Suprachiasmatic nucleus

SCN acts as a master clock in the mammalian brain [17, 18]. The SCN is a paired structure, bilaterally situated on either side of the third ventricle just above the optic chiasm [10, 18]. The neurons of the SCN are the smallest in size (~10 μm) and are closely packed in the core and shell region. The nuclei of SCN get photic signals through the RHT after exposure to light on the retina [10, 11]. Melanopsin (OPN4) containing non-visual retinal ganglion cells (RGCs) are most sensitive to blue light (464–484 nm wavelengths) and transmit the impulse to the SCN via RHT [19, 20]. RHT starts the signal transduction process in the SCN and ultimately regulates the expression of several clock genes. Additionally, peripheral tissues also express clock genes. RHT is a glutamatergic pathway. Glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP) act as the primary neurotransmitters. Glutamate acts through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. Activation of glutamatergic receptors increases intracellular calcium that activates different kinases such as calcium/calmodulin-dependent protein kinase (CaMK), mitogen-activated protein kinase (MAPK), and protein kinase A (PKA). The subsequent result is phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Phosphorylated CREB (p-CREB) then translocates to the nucleus and binds with calcium/cAMP response elements (CREs) in association with co-activators for the regulation of gene expression [18, 21–23]. Tischkau et al. [23] reported that the 5’-flanking region of Per1 and Per2 genes carried CRE that interacts with CREB for the expression of Per genes. The mutational study indicated the role of CRE in the expression of Per genes [17]. On the other hand, output signals from SCN reach the peripheral organs for the regulation of physiological and behavioral functions [24].

SCN makes a complex connection with the peripheral tissue clocks through the neural and hormonal mediators for the synchronization of circadian oscillations [12, 13]. Despite SCN-mediated regulation, all cells of the body have an endogenous clock system that can function autonomously to maintain circadian oscillations. At the molecular level, the activity of the circadian clock is driven by a complex network of transcription-translation feedback loop that regulates the rhythmic expression of clock-related genes. Transcription factors circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) induce the expression of core clock components, Per and cryptochrome (Cry). Subsequently, they regulate the activity of CLOCK and BMAL1 [25]. The output signals from the SCN neurons are associated with the expression of clock-controlled genes (CCGs). These genes contain promoter sequence (CACGTG) for binding of CLOCK-BMAL1 complex (E-box) in their upstream for the operation of the transcriptional cascade. The promoter region of arginine vasopressin (Avp), D-element binding protein (Dbp), and prokineticin 2 (Pk2) contain E-box. AVP acts as a neurotransmitter, DBP is a transcription factor, and PK2 is a regulator of different biological functions (sleep cycle, behavioral rhythm, and others) [26]. The endogenous clock system is synchronized with several environmental time cues (zeitgebers) like temperature, LD cycle, physical activity, and feeding behavior [27–29]. The external zeitgebers regulate the expression of the molecular components of the endogenous clock [26].

Events of expression of the clock genes

Approximately 12–14 core clock genes are most important for the regulation of human circadian rhythm [6, 30, 31]. The complex transcriptional/translational feedback loops (TTFLs) control the overall expression of core clock genes (Figure 1) [32, 33]. The common core clock genes are 3 Per genes (Per1–3), 2 Cry genes (Cry1–2), Bmal1, Clock, 3 retinoid-related orphan receptor (Ror, Ror α, β, and γ) genes, 2 genes of reverse-erythroblastosis (Rev-Erb; Rev-Erb α and β). A specific enzyme casein kinase 1 (CK1; CK1δ and ε) is a part of the mammalian circadian system. Furthermore, some other genes [neuronal period-aryl hydrocarbon receptor nuclear translocator single-minded protein 2 (Npas2/Mop4), Aryl hydrocarbon receptor nuclear translocator-like protein 2 (Arntl2/Mop9), and F-box/LRR repeat protein 3 (Fbxl3)] are also associated with clock functions.

