Circadian Rhythm Disorders Aggravate Periodontitis by Modulating BMAL1

Circadian rhythms regulate the body’s homeostasis through the temporal control of tissue-specific circadian rhythm control genes. Circadian rhythm disorders (CRD) affect the expression levels of circadian rhythms-associated genes in brain and muscle aryl hydrocarbon receptor nuclear translocator-like-1(BMAL1), which is thought to contribute to metabolic disorders and an altered immune system. However, the relationship between CRD and the development of periodontitis was poorly reported. Therefore, this study aimed to investigate the role played by BMAL1 in periodontitis. We used a modified multi-platform approach (MMPM) to induce circadian rhythm disturbances in rats to investigate the role of BMAL1 in periodontitis. Our results showed significant downregulation of BMAL1 in the CRD with periodontitis group, significant resorption of alveolar bone, increased osteoclast differentiation, and upregulation of the inflammatory signaling molecule NF-κB. In addition, apoptosis and oxidative stress levels were increased in periodontal tissues. Collectively, our study suggests that BMAL1 is a key regulator in periodontitis exacerbated by CRD and that CRD may lead to the downregulation of BMAL1, thereby exacerbating oxidative stress and apoptosis in periodontal tissues. Our study found that BMAL1 may be associated with the progression of periodontitis and provides a new perspective on the treatment of periodontitis.     

The Influence of Circadian Rhythm on the Activity of Oxidative Stress Enzymes

The circadian system synchronizes daily with the day–night cycle of our environment. Disruption of this rhythm impacts the emergence and development of many diseases caused, for example, by the overproduction of free radicals, leading to oxidative damage of cellular components. The goal of this study was to determine the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione transferase (GST), glutathione reductase (R-GSSG), and the concentration of glutathione (GSH) in the circadian rhythm. The study group comprised 66 healthy volunteers (20–50 years; 33 women; 33 men). The blood was collected at 2, 8 a.m., and 2, 8 p.m. All samples marked the serum melatonin concentration to confirm the correct sleeping rhythm and wakefulness throughout the day. The activity of study enzymes and the concentration of GSH were measured by the spectrophotometric method. Confirmed the existence of circadian regulation of oxidative stress enzymes except for GST activity. The peak of activity of study enzymes and GSH concentration was observed at 2 a.m. The increased activity of enzymes and the increase in GSH concentration observed at night indicate that during sleep, processes allowing to maintain of the redox balance are intensified, thus limiting the formation of oxidative stress.     

Development of an Aged Full-Thickness Skin Model Using Flexible Skin-on-a-Chip Subjected to Mechanical Stimulus Reflecting the Circadian Rhythm

The skin is subject to both intrinsic aging caused by metabolic processes in the body and extrinsic aging caused by exposure to environmental factors. Intrinsic aging is an important obstacle to in vitro experimentation as its long-term progression is difficult to replicate. Here, we accelerated aging of a full-thickness skin equivalent by applying periodic mechanical stimulation, replicating the circadian rhythm for 28 days. This aging skin model was developed by culturing a full-thickness, three-dimensional skin equivalent with human fibroblasts and keratinocytes to produce flexible skin-on-a-chip. Accelerated aging associated with periodic compressive stress was evidenced by reductions in the epidermal layer thickness, contraction rate, and secretion of Myb. Increases in β-galactosidase gene expression and secretion of reactive oxygen species and transforming growth factor-β1 were also observed. This in vitro aging skin model is expected to greatly accelerate drug development for skin diseases and cosmetics that cannot be tested on animals.     

Circadian Rhythm Dysregulation and Leukemia Development: The Role of Clock Genes as Promising Biomarkers

The circadian clock (CC) is a daily system that regulates the oscillations of physiological processes and can respond to the external environment in order to maintain internal homeostasis. For the functioning of the CC, the clock genes (CG) act in different metabolic pathways through the clock-controlled genes (CCG), providing cellular regulation. The CC’s interruption can result in the development of different diseases, such as neurodegenerative and metabolic disorders, as well as cancer. Leukemias correspond to a group of malignancies of the blood and bone marrow that occur when alterations in normal cellular regulatory processes cause the uncontrolled proliferation of hematopoietic stem cells. This review aimed to associate a deregulated CC with the manifestation of leukemia, looking for possible pathways involving CG and their possible role as leukemic biomarkers.     

