Galactose-modified small molecule modulator targets RORα to enhance circadian rhythm and alleviate periodontitis-associated alveolar bone loss

Circadian rhythm disturbances are frequently reported in patients recovering from traumatic brain injury (TBI). Since circadian clock output is mediated by some of the same molecular signaling cascades that regulate memory formation (cAMP/MAPK/CREB), cognitive problems reported by TBI survivors may be related to injury-induced dysregulation of the circadian clock. In laboratory animals, aberrant circadian rhythms in the hippocampus have been linked to cognitive and memory dysfunction. Here, we addressed the hypothesis that circadian rhythm disruption after TBI is mediated by changes in expression of clock genes in the suprachiasmatic nuclei (SCN) and hippocampus. After fluid-percussion TBI or sham surgery, male Sprague-Dawley rats were euthanized at 4 h intervals, over a 48 h period for tissue collection. Expression of circadian clock genes was measured using quantitative real-time PCR in the SCN and hippocampus obtained by laser capture and manual microdissection respectively. Immunofluorescence and Western blot analysis were used to correlate TBI-induced changes in circadian gene expression with changes in protein expression. In separate groups of rats, locomotor activity was monitored for 48 h. TBI altered circadian gene expression patterns in both the SCN and the hippocampus. Dysregulated expression of key circadian clock genes, such as Bmal1 and Cry1, was detected, suggesting perturbation of transcriptional-translational feedback loops that are central to circadian timing. In fact, disruption of circadian locomotor activity rhythms in injured animals occurred concurrently. These results provide an explanation for how TBI causes disruption of circadian rhythms as well as a rationale for the consideration of drugs with chronobiotic properties as part of a treatment strategy for TBI.