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Figure 1. 

Regulation of expression of core clock genes in the SCN through the positive and negative feedback loop in the mammalian circadian system. P: PER; C: CRY; (-): repression; (+): induction; CL: CLOCK; BM: BMAL1; AC: acetyl group; Pi: phosphate; RORE: Ror response element; FBXL3: F-box protein, E3 ligase; Ccg: clock-controlled genes

Note. Adapted from “Melatonin: an endogenous miraculous indolamine, fights against cancer progression,” by Samanta S. J Cancer Res Clin Oncol. 2020;146:1893–922 (https://doi.org/10.1007/s00432-020-03292-w). © Springer-Verlag GmbH Germany, part of Springer Nature 2020.

The expression of Per, Cry, Ror α, and Rev-Erb α is mediated by the CLOCK-BMAL1 complex (Figure 1). CLOCK-BMAL1 heterodimer initially influences the rhythmic expression of the Per and Cry genes after binding at the E-box. Translation of PER and CRY in the cytoplasm promotes their accumulation and forms a heterodimer. Heterodimeric PER and CRY move into the nucleus and inhibit the transactivating effects of the CLOCK-BMAL1 complex, leading to the termination of transcription of Per, Cry, Ror, and Rev-Erb genes (Figure 1). This inhibition completes the negative feedback effects (Figure 1) [34, 35]. CRY and PER concentrations decrease at night, resulting in the discontinuation of their repressive activity. This event starts a new cycle of CLOCK-BMAL1 complex-mediated transcriptional activation [6, 36]. Cytoplasmic CKs [CK1δ and CK1ε] and F-box protein (FbxL3) are involved in the degradation of PER and CRY. CK1δ and CK1ε cleave the PER proteins after phosphorylation and ubiquitination [37, 38]. The ubiquitin E3 ligase (F-box protein), called FbxL3 degrades CRYs [39].

The positive feedback loop starts when CLOCK and BMAL1 induce the expression of other clock genes. CLOCK-BMAL1 complex recognizes E-box, which bears a specific nucleotide sequence CACGTG at the upstream of the core clock genes [40, 41]. This interaction exerts inductive effects on the expression of core clock genes. The orphan nuclear receptors Ror α and Rev-Erb α regulate the positive feedback loop. They translocate to the nucleus from the cytoplasm and recognize the RORE that contains a specific sequence (AAAGTAGGTCA) upstream of the Bmal1 promoter. Ror α induces the expression of Bmal1, while Rev-Erb α represses Bmal1 transcription. This antagonistic effect controls the rhythmic expression of Bmal1 [28, 34, 41]. The mutation of the Clock gene significantly downregulates the expression of the Per1–3 and Cry1–2 levels in SCN [42, 43]. In addition to CLOCK, NPAS2 (MOP4) can form a heterodimer with BMAL1 in the SCN to regulate the transcriptional activity. The expression of NPAS2 commonly occurs in peripheral vascularized tissues. The peripheral cells remain rhythmic in the absence of CLOCK; however, Npas2 knockout cells exhibit arrhythmic behavior [44].

Sleep disorder

Human circadian rhythm disorders are related to the activity of the internal clocks and the external LD cycle. The American Academy of Sleep Medicine has classified circadian rhythm sleep disorders (CRSDs) into several categories. These include advanced sleep phase disorder/syndrome (ASPD/ASPS), delayed sleep phase disorder/syndrome (DSPD/DSPS), free-running disorder (FRD), and irregular sleep-wake rhythm (ISWR) [26]. The features of these disorders have given in Table 1. Sleep disorders are also common phenomena in jet lag and shift work, but they are treated as extrinsic disorders and do not relate to circadian clock dysfunction. The jet lag and shift work-mediated CRSDs occur due to voluntary or imposed shifts in the sleeping time. Several non-communicable disorders like stroke, mania, depression, intracranial infection, head injury, and central nervous system (CNS) stimulant or depressant drugs are associated with CRSDs [26].

