Pulmonary Pathologies and Their Relationship with Circadian Cycle: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Arnoldo Aquino-Gálvez.

The function of the circadian cycle is to determine the natural 24 h biological rhythm, which includes physiological, metabolic, and hormonal changes that occur daily in the body. This cycle is controlled by an internal biological clock that is present in the body’s tissues and helps regulate various processes such as sleeping, eating, and others. Interestingly, animal models have provided enough evidence to assume that the alteration in the circadian system leads to the appearance of numerous diseases. Alterations in breathing patterns in lung diseases can modify oxygenation and the circadian cycles; however, the response mechanisms to hypoxia and their relationship with the clock genes are not fully understood. Hypoxia is a condition in which the lack of adequate oxygenation promotes adaptation mechanisms and is related to several genes that regulate the circadian cycles, the latter because hypoxia alters the production of melatonin and brain physiology. Additionally, the lack of oxygen alters the expression of clock genes, leading to an alteration in the regularity and precision of the circadian cycle. In this sense, hypoxia is a hallmark of a wide variety of lung diseases.

  • circadian cycle
  • lung diseases
  • hypoxia
  • genes
  • idiopathic pulmonary fibrosis

1. Introduction

The respiratory system is also subject to circadian rhythm regulation by the suprachiasmatic nucleus (SCN), mainly mediated by the vagus nerve [43][1]. In addition to this central regulation, a “pulmonary clock” was also described, by examining the expression of clock genes in multiple tissues in mice and humans [43,44][1][2]. Disturbances in the circadian clock during chronic lung diseases could play a role in increased oxidative stress, the inflammatory response, metabolic imbalances, hypoxia/hyperoxia, mucus secretion, autophagy, and lung function disorders [17][3]. Proper synchronization and maintenance of the circadian rhythm are essential for normal lung function. An alteration in the circadian clock, due to genetic or environmental factors, produces stress [19][4].

2. Asthma

Asthma is a heterogeneous disease characterized by chronic inflammation and airway hyperresponsiveness and remodeling resulting in a wide variety of clinical presentations [49][5]. Circadian rhythm disruption seems to influence asthma development and symptomology. The pulmonary function seems to be subject to day–night fluctuations, with an increase in airway resistance during sleep at night [50][6]. Some patients present nocturnal worsening of symptoms [51][7]. Multiple factors could contribute to this rhythmic worsening, including an increase in peak serum melatonin levels [52][8], the supine position, which can induce airflow obstruction [53][9], and air temperature cooling [54][10], among others. Night workers also seem to have an increased risk of developing asthma [55][11]. The inflammatory state also seems to be influenced by the circadian clock. Cortisol, an important immunosuppressor and anti-inflammatory hormone, shows daily fluctuations in its circulating levels, and its nadir (time point characterized by the lowest concentration) is reached at midnight. Moreover, children with asthma have lower circulating cortisol levels [56][12], and disturbances in the fluctuations of cortisol have been associated with nocturnal asthma severity [17,57][3][13].
Alterations in clock genes are associated with asthma severity. Asthmatic patients showed a significant downregulation of these genes [58,59][14][15]; specifically, PER3 levels appeared diminished in nocturnal asthma [59][15], and BMAL1 knock-out mice developed an asthmatic phenotype after viral exposure [58][14]. Interestingly, inhibition of the BMAL1/FOXA2 signaling pathway produced increases in nocturnal IL-6 levels in respiratory tract epithelial cells [60][16]. Furthermore, the induction of asthma was associated with a marked increase in lung inflammation in mice lacking BMAL1 expression in myeloid cells, increasing the number of eosinophils and IL-5 serum levels (Figure 1) [61][17].

3. Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD), a progressive chronic respiratory disorder characterized by an obstructive ventilatory pattern [62][18], which unlike asthma is rarely reversible, is very often related to smoking or exposure to pollutants as well as to accelerated lung aging, leading to chronic respiratory failure [62,63][18][19]. Interestingly, COPD seems to follow a diurnal pattern, with patients reporting a substantial worsening of symptoms in the morning [62][18]. This could be related to the changes in peak expiratory flow (PEF), which is subject to circadian variations, peaking in the afternoon [64,65][20][21], while the maximum volume of air exhaled in the first second (FEV 1) is the lowest during the morning hours [66][22]. Moreover, in murine models, cigarette smoke (CS) was shown to reduce the activity of sirtuin 1 deacetylase (SIRT1), a marker of aging and inflammation, which regulates BMAL and PER2 through acetylation (Figure 1) [63,67,68][19][23][24].
The molecular clock seems to have a mutual relation with the inflammatory response and is altered in pathological states such as COPD. In human airway epithelial cells and lung tissue of REV-ERBα KO mice, CS exposure produced a heightened inflammatory response, with an increase in neutrophils and the release of proinflammatory cytokines (IL-6, MCP-1, and KC), in addition to the expression of p16 (a pro-senescence marker) and of markers of chronic lung remodeling, as observed in emphysema/COPD [69,70][25][26]. REV-ERBα is a nuclear heme receptor, a transcriptional repressor (binding and interacting with HDAC3 and NcoR), and a critical component of the molecular clock driving the daily rhythmicity of metabolism and inflammatory and immune responses [69][25]. In contrast to the antagonistic regulator REV-ERB, the retinoic acid-like orphan receptor alpha/gamma (RORα/γ) acts as an activator, and these molecules together are considered a “stabilizing loop” of the molecular clock [69][25]. Moreover, RORα levels are elevated in the lungs of COPD patients, but interestingly, RORα-deficient mice are protected against emphysema induced by elastase and CS exposure [71][27]. Interestingly, RORα responds to DNA damage, and a decrease in this protein is associated with low levels of apoptosis [67][23]. Interestingly, BMAL1 has also been shown to be underexpressed in human bronchial epithelial cells, lung tissue, peripheral blood mononuclear cells (PBMCs), sputum cell from COPD patients, and healthy cells exposed to CS [68,72,73][24][28][29]. The BMAL1 and CLOCK proteins seem to play an integral role in regulating cellular senescence, since the decrease in their expression by CS exposure upregulates senescence mediated by the MAPK pathways, a process implicated in the development of COPD (Figure 1) [73][29].

