-0.

[163] J. Zhang, X. Ma, Z. Li, et al., “Identification of Key Genes and Diagnostic Model Associated With Circadian Rhythms and Parkinson's Disease by Bioinformatics Analysis,” Frontiers in Aging Neuroscience 16 (2024): 1458476.

[164] E. B. Diago, S. Martinez-Horta, S. S. Lasaosa, et al., “Circadian Rhythm, Cognition, and Mood Disorders in Huntington's Disease,” J Huntingtons Dis 7, no. 2 (2018): 193-198.

[165] S. Saade-Lemus and A. Videnovic, “Sleep Disorders and Circadian Disruption in Huntington's Disease,” J Huntingtons Dis 12, no. 2 (2023): 121-131.

[166] I. Khyati Malik, N. Agrawal, and V. Kumar, “Melatonin and Curcumin Reestablish Disturbed Circadian Gene Expressions and Restore Locomotion Ability and Eclosion Behavior in Drosophila Model of Huntington's Disease,” Chronobiology International 38, no. 1 (2021): 61-78.

[167] E. Bellosta Diago, J. Perez Perez, S. Santos Lasaosa, et al., “Circadian Rhythm and Autonomic Dysfunction in Presymptomatic and Early Huntington's Disease,” Parkinsonism & Related Disorders 44 (2017): 95-100.

[168] S. L. Chellappa, N. Vujovic, J. S. Williams, and F. Scheer, “Impact of Circadian Disruption on Cardiovascular Function and Disease,” Trends in Endocrinology and Metabolism 30, no. 10 (2019): 767-779.

[169] J. Lin, H. Kuang, J. Jiang, et al., “Circadian Rhythms in Cardiovascular Function: Implications for Cardiac Diseases and Therapeutic Opportunities,” Medical Science Monitor 29 (2023): e942215.

[170] Z. Zhang, B. Yu, X. Wang, et al., “Circadian Rhythm and Atherosclerosis (Review),” Exp Ther Med 20, no. 5 (2020): 96.

[171] M. Schilperoort, R. van den Berg, L. A. Bosmans, et al., “Disruption of Circadian Rhythm by Alternating Light-dark Cycles Aggravates Atherosclerosis Development in APOE*3-Leiden.CETP Mice,” Journal of Pineal Research 68, no. 1 (2020): e12614.

[172] M. Xie, Q. Tang, J. Nie, et al., “BMAL1-Downregulation Aggravates Porphyromonas Gingivalis-Induced Atherosclerosis by Encouraging Oxidative Stress,” Circulation Research 126, no. 6 (2020): e15-e29.

[173] J. Yao, J. Liang, and H. Li, “Screening for Key Genes in Circadian Regulation in Advanced Atherosclerosis: A Bioinformatic Analysis,” Frontiers in Cardiovascular Medicine 9 (2022): 990757.

[174] M. Kanki, A. P. Nath, R. Xiang, et al., “Poor Sleep and Shift Work Associate With Increased Blood Pressure and Inflammation in UK Biobank Participants,” Nature Communications 14, no. 1 (2023): 7096.

[175] H. M. Costello and M. L. Gumz, “Circadian Rhythm, Clock Genes, and Hypertension: Recent Advances in Hypertension,” Hypertension 78, no. 5 (2021): 1185-1196.

[176] B. P. Delisle, J. L. Stumpf, J. L. Wayland, et al., “Circadian Clocks Regulate Cardiac Arrhythmia Susceptibility, Repolarization, and Ion Channels,” Current Opinion in Pharmacology 57 (2021): 13-20.

[177] D. Jeyaraj, S. M. Haldar, X. Wan, et al., “Circadian Rhythms Govern Cardiac Repolarization and Arrhythmogenesis,” Nature 483, no. 7387 (2012): 96-99.

[178] E. A. Schroder, D. E. Burgess, X. Zhang, et al., “The Cardiomyocyte Molecular Clock Regulates the Circadian Expression of Kcnh2 and Contributes to Ventricular Repolarization,” Heart Rhythm 12, no. 6 (2015): 1306-1314.

[179] N. Scichilone, R. Antonelli Incalzi, F. Blasi, et al., “Circadian Rhythm of COPD Symptoms in Clinically Based Phenotypes. Results From the STORICO Italian Observational Study,” BMC Pulmonary Medicine 19, no. 1 (2019): 171.