Neurodegenerative diseases

Neurodegenerative diseases are associated with progressive loss of vulnerable neurons in the brain, leading to decreased brain functions. Progressive loss of memory and cognitive impairments, and difficulty in moving and speaking are the common symptoms of neurodegenerative diseases [59, 60]. Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Pick’s disease, and progressive supranuclear palsy (PSP) are bidirectionally associated with circadian disruption [61–67]. Accumulation of insoluble misfolded or mutant protein aggregates like α-synuclein in PD, β-amyloid plaque and tau in AD, and huntingtin in HD, occur in these diseases [68]. Proteotoxic stress, impaired activity of ubiquitin–proteasomal and autophagosomal/lysosomal systems, mitochondrial dysfunction, glutamate toxicity, neuroinflammation, aging, and circadian dysfunction accelerate neurodegenerative disorders [63, 66, 69–71].

The circadian clock regulates the rhythmic expression of numerous genes and is also involved in protein processing and transmission of protein aggregates [68, 72, 73]. Circadian dysfunction promotes the formation of misfolded-protein aggregates and their transport. A proper sleep pattern can help to remove the misfolded protein. However, circadian deregulation also causes sleep disorders that accelerate the pathology of neurodegenerative diseases. At the experimental level, a study on postmortem tissue of patients with neurodegenerative disorders shows disruption in rhythmic expression of circadian genes [74]. This finding is also similar to the aging brain [75].

Disruption of circadian clock functions enhances oxidative stress (OS) that induces neurodegeneration [76]. In the brain, BMAL1 regulates the transcription of redox-related genes like nicotinamide adenine dinucleotide phosphate (NADPH) dependent quinone dehydrogenase (QR2), and aldehyde dehydrogenase 2 (ALDH2). The expression of these genes essentially regulates OS and neuronal damage [77, 78]. The clock components also interact with silent information regulator transcript 1 [SIRT1, nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin 1] for maintaining the cellular redox homeostasis [79] and the transcription of both CLOCK and BMAL1 in SCN [80]. Dysfunction of circadian rhythm and antioxidant activity influences PD and AD [66, 81].

Circadian dysfunction also decreases melatonin secretion. Melatonin is considered the hormone of darkness and shows its peak at midnight. This indolamine is involved in several regulatory functions and acts as a potent endogenous antioxidant. Melatonin and its derivatives reduce OS and protect the cells against OS-induced damage, maintain the proliferation of normal cells and prevent apoptosis-mediated cell degeneration [82, 83]. Shift work and night work hamper melatonin secretion and decrease its protective role against stress-induced various diseases, including neurodegenerative disorders. Moreover, circadian dysfunction alters the pattern of rhythmic secretion of different hormones from the pituitary. The output signal from the SCN regulates the activity of the hypothalamic-pituitary axis and secretion of tropic hormones. Misalignment of circadian rhythm increases the secretion of adrenocorticotropic hormone (ACTH), followed by the release of cortisol. Excess cortisol disrupts the sleep-wake cycle that promotes neurodegeneration [84].