4. Lung Cancer

Lung cancer is the most commonly diagnosed cancer type in both sexes combined (11.6%) and the leading cause of cancer death among men [74][30]. Smoking has a causal link with the development of lung cancer, as shown by extensive epidemiologic research evidence [75,76,77][31][32][33]. In recent years, the relationship between sleep (duration, quality, and timing) and cancer risk has been consolidated particularly in regard to the development of lung cancer [78,79,80,81][34][35][36][37]. For instance, insomnia was causally associated with an increased risk of lung adenocarcinoma, while sleep with typical duration showed a protective effect on the risk of lung adenocarcinoma [82,83][38][39]. Also, clock genes, primarily BMAL1, have been implicated in tumorigenesis [84,85][40][41].
Clock genes’ behavior seems to depend on the type of lung cancer. In a recent study, the overexpression of CRY2, BMAL1, and RORα and the underexpression of Timeless and NPAS2 were associated with a favorable prognosis of lung adenocarcinoma. On the other hand, heightened expression of Sharp2 was observed in squamous cell carcinoma and was associated with poor survival. In the case of non-small cell lung cancer (NSCLC), clock genes establish a cancer circadian rhythm, asynchronic with respect to that of healthy tissues [86][42]. Moreover, CS exposure decreased Nr1d1 expression in both tumor-resistant and tumor-susceptible mice, making them more prone to developing CS-related lung cancer (Figure 1) [87][43].
The circadian rhythm also seems to regulate the expression of tumor suppressor genes and proto-oncogenes, such as p53, a critical tumor suppressor protein involved in the DNA damage response and apoptosis, whose transcription, stability, and activity are modulated by BMAL1 and PER2 [88,89,90][44][45][46]. While BMAL1 binds to the promoter region of p53, PER2 binds to the p53 protein, providing stabilization and nuclear translocation for its activation, in the presence of DNA damage in cells [88,89,90,91,92,93][44][45][46][47][48][49]. Furthermore, BMAL1 suppresses cell invasion by blocking the PI3K-AKT-MMP-2 pathway, as seen in BMAL1 KO human lung cancer and glioma cell lines [94][50]. The PI3K-AKT-MMP-2 pathway is involved in a myriad of cellular processes that can be altered in cancerous environments, including cellular apoptosis, migration/invasion, cell growth, and angiogenesis, among others, through the regulation of FOXO, mTORC1/2, XIAP, Bcl2, and MDM2, the last of which inhibits p53 activity (Figure 1) [95][51].
Melatonin is also an important regulator of oncogenic processes, especially those induced by hypoxia, and could serve as a potential therapeutic agent. Among the key anti-cancer mechanisms of melatonin are the inhibition of hypoxia-induced proliferation in cancer cells, the induction of apoptosis, anti-angiogenesis mechanisms, the inhibition of HIFs, the reduction in hypoxia-induced reactive oxygen species (ROS), the inhibition of cancer cell migration and invasion, the attenuation of epithelial–mesenchymal transition (EMT), the inhibition of endoplasmic reticulum stress, the reversion of altered states of metabolism (e.g., the Warburg effect), and the improvement of chemoradiotherapy sensitivity [96,97,98][52][53][54].
NSCLC is associated with an overactivation of AKT [99][55]. In a study with 1144 patients with such a disease, 3.7% of the patients were identified to have PIK3CA mutations in exons 9 and 20, and up to 57.1% of the patients showed additional aberrations in oncogenic drivers [100][56]. Furthermore, the gene ARNTL (that encodes the BMAL protein) was found to protect against lung adenocarcinoma growth, and the ARNTL gene was shown to increase the expression of the circular RNA circGUCY1A2 and activate the miR-200c-3p/PTEN axis, initiating a tumor suppressive activity [101][57].
The proteins differentiated embryonic chondrocyte expressed gene 1 (DEC1; BHLHE40/Stra13/Sharp2) and 2 (DEC2; BHLHE41/Sharp1), related to the circadian genes, can act as repressors and coactivators of BMAL1 and CLOCK or NPAS [102][58]. These two proteins are implicated in regulating cell differentiation, circadian rhythms, apoptosis, the response to hypoxia, EMT, and carcinogenesis [103,104][59][60]. As stated, HIFs are activated during hypoxia and are described to participate in different aspects of cancer pathophysiology. Interestingly, Sharp1 interacts with HIF-1α, driving it to proteosome degradation and preventing the formation of the HIF-1α/1β heterodimer that promotes metastatic gene expression [105][61]. Sharp1 suppresses metastasis in various types of tumors including breast, endometrial, prostate, thyroid, and lung cancers [106,107,108,109,110][62][63][64][65][66]. Paradoxically, in human breast cancer cells, HIF-2α was shown to increase Sharp1 expression through the activation of AKT in a hypoxic state, which in turn promoted c-Myc expression and favored cellular proliferation (Figure 1) [104][60].
Concerning the antitumor effects, the overexpression of Sharp1 inhibited the formation of colonies of lung cancer cells (A549, NCI-H520, and NCI-H596 cells) by promoting a decrease in cyclin D1 (CCND1) expression [109][65]. In this sense, Sharp1 and Sharp2 seem to have opposing roles in cancer progression. While Sharp1 was shown to suppress EMT and metastasis by attenuating NOTCH1 signaling in endometrial cancer cells [111][67] and TGF-β-associated EMT in prostate cancer PC-3 cells [110][66], Sharp2 favored TGF-β-associated EMT [103][59] and interplayed with NOTCH1 to favor cell growth and invasiveness [110][66]. Furthermore, in fibroblasts, Sharp1 was activated during DNA damage and was involved in cell cycle arrest and apoptosis; an aberrant expression of Sharp1 could thus participate in tumorigenesis [112][68]. Unexpectedly, in various cancer cell lines, the hypoxia-induced expression of both Sharp1 and Sharp2 downregulated the MLH1 protein, an essential component of the DNA mismatch repair (MMR) system [113][69]. However, as stated, Sharp1/2 can have both repressor and oncogenic activity, and their function seems to vary by tissue type [114][70].

5. Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease primarily affecting the elderly, characterized by irreversible damage and an unknown etiology, which offers limited treatment options. Typically, patients diagnosed with IPF face a grim prognosis, succumbing to respiratory failure within two to five years [115,116,117][71][72][73]. The pathogenesis of IPF involves the activation of epithelial cells in response to various injuries, leading to the release of mediators that contribute to fibrosis. These mediators include cytokines and growth factors, notably, platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), tumor necrosis factor α (TNFα), endothelin-1 (ET-1), and connective tissue growth factor (CTGF) [118][74]. Particularly, TGF-β1 plays a central role in fibrotic tissue formation within the lungs, which is a key driver of IPF development [119][75]. TGF-β1 promotes fibroblast-to-myofibroblast differentiation, EMT, and the production of matrix metalloproteinases, all contributing to the formation of fibroblast foci [120][76]. These foci generate excessive extracellular matrix deposition, predominantly, collagen deposition, leading to lung architectural scarring and destruction [118,121,122,123,124][74][77][78][79][80]. Circadian oscillations within the lung epithelium were associated with inflammatory responses in IPF patients [125][81]. These oscillations are implicated in the remodeling of the lung’s extracellular matrix, largely due to increased levels of the REV-ERBα protein, a negative regulator of BMAL1, which itself contributes to the regulation of inflammatory mediators [126][82].
A reduced expression in the BHLHE41 gene [134][83] was observed in hypoxic lung fibroblasts obtained from IPF individuals. As mentioned earlier, the protein encoded by this gene is recognized as a tumor suppressor. Consequently, the absence of its expression in the lung fibroblasts of IPF patients led us to hypothesize that BHLHE41 may play a significant role in fibrosis progression. Such a hypothesis gains credence considering the observation that TGF-β induces the upregulation of BHLHE40 and the downregulation of BHLHE41 in prostate cancer cells (PC-3) [103][59]. It is worth noting that TGF-β triggers the phosphorylation of Smad2, subsequently leading to the activation of mesenchymal markers such as N-cadherin and vimentin, while concurrently suppressing epithelial markers like E-cadherin [103][59]. This suggests that TGF-β may initiate EMT, a process known to be involved in developing pulmonary fibrosis. Furthermore, evidence indicates that the two genes BHLHE40 and BHLHE41 may have opposing effects in the context of cancer development.
Figure 1. The molecular circadian clock involves an autoregulatory loop encompassing the transcription activators BMAL1, CLOCK and/or NPAS2, regulated by the repressors Per and CRY. During hypoxia, HIF-1α and HIF-2α activation increases. These molecules have a dual regulation: HIF-1α and BMAL1 bind together to clock gene promoters, while clock proteins bind to the promoter of HIF-1α. Per3 levels were found to be diminished in asthma. BMAL1 levels seem to be diminished in animal models or patients with asthma, COPD, or LC and are also diminished by CS exposure; inhibition of or decrease in BMAL1 can lead to an increase in IL-5 and IL-6 expression and in the number of eosinophils in the presence of asthma. COPD or CS exposure reduces SIRT1 expression, which regulates BMAL1 and PER2. Moreover, CS exposure in REV-ERBα KO mice increased the number of neutrophils and the expression of proinflammatory cytokines. In COPD, the levels of RORα, the counterpart to REV-ERBα and a regulator of BMAL1, are diminished. BMAL1 also regulates p53 expression, and PER binds to p53, regulating the stabilization and nuclear translocation of the protein. BMAL1 can also block the AKT signaling pathway, which is overactivated in lung cancer. Furthermore, the protein Sharp1 was shown to interact with HIF-1α to induce its proteasomal degradation and prevent its union with HIF-1β, which promotes the expression of metastatic genes. In IPF, the increment in REV-ERBα leads to ECM remodeling, and REV-ERBα suppression promotes fibroblast-to-myofibroblast differentiation. NRF2 is positively regulated by BMAL1-CLOCK, and NRF2 increases the expression of Gclm and Gsta3, proteins involved in glutathione metabolism. Additionally, Sharp1 expression is reduced in IPF. In OSA, HIFs are overactivated and increase the expression of Clock, BMAL1, and CRY2. A, asthma; COPD, chronic obstructive pulmonary disease; LC, lung cancer; IPF, idiopathic pulmonary disease; OSA, obstructive sleep apnea; O2, oxygen; BMAL1, brain and muscle ARNT-like 1; NPAS2, neuronal PAS domain protein 2; CLOCK, circadian locomotor output cycles kaput; PER, period; CRY, cryptochrome; SIRT1, sirtuin1; HIF, hypoxia-inducible factor; IL-5, interleukin 5; IL-6, interleukin 6; MCP-1, monocyte chemoattractant protein 1; KC, keratinocyte chemoattractant; AKT, protein kinase B; ECM, extracellular matrix; NRF2, nuclear factor erythroid 2-related factor 2; ARE, antioxidant response element.

6. Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is the most common type of sleep-related breathing disorder, characterized by repeated episodes of complete or partial airway collapse in association with a decrease in oxygen saturation or with arousal from sleep. These episodes lead to fragmented and nonrestorative sleep that, over time, impact negatively on cardiovascular health, cognitive performance, and quality of life [135,136][84][85]. Apnea is defined as an interruption of airflow for at least ten seconds, resulting in a complete lack of breathing; these events are obstructive, central, or mixed. Obstructive apneas occur when the airway is blocked, but respiratory effort is present in the thorax and abdomen. In central apneas, there is no respiratory effort or airflow, indicating that the brain is not sending signals to stimulate breathing. Mixed apneas are a combination of these two dysfunctions [136,137,138,139][85][86][87][88]. The standard diagnosis for OSA involves nocturnal polysomnography, which records the number of apneas and hypopneas per hour of effective sleep. The Apnea–Hypopnea Index (AHI) is used to assess the severity of the condition [140,141,142,143][89][90][91][92]. The main symptoms of OSA include loud snoring, nighttime awakenings, daytime sleepiness, and fatigue [135,143][84][92]. Possible additional signs include morning headaches, memory and concentration problems, night sweats, and wheezing [136][85]. OSA patients often experience cycles of oxygen desaturation followed by reoxygenation during sleep [144,145][93][94]. States of hypoxia, such as the prolonged period of hypobaric hypoxia present during long-duration flights, are shown to disrupt multiple processes regulated by the circadian rhythm, including the maintenance of core body temperature [146][95], melatonin secretion [147][96], and the cortisol secretion cycle [148][97]. These changes significantly modify sleep (latency, time, and quality of sleep) and can be influenced by individual characteristics such as age, physical fitness, and the sympathetic reaction to hypoxia.
To provide further support for this association, bidirectional interactions between HIF-1α and the circadian clock have been demonstrated. For instance, BMAL1 and CLOCK form heterodimers and regulate the rhythmic expression of HIF-1α [41][98]. Moreover, in a hypoxic environment, alterations in the expression of circadian genes were observed. Overexpression of HIF-1α and HIF-2α was shown to increase the gene expression of CLOCK, BMAL1, and CRY2, while decreasing the expression of PER1, PER2, PER3, CRY1, and CKIε [149][99]. In a separate study involving individuals with obstructive sleep apnea (OSA), it was noted that the transcription of BMAL1, CLOCK, and CRY2 was irregular, and the levels of CRY1 and PER3 significantly decreased at midnight. This suggests that the latter two genes could potentially serve as prognostic markers for OSA severity (Figure 1) [150][100]. Although the role of circadian gene polymorphisms in respiratory pathologies is relatively unexplored, recent findings suggest their potential significance. For instance, a study revealed that mutations in the BHLHE41 gene were associated with reduced total sleep [151][101].

7. Influenza and COVID-19

Influenza, a highly contagious and often fatal disease, claims nearly half a million lives annually worldwide. Until now, four distinct types of influenza viruses have been recognized: A, B, C, and D. Only types A and C viruses are recognized to infect humans. Types A and B viruses co-circulate as the primary seasonal strains, giving rise to a spectrum of respiratory infections and related complications, ranging from mild to severe, in human populations. The typical influenza symptoms encompass fever, fatigue, cough, and body aches [152,153,154,155][102][103][104][105]. Almost 10% of the global population falls prey to influenza each year [152[102][104],154], since this virus incubates for a period ranging from 1 to 4 days [156][106].
Lung damage inflicted by influenza is associated with disruptions in the circadian clock, compromised lung function, and decreased survival rates [157][107]. The protein BMAL1 plays a pivotal role in alveolar epithelial cells (AECs), with specific BMAL1 deletion disrupting lung neutrophil infiltration, biomechanical functions, and the response to influenza infection [158][108]. Conversely, the genetic deletion of BMAL1 and the overexpression or activation of REV-ERB using synthetic agonists inhibit the replication of hepatitis C virus (HCV) and related flaviviruses like dengue and Zika. The overexpression of REV-ERB denies HCV cell entry, viral RNA replication, and the release of infectious particles through lipid signaling pathway disruption [159][109]. REV-ERB agonists inhibit HIV transcription and replication in vivo in primary cell lines [160][110]. Together, these findings indicate the important role of circadian genes in viral infections and their influence on immune responses.
In recent times, the world endured one of its most devastating pandemics, resulting in the loss of millions of lives due to a Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak, responsible for Coronavirus Disease 2019 (COVID-19) [161,162][111][112]. During the COVID-19 pandemic, two factors significantly impacted sleep quality: irregular schedules and confinement [163,164][113][114]. Such disruptions altered the daily routines, including office and work schedules, social engagements, and recreational activities [163][113]. It is well documented that even a single night of sleep deprivation can lead to mood swings and a weakened immune system [163,165][113][115]. This connection could result in disturbances in mitochondrial metabolism and influence the normal functions of the immune response [166][116]. Interestingly, several viruses inhibit mitochondrial melatonin production [166][116]; notably, the loss of circadian activation coincides with suppressed REV-ERBα expression, indicating a possible link between clock genes and inflammatory pathways [167][117].
The circadian clock influences both innate and adaptive immune systems, impacting processes from leukocyte mobilization and chemotaxis to cytokine release and T-cell differentiation [168][118]. The pathogenicity of viral infections can be influenced by the host’s circadian clock through two primary mechanisms: (1) a direct regulation of viral replication within the target cells; (2) indirect effects on innate and adaptive immune responses [169,170,171][119][120][121]. Intriguingly, recent studies concluded that the circadian clock, via REV-ERBα and BMAL1, significantly influences the airway inflammatory responses [125,172][81][122]. Circadian cycle genes regulate cytokines, including IL-6, a function that exhibits diurnal variation and has implications in inflammatory processes, as seen in patients with rheumatoid arthritis [173][123]. Such a relationship could also shed light on pharmacological treatments variability; for instance, the effectiveness of glucocorticoids depends on the intact functioning of the circadian clock in the airways [125][81]. Therefore, viral infections, inflammatory responses, and circadian clock genes appear to share intricate pathways, and comprehending these connections may enhance ourthe understanding of the pathogenesis of such infectious diseases.

