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Exploring the Impact of the Biological Clock on Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (20 April 2026) | Viewed by 3568

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Guest Editor
1. School of Sport and Health Sciences, University of Central Lancashire, Preston PR1 2HE, UK
2. School of Health, Social Work and Sport, University of Central Lancashire, Preston, UK
Interests: metabolic syndrome; insulin resistance; obesity; tyep-2 diabetes; metabolic inflammation; chrononutrition; molecular nutrition
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Special Issue Information

Dear Colleagues,

The biological clock coordinates biochemical, physiological, and behavioural processes in every living organism. As Albert Einstein said, “The only reason for time is so that everything does not happen at once”. Internal timekeeping mechanisms both ensure the temporal separation of molecular events and respond accurately to environmental cues (zeitgebers).

The mammalian circadian clock has three distinct hierarchical levels: the central clock in the suprachiasmatic centre, the peripheral clocks of organs/tissues, and the clock gene system at the cellular level. While the role of photic zeitgebers in setting the biological rhythm has been widely investigated, non-photic zeitgebers, particularly dietary ingredients (nutrients and non-nutrients), have only begun to be researched.

Achieving a synchronized response is a crucial outcome of the circadian regulatory process. In a population of synchronized cells, the cellular response to different stimuli is more efficient than in asynchronized cells. The primary features of numerous non-communicable diseases involve the metabolic disarray resulting from cellular oxidative stresses, inflammatory responses, and metabolite handling. Consequently, understanding the role of circadian regulatory mechanisms in intracellular signalling is crucial for grasping how organisms interact with environmental cues in both health and disease.

This Special Issue of the International Journal of Molecular Sciences will showcase original research on the regulation of the mammalian circadian clock at various levels and its interaction with different zeitgebers, including endogenous and exogenous metabolites, with the potential application of chronobiology in medicine and human nutrition.

Topics of interest in this Special Issue include, but are not limited to, the following:

  1. The interaction of the master clock, peripheral clock, and clock genes with the endogenous and exogenous metabolites;
  2. The regulation of the circadian clock system, cellular synchrony, and molecular entrainment;
  3. The regulation of cell synchrony in different biological models by various stimuli including hormonal stimuli (melatonin, cortisol), nutritional stimuli, xenobiotics, drugs, toxins, etc.;
  4. The molecular pathways of clock genes in energy homeostasis, satiety and hunger–energy mechanisms, insulin resistance and diabetes, neurodegenerative diseases, ageing, and cancers;
  5. Biomarkers for the assessment of the state of the circadian rhythm at the three hierarchical levels.

In addition, review articles on the exploration of pharmacological and nutritional approaches targeting the circadian clock for the prevention and treatment of non-communicable diseases are also welcomed.

Dr. Bojlul Bahar
Guest Editor

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Keywords

  • circadian rhythm
  • inflammation
  • oxidative stress
  • energy balance
  • metabolic syndrome
  • ageing
  • cancer
  • diabetes
  • obesity
  • entrainment
  • synchrony
  • melatonin

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Published Papers (3 papers)