Melatonin Regulates Aging and Neurodegeneration through Energy Metabolism,Epigenetics, Autophagy and Circadian Rhythm Pathways

Brain aging is linked to certain types of neurodegenerative diseases and identifying new therapeutic targets has become critical. Melatonin, a pineal hormone, associates with molecules and signaling pathways that sense and influence energy metabolism, autophagy, and circadian rhythms, including insulin-like growth factor 1 (IGF-1), Forkhead box O (FoxOs), sirtuins and mammalian target of rapamycin (mTOR) signaling pathways. This review summarizes the current understanding of how melatonin, together with molecular, cellular and systemic energy metabolisms, regulates epigenetic processes in the neurons. This information will lead to a greater understanding of molecular epigenetic aging of the brain and anti-aging mechanisms to increase lifespan under healthy conditions.     

Rickettsial Pathogen Perturbs Tick Circadian Gene to Infect the Vertebrate Host

Ixodes scapularis is a medically important tick that transmits several microbes to humans, including rickettsial pathogen Anaplasma phagocytophilum. In nature, these ticks encounter several abiotic factors including changes in temperature, humidity, and light. Many organisms use endogenously generated circadian pathways to encounter abiotic factors. In this study, we provide evidence for the first time to show that A. phagocytophilum modulates the arthropod circadian gene for its transmission to the vertebrate host. We noted a circadian oscillation in the expression of arthropod clock, bmal1, period and timeless genes when ticks or tick cells were exposed to alternate 12 h light: 12 h dark conditions. Moreover, A. phagocytophilum significantly modulates the oscillation pattern of expression of these genes. In addition, increased levels of clock and bmal1 and decreased expression of Toll and JAK/STAT pathway immune genes such as pelle and jak, respectively, were noted during A. phagocytophilum transmission from ticks to the vertebrate host. RNAi-mediated knockdown of clock gene expression in ticks resulted in the reduced expression of jak and pelle that increased bacterial transmission from ticks to the murine host. Furthermore, clock-deficient ticks fed late and had less engorgement weights. These results indicate an important role for circadian modulation of tick gene expression that is critical for arthropod blood feeding and transmission of pathogens from vector to the vertebrate host.     

The Influence of Light Quality,Circadian Rhythm,and Photoperiod on the CBF-Mediated Freezing Tolerance

Low temperature adversely affects crop yields by restraining plant growth and productivity. Most temperate plants have the potential to increase their freezing tolerance upon exposure to low but nonfreezing temperatures, a process known as cold acclimation. Various physiological, molecular, and metabolic changes occur during cold acclimation, which suggests that the plant cold stress response is a complex, vital phenomenon that involves more than one pathway. The C-Repeat Binding Factor (CBF) pathway is the most important and well-studied cold regulatory pathway that imparts freezing tolerance to plants. The regulation of freezing tolerance involves the action of phytochromes, which play an important role in light-mediated signalling to activate cold-induced gene expression through the CBF pathway. Under normal temperature conditions, CBF expression is regulated by the circadian clock through the action of a central oscillator and also day length (photoperiod). The phytochrome and phytochrome interacting factor are involved in the repression of the CBF expression under long day (LD) conditions. Apart from the CBF regulon, a novel pathway involving the Z-box element also mediates the cold acclimation response in a light-dependent manner. This review provides insights into the progress of cold acclimation in relation to light quality, circadian regulation, and photoperiodic regulation and also explains the underlying molecular mechanisms of cold acclimation for introducing the engineering of economically important, cold-tolerant plants.     

Protecting the Melatonin Rhythm through Circadian Healthy Light Exposure

Currently, in developed countries, nights are excessively illuminated (light at night), whereas daytime is mainly spent indoors, and thus people are exposed to much lower light intensities than under natural conditions. In spite of the positive impact of artificial light, we pay a price for the easy access to light during the night: disorganization of our circadian system or chronodisruption (CD), including perturbations in melatonin rhythm. Epidemiological studies show that CD is associated with an increased incidence of diabetes, obesity, heart disease, cognitive and affective impairment, premature aging and some types of cancer. Knowledge of retinal photoreceptors and the discovery of melanopsin in some ganglion cells demonstrate that light intensity, timing and spectrum must be considered to keep the biological clock properly entrained. Importantly, not all wavelengths of light are equally chronodisrupting. Blue light, which is particularly beneficial during the daytime, seems to be more disruptive at night, and induces the strongest melatonin inhibition. Nocturnal blue light exposure is currently increasing, due to the proliferation of energy-efficient lighting (LEDs) and electronic devices. Thus, the development of lighting systems that preserve the melatonin rhythm could reduce the health risks induced by chronodisruption. This review addresses the state of the art regarding the crosstalk between light and the circadian system.     