References

  1. Bando, H.; Nishio, T.; Van Der Horst, G.T.J.; Masubuchi, S.; Hisa, Y.; Okamura, H. Vagal Regulation of Respiratory Clocks in Mice. J. Neurosci. 2007, 27, 4359–4365.
  2. Gibbs, J.E.; Beesley, S.; Plumb, J.; Singh, D.; Farrow, S.; Ray, D.W.; Loudon, A.S. Circadian timing in the lung; a specific role for bronchiolar epithelial cells. Endocrinology. 2009, 150, 268–276.
  3. Giri, A.; Wang, Q.; Rahman, I.; Sundar, I.K. Circadian molecular clock disruption in chronic pulmonary diseases. Trends Mol. Med. 2022, 28, 513–527.
  4. Nosal, C.; Ehlers, A.; Haspel, J.A. Why Lungs Keep Time: Circadian Rhythms and Lung Immunity. Annu. Rev. Physiol. 2020, 82, 391–412.
  5. Holgate, S.T.; Wenzel, S.; Postma, D.S.; Weiss, S.T.; Renz, H.; Sly, P.D. Asthma. Nat. Rev. Dis. Primers 2015, 1, 15025.
  6. Ballard, R.D.; Saathoff, M.C.; Patel, D.K.; Kelly, P.L.; Martin, R.J. Effect of sleep on nocturnal bronchoconstriction and ventilatory patterns in asthmatics. J. Appl. Physiol. 1989, 67, 243–249.
  7. Scheer, F.A.J.L.; Hilton, M.F.; Evoniuk, H.L.; Shiels, S.A.; Malhotra, A.; Sugarbaker, R.; Ayers, R.T.; Israel, E.; Massaro, A.F.; Shea, S.A. The Endogenous Circadian System Worsens Asthma at Night Independent of Sleep and Other Daily Behavioral or Environmental Cycles. Proc. Natl. Acad. Sci. USA 2021, 118, e2018486118.
  8. Sutherland, E.R.; Ellison, M.C.; Kraft, M.; Martin, R.J. Elevated serum melatonin is associated with the nocturnal worsening of asthma. J. Allergy Clin. Immunol. 2003, 112, 513–517.
  9. Jönsson, E.; Mossberg, B. Impairment of ventilatory function by supine posture in asthma. Eur. J. Respir. Dis. 1984, 65, 496–503.
  10. Chen, W.Y.; Chai, H. Airway cooling and nocturnal asthma. Chest 1982, 81, 675–680.
  11. Maidstone, R.J.; Turner, J.; Vetter, C.; Dashti, H.S.; Saxena, R.; Scheer, F.A.J.L.; Shea, S.A.; Kyle, S.D.; Lawlor, D.A.; Loudon, A.S.I. Night Shift Work Is Associated with an Increased Risk of Asthma. Thorax 2021, 76, 53–60.
  12. Landstra, A.M.; Postma, D.S.; Boezen, H.M.; van Aalderen, W.M. R ole of serum cortisol levels in children with asthma. Am. J. Respir. Crit. Care Med. 2002, 165, 708–712.
  13. Sutherland, E.R.; Ellison, M.C.; Kraft, M.; Martin, R.J. Altered Pituitary-adrenal Interaction in Nocturnal Asthma. J. Allergy Clin. Immunol. 2003, 112, 52–57.
  14. Ehlers, A.; Xie, W.; Agapov, E.; Brown, S.; Steinberg, D.; Tidwell, R.; Sajol, G.; Schutz, R.; Weaver, R.; Yu, H. BMAL1 Links the Circadian Clock to Viral Airway Pathology and Asthma Phenotypes. Mucosal Immunol. 2018, 11, 97–111.
  15. Chen, H.-C.; Chen, Y.-C.; Wang, T.-N.; Fang, W.-F.; Chang, Y.-C.; Chen, Y.-M.; Chen, I.-Y.; Lin, M.-C.; Yang, M.-Y. Disrupted Expression of Circadian Clock Genes in Patients with Bronchial Asthma. J. Asthma Allergy 2021, 14, 371–380.
  16. Tang, L.; Liu, L.; Sun, X.; Hu, P.; Zhang, H.; Wang, B.; Zhang, X.; Jiang, J.; Zhao, X.; Shi, X. BMAL1/FOXA2-induced rhythmic fluctuations in IL-6 contribute to nocturnal asthma attacks. Front. Immunol. 2022, 13, 947067.
  17. Zasłona, Z.; Case, S.; Early, J.O.; Lalor, S.J.; McLoughlin, R.M.; Curtis, A.M.; O’Neill, L.A.J. The circadian protein BMAL1 in myeloid cells is a negative regulator of allergic asthma. Am. J. Physiol. Lung Cell. Mol. Physiol. 2017, 312, L855–L860.
  18. Partridge, M.R.; Karlsson, N.; Small, I.R. Patient insight into the impact of chronic obstructive pulmonary disease in the morning: An internet survey. Curr. Med. Res. Opin. 2009, 25, 2043–2048.
  19. Vij, N.; Chandramani-Shivalingappa, P.; Van Westphal, C.; Hole, R.; Bodas, M. Cigarette Smoke-induced Autophagy Impairment Accelerates Lung Aging, Copd-emphysema Exacerbations and Pathogenesis. Am. J. Physiol. Cell Physiol. 2018, 314, C73–C87.
  20. Casale, R.; Pasqualetti, P. Cosinor analysis of circadian peak expiratory flow variability in normal subjects, passive smokers, heavy smokers, patients with chronic obstructive pulmonary disease and patients with interstitial lung disease. Respir. Int. Rev. Thorac. Dis. 1997, 64, 251–256.
  21. Dawkins, K.D.; Muers, M.F. Diurnal Variation in Airflow Obstruction in Chronic Bronchitis. Thorax 1981, 36, 618–621.
  22. Calverley, P.M.A. Effect of Tiotropium Bromide on Circadian Variation in Airflow Limitation in Chronic Obstructive Pulmonary Disease. Thorax 2003, 58, 855–860.
  23. Sundar, I.K.; Yao, H.; Sellix, M.T.; Rahman, I. Circadian Molecular Clock in Lung Pathophysiology. Am. J. Physiol. Lung Cell. Mol. Physiol. 2015, 309, L1056–L1075.
  24. Hwang, J.W.; Sundar, I.K.; Yao, H.; Sellix, M.T.; Rahman, I. Circadian clock function is disrupted by environmental tobacco/cigarette smoke, leading to lung inflammation and injury via a SIRT1-BMAL1 pathway. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biology 2014, 28, 176–194.
  25. Sundar, I.K.; Rashid, K.; Sellix, M.T.; Rahman, I. The Nuclear Receptor and Clock Gene Rev-erbα Regulates Cigarette Smoke-induced Lung Inflammation. Biochem. Biophys. Res. Commun. 2017, 493, 1390–1395.
  26. Wang, Q.; Sundar, I.K.; Lucas, J.H.; Muthumalage, T.; Rahman, I. Molecular Clock Rev-erbα Regulates Cigarette Smoke–induced Pulmonary Inflammation and Epithelial-mesenchymal Transition. JCI Insight 2021, 6, e145200.