[180] I. K. Sundar, H. Yao, M. T. Sellix, and I. Rahman, “Circadian Molecular Clock in Lung Pathophysiology,” American Journal of Physiology Lung Cellular and Molecular Physiology 309, no. 10 (2015): L1056-1075.

[181] H. Yao, I. K. Sundar, Y. Huang, et al., “Disruption of Sirtuin 1-Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease,” American Journal of Respiratory Cell and Molecular Biology 53, no. 6 (2015): 782-792.

[182] J. W. Hwang, I. K. Sundar, H. Yao, M. T. Sellix, and I. Rahman, “Circadian Clock Function Is Disrupted by Environmental Tobacco/Cigarette Smoke, Leading to Lung Inflammation and Injury via a SIRT1-BMAL1 Pathway,” FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology 28, no. 1 (2014): 176-194.

[183] P. S. Cunningham, P. Meijer, A. Nazgiewicz, et al., “The Circadian Clock Protein REVERBα Inhibits Pulmonary Fibrosis Development,” Proceedings of the National Academy of Sciences of the United States of America 117, no. 2 (2020): 1139-1147.

[184] C. Dong, R. Gongora, M. L. Sosulski, F. Luo, and C. G. Sanchez, “Regulation of Transforming Growth Factor-beta1 (TGF-β1)-induced Pro-fibrotic Activities by Circadian Clock Gene BMAL1,” Respiratory Research 17 (2016): 4.

[185] F. A. J. L. Scheer, M. F. Hilton, H. L. Evoniuk, et al., “The Endogenous Circadian System Worsens Asthma at Night Independent of Sleep and Other Daily Behavioral or Environmental Cycles,” Proceedings of the National Academy of Sciences 118, no. 37 (2021).

[186] A. M. Landstra, D. S. Postma, H. M. Boezen, and W. M. van Aalderen, “Role of Serum Cortisol Levels in Children With Asthma,” American Journal of Respiratory and Critical Care Medicine 165, no. 5 (2002): 708-712.

[187] H. Jacob, A. M. Curtis, and C. J. Kearney, “Therapeutics on the Clock: Circadian Medicine in the Treatment of Chronic Inflammatory Diseases,” Biochemical Pharmacology 182 (2020): 114254.

[188] M. Noonan, J. P. Karpel, G. W. Bensch, et al., “Comparison of Once-daily to Twice-daily Treatment With mometasone furoate Dry Powder Inhaler,” Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology 86, no. 1 (2001): 36-43.

[189] D. S. Postma, C. Sevette, Y. Martinat, N. Schlösser, J. Aumann, and H. Kafé, “Treatment of Asthma by the Inhaled Corticosteroid Ciclesonide Given either in the Morning or Evening,” The European Respiratory Journal 17, no. 6 (2001): 1083-1088.

[190] A. Ehlers, W. Xie, E. Agapov, et al., “BMAL1 links the Circadian Clock to Viral Airway Pathology and Asthma Phenotypes,” Mucosal Immunology 11, no. 1 (2018): 97-111.

[191] D. Y. Lee, I. Jung, S. Y. Park, et al., “Attention to Innate Circadian Rhythm and the Impact of Its Disruption on Diabetes,” Diabetes Metab J 48, no. 1 (2024): 37-52.

[192] H. T. Tran, T. Kondo, A. Ashry, et al., “Effect of Circadian Clock Disruption on Type 2 Diabetes,” Front Physiol 15 (2024): 1435848.

[193] C. J. Morris, J. N. Yang, J. I. Garcia, et al., “Endogenous Circadian System and Circadian Misalignment Impact Glucose Tolerance via Separate Mechanisms in Humans,” PNAS 112, no. 17 (2015): E2225-2234.

[194] A. Sharma, M. C. Laurenti, C. Dalla Man, et al., “Glucose Metabolism During Rotational Shift-work in Healthcare Workers,” Diabetologia 60, no. 8 (2017): 1483-1490.

[195] O. M. Buxton, S. W. Cain, S. P. O'Connor, et al., “Adverse Metabolic Consequences in Humans of Prolonged Sleep Restriction Combined With Circadian Disruption,” Science Translational Medicine 4, no. 129 (2012): 129ra143.

[196] J. P. Chaput, A. W. McHill, R. C. Cox, et al., “The Role of Insufficient Sleep and Circadian Misalignment in Obesity,” Nature Reviews Endocrinology 19, no. 2 (2023): 82-97.