Primary open-angle glaucoma as a causal factor for circadian disruption: Living by the clock, in alignment with external time cues is an important condition for human health and well-being. Periodic changes in the ambient light serve as a key factor to synchronize the endogenously generated circadian rhythms. The retina perceives the photic signals and transmits them to the central body clock, the suprachiasmatic nuclei (SCN), via the retinohypothalamic tract. Primary open angle glaucoma (POAG) is an optic neuropathy, in which disease progression can be monitored by assessing damage to the retinal ganglion cells (RGCs) (Pérez-Rico et al., 2010; Feigl et al., 2011; Kankipati et al., 2011). Damage of retinal ganglion cells, particularly of intrinsically photosensitive RGCs (ipRGCs), is also one of the causes of circadian disruption. Pathophysiological mechanisms of POAG are complex, including elevated intraocular pressure (IOP), which adds mechanical stress, causing damage, dysfunction, and death of the RGCs (Figure 1). Glaucoma progression affects both image-forming and non-image-forming visual functions of RGCs. A central role of ipRGCs is to convey non-image-forming photic information to the clock. Their damage reduces light signaling to the SCN. Already in early stages of glaucoma, ipRGCs are dysfunctional (Pérez-Rico et al., 2010; Feigl et al., 2011; Kankipati et al., 2011).Figure 1: Melatonin potential to counteract complex circadian alterations with aging, neurodegeneration, specifically in glaucoma.ipRGCs: Intrinsically photosensitive retinal ganglion cells; SNPs: single nucleotide polymorphisms.As RGCs are progressively altered, and non-image-forming function is affected, circadian rhythms are disrupted, sleep is impaired, and mood is altered (Graticelli et al., 2015; Gubin et al., 2019, 2021). Circadian rhythm alterations are found in POAG as compared to age-matched healthy peers (Gubin et al., 2019). Circadian disruption worsens in advanced POAG (Gubin et al., 2019, Neroev et al., 2020), correlating to the increasing loss of ipRGCs with disease progression (Obara et al., 2016). Circadian rhythms also change with increasing age. Age-dependent circadian alterations are not necessarily related to retinal damage, as photic transduction to the central clock is not always compromised. When they are related to retinal damage, they can be due to either neurodegenerative ipRGCs damage, or to ipRGC damage caused by increased mean or deregulated circadian IOP. The intriguing principal difference between the presence or absence of retinal damage in aging is that the reduced light transmitted to the SCN by damaged ipRGCs phase-delays circadian rhythms, but ipRGC-uncompromised aging is commonly associated with phase-advanced circadian rhythms (Gubin et al., 2019). Since individual differences in sensitivity to light, and/or in endogenous melatonin production may interfere with this theoretical modeling, the search for specific genetic factors that may determine such individual differences constitutes a promising approach. In conditions where photic entrainment is compromised, not only is the alignment with external time cues altered, so can be the variability of overt physiologic functions. We showed that large inter-individual variability obscured the circadian IOP rhythm in POAG (Neroev et al., 2020). Circadian IOP rhythms had specific alterations manifested in advanced, but not in mild POAG, which were associated with the progressive damage and dysfunction of RGCs. In patients with RGCs' global loss volume above 15%, as assessed by high-definition optical coherence tomography, the 24-hour IOP rhythm peaked during the night, whereas in patients with stable POAG and a two-eye mean RGCs' global loss volume less than 10%, the IOP peaked predominantly during the daytime. Misalignment between circadian rhythms in body temperature and IOP increased as a function of global loss volume loss. Higher nocturnal IOP in POAG may adversely affect the disease state, fostering damage to RGCs (Neroev et al., 2020). Depending on individual genetic factors, these changes may manifest themselves to a different degree. Individual clock properties depend on numerous genetic factors, comprising clock genes and melatonin receptor genes, melatonin nuclear receptor 1b (MTNR1b) in particular, which may account for large individual differences in light sensitivity. Our pilot study of gene polymorphisms in POAG showed that the D-allele of the Angiotensin-converting enzyme holding a deletion of the 16th intron Alu repeat was significantly associated with alterations of the circadian IOP rhythm. It may also account for the resistance to IOP-lowering therapy (Neroev et al., 2020). Endogenous melatonin production in primary open-angle glaucoma: Glaucoma patients experienced reduced post-illumination pupil response (Kankipati et al., 2011) and reduced nocturnal melatonin suppression by light (Pérez-Rico et al., 2010). Clinical evidence for changes in the timing and mean values of endogenous melatonin production in POAG was also evident (reviewed in Gubin et al., 2021): in POAG, salivary melatonin can be lower than in age-matched controls without POAG; even greater alterations were observed In advanced stages of the disease. The main alteration concerned the time of maximal secretion of melatonin. Such altered melatonin production in POAG and other neurodegenerative pathologies can stem from different factors, including diminished light signaling due to a reduced sensitivity to light. The presence of certain gene polymorphisms can increase the susceptibility of carriers to these factors. We investigated 24-hour profiles of salivary melatonin under controlled lighting conditions and analyzed several clock genes and polymorphisms of the melatonin receptor gene MTNR1b (Gubin et al., 2021). Patients diagnosed with stable POAG had unaltered circadian rhythms of salivary melatonin and body temperature, which peaked at the anticipated time. Circadian rhythms of both variables were delayed, however, in patients diagnosed with advanced POAG (Gubin et al., 2019, 2021). Their 24-hour mean value and circadian amplitude of melatonin were also reduced (Gubin et al., 2021). Analysis of selected polymorphisms in clock and melatonin