  27. Shi, Y.; Cao, J.; Gao, J.; Zheng, L.; Goodwin, A.; An, C.H.; Patel, A.; Lee, J.S.; Duncan, S.R.; Kaminski, N. Retinoic Acid–related Orphan Receptor-α Is Induced in the Setting of DNA Damage and Promotes Pulmonary Emphysema. Am. J. Respir. Crit. Care Med. 2012, 186, 412–419.
  28. Yao, H.; Sundar, I.K.; Huang, Y.; Gerloff, J.; Sellix, M.T.; Sime, P.J.; Rahman, I. Disruption of Sirtuin 1–mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Cell Mol. Biol. 2015, 53, 782–792.
  29. Li, L.; Zhang, M.; Zhao, C.; Cheng, Y.; Liu, C.; Shi, M. Circadian Clock Gene Clock-bmal1 Regulates Cellular Senescence in Chronic Obstructive Pulmonary Disease. BMC Pulm. Med. 2022, 22, 435.
  30. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J. Clin. 2018, 68, 394–424.
  31. Larsson, S.C.; Carter, P.; Kar, S.; Vithayathil, M.; Mason, A.M.; Michaëlsson, K.; Burgess, S. Smoking, Alcohol Consumption, and Cancer: A Mendelian Randomisation Study in UK Biobank and International Genetic Consortia Participants. PLOS Med. 2020, 17, e1003178.
  32. Gandini, S.; Botteri, E.; Iodice, S.; Boniol, M.; Lowenfels, A.B.; Maisonneuve, P.; Boyle, P. Tobacco Smoking and Cancer: A Meta-analysis. Int. J. Cancer 2008, 122, 155–164.
  33. Aredo, J.V.; Luo, S.J.; Gardner, R.M.; Sanyal, N.; Choi, E.; Hickey, T.P.; Riley, T.L.; Huang, W.-Y.; Kurian, A.W.; Leung, A.N. Tobacco Smoking and Risk of Second Primary Lung Cancer. J. Thorac. Oncol. 2021, 16, 968–979.
  34. Wang, J.; Tang, H.; Duan, Y.; Yang, S.; An, J. Association Between Sleep Traits and Lung Cancer: A Mendelian Randomization Study. J. Immunol. Res. 2021, 2021, 1893882.
  35. Huang, B.-H.; Duncan, M.J.; Cistulli, P.A.; Nassar, N.; Hamer, M.; Stamatakis, E. Sleep and Physical Activity in Relation to All-cause, Cardiovascular Disease and Cancer Mortality Risk. Br. J. Sport. Med. 2022, 56, 718–724.
  36. Stone, C.R.; Haig, T.R.; Fiest, K.M.; Mcneil, J.; Brenner, D.R.; Friedenreich, C.M. The Association between Sleep Duration and Cancer-specific Mortality: A Systematic Review and Meta-analysis. Cancer Causes Control 2019, 30, 501–525.
  37. Xie, J.; Zhu, M.; Ji, M.; Fan, J.; Huang, Y.; Wei, X.; Jiang, X.; Xu, J.; Yin, R.; Wang, Y.; et al. Relatsh Between Sleep Trait Lung Cancer Risk: A Prospect. Cohort Study UK Biobank. Sleep 2021, 44, zsab089.
  38. Huo, Z.; Ge, F.; Li, C.; Cheng, H.; Lu, Y.; Wang, R.; Wen, Y.; Yue, K.; Pan, Z.; Peng, H.; et al. Genetically predicted insomnia and lung cancer risk: A Mendelian randomization study. Sleep Med. 2021, 87, 183–190.
  39. Cao, Q.; Zhang, Q.; Li, X.C.; Ren, C.F.; Qiang, Y. Impact of sleep status on lung adenocarcinoma risk: A prospective cohort study. Eur. Rev. Med. Pharmacol. Sci. 2022, 26, 7641–7648.
  40. Zeng, Z.L.; Wu, M.W.; Sun, J.; Sun, Y.L.; Cai, Y.C.; Huang, Y.J.; Xian, L.J. Effects of the biological clock gene Bmal1 on tumour growth and anti-cancer drug activity. J. Biochem. 2010, 148, 319–326.
  41. Sulli, G.; Lam, M.T.Y.; Panda, S. Interplay between Circadian Clock and Cancer: New Frontiers for Cancer Treatment. Trends Cancer 2019, 5, 475–494.
  42. Qiu, M.; Chen, Y.B.; Jin, S.; Fang, X.F.; He, X.X.; Xiong, Z.F.; Yang, S.L. Research on circadian clock genes in non-small-cell lung carcinoma. Chronobiol. Int. 2019, 36, 739–750.
  43. Vasu, V.T.; Cross, C.E.; Gohil, K. Nr1d1, an important circadian pathway regulatory gene, is suppressed by cigarette smoke in murine lungs. Integr. Cancer Ther. 2009, 8, 321–328.
  44. Jiang, W.; Zhao, S.; Jiang, X.; Zhang, E.; Hu, G.; Hu, B.; Zheng, P.; Xiao, J.; Lu, Z.; Lu, Y.; et al. The circadian clock gene Bmal1 acts as a potential anti-oncogene in pancreatic cancer by activating the p53 tumor suppressor pathway. Cancer Lett. 2016, 371, 314–325.
  45. Gotoh, T.; Vila-Caballer, M.; Santos, C.S.; Liu, J.; Yang, J.; Finkielstein, C.V. The Circadian Factor Period 2 Modulates P53 Stability and Transcriptional Activity in Unstressed Cells. Mol. Biol. Cell 2014, 25, 3081–3093.
  46. Gotoh, T.; Kim, J.K.; Liu, J.; Vila-Caballer, M.; Stauffer, P.E.; Tyson, J.J.; Finkielstein, C.V. Model-driven Experimental Approach Reveals the Complex Regulatory Distribution of P53 by the Circadian Factor Period 2. Proc. Natl. Acad. Sci. USA 2016, 113, 13516–13521.
  47. Gotoh, T.; Vila-Caballer, M.; Liu, J.; Schiffhauer, S.; Finkielstein, C.V. Association of the Circadian Factor Period 2 to P53 Influences P53′s Function in Dna-damage Signaling. Mol. Biol. Cell 2015, 26, 359–372.
  48. Zhanfeng, N.; Chengquan, W.; Hechun, X.; Jun, W.; Lijian, Z.; Dede, M.; Wenbin, L.; Lei, Y. Period2 Downregulation Inhibits Glioma Cell Apoptosis by Activating the MDM2-TP53 Pathway. Oncotarget 2016, 7, 27350–27362.
  49. Fu, L.; Pelicano, H.; Liu, J.; Huang, P.; Lee, C.C. The Circadian Gene Period2 Plays an Important Role in Tumor Suppression and DNA Damage Response in Vivo. Cell 2002, 111, 41–50.
  50. Jung, C.-H.; Kim, E.M.; Park, J.K.; Hwang, S.-G.; Moon, S.-K.; Kim, W.-J.; Um, H.-D. Bmal1 Suppresses Cancer Cell Invasion by Blocking the Phosphoinositide 3-kinase-akt-mmp-2 Signaling Pathway. Oncol. Rep. 2013, 29, 2109–2113.