Cosmeceutical Therapy: Engaging the Repercussions of UVR Photoaging on the Skin’s Circadian Rhythm

Sunlight is an important factor in regulating the central circadian rhythm, including the modulation of our sleep/wake cycles. Sunlight had also been discovered to have a prominent influence on our skin’s circadian rhythm. Overexposure or prolonged exposure to the sun can cause skin photodamage, such as the formation of irregular pigmentation, collagen degradation, DNA damage, and even skin cancer. Hence, this review will be looking into the detrimental effects of sunlight on our skin, not only at the aspect of photoaging but also at its impact on the skin’s circadian rhythm. The growing market trend of natural-product-based cosmeceuticals as also caused us to question their potential to modulate the skin’s circadian rhythm. Questions about how the skin’s circadian rhythm could counteract photodamage and how best to maximize its biopotential will be discussed in this article. These discoveries regarding the skin’s circadian rhythm have opened up a completely new level of understanding of our skin’s molecular mechanism and may very well aid cosmeceutical companies, in the near future, to develop better products that not only suppress photoaging but remain effective and relevant throughout the day.     

Morphofunctional State and Circadian Rhythms of the Liver under the Influence of Chronic Alcohol Intoxication and Constant Lighting

A study of the influence of chronic alcohol intoxication, constant illumination and their combined effects on the morphofunctional state of the rat liver and the circadian rhythms (CR) of the studied parameters of the organism was carried out. It was found that both alcohol and constant illumination caused significant changes in the structure of the liver, as well as in the circadian rhythmicity of micromorphometric parameters of hepatocytes, ALT, and total and direct bilirubin rhythms; however, the combined effects of ethanol and constant illumination had the most significant effect on the studied parameters of the organism. These two factors caused disturbances in the circadian rhythms of the micromorphometric parameters of hepatocytes, disruption of the circadian rhythms of total protein, albumin, AST, ALT, and direct and total bilirubin, as well as disturbances in the expression and rhythmicity of the studied clock genes against a background of the development of an inflammatory process in the liver.     

Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis

Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings have suggested strong correlations between the circadian clock and cardiovascular diseases. Desynchronization between the circadian rhythm and body metabolism contributes to the development of cardiovascular diseases including arteriosclerosis and thrombosis. Circadian rhythms are involved in controlling inflammatory processes and metabolisms, which can influence the pathology of arteriosclerosis and thrombosis. Circadian clock genes are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system. The circadian machinery in the vascular system may be a novel therapeutic target for the prevention and treatment of cardiovascular diseases. The research on circadian rhythms in cardiovascular diseases is still progressing. In this review, we briefly summarize recent studies on circadian rhythms and cardiovascular homeostasis, focusing on the circadian control of inflammatory processes and metabolisms. Based on the recent findings, we discuss the potential target molecules for future therapeutic strategies against cardiovascular diseases by targeting the circadian clock.     

Role of Circadian Transcription Factor Rev-Erb in Metabolism and Tissue Fibrosis

Circadian rhythms significantly affect metabolism, and their disruption leads to cardiometabolic diseases and fibrosis. The clock repressor Rev-Erb is mainly expressed in the liver, heart, lung, adipose tissue, skeletal muscles, and brain, recognized as a master regulator of metabolism, mitochondrial biogenesis, inflammatory response, and fibrosis. Fibrosis is the response of the body to injuries and chronic inflammation with the accumulation of extracellular matrix in tissues. Activation of myofibroblasts is a key factor in the development of organ fibrosis, initiated by hormones, growth factors, inflammatory cytokines, and mechanical stress. This review summarizes the importance of Rev-Erb in ECM remodeling and tissue fibrosis. In the heart, Rev-Erb activation has been shown to alleviate hypertrophy and increase exercise capacity. In the lung, Rev-Erb agonist reduced pulmonary fibrosis by suppressing fibroblast differentiation. In the liver, Rev-Erb inhibited inflammation and fibrosis by diminishing NF-κB activity. In adipose tissue, Rev- Erb agonists reduced fat mass. In summary, the results of multiple studies in preclinical models demonstrate that Rev-Erb is an attractive target for positively influencing dysregulated metabolism, inflammation, and fibrosis, but more specific tools and studies would be needed to increase the information base for the therapeutic potential of these substances interfering with the molecular clock.     