[197] J. Qian, C. J. Morris, R. Caputo, and F. Scheer, “Circadian Misalignment Increases 24-hour Acylated Ghrelin in Chronic Shift Workers: A Randomized Crossover Trial,” Obesity (Silver Spring) 31, no. 9 (2023): 2235-2239.

[198] A. Aggarwal, M. J. Costa, B. Rivero-Gutierrez, L. Ji, S. L. Morgan, and B. J. Feldman, “The Circadian Clock Regulates Adipogenesis by a Per3 Crosstalk Pathway to Klf15,” Cell Reports 21, no. 9 (2017): 2367-2375.

[199] A. Chaix, T. Lin, H. D. Le, M. W. Chang, and S. Panda, “Time-Restricted Feeding Prevents Obesity and Metabolic Syndrome in Mice Lacking a Circadian Clock,” Cell Metabolism 29, no. 2 (2019): 303-319. e304.

[200] F. Bishehsari, F. Levi, F. W. Turek, and A. Keshavarzian, “Circadian Rhythms in Gastrointestinal Health and Diseases,” Gastroenterology 151, no. 3 (2016): e1-5.

[201] M. Astone, R. E. Oberkersch, G. Tosi, A. Biscontin, and M. M. Santoro, “The Circadian Protein BMAL1 Supports Endothelial Cell Cycle During Angiogenesis,” Cardiovascular Research 119, no. 10 (2023): 1952-1968.

[202] S. K. Chun, B. M. Fortin, R. C. Fellows, et al., “Disruption of the Circadian Clock Drives Apc Loss of Heterozygosity to Accelerate Colorectal Cancer,” Science Advances 8, no. 32 (2022): eabo2389.

[203] L. Pang, M. Dunterman, W. Xuan, et al., “Circadian Regulator CLOCK Promotes Tumor Angiogenesis in Glioblastoma,” Cell Reports 42, no. 2 (2023): 112127.

[204] L. Guo, H. Cen, J. Weng, et al., “PER2 integrates Circadian Disruption and Pituitary Tumorigenesis,” Theranostics 13, no. 8 (2023): 2657-2672.

[205] M. Das, C. Haldar, and S. K. Yadav, “Shift and Longtime Light Induces Endometrioid Adenocarcinoma via Activation of PKC-α/Akt Pathway in Female Golden Hamster: Involvement of Altered Aanat and Bmal1 Rhythm,” Journal of Pineal Research 75, no. 2 (2023): e12894.

[206] Z. Zhang, M. Zhao, Q. Wang, et al., “Forkhead Box Protein FOXK1 Disrupts the Circadian Rhythm to Promote Breast Tumorigenesis in Response to Insulin Resistance,” Cancer Letters 599 (2024): 217147.

[207] T. Yang, W. Huang, T. Ma, et al., “The PRMT6/PARP1/CRL4B Complex Regulates the Circadian Clock and Promotes Breast Tumorigenesis,” Advanced Science (Weinheim, Baden-Wurttemberg, Germany) 10, no. 14 (2023): e2202737.

[208] D. Liu, B. Wei, L. Liang, et al., “The Circadian Clock Component RORA Increases Immunosurveillance in Melanoma by Inhibiting PD-L1 Expression,” Cancer Research 84, no. 14 (2024): 2265-2281.

[209] E. Murgo, E. De Santis, F. Sansico, et al., “The Circadian Clock Circuitry Modulates Leukemia Initiating Cell Activity in T-cell Acute Lymphoblastic Leukemia,” Journal of Experimental & Clinical Cancer Research: CR 42, no. 1 (2023): 218.

[210] B. Li, Q. Chen, Y. Feng, et al., “Glucose Restriction Induces AMPK-SIRT1-mediated Circadian Clock Gene per Expression and Delays NSCLC Progression,” Cancer Letters 576 (2023): 216424.

[211] Y. Han, F. Meng, J. Venter, et al., “miR-34a-dependent Overexpression of Per1 Decreases Cholangiocarcinoma Growth,” Journal of Hepatology 64, no. 6 (2016): 1295-1304.

[212] Q. Xiao, R. R. Jones, P. James, and R. Z. Stolzenberg-Solomon, “Light at Night and Risk of Pancreatic Cancer in the NIH-AARP Diet and Health Study,” Cancer Research 81, no. 6 (2021): 1616-1622.

[213] P. F. Innominato, C. Focan, T. Gorlia, et al., “Circadian Rhythm in Rest and Activity: A Biological Correlate of Quality of Life and a Predictor of Survival in Patients With Metastatic Colorectal Cancer,” Cancer Research 69, no. 11 (2009): 4700-4707.