Formation of neurofibrillary tangles and deposition of extracellular amyloid beta (Aβ) have been observed in AD patients. Missense mutations, single nucleotide polymorphisms (SNPs), and deregulated alternative splicing promote malformed tau protein synthesis [85, 86], which is very unstable and fails to bind with microtubule [87]. This protein accumulates as phosphorylated tau that contributes to neurofibrillary tangles formation. β-secretase and γ-secretase cleave the amyloid precursor protein to generate Aβ which forms β-amyloid plaques [88, 89]. Ma et al. [90] reported that circadian dysfunction increased Aβ synthesis by increasing β-secretase activity. Wang et al. [91] reported that Aβ altered Per1 and Per2 expression in SCN, which are associated with AD. Experiments on drosophila indicated that sufficient expression of PER exerted neuroprotection against oxidative damage [92]. PER also maintains the sleep-wake cycle and working memory [93]. Ablation of Per decreases antioxidant activity and increases OS that collectively influences neurodegeneration [92, 94]. Altered light exposure-mediated circadian desynchrony promotes AD in mice due to alteration in the expression of SIRT1 and activation of OS pathways in the hippocampus [95]. Aβ promotes the degradation of BMAL1, followed by circadian deregulation and advancement of AD [96]. Kress et al. [97] reported that Bmal1 knockout increases Aβ plaque formation. Deregulated expression of BMAL1 also disrupts PER and CRY expression and redox homeostasis that contributes to AD [98]. Li et al. [99] reported that CK1δ promotes phosphorylated tau deposition and neurofibrillary tangle formation. Administration of CK1 inhibitor protects the prefrontal cortex and hippocampus from Aβ plaque formation [100]. Thus, CK is also associated with AD development.

Circadian dysfunction and neuroinflammation are the common risk factor for PD. PD patients show deposition of α-synuclein as Lewy bodies. It has been suggested that α-synuclein is involved in the transport of synaptic vesicles [101]. However, aggregation of misfolded α-synuclein causes PD. A study on C57BL/6 mice in abnormal LD cycles (20:4 LD) exhibits neuroinflammation and poor motor skills. Kudo et al. [102] reported that circadian dysfunction overexpresses α-synuclein in a mouse model of PD. SNPs study in PD patients indicated a greater number of SNPs in Bmal1 and Per1 gene [103]. Although circadian dysfunction and neurodegenerative diseases are bidirectionally associated, the mutation in the Parkin gene (PRKN) increases the expression of CLOCK, CRY1, and CRY2 and decreases PER2 output. Additionally, mutant PRKN decreases mitochondrial oxygen consumption and energy production [104]. Breen et al. [105] observed the arrhythmic expression of BMAL1, PER2, and Rev-Erb α occurs in the sample taken from PD patients. Liu et al. [106] reported that deregulation of BMAL1 activity occurred in 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-treated mice, resulting in the reduction of dopaminergic neurons, decreased activity of tyrosine hydroxylase, and low levels of dopamine. Thus, improper BMAL1 activity may potentiate the pathogenesis of PD. The formation of mutant huntingtin (mHTT) protein initiates the pathologies of HD. Deregulated PER1 and PER2 expression had been observed in mice with HD [107, 108]. Smarr et al. [109] observed that SCN neurons decreased daytime firing in HD models. PSP patients exhibit poor sleep quality, sleep apnea, restless leg syndrome, and difficulty in falling asleep and staying asleep [110]. Circadian dysfunction influences PSP. CK1δ is also involved in neurofibrillary tangle formation in PSP and Pick disease [111].

Psychiatric disorders

Circadian disruption is associated with shift work, night work, jet lag, and exposure to outdoor light at night. A significant night-time light pollution occurs due to artificial light, which is a serious problem in different metro cities throughout the world. Light-at-night desynchronizes the circadian rhythm that promotes psycho-behavioral disorders along with several negative consequences for health. Seasonal affective disorder (SAD) may occur due to alteration of the LD cycle in the natural system during seasonal variation. Short day lengths in winter and prolonged day-light during long summer days have been observed in boreal and austral countries. People of this region can suffer from dysthymia during the short day lengths and euthymia during the long summer days.

Circadian disruption hampers the regular sleep-wake cycle and also suppresses melatonin secretion and night-time melatonin peak. The nocturnal melatonin peak maintains different physiological activities, including sleep cycle, hormone secretion, neurological activity, and psychological behavior. Impaired melatonin secretion advances different psychological disorders such as SAD, bipolar disorder (BD), unipolar depression, schizophrenia, autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) [112–114]. Treatment with melatonin in pharmacological doses improves psychiatric problems [115, 116]. Circadian rhythm dysfunction deregulates the sleep-wake cycle that influences psychological disorders. ASD is very common in children and is associated with a desynchronized sleep-wake cycle. Lai et al. [117] also reported that sleep disorders are a common problem in patients with autism. Daytime sleepiness in children increases the risk of ADHD [118].