The Circadian Clock in the Retinal Pigment Epithelium Controls the Diurnal Rhythm of Phagocytic Activity

The diurnal peak of phagocytosis by the retinal pigment epithelium (RPE) of photoreceptor outer segments (POS) is under circadian control and believed that this process involves interactions from the retina and RPE. Previous studies have demonstrated that a functional circadian clock exists within multiple retinal cell types and RPE. Thereby, the aim of this study was to determine whether the clock in the retina or RPE controls the diurnal phagocytic peak and whether disruption of the circadian clock in the RPE would affect cellular function and the viability during aging. To that, we generated and validated an RPE tissue-specific KO of the essential clock gene, Bmal1, and then determined the daily rhythm in phagocytic activity by the RPE in mice lacking a functional circadian clock in the retina or RPE. Then, using electroretinography, spectral domain-optical coherence tomography, and optomotor response of visual function we determined the effect of Bmal1 removal in young (6 months) and old (18 months) mice. RPE morphology and lipofuscin accumulation was determined in young and old mice. Our data shows that the clock in the RPE, rather than the retina clock, controls the diurnal phagocytic peak. Surprisingly, absence of a functional RPE clock and phagocytic peak does not result in any detectable age-related degenerative phenotype in the retina or RPE. Thus, our results demonstrate that the circadian clock in the RPE controls the daily peak of phagocytic activity. However, the absence of the clock in the RPE does not result in deterioration of photoreceptors or the RPE during aging.     

Peripheral Skin Temperature and Circadian Biological Clock in Shift Nurses after a Day off

The circadian biological clock is essentially based on the light/dark cycle. Some people working with shift schedules cannot adjust their sleep/wake cycle to the light/dark cycle, and this may result in alterations of the circadian biological clock. This study explored the circadian biological clock of shift and daytime nurses using non-invasive methods. Peripheral skin temperature, cortisol and melatonin levels in saliva, and Per2 expression in pubic hair follicle cells were investigated for 24 h after a day off. Significant differences were observed in peripheral skin temperature and cortisol levels between shift and daytime nurses. No differences in melatonin levels were obtained. Per2 maximum values were significantly different between the two groups. Shift nurses exhibited lower circadian variations compared to daytime nurses, and this may indicate an adjustment of the circadian biological clock to continuous shift schedules. Non-invasive procedures, such as peripheral skin temperature measurement, determination of cortisol and melatonin in saliva, and analysis of clock genes in hair follicle cells, may be effective approaches to extensively study the circadian clock in shift workers.     

Disruption of Circadian Rhythm Genes in Obstructive Sleep Apnea Patients—Possible Mechanisms Involved and Clinical Implication

Obstructive sleep apnea (OSA) is a chronic condition characterized by recurrent pauses in breathing caused by the collapse of the upper airways, which results in intermittent hypoxia and arousals during the night. The disorder is associated with a vast number of comorbidities affecting different systems, including cardiovascular, metabolic, psychiatric, and neurological complications. Due to abnormal sleep architecture, OSA patients are at high risk of circadian clock disruption, as has been reported in several recent studies. The circadian clock affects almost all daily behavioral patterns, as well as a plethora of physiological processes, and might be one of the key factors contributing to OSA complications. An intricate interaction between the circadian clock and hypoxia may further affect these processes, which has a strong foundation on the molecular level. Recent studies revealed an interaction between hypoxia-inducible factor 1 (HIF-1), a key regulator of oxygen metabolism, and elements of circadian clocks. This relationship has a strong base in the structure of involved elements, as HIF-1 as well as PER, CLOCK, and BMAL, belong to the same Per-Arnt-Sim domain family. Therefore, this review summarizes the available knowledge on the molecular mechanism of circadian clock disruption and its influence on the development and progression of OSA comorbidities.     

Diurnal Expression of the Per2 Gene and Protein in the Lateral Habenular Nucleus

The suprachiasmatic nucleus plays an important role in generating circadian rhythms in mammals. The lateral habenular nucleus (LHb) is closely linked to this structure. Interestingly, the LHb shows a rhythmic firing rate in vivo and in vitro, and sustained oscillation of rhythmic genes in vitro. However, under the in vivo condition, whether rhythmic gene expression in the LHb has circadian rhythms remains unknown. In this study, we examined LHb tissue in rats to determine Period2 (Per2) gene and protein expression at six zeitgeber time points (ZT2, ZT6, ZT10, ZT14, ZT18, and ZT22) in a 12-h light and 12-h dark (LD) environment. We found that in the LD environment, Per2 gene expression and PER2 protein levels in the LHb were higher in the day and lower in the night, showing periodic oscillation, with a peak at ZT10 and a trough at ZT22 (Per2 mRNA) and ZT18 (PER2 protein). We conclude that Per2 expression and PER2 protein levels in the LHb have rhythmic oscillation in vivo. This study provides a basis for further study on the role of the LHb in the circadian rhythm system.