  51. Iksen; Pothongsrisit, S.; Pongrakhananon, V. Targeting the Pi3k/akt/mtor Signaling Pathway in Lung Cancer: An Update Regarding Potential Drugs and Natural Products. Molecules 2021, 26, 4100.
  52. Bastani, S.; Akbarzadeh, M.; Rastgar Rezaei, Y.; Farzane, A.; Nouri, M.; Mollapour Sisakht, M.; Fattahi, A.; Akbarzadeh, M.; Reiter, R.J. Melatonin as a Therapeutic Agent for the Inhibition of Hypoxia-induced Tumor Progression: A Description of Possible Mechanisms Involved. Int. J. Mol. Sci. 2021, 22, 10874.
  53. Zhao, H.; Wu, Q.-Q.; Cao, L.-F.; Qing, H.-Y.; Zhang, C.; Chen, Y.-H.; Wang, H.; Liu, R.-R.; Xu, D.-X. Melatonin Inhibits Endoplasmic Reticulum Stress and Epithelial-mesenchymal Transition During Bleomycin-induced Pulmonary Fibrosis in Mice. PLoS ONE 2014, 9, e97266.
  54. Shen, H.; Cook, K.; Gee, H.E.; Hau, E. Hypoxia, Metabolism, and the Circadian Clock: New Links to Overcome Radiation Resistance in High-grade Gliomas. J. Exp. Clin. Cancer Res. 2020, 39, 129.
  55. Balsara, B.R.; Pei, J.; Mitsuuchi, Y.; Page, R.; Klein-Szanto, A.; Wang, H.; Unger, M.; Testa, J.R. Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 2004, 25, 2053–2059.
  56. Scheffler, M.; Bos, M.; Gardizi, M.; König, K.; Michels, S.; Fassunke, J.; Heydt, C.; Künstlinger, H.; Ihle, M.; Ueckeroth, F. PIK3CA Mutations in Non-small Cell Lung Cancer (NSCLC): Genetic Heterogeneity, Prognostic Impact and Incidence of Prior Malignancies. Oncotarget 2015, 6, 1315–1326.
  57. Zhao, D.; Dong, Y.; Duan, M.; He, D.; Xie, Q.; Peng, W.; Cui, W.; Jiang, J.; Cheng, Y.; Zhang, H. Circadian Gene ARNTL Initiates Circgucy1a2 Transcription to Suppress Non-small Cell Lung Cancer Progression via Mir-200c-3p/pten Signaling. J. Exp. Clin. Cancer Res. 2023, 42, 229.
  58. Rossner, M.J.; Oster, H.; Wichert, S.P.; Reinecke, L.; Wehr, M.C.; Reinecke, J.; Eichele, G.; Taneja, R.; Nave, K.-A. Disturbed Clockwork Resetting in Sharp-1 and Sharp-2 Single and Double Mutant Mice. PLoS ONE 2008, 3, e2762.
  59. Liu, Q.; Wu, Y.; Seino, H.; Haga, T.; Yoshizawa, T.; Morohashi, S.; Kijima, H. Correlation between DEC1/DEC2 and Epithelial-mesenchymal Transition in Human Prostate Cancer PC-3 Cells. Mol. Med. Rep. 2018, 18, 3859–3865.
  60. Wu, Y.; Sato, H.; Suzuki, T.; Yoshizawa, T.; Morohashi, S.; Seino, H.; Kawamoto, T.; Fujimoto, K.; Kato, Y.; Kijima, H. Involvement of C-myc in the Proliferation of MCF-7 Human Breast Cancer Cells Induced by Bhlh Transcription Factor DEC2. Int. J. Mol. Med. 2015, 35, 815–820.
  61. Amelio, I.; Melino, G. The “sharp” blade against Hif-mediated Metastasis. Cell Cycle 2012, 11, 4530–4535.
  62. Montagner, M.; Enzo, E.; Forcato, M.; Zanconato, F.; Parenti, A.; Rampazzo, E.; Basso, G.; Leo, G.; Rosato, A.; Bicciato, S. SHARP1 Suppresses Breast Cancer Metastasis by Promoting Degradation of Hypoxia-inducible Factors. Nature 2012, 487, 380–384.
  63. Liao, Y.; Lu, W.; Che, Q.; Yang, T.; Qiu, H.; Zhang, H.; He, X.; Wang, J.; Qiu, M.; Zou, Y. SHARP1 Suppresses Angiogenesis of Endometrial Cancer by Decreasing Hypoxia-inducible Factor-1α Level. PLoS ONE 2014, 9, e99907.
  64. Piccolo, S.; Enzo, E.; Montagner, M. p63, Sharp1, and HIFs: Master regulators of metastasis in triple-negative breast cancer. Cancer Res. 2013, 73, 4978–4981.
  65. Falvella, F.S.; Colombo, F.; Spinola, M.; Campiglio, M.; Pastorino, U.; Dragani, T.A. BHLHB3: A Candidate Tumor Suppressor in Lung Cancer. Oncogene 2008, 27, 3761–3764.
  66. Gallo, C.; Fragliasso, V.; Donati, B.; Torricelli, F.; Tameni, A.; Piana, S.; Ciarrocchi, A. The Bhlh Transcription Factor DEC1 Promotes Thyroid Cancer Aggressiveness by the Interplay with NOTCH1. Cell Death Dis. 2018, 9, 871.
  67. Liao, Y.; He, X.; Qiu, H.; Che, Q.; Wang, F.; Lu, W.; Chen, Z.; Qiu, M.; Wang, J.; Wang, H. Suppression of the Epithelial-mesenchymal Transition by SHARP1 Is Linked to the NOTCH1 Signaling Pathway in Metastasis of Endometrial Cancer. BMC Cancer 2014, 14, 487.
  68. Liu, J.-J.; Chung, T.-K.; Li, J.; Taneja, R. Sharp-1 Modulates the Cellular Response to DNA Damage. FEBS Lett. 2010, 584, 619–624.
  69. Nakamura, H.; Tanimoto, K.; Hiyama, K.; Yunokawa, M.; Kawamoto, T.; Kato, Y.; Yoshiga, K.; Poellinger, L.; Hiyama, E.; Nishiyama, M. Human Mismatch Repair Gene, MLH1, Is Transcriptionally Repressed by the Hypoxia-inducible Transcription Factors, DEC1 and DEC2. Oncogene 2008, 27, 4200–4209.
  70. Liu, Y.; Wang, L.; Lin, X.-Y.; Wang, J.; Yu, J.-H.; Miao, Y.; Wang, E.-H. The Transcription Factor DEC1 (BHLHE40/STRA13/SHARP-2) Is Negatively Associated with TNM Stage in Non-small-cell Lung Cancer and Inhibits the Proliferation through Cyclin D1 in A549 and BE1 Cells. Tumor Biol. 2013, 34, 1641–1650.
  71. Raghu, G.; Collard, H.R.; Egan, J.J.; Martinez, F.J.; Behr, J.; Brown, K.K.; Colby, T.V.; Cordier, J.-F.; Flaherty, K.R.; Lasky, J.A. An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. Am. J. Respir. Crit. Care Med. 2011, 183, 788–824.
  72. Noble, P.W.; Barkauskas, C.E.; Jiang, D. Pulmonary Fibrosis: Patterns and Perpetrators. J. Clin. Investig. 2012, 122, 2756–2762.
  73. Kim, R.; Meyer, K.C. Therapies for interstitial lung disease: Past, present and future. Ther. Adv. Respir. Dis. 2008, 2, 319–338.