Several authors discussed the relationship between circadian rhythm dysfunction and psychiatric disorders, specifically depression and mood problems [119–123]. Jet lag is a common problem for international flight crews. Sack [124] suggested that mood changes, particularly dysphoric mood, are associated with jet lag. Experimental data indicated that an eastward journey over a month promoted sleep deprivation and increased the risk of anxiety and depression [125]. Major depressive disorder (MDD) is a disease of alteration in mood and is associated with increased sadness and irritability. Alteration in sleep, sexual desire, or appetite, inability to experience pleasure, slowing of speech or actions, crying, and suicidal thoughts are the symptomatic changes in the patients [126]. Several reports suggested that shift work and night work-dependent circadian rhythm dysfunction increases the outcome of MDD. Jet lag or social jet lag also influences MDD [122]. Decreased latency to rapid eye movement (REM) sleep, duration of slow-wave sleep and increased duration of REM sleep, disruption of melatonin and cortisol rhythms, and elevated nocturnal body temperature are associated with MDD [127]. Studies with postmortem brains of patients with MDD revealed that the core clock genes had expressed in reduced amplitude, shifted peaks, and phases [128]. Additionally, bilaterally ablation of SCN decreases immobility during forced swim tests on rats [129]. Applications of bright light therapy, wake therapy, social rhythm therapy, and antidepressants can improve MDD [122]. SCN-specific Bmal1-knockdown in mice and exposure to T22 LD cycle-induced desynchrony of the SCN in rats accelerates depressive-like behavior [130, 131].

Circadian rhythm disruption can increase the risk of anxiety. A study reported that non-shift workers had started to suffer from anxiety if they were facing rotating shift work schedules [132]. Similarly, nurses also showed higher anxiety scores on the Hospital Anxiety and Depression Scale [133]. Improper expression of core clock components influences anxiety-like disorders. Delta19 (Δ19) mutations in the Clock gene of mice decreased the symptoms of anxiety [134]. Per1 and Per2 deficient mice showed greater anxiety-related problems; however, lack of individual expression of either Per1 or Per2 had no effects on anxiety [135].

BD is characterized by cyclical changes in mood between mania and depression separated by an interval of normal affect. The episodes of mood in BD depend on the behavior of the person, sleep cycle, physical activity, and energy expenditure. A meta-analysis study has established the relationship between circadian rhythm disruption and BD [136]. Jet lag can influence the BD. Traveling in different time zones, particularly east to west occurs depression, whereas traveling from west to east develops mania [137]. Le-Niculescu et al. [138] reported that core clock genes were associated with BD. Polymorphisms in circadian clock-associated genes increase the risk of development of BD [139]. Lithium slows down the fast-running circadian clock and normalizes the circadian rhythm, which is an effective treatment for BD. Moreover, bright light therapy can improve BD [122, 139].

Schizophrenia is a typical mental disorder. The symptoms are delusion, hallucination, thought disorders, movement disorders, anhedonia, alogia, cognitive failure, and attention deficits. There are several reasons for schizophrenia. These include genetic factors (familiar), environmental (poverty, stress, exposure to viruses, and nutritional problems before birth), imbalances in neurotransmitters, and abnormalities in brain functions. Moreover, circadian rhythm disruption and sleep disorders are also associated with schizophrenia [122, 140, 141]. Studies on postmortem brain tissues of schizophrenia revealed the arrhythmic expression of many genes in the prefrontal cortex and rhythmic expression of mitochondrial genes, compared to healthy individuals [142]. Schizophrenia individuals show hyperactivity of the hypothalamic-pituitary-adrenal axis that stimulates stress-induced activities and motor functions [143, 144]. Circadian rhythm dysfunction alters the melatonin secretion in individuals, which promotes schizophrenia [145]. SNPs studies indicated that mutation in Ror β, Per2, Per3, and neuronal PAS domain protein 2 (Npas2) were associated with schizophrenia [146]. Peripheral tissues of schizophrenia tissues also showed arrhythmic expression of Clock, Per2, and Cry1 genes [147].