[214] M. Y. Chong, K. G. Frenken, S. Eussen, et al., “Longitudinal Associations of Diurnal Rest-activity Rhythms With Fatigue, Insomnia, and Health-related Quality of Life in Survivors of Colorectal Cancer up to 5 Years Post-treatment,” The International Journal of Behavioral Nutrition and Physical Activity 21, no. 1 (2024): 51.

[215] N. Zisapel, “New Perspectives on the Role of Melatonin in human Sleep, Circadian Rhythms and Their Regulation,” British Journal of Pharmacology 175, no. 16 (2018): 3190-3199.

[216] R. L. Riha, “The Use and Misuse of Exogenous Melatonin in the Treatment of Sleep Disorders,” Current Opinion in Pulmonary Medicine 24, no. 6 (2018): 543-548.

[217] J. H. Choi, A. R. Jang, M. J. Park, D. I. Kim, and J. H. Park, “Melatonin Inhibits Osteoclastogenesis and Bone Loss in Ovariectomized Mice by Regulating PRMT1-Mediated Signaling,” Endocrinology 162, no. 6 (2021): bqab057.

[218] L. Xu, L. Zhang, Z. Wang, et al., “Melatonin Suppresses Estrogen Deficiency-Induced Osteoporosis and Promotes Osteoblastogenesis by Inactivating the NLRP3 Inflammasome,” Calcified Tissue International 103, no. 4 (2018): 400-410.

[219] D. P. Cardinali, “Melatonin as a Chronobiotic/Cytoprotective Agent in Bone. Doses Involved,” Journal of Pineal Research 76, no. 1 (2024): e12931.

[220] A. Bagherifard, A. Hosseinzadeh, F. Koosha, et al., “Melatonin and Bone-related Diseases: An Updated Mechanistic Overview of Current Evidence and Future Prospects,” Osteoporosis International 34, no. 10 (2023): 1677-1701.

[221] S. Yu, Q. Tang, G. Chen, et al., “Circadian Rhythm Modulates Endochondral Bone Formation via MTR1/AMPKbeta1/BMAL1 Signaling Axis,” Cell Death and Differentiation 29, no. 4 (2022): 874-887.

[222] L. A. Solt, Y. Wang, S. Banerjee, et al., “Regulation of Circadian Behaviour and Metabolism by Synthetic REV-ERB Agonists,” Nature 485, no. 7396 (2012): 62-68.

[223] C. Song, P. Tan, Z. Zhang, et al., “REV-ERB Agonism Suppresses Osteoclastogenesis and Prevents Ovariectomy-induced Bone Loss Partially via FABP4 Upregulation,” Faseb Journal 32, no. 6 (2018): 3215-3228.

[224] M. Luchavova, V. Zikan, D. Michalska, I. Raska,, A. A. Kubena, and J. J. Stepan, “The Effect of Timing of Teriparatide Treatment on the Circadian Rhythm of Bone Turnover in Postmenopausal Osteoporosis,” European Journal of Endocrinology 164, no. 4 (2011): 643-648.

[225] L. Pineiro-Alonso, I. Rubio-Prego, A. Lobyntseva, E. González-Freire, R. Langer, and M. J. Alonso, “Nanomedicine for Targeting Brain Neurodegeneration: Critical Barriers and Circadian Rhythm Considerations,” Advanced Drug Delivery Reviews 222 (2025): 115606.

[226] M. Le Meur, J. Pignatelli, P. Blasi, and V. Palomo, “Nanoparticles Targeting the central Circadian Clock: Potential Applications for Neurological Disorders,” Advanced Drug Delivery Reviews 220 (2025): 115561.

[227] J. Lin, Q. Zhang, Y. Xin, et al., “Spatiotemporal Circadian Oscillator Manipulation for Enhanced Ovarian Cancer Therapy Using a Versatile Nanoplatform,” ACS Applied Materials & Interfaces 17, no. 24 (2025): 35023-35039.

[228] G. Sulli, E. N. C. Manoogian, P. R. Taub, and S. Panda, “Training the Circadian Clock, Clocking the Drugs, and Drugging the Clock to Prevent, Manage, and Treat Chronic Diseases,” Trends in Pharmacological Sciences 39, no. 9 (2018): 812-827.

[229] C. M. Swanson, “Sleep Disruptions and Bone Health: What Do We Know so Far?,” Curr Opin Endocrinol Diabetes Obes 28, no. 4 (2021): 348-353.