  74. Yue, X.; Shan, B.; Lasky, J.A. TGF-β: Titan of Lung Fibrogenesis. Curr. Enzym. Inhib. 2010, 6, 67–77.
  75. Gharaee-Kermani, M.; Hu, B.; Phan, S.H.; Gyetko, M.R. Recent advances in molecular targets and treatment of idiopathic pulmonary fibrosis: Focus on TGFbeta signaling and the myofibroblast. Curr. Med. Chem. 2009, 16, 1400–1417.
  76. Khalil, N.; Xu, Y.D.; O’Connor, R.; Duronio, V. Proliferation of Pulmonary Interstitial Fibroblasts Is Mediated by Transforming Growth Factor-β1-induced Release of Extracellular Fibroblast Growth Factor-2 and Phosphorylation of P38 MAPK and JNK. J. Biol. Chem. 2005, 280, 43000–43009.
  77. King, T.E., Jr.; Pardo, A.; Selman, M. Idiopathic pulmonary fibrosis. Lancet 2011, 378, 1949–1961.
  78. Zhang, K.; Flanders, K.C.; Phan, S.H. Cellular localization of transforming growth factor-beta expression in bleomycin-induced pulmonary fibrosis. Am. J. Pathol. 1995, 147, 352–361.
  79. Sime, P.J.; Xing, Z.; Graham, F.L.; Csaky, K.G.; Gauldie, J. Adenovector-mediated Gene Transfer of Active Transforming Growth Factor-beta1 Induces Prolonged Severe Fibrosis in Rat Lung. J. Clin. Investig. 1997, 100, 768–776.
  80. Warshamana, G.S.; Pociask, D.A.; Fisher, K.J.; Liu, J.-Y.; Sime, P.J.; Brody, A.R. Titration of Non-replicating Adenovirus as a Vector for Transducing Active Tgf-β1 Gene Expression Causing Inflammation and Fibrogenesis in the Lungs of C57BL/6 Mice. Int. J. Exp. Pathol. 2002, 83, 183–202.
  81. Gibbs, J.; Ince, L.; Matthews, L.; Mei, J.; Bell, T.; Yang, N.; Saer, B.; Begley, N.; Poolman, T.; Pariollaud, M. An Epithelial Circadian Clock Controls Pulmonary Inflammation and Glucocorticoid Action. Nat. Med. 2014, 20, 919–926.
  82. Cunningham, P.S.; Meijer, P.; Nazgiewicz, A.; Anderson, S.G.; Borthwick, L.A.; Bagnall, J.; Kitchen, G.B.; Lodyga, M.; Begley, N.; Venkateswaran, R.V. The Circadian Clock Protein Reverbα Inhibits Pulmonary Fibrosis Development. Proc. Natl. Acad. Sci. USA 2020, 117, 1139–1147.
  83. Romero, Y.; Balderas-Martínez, Y.I.; Vargas-Morales, M.A.; Castillejos-López, M.; Vázquez-Pérez, J.A.; Calyeca, J.; Torres-Espíndola, L.M.; Patiño, N.; Camarena, A.; Carlos-Reyes, Á. Effect of Hypoxia in the Transcriptomic Profile of Lung Fibroblasts from Idiopathic Pulmonary Fibrosis. Cells 2022, 11, 3014.
  84. Patel, S.R. Obstructive Sleep Apnea. Ann. Intern. Med. 2019, 171, ITC81–ITC96.
  85. Rundo, J.V. Obstructive Sleep Apnea Basics. Clevel. Clin. J. Med. 2019, 86, 2–9.
  86. Dempsey, J.A. Central Sleep Apnea: Misunderstood and Mistreated! F1000Research 2019, 8, 981.
  87. Ishikawa, O.; Oks, M. Central Sleep Apnea. Clin. Geriatr. Med. 2021, 37, 469–481.
  88. Şenel, G.B.; Aliş, C.; Karadeniz, D. Are We Underestimating the Central Components of the Mixed Apneas?-A Hypothesis for Revised Scoring. J. Clin. Neurophysiol. Off. Publ. Am. Electroencephalogr. Soc. 2023, 40, 165–172.
  89. Semelka, M.; Wilson, J.; Floyd, R. Diagnosis and Treatment of Obstructive Sleep Apnea in Adults. Am. Fam. Physician 2016, 94, 355–360.
  90. Qaseem, A.; Dallas, P.; Owens, D.K.; Starkey, M.; Holty, J.E.; Shekelle, P.; Clinical Guidelines Committee of the American College of Physicians. Diagnosis of obstructive sleep apnea in adults: A clinical practice guideline from the American College of Physicians. Ann. Intern. Med. 2014, 161, 210–220.
  91. Walia, R.; Achilefu, A.; Crawford, S.; Jain, V.; Wigley, S.D.; McCarthy, L.H. Are at-home sleep studies performed using portable monitors (PMs) as effective at diagnosing obstructive sleep apnea (OSA) in adults as sleep laboratory-based polysomnography (PSG)? J. Okla. State Med. Assoc. 2014, 107, 642–644.
  92. Epstein, L.J.; Kristo, D.; Strollo, P.J., Jr.; Friedman, N.; Malhotra, A.; Patil, S.P.; Ramar, K.; Rogers, R.; Schwab, R.J.; Weaver, E.M.; et al. Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J. Clin. Sleep Med. 2009, 5, 263–276.
  93. Bonsignore, M.R.; Baiamonte, P.; Mazzuca, E.; Castrogiovanni, A.; Marrone, O. Obstructive Sleep Apnea and Comorbidities: A Dangerous Liaison. Multidiscip. Respir. Med. 2019, 14, 8.
  94. Marin-Oto, M.; Vicente, E.E.; Marin, J.M. Long Term Management of Obstructive Sleep Apnea and Its Comorbidities. Multidiscip. Respir. Med. 2019, 14, 21.
  95. Coste, O.; Beaumont, M.; Batéjat, D.; Beers, P.V.; Touitou, Y. Prolonged mild hypoxia modifies human circadian core body temperature and may be associated with sleep disturbances. Chronobiol. Int. 2004, 21, 419–433.
  96. Coste, O.; Beaumont, M.; Batéjat, D.; Beers, P.V.; Charbuy, H.; Touitou, Y. Hypoxic Depression of Melatonin Secretion After Simulated Long Duration Flights in Man. J. Pineal Res. 2004, 37, 1–10.
  97. Coste, O.; Beers, P.V.; Bogdan, A.; Charbuy, H.; Touitou, Y. Hypoxic alterations of cortisol circadian rhythm in man after simulation of a long duration flight. Steroids 2005, 70, 803–810.
  98. Wu, Y.; Tang, D.; Liu, N.; Xiong, W.; Huang, H.; Li, Y.; Ma, Z.; Zhao, H.; Chen, P.; Qi, X. Reciprocal Regulation Between the Circadian Clock and Hypoxia Signaling at the Genome Level in Mammals. Cell Metab. 2017, 25, 73–85.