receptor genes revealed that these changes were observed specifically in carriers of the MTNR1B rs10830963 G-allele with advanced POAG. Overt changes of circadian phenotypes in POAG patients occur when several factors are present in combination: for example, when RGC loss exceeds a certain threshold in carriers of those genotypes, known to be associated with a prolonged duration of melatonin production. The MTNR1B rs10830963 G-allele is mainly known for its association with an elevated fasting glucose and the risk of type 2 diabetes, but it is also listed as a factor predicting POAG independently of diabetes (Shen et al., 2016), a fact supporting the assumption that melatonin may have pleiotropic physiological functions in the development of POAG. Melatonin to counteract non-image-forming visual function deterioration in primary open-angle glaucoma: To enhance circadian entrainment, morning light therapy and evening melatonin administration can both be effective. While studies aimed at estimating the merit of morning light therapy or outdoor light exposure in POAG are lacking, some studies provide evidence for a beneficial effect of exogenously administered melatonin in glaucoma and neurodegenerative pathologies (González Fleitas et al., 2021; Gubin et al., 2021). Melatonin transmits environmental light signals, thus facilitating the synchronization of peripheral clocks. It can thus mitigate several conditions such as glaucoma and its progression: disruption of circadian rhythms, compromised sleep, and mood (Tosini et al., 2012; Gubin et al., 2021) (Figure 1). Melatonin improves internal synchronization, ameliorating circadian alignment between local (IOP) and systemic (temperature) circadian rhythms (Gubin et al., 2021), which were progressively desynchronized with greater RGCs loss in POAG (Neroev et al., 2020). Melatonin is produced endogenously with a pronounced 24-hour rhythm governed by the SCN. Peak production occurs at night. Its specific timing may differ among individuals. Exact endogenous factors that predetermine these differences are not known but may include single nucleotide polymorphisms within candidate genes or melatonin receptors that influence sensitivity to light. Melatonin receptors (MTNR1B) are widespread in numerous brain regions. Their structure may determine the specific response to (both endogenous and exogenous) melatonin. We investigated the effect of oral melatonin administration (daily at 10:30 p.m. for 90 days) on the circadian rhythms of IOP, body temperature, and the pattern electroretinogram in patients diagnosed with stable or advanced POAG, also assessing effects on sleep and mood (Gubin et al., 2021). Melatonin administration increased the stability of the circadian body temperature rhythm, improving its alignment with the circadian IOP rhythm. Melatonin decreased IOP to a different extent at different times of the day and decreased the standard deviation of IOP with statistical significance. Larger changes were found in patients with initially higher 24-hour mean values of IOP. Melatonin improved RGCs function in patients with advanced POAG by increasing the amplitude of pattern electroretinogram that correlated positively with the degree of RGCs loss. Melatonin had more pronounced positive effects on sleep and mood in patients with advanced POAG, who had greater damage of their RGCs. Taken together melatonin has the potential to restore disrupted circadian rhythms in POAG. Its systemic effect is distinct from its local effect on the retinal circadian rhythms. Similar to light exposure, physiological effects of melatonin depend on the time of its administration. Personalizing melatonin administration in terms of its timing and dosing, accounting for the genetic profile, is expected to further refine its multiple benefits. Melatonin may provide beneficial effects in POAG stemming from both its ability to reduce IOP and its potential to prevent RGC damage derived from mechanisms of neurodegeneration (Hardeland, 2021) (Figure 1). These effects may not only mitigate circadian disruption but also improve other aspects of health and well-being. Circadian alignment may strengthen human physiological functions and help slow neurodegeneration. The choice of an optimal melatonin dosing, however, is not yet clear (Hardeland, 2021). Consideration of the best timing should be based on internal circadian parameters and on genes that may account for personal differences in melatonin efficacy. Concluding remarks: In assessing disruptions in the non-image-forming visual system in POAG patients, one needs to discriminate between different situations. There may be complex, non-specific changes in circadian rhythms with age. Changes related to neurogenerative disease, including Alzheimer's disease, Parkinson's disease, and POAG, might promote alterations in neural structures: SCN, pineal, retina. Changes specific to POAG include additional RGC damage caused by the elevated IOP, together with abnormal circadian patterns of physiological variables such as IOP, body temperature, pattern electroretinogram, and melatonin (Figure 1). The circadian IOP pattern with relatively higher values during the resting span may foster harmful effects of IOP on RGCs, since tissue sensitivity may vary depending on circadian time (Neroev et al., 2020). Numerous candidate gene polymorphisms may play a role, alone or in combination with others, affecting the susceptibility to POAG itself (as a primary pathology of vision), or POAG-associated alterations of circadian rhythms, sleep, and mood, linked to non-visual pathways. To answer this question, clinical data combined with circadian profiles of melatonin and other physiological variables, chronotype questionnaires, sleep and mood information, to be checked against single nucleotide polymorphisms databases, should be collected on large cohorts. Constructive collaboration among ophthalmologists, chronobiologists, and geneticists is therefore advocated. The present work was supported by the Russian Foundation for Basic Research (grant No. 19-015-00329) (to DG), and by Government of Tyumen District, Decree of 20.11.2020 No. 928-rp (to DG). The authors have no proprietary or commercial interest in any materials discussed in this article.