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Research

18 pages, 6621 KB  
Article
Deletion of Bmal1, a Component of the Molecular Clock, Exacerbates Kidney Damage After Ischemia–Reperfusion by Decreasing Pparα Expression
by Satoshi Kitaura, Taira Wada, Yoshimasa Asano and Shigeki Shimba
Int. J. Mol. Sci. 2026, 27(9), 4091; https://doi.org/10.3390/ijms27094091 - 2 May 2026
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Abstract
Brain and muscle Arnt-like protein 1 (BMAL1) is a transcription factor that forms heterodimers with circadian locomotor output cycles kaput (CLOCK) and drives transcription from E-box elements, thereby regulating the circadian rhythms of gene expression. The kidney expresses numerous rhythmic genes and exhibits [...] Read more.
Brain and muscle Arnt-like protein 1 (BMAL1) is a transcription factor that forms heterodimers with circadian locomotor output cycles kaput (CLOCK) and drives transcription from E-box elements, thereby regulating the circadian rhythms of gene expression. The kidney expresses numerous rhythmic genes and exhibits circadian physiological function regulation. Circadian rhythm abnormalities, such as sleep disorders and excessive daytime sleepiness, are particularly frequent in patients with chronic kidney disease (CKD). Furthermore, reduced amplitude and phase disruption in clock gene expression rhythms have been reported in mouse CKD models. These results suggest that circadian disruption is associated with renal pathophysiology. However, the role of BMAL1 in the repair process following acute kidney injury (AKI) remains unclear; therefore, this study aimed to elucidate its role in kidney repair following ischemia–reperfusion injury (IRI). We found that the tamoxifen (TAM)-inducible global Bmal1 knockout (BKO) mouse kidneys exhibited increased lipid accumulation, enhanced fibrosis, and delayed kidney repair post-IRI, and that these abnormalities were associated with reduced Peroxisome proliferator-activated receptor alpha (Pparα) expression. Furthermore, treatment with a PPARα agonist reduced these abnormalities in BKO mice. Collectively, our findings demonstrate that the BMAL1–PPARα axis promotes post-AKI kidney repair. Full article
(This article belongs to the Special Issue Exploring the Impact of the Biological Clock on Health and Disease)
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17 pages, 3792 KB  
Article
Circadian Controlled Transcription in Brain and Peripheral Organs of Juvenile and Adult Mice
by Yasemin Kubra Akyel, Kaan Arslan, Cansu Kose and Aziz Sancar
Int. J. Mol. Sci. 2026, 27(8), 3408; https://doi.org/10.3390/ijms27083408 - 10 Apr 2026
Viewed by 843
Abstract
Circadian clocks generate daily rhythms of gene expression that influence physiology, disease, and responses to therapeutics, yet how circadian transcription differs between juvenile and adult organisms remains unresolved. Here, we used genome-wide eXcision Repair sequencing (XR-seq) to quantify transcription-coupled repair as an indirect, [...] Read more.
Circadian clocks generate daily rhythms of gene expression that influence physiology, disease, and responses to therapeutics, yet how circadian transcription differs between juvenile and adult organisms remains unresolved. Here, we used genome-wide eXcision Repair sequencing (XR-seq) to quantify transcription-coupled repair as an indirect, high-sensitivity measure of transcription. We profiled the brain, liver, kidney, and testis from juvenile and adult C57BL6/J mice across a 24 h cycle and show that XR-seq enables sensitive circadian transcription mapping. In all organs except the testis, rhythmic transcription phases clustered near dawn and dusk. While core clock gene rhythms are largely preserved between juveniles and adults, rhythms of many clock-controlled genes differ markedly by age. Rhythmic genes are strongly organ-specific yet their overlap between ages is limited, indicating substantial developmental changes in circadian control. Together, these data provide a multi-organ map of juvenile versus adult circadian transcription and indicate that adult therapeutic schedules may not translate to juveniles. Full article
(This article belongs to the Special Issue Exploring the Impact of the Biological Clock on Health and Disease)
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27 pages, 4842 KB  
Article
Diurnal Regulation and Gene-Specific Vulnerability of Oxidative Alcohol-Metabolizing Enzymes to Circadian Disruption
by Yool Lee, Ali Keshavarzian and Byoung-Joon Song
Int. J. Mol. Sci. 2026, 27(4), 2041; https://doi.org/10.3390/ijms27042041 - 22 Feb 2026
Viewed by 1165
Abstract
Oxidative alcohol metabolism in the liver relies on sequential enzymatic reactions involving alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and aldehyde dehydrogenase (ALDH) isozymes. However, the circadian regulation of these enzymes, their susceptibility to genetic, environmental, and metabolic disruption, and their functional implications [...] Read more.
Oxidative alcohol metabolism in the liver relies on sequential enzymatic reactions involving alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and aldehyde dehydrogenase (ALDH) isozymes. However, the circadian regulation of these enzymes, their susceptibility to genetic, environmental, and metabolic disruption, and their functional implications toward alcohol-mediated tissue injury remain incompletely defined. To address this gap, we performed a comprehensive integrative analysis of the publicly available circadian transcriptome datasets spanning genetic clock disruption, acute sleep deprivation, chronic high-fat diet feeding, and occupational shift work to systematically characterize the temporal regulation and disruption vulnerability of the major alcohol-metabolizing enzymes. Mouse tissue-cycling analyses revealed pronounced gene- and tissue-specific diurnal regulation, with Adh1 oscillating primarily in adipose tissues; Cyp2e1 and mitochondrial Aldh2 cycling broadly across kidney, aorta, lung, adrenal gland, and liver; and cytosolic Aldh1b1 being uniformly arrhythmic. In the liver, Cyp2e1 and Aldh2 exhibited robust ~24 h oscillations that peaked during the light/resting phase, while Adh1 showed inconsistent rhythmicity and Aldh1b1 remained arrhythmic. Notably, Cyp2e1 and Aldh2 rhythms persisted in Bmal1 knockout and Clock mutant livers under light–dark conditions, despite complete loss of core clock gene oscillations, yet were abolished in constant darkness, revealing that systemic zeitgeber cues can mask the loss of intrinsic clock function to maintain apparent rhythmicity in these metabolic genes. Systematic cross-paradigm comparison established a novel gene-specific vulnerability hierarchy. Aldh2 was found to be most disrupted by environmental and metabolic perturbations, with acute sleep deprivation eliminating its rhythmicity and temporal expression pattern and a Western-style high-fat diet inducing pronounced phase delays and rhythm loss relative to low-fat diet controls. Both disruptions paralleled alterations in hepatocyte nuclear factor 4α (Hnf4a), newly implicating HNF4α as a potential mediator of ALDH2 circadian instability. In humans, ALDH2 and CYP2E1 exhibited conserved but phase-inverted circadian rhythms across multiple tissues relative to mice, and, importantly, night-shift workers showed markedly dampened and phase-shifted ALDH2 rhythms in peripheral blood mononuclear cells, providing the molecular link between occupational circadian misalignment and impaired acetaldehyde detoxification. Collectively, our detailed and innovative analytical approach reveals gene- and tissue-specific circadian regulation of alcohol-metabolizing enzymes, identifies ALDH2 as uniquely vulnerable to circadian misalignment, underscores the importance of circadian timing for optimal hepatic detoxification and resistance to tissue injury, and suggests that monitoring circadian rhythms could help tailor individualized advice on alcohol consumption for shift workers and populations with irregular sleep schedules, informing precision medicine approaches for alcohol-related disorders. Full article
(This article belongs to the Special Issue Exploring the Impact of the Biological Clock on Health and Disease)
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