Cardiovascular disorder

Disruption of circadian rhythm is associated with cardiovascular diseases (CVD). Diurnal rhythms have been observed in heart rate, blood pressure, blood catecholamine secretion, cortisol secretion, platelet aggregation, and others. Changes in circadian rhythm modulate the sympathetic activity, secretion of catecholamines, and aldosterone biosynthesis, as the sympathetic activity controls the adrenal medullary functions as well as the renin-angiotensin system. The synergistic effect is impaired heart rate and blood pressure. Alteration in the circadian clock system also changes the fuel metabolism in cardiomyocytes. Normally, nicotinamide phosphoribosyltransferase (NAMPT) regulates NAD biosynthesis. Dysregulation of NAD synthesis alters the utilization of fatty acids, the primary fuel source. This activity is mediated by the peroxisome proliferators activated receptor γ (PPARγ) signaling system. Circadian dysfunction in endothelial cells alters the activity of Akt and nitric oxide (NO) signaling. NO is essential for vascular relaxation. Dysregulation of NO activity initiates hypertension (Figure 2) [148–150].

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Figure 2. 

Effects of circadian clock dysfunction on different tissues and progression of various disorders. NMDAR: NMDA receptor; AMPAR: AMPA receptor; Cyp7A1: cholesterol 7α-hydroxylase; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; PEPCK: phosphoenolpyruvate carboxykinase; NAFLD: non-alcoholic fatty liver disease; HCC: hepatocellular carcinoma; GI: gastrointestinal; E: epinephrine; NE: norepinephrine; CHK 1: checkpoint kinase 1; WEE1: a specific G2 check point kinase; p53: tumor suppressor protein 53; ↑: increase; ↓: decrease

Metabolic disorder

In the recent era, metabolic disorders are a serious problem in our society. These include obesity, hyperglycemia, type 2 diabetes, dyslipidemia, and hypertension [149, 151, 152]. Metabolic disorders alter blood triglyceride, high-density lipoprotein, and fasting blood glucose levels, as well as inflammatory markers [C-reactive protein, tumor necrosis factor-α (TNF-α), interleukin-6, and plasminogen activator inhibitor type 1] and anti-inflammatory components [149]. Circadian clock disorder is a vital contributor to cancer, diabetes, obesity, and cardiometabolic disorders (Figure 2) [153]. Various nuclear hormone receptors like PPARα, PPARγ, Rev-Erb α, Ror α, hepatocyte nuclear factor 4α (HNF4α), thyroid hormone receptor α (TRα), and nuclear receptor related 1 (NURR1) directly regulate the metabolic pathway. The circadian clock has a link with these nuclear hormone receptors. Imbalance in the circadian clock affects PPARγ-mediated lipogenesis and lipid storage, PPARα-dependent ketogenesis, and hepatic fatty acid oxidation [154]. The occurrence of type 2 diabetes mellitus and obesity are much higher in night shift workers than the day shift workers [153, 155]. An animal model study in an alternative LD cycle revealed that the profile of blood glucose, insulin, and triglyceride levels differ according to the alternative circadian system [156]. Polymorphic variations indicate that clock genes like Clock, Per2, Per3, Bmal2, Cry1, and Cry2 are responsible for metabolic disorders [157]. Mutant animals exhibit chronodisruption and disorder in lipid metabolism by changing the pattern of cholesterol metabolism, expression of lipase enzyme, and production of glycerol and free fatty acids during the circadian period; all of which are associated with adipocyte hypertrophy and dyslipidemia [158]. Gabriel and Zierath [159] reported that skeletal muscle has a strong circadian profile. Shift workers are prone to insulin resistance and type 2 diabetes. Timed exercise is most beneficial for improving health and metabolic diseases. Different organs are directly or indirectly affected by metabolic disorders (Figure 2).