[230] C. M. Swanson, S. A. Shea, K. L. Stone, et al., “Obstructive Sleep Apnea and Metabolic Bone Disease: Insights Into the Relationship Between Bone and Sleep,” Journal of Bone and Mineral Research 30, no. 2 (2015): 199-211.

[231] R. Terzi and Z. Yilmaz, “Bone Mineral Density and Changes in Bone Metabolism in Patients With Obstructive Sleep Apnea Syndrome,” Journal of Bone and Mineral Metabolism 34, no. 4 (2016): 475-481.

[232] T. Huang, S. S. Tworoger, S. Redline, G. C. Curhan, and J. M. Paik, “Obstructive Sleep Apnea and Risk for Incident Vertebral and Hip Fracture in Women,” Journal of Bone and Mineral Research 35, no. 11 (2020): 2143-2150.

[233] A. Bukowska-Damska, E. Skowronska-Jozwiak, P. Kaluzny, and A. Lewinski, “Night Shift Work and Osteoporosis—bone Turnover Markers Among Female Blue-collar Workers in Poland,” Chronobiology International 39, no. 6 (2022): 818-825.

[234] D. Feskanich, S. E. Hankinson, and E. S. Schernhammer, “Nightshift Work and Fracture Risk: The Nurses' Health Study,” Osteoporosis International 20, no. 4 (2009): 537-542.

[235] F. Damiola, N. Le Minh, N. Preitner, B. Kornmann, F. Fleury-Olela, and U. Schibler, “Restricted Feeding Uncouples Circadian Oscillators in Peripheral Tissues From the central Pacemaker in the Suprachiasmatic Nucleus,” Genes & Development 14, no. 23 (2000): 2950-2961.

[236] K. Ella, A. R. Sudy, Z. Bur, et al., “Time Restricted Feeding Modifies Leukocyte Responsiveness and Improves Inflammation Outcome,” Frontiers in Immunology 13 (2022): 924541.

[237] N. Makarem, F. M. Zuraikat, B. Caceres, et al., “Variable Eating Patterns: A Potential Novel Risk Factor for Systemic Inflammation in Women,” Annals of Behavioral Medicine 57, no. 1 (2023): 93-97.

[238] M. Adawi, G. Damiani, N. L. Bragazzi, et al., “The Impact of Intermittent Fasting (Ramadan Fasting) on Psoriatic Arthritis Disease Activity, Enthesitis, and Dactylitis: A Multicentre Study,” Nutrients 11, no. 3 (2019): 601.

[239] G. Damiani, A. Watad, C. Bridgewood, et al., “The Impact of Ramadan Fasting on the Reduction of PASI Score, in Moderate-To-Severe Psoriatic Patients: A Real-Life Multicenter Study,” Nutrients 11, no. 2 (2019): 277.

[240] G. Damiani, N. Mahroum, P. D. M. Pigatto, et al., “The Safety and Impact of a Model of Intermittent, Time-Restricted Circadian Fasting (“Ramadan Fasting”) on Hidradenitis Suppurativa: Insights From a Multicenter, Observational, Cross-Over, Pilot, Exploratory Study,” Nutrients 11, no. 8 (2019): 1781.

[241] F. Motta, E. Barone, A. Sica, and C. Selmi, “Inflammaging and Osteoarthritis,” Clinical Reviews in Allergy & Immunology 64, no. 2 (2023): 222-238.

[242] J. Zhang, Y. Chen, Y. Zhong, et al., “Intermittent Fasting and Cardiovascular Health: A Circadian Rhythm-based Approach,” Science Bulletin 70, no. 14 (2025): 2377-2389.

[243] C. R. Martens, M. J. Rossman, M. R. Mazzo, et al., “Short-term Time-restricted Feeding Is Safe and Feasible in Non-obese Healthy Midlife and Older Adults,” Geroscience 42, no. 2 (2020): 667-686.

[244] T. Wei, Y. Cheng, J. Ge, M. Zhu, H. Chen, and Q. Feng, “The Pro-Apoptotic Effect of Glucose Restriction in NSCLC via AMPK-Regulated Circadian Clock Gene Bmal1,” Cancer Science 116, no. 8 (2025): 2101-2112.