Preface

The intergeniculate leaflet does not mediate the disruptive effects of constant light on circadian rhythms in the rat

The influence of circadian rhythms on memory has long been studied; however, the molecular prerequisites for their interaction remain elusive. The hippocampus, which is a region of the brain important for long-term memory formation and temporary maintenance, shows circadian rhythmicity in pathways central to the memory-consolidation process. As neuronal plasticity is the translation of numerous inputs, illuminating the direct molecular links between circadian rhythms and memory consolidation remains a daunting task. However, the elucidation of how clock genes contribute to synaptic plasticity could provide such a link. Furthermore, the idea that memory training could actually function as a zeitgeber for hippocampal neurons is worth consideration, based on our knowledge of the entrainment of the circadian clock system. The integration of many inputs in the hippocampus affects memory consolidation at both the cellular and the systems level, leaving the molecular connections between circadian rhythmicity and memory relatively obscure but ripe for investigation.

The circadian clock controls daily rhythms in animal physiology, metabolism, and behavior, such as the sleep‐wake cycle. Disruption of circadian rhythms has been revealed in many diseases including neurodegenerative disorders. Interestingly, patients with many neurodegenerative diseases often show problems with circadian clocks even years before other symptoms develop. Here we review the recent studies identifying the association between circadian rhythms and several major neurodegenerative disorders. Early intervention of circadian rhythms may benefit the treatment of neurodegeneration.

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 circadian rhythm is an endogenous process that has a periodicity of approximately 24 hours and stimulates the anticipation of repeated and regular events that occur daily, enabling the regulation of most major physiological systems in humans and animals. Thus, studies have shown that disruption of circadian rhythm and sleep is a frequent cause of a series of pathologies for the general population, including pregnant women and their fetus. The purpose of this article is to review the literature on the relationship between circadian rhythm and sleep disorders in pregnant women and the influence on the development of the fetus, as well as the future developing adult. Pregnancy is a critical period in which the systems of organs of a new human body are developing, and any disturbance in the environment in which the fetus grows can lead to developmental disorders that alter the metabolic and physiological functions of the fetus. Thus, maintaining an undisturbed circadian rhythm, including during pregnancy, protects the health of both the mother and the child, reducing the susceptibility to the development of certain postnatal diseases later in life.

With the exception of high latitudes, life has evolved under bright days and dark nights. Most organisms have developed endogenously driven circadian rhythms that are synchronized to this daily light/dark cycle. In recent years, humans have shifted away from the naturally occurring solar light cycle in favor of artificial and sometimes irregular light schedules produced by electric lighting. Exposure to unnatural light cycles is increasingly associated with obesity and metabolic syndrome; however, the means by which environmental lighting alters metabolism are poorly understood. Thus, we exposed mice to dim light at night and investigated changes in the circadian system and metabolism. Here we report that exposure to ecologically relevant levels of dim (5 lux) light at night altered core circadian clock rhythms in the hypothalamus at both the gene and protein level. Circadian rhythms in clock expression persisted during light at night; however, the amplitude of Per1 and Per2 rhythms was attenuated in the hypothalamus. Circadian oscillations were also altered in peripheral tissues critical for metabolic regulation. Exposure to dimly illuminated, as compared to dark, nights decreased the rhythmic expression in all but one of the core circadian clock genes assessed in the liver. Additionally, mice exposed to dim light at night attenuated Rev-Erb expression in the liver and adipose tissue. Changes in the circadian clock were associated with temporal alterations in feeding behavior and increased weight gain. These results are significant because they provide evidence that mild changes in environmental lighting can alter circadian and metabolic function. Detailed analysis of temporal changes induced by nighttime light exposure may provide insight into the onset and progression of obesity and metabolic syndrome, as well as other disorders involving sleep and circadian rhythm disruption.

Obstructive sleep apnea is the most common sleep-related breathing disorder worldwide and remains underdiagnosed. Its multiple associated comorbidities contribute to a decreased quality of life and work performance as well as an increased risk of death. Standard treatment seems to have limited effects on cardiovascular and metabolic aspects of the disease, emphasising the need for early diagnosis and additional therapeutic approaches. Recent evidence suggests that the dysregulation of circadian rhythms, processes with endogenous rhythmicity that are adjusted to the environment through various cues, is involved in the pathogenesis of comorbidities. In patients with obstructive sleep apnea, altered circadian gene expression patterns have been demonstrated. Obstructive respiratory events may promote circadian dysregulation through the effects of sleep disturbance and intermittent hypoxia, with subsequent inflammation and disruption of neural and hormonal homeostasis. In this review, current knowledge on obstructive sleep apnea, circadian rhythm regulation, and circadian rhythm sleep disorders is summarised. Studies that connect obstructive sleep apnea to circadian rhythm abnormalities are critically evaluated. Furthermore, pathogenetic mechanisms that may underlie this association, most notably hypoxia signalling, are presented. A bidirectional relationship between obstructive sleep apnea and circadian rhythm dysregulation is proposed. Approaching obstructive sleep apnea as a circadian rhythm disorder may prove beneficial for the development of new, personalised diagnostic, therapeutic and prognostic tools. However, further studies are needed before the clinical approach to obstructive sleep apnea includes targeting the circadian system.

Clock genes Cryptochrome (Cry1) and Cry2 are essential for expression of circadian rhythms in mice under constant darkness (DD). However, circadian rhythms in clock gene Per1 expression or clock protein PER2 are detected in the cultured suprachiasmatic nucleus (SCN) of neonatal Cry1 and Cry2 double deficient (Cry1 -/-/Cry2 -/-