Circadian dysregulation and cancer progression

SCN-mediated dysfunction of circadian events advances cancers in the different tissues. Clock components regulate the expression of factors related to the cell cycle, DNA repair, metabolism, redox homeostasis, and others. They control the secretion of cytokines, hormones, neurotransmitters, tumor-specific metabolites, and the activity of oncogenic proteins. Collectively, disruption of circadian function alters cellular functions, leading to the progression of cancer development (Figure 2) [184]. In our modern society, people are involved in shift work and night work. They have been exposed to bright light-at-night in industrial sectors, the medical profession, transport services, and others, resulting in misalignment of circadian rhythm that leads to disruption of the sleep-wake cycle, metabolic disorder, and cancer progression. The epidemiological and experimental studies revealed that circadian dysfunction was associated with cancer. International Agency for Research on Cancer (IARC) has categorized the shift-work as “carcinogenic to humans (Group 2A)” [185]. A recent report indicates that night shift work enhances the risks of breast, prostate, and colorectal cancer [186–188].

The study of SNP indicates the role of clock genes in disease progression, including cancer [6, 28, 157, 189]. Any alteration or improper expression of clock genes such as Clock, Bmal1, Ck1ε, Cry1–2, Npas2, and Per1–3 promotes the formation of different cancers like breast, colorectal, prostate, pancreatic, and non-Hodgkin lymphoma [6, 28, 190]. Deregulation of expression of the core clock genes Per1, Per2, Per3, Cry1, Cry2, Bmal1, and Clock are associated with the development of cancer in humans [30, 191]. Impaired expression of Per1, Per2 and/or Per3 had been observed in several cancers, including breast [191, 192], prostate [193, 194], oral [195], pancreatic [196, 197], hepatocellular [198], colorectal [199], non-small cell lung cancer [200], renal [201], bladder [202], myeloid leukemia [203, 204], glioma [205], and squamous cell carcinoma [206]. The cell cycle suppressor protein WEE1 is also regulated by PER and CRY. Alteration in Cry expression deregulates the synthesis of WEE1 (a specific G2 check point kinase, cell cycle suppressor protein) and cyclin D1; the result is impaired cell proliferation and tumor growth [207, 208]. Mutation in the Cry2 gene increases the risk of lymphoma [209]. Valenzuela et al. [157] reported that polymorphisms of Clock, Per2, Per3, Bmal1, Cry1, Cry2, Tim, and Ror β genes are associated with breast colorectal and prostate cancer. Variants of Cry genes increase the risk of non-Hodgkin’s lymphoma [209, 210]. Circadian disruption causes dyslipidemia as well as NAFLD [211]. SNP of Per3 and Cry1 genes promotes HCC [212]. Shift work changes the lifestyle and pattern of metabolism that cause NAFLD and then non-alcoholic steatohepatitis (NASH); the result is hepatic fibrosis followed by cirrhosis and finally HCC [213]. Bile acid can influence the progression of HCC [211]. Circadian disruption affects cholesterol, bile acid, and xenobiotic metabolism. Bile acids promote non-genotoxic HCC by inducing NAFLD, and NASH. Chronodisruption increases the risk of ovarian cancers in females who are involved in night shift work. This might be associated with inappropriate expression of circadian genes [214]. Jim et al. [215] reported that variation in Arntl, Cry2, CK1ε, NpasS2, Per3, and Rev1 genes influences ovarian cancer.