[245] D. Marzoll, F. E. Serrano, A. Shostak, C. Schunke, A. C. R. Diernfellner, and M. Brunner, “Casein Kinase 1 and Disordered Clock Proteins Form Functionally Equivalent, Phospho-Based Circadian Modules in Fungi and Mammals,” Proceedings of the National Academy of Sciences 119 no. 9 (2022), https://doi.org/10.1073/pnas.2118286119.

[246] H. Yoshitane, Y. Asano, A. Sagami, et al., “Functional D-box Sequences Reset the Circadian Clock and Drive mRNA Rhythms,” Communications Biology 2 (2019): 300.

[247] T. Hirai, K. Tanaka, and A. Togari, “alpha1-adrenergic Receptor Signaling in Osteoblasts Regulates Clock Genes and Bone Morphogenetic Protein 4 Expression Through Up-regulation of the Transcriptional Factor Nuclear Factor IL-3 (Nfil3)/E4 Promoter-binding Protein 4 (E4BP4),” Journal of Biological Chemistry 289, no. 24 (2014): 17174-17183.

[248] L. Jinteng, X. Peitao, Y. Wenhui, et al., “BMAL1-TTK-H2Bub1 Loop Deficiency Contributes to Impaired BM-MSC-mediated Bone Formation in Senile Osteoporosis,” Mol Ther Nucleic Acids 31 (2023): 568-585.

[249] Q. Y. Wu, J. Wang, X. Tong, et al., “Emerging Role of Circadian Rhythm in Bone Remodeling,” J Mol Med (Berl) 97, no. 1 (2019): 19-24.

[250] T. Takarada, C. Xu, H. Ochi, et al., “Bone Resorption Is Regulated by Circadian Clock in Osteoblasts,” Journal of Bone and Mineral Research 32, no. 4 (2017): 872-881.

[251] V. Calabrese, C. Mancuso, M. Calvani, E. Rizzarelli, D. A. Butterfield, and A. M. Stella, “Nitric Oxide in the central Nervous System: Neuroprotection versus Neurotoxicity,” Nature Reviews Neuroscience 8, no. 10 (2007): 766-775.

[252] R. Siracusa, M. Scuto, R. Fusco, et al., “Anti-inflammatory and Anti-oxidant Activity of Hidrox((R)) in Rotenone-Induced Parkinson's Disease in Mice,” Antioxidants (Basel) 9, no. 9 (2020): 824.

[253] L. Li, B. Chen, R. Zhu, et al., “Fructus Ligustri Lucidi Preserves Bone Quality Through the Regulation of Gut Microbiota Diversity, Oxidative Stress, TMAO and Sirt6 Levels in Aging Mice,” Aging (Albany NY) 11, no. 21 (2019): 9348-9368.

[254] M. Wilking, M. Ndiaye, H. Mukhtar, and N. Ahmad, “Circadian Rhythm Connections to Oxidative Stress: Implications for human Health,” Antioxid Redox Signaling 19, no. 2 (2013): 192-208.

[255] V. Calabrese, C. Cornelius, A. T. Dinkova-Kostova, and E. J. Calabrese, “Vitagenes, Cellular Stress Response, and Acetylcarnitine: Relevance to Hormesis,” Biofactors 35, no. 2 (2009): 146-160.

[256] V. Calabrese, C. Cornelius, A. T. Dinkova-Kostova, E. J. Calabrese, and M. P. Mattson, “Cellular Stress Responses, the Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders,” Antioxid Redox Signaling 13, no. 11 (2010): 1763-1811.

[257] D. Arens, I. Sigrist, M. Alini, P. Schawalder, E. Schneider, and M. Egermann, “Seasonal Changes in Bone Metabolism in Sheep,” Veterinary Journal 174, no. 3 (2007): 585-591.

[258] G. Lombardi, A. Colombini, M. Freschi, R. Tavana, and G. Banfi, “Seasonal Variation of Bone Turnover Markers in Top-level Female Skiers,” European Journal of Applied Physiology 111, no. 3 (2011): 433-440.

[259] T. Sato, K. Sakuraba, Y. Tsuchiya, S. Maruyama, and E. Ochi, “Seasonal Variations of Bone Metabolism and Bone Mineral Density in Collegiate Alpine Skiers,” Journal of Strength and Conditioning Research 32, no. 5 (2018): 1448-1454.

[260] N. Ohnishi, Y. Tahara, D. Kuriki, A. Haraguchi, and S. Shibata, “Warm Water Bath Stimulates Phase-shifts of the Peripheral Circadian Clocks in PER2::LUCIFERASE Mouse,” PLoS ONE 9, no. 6 (2014): e100272.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.