  99. Yu, C.; Yang, S.-L.; Fang, X.; Jiang, J.-X.; Sun, C.-Y.; Huang, T. Hypoxia Disrupts the Expression Levels of Circadian Rhythm Genes in Hepatocellular Carcinoma. Mol. Med. Rep. 2015, 11, 4002–4008.
  100. Yang, M.Y.; Lin, P.W.; Lin, H.C.; Lin, P.M.; Chen, I.Y.; Friedman, M.; Hung, C.F.; Salapatas, A.M.; Lin, M.C.; Lin, S.F. Alternations of Circadian Clock Genes Expression and Oscillation in Obstructive Sleep Apnea. J. Clin. Med. 2019, 8, 1634.
  101. Pellegrino, R.; Kavakli, I.H.; Goel, N.; Cardinale, C.J.; Dinges, D.F.; Kuna, S.T.; Maislin, G.; Van Dongen, H.P.; Tufik, S.; Hogenesch, J.B.; et al. A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans. Sleep 2014, 37, 1327–1336.
  102. Clayville, L.R. Influenza update: A review of currently available vaccines. P T A Peer-Rev. J. Formul. Manag. 2011, 36, 659–684.
  103. Gaitonde, D.Y.; Moore, F.C.; Morgan, M.K. Influenza: Diagnosis and Treatment. Am. Fam. Physician. 2019, 100, 751–758.
  104. Javanian, M.; Barary, M.; Ghebrehewet, S.; Koppolu, V.; Vasigala, V.; Ebrahimpour, S. A brief review of influenza virus infection. J. Med. Virol. 2021, 93, 4638–4646.
  105. Nakagawa, H.; Noma, H.; Kotake, O.; Motohashi, R.; Yasuda, K.; Shimura, M. Optic Neuritis and Acute Anterior Uveitis Associated with Influenza A Infection: A Case Report. Int. Med. Case Rep. J. 2017, 10, 1–5.
  106. Dharmapalan, D. Influenza. Indian J. Pediatr. 2020, 87, 828–832.
  107. Sundar, I.K.; Ahmad, T.; Yao, H.; Hwang, J.-W.; Gerloff, J.; Lawrence, B.P.; Sellix, M.T.; Rahman, I. Influenza A Virus-dependent Remodeling of Pulmonary Clock Function in a Mouse Model of COPD. Sci. Rep. 2015, 5, 9927.
  108. Zhang, Z.; Hunter, L.; Wu, G.; Maidstone, R.; Mizoro, Y.; Vonslow, R.; Fife, M.; Hopwood, T.; Begley, N.; Saer, B. Genome-wide Effect of Pulmonary Airway Epithelial Cell–specific Bmal1 Deletion. FASEB J. 2019, 33, 6226–6238.
  109. Zhuang, X.; Magri, A.; Hill, M.; Lai, A.G.; Kumar, A.; Rambhatla, S.B.; Donald, C.L.; Lopez-Clavijo, A.F.; Rudge, S.; Pinnick, K. The Circadian Clock Components BMAL1 and Rev-erbα Regulate Flavivirus Replication. Nat. Commun. 2019, 10, 377.
  110. Borrmann, H.; Davies, R.; Dickinson, M.; Pedroza-Pacheco, I.; Schilling, M.; Vaughan-Jackson, A.; Magri, A.; James, W.; Balfe, P.; Borrow, P. Pharmacological Activation of the Circadian Component REV-ERB Inhibits HIV-1 Replication. Sci. Rep. 2020, 10, 13271.
  111. Guan, W.-J.; Ni, Z.-Y.; Hu, Y.; Liang, W.-H.; Ou, C.-Q.; He, J.-X.; Liu, L.; Shan, H.; Lei, C.-L.; Hui, D.S.C. Clinical Characteristics of Coronavirus Disease 2019 in China. New Engl. J. Med. 2020, 382, 1708–1720.
  112. Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R. A Novel Coronavirus from Patients with Pneumonia in China, 2019. New Engl. J. Med. 2020, 382, 727–733.
  113. Morin, C.M.; Carrier, J.; Bastien, C.; Godbout, R. Sleep and Circadian Rhythm in Response to the COVID-19 Pandemic. Can. J. Public Health 2020, 111, 654–657.
  114. Lai, J.; Ma, S.; Wang, Y.; Cai, Z.; Hu, J.; Wei, N.; Wu, J.; Du, H.; Chen, T.; Li, R. Factors Associated with Mental Health Outcomes Among Health Care Workers Exposed to Coronavirus Disease 2019. JAMA Netw. Open 2020, 3, e203976.
  115. Irwin, M.R. Sleep and Inflammation: Partners in Sickness and in Health. Nat. Rev. Immunol. 2019, 19, 702–715.
  116. Anderson, G.; Reiter, R.J. Melatonin: Roles in Influenza, COVID-19, and Other Viral Infections. Rev. Med. Virol. 2020, 30, e2109.
  117. Gibbs, J.E.; Blaikley, J.; Beesley, S.; Matthews, L.; Simpson, K.D.; Boyce, S.H.; Farrow, S.N.; Else, K.J.; Singh, D.; Ray, D.W. The Nuclear Receptor Rev-erbα Mediates Circadian Regulation of Innate Immunity Through Selective Regulation of Inflammatory Cytokines. Proc. Natl. Acad. Sci. USA 2012, 109, 582–587.
  118. Haspel, J.A.; Anafi, R.; Brown, M.K.; Cermakian, N.; Depner, C.; Desplats, P.; Gelman, A.E.; Haack, M.; Jelic, S.; Kim, B.S. Perfect Timing: Circadian Rhythms, Sleep, and Immunity—An NIH Workshop Summary. JCI Insight 2020, 5, e131487.
  119. Costantini, C.; Renga, G.; Sellitto, F.; Borghi, M.; Stincardini, C.; Pariano, M.; Zelante, T.; Chiarotti, F.; Bartoli, A.; Mosci, P.; et al. Microbes Era Circadian Medicine. Front. Cell. Infect. Microbiol. 2020, 10, 30.
  120. Zhuang, X.; Rambhatla, S.B.; Lai, A.G.; Mckeating, J.A. Interplay between Circadian Clock and Viral Infection. J. Mol. Med. 2017, 95, 1283–1289.
  121. Mazzoccoli, G.; Vinciguerra, M.; Carbone, A.; Relógio, A. The Circadian Clock, the Immune System, and Viral Infections: The Intricate Relationship between Biological Time and Host-virus Interaction. Pathogens 2020, 9, 83.
  122. Pariollaud, M.; Gibbs, J.E.; Hopwood, T.W.; Brown, S.; Begley, N.; Vonslow, R.; Poolman, T.; Guo, B.; Saer, B.; Jones, D.H. Circadian Clock Component Rev-erbα Controls Homeostatic Regulation of Pulmonary Inflammation. J. Clin. Investig. 2018, 128, 2281–2296.
  123. Perry, M.G.; Kirwan, J.R.; Jessop, D.S.; Hunt, L.P. Overnight Variations in Cortisol, Interleukin 6, Tumour Necrosis Factor A and Other Cytokines in People with Rheumatoid Arthritis. Ann. Rheum. Dis. 2009, 68, 63–68.
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