Infertility disorder

Human infertility disorder is multifactorial, and one-third of the cases are male-associated. The activity of the reproductive system depends on the expression of the steroidogenic acute regulatory protein (STAR), rate of steroidogenesis, and luteinizing hormone (LH) surge before ovulation in females; while maintenance of sperm attributes in males are also crucial. All these activities are directly or indirectly associated with clock gene expression, as the SNP of Clock and Bmal1 is correlated with infertility [216–218].

Circadian disruption, physical performance, and accident rates

In our modern life, several activities such as medical services, uninterrupted power supply, operation of nuclear power plants, transport services, monitoring of satellite movements and the space shuttle, continuous operation of industrial work, and military activities are going on round the clock. In these sectors, people are working on different shifts. Sometimes the shifts are extended due to a shortage of manpower, and demand for service. The shifting duties, as well as extended shift, disrupts the circadian clock functions and various physiological rhythms (sleep cycle, melatonin secretion, core body temperature regulation, ACTH/cortisol secretion, plasma triacylglycerol, glucose homeostasis, and metabolic activities) of the body [14, 35]. Disruption of circadian rhythm is detrimental to health, particularly for CVD [219]. Circadian dysfunction also decreases alertness, cognitive functions, mood, social activities, and performance of physical work of an individual [220, 221]. Physical performance of the body depends on hormone secretion, core body temperature, and metabolic activity. The healthy individuals with normal LD cycles (12:12 LD) exhibit the highest physical performance and work efficiency in the daytime. The work capacity tends to decrease from the evening and reaches the minimum level within the period 2.00 A.M. to 4.00 A.M. when the core body temperature remains at the lowest value [222]. During this period, the body feels fatigued, which increases the chance of an accident.

The continuous phase changes in shift work and night work (about 20% in the industrialized nations) cause potential health hazards, and safety problems [219]. Many accidents (road, industrial, power plant) happen due to ill adaptation of circadian clock functions, feeling of fatigue, poor physical performance, decreased alertness, and mental disturbance [223–225]. A survey-based study related to the rate of vehicle accidents revealed that the number of accidents/collisions maximally happened after 2.00 A.M. Despite many reasons for the accident, the dysfunction of circadian events could not be ignored [226]. The major disastrous events like the Exxon Valdez supertanker accident in Alaska, the Chernobyl disaster (26th April 1986 at 1.23 A.M.), and the U.S. commercial nuclear power plant accident at 3 Mile Island, Pennsylvania (28th March 1979 at 4.00 A.M.) happened at the late night and circadian dysfunction mediated poor physical performance might be associated in these mishaps [226–228].

Circadian rhythm and jet lag

Jet lag is a transient disruption of the circadian system during transmeridian flights. It is the result of a temporary loss of synchrony between biological clock functions and an alternate LD cycle in the new time zone. The result is an abrupt change in the sleep-wake cycle according to the local time. Jet lag disrupts the feeding/fasting cycle, rest/activity cycle, and sleep-wake cycle [35]. The common symptoms of jet lag are fatigue and sleepiness during the day in the new time zone, inability to satisfactory sleep at night, loss of appetite, indigestion, cognitive distress, inability to co-ordinate with activity, loss of motivation, irritability, headache, and obesity [229–231]. The exogenous and endogenous components of the circadian system are mismatched until the internal clock is gradually re-entrained. The profiles of the body temperature, sleep-wake cycle, and endocrine functions have readjusted to local time, and the discomforts of jet lag disappear slowly. Recently, the use of melatonin is more popular to adjust the circadian rhythm rapidly. Light treatment may also give beneficial effects. However, light treatment and melatonin treatment counteract each other as melatonin production is reduced by light [232, 233]. Chronic jet lag is a common phenomenon for shift workers, flight attendants, and flight crews. Different studies indicated that chronic jet lag influences the elevated level of cortisol, poor cognitive functions, low working memory, learning problems, and higher rates of breast and prostate cancer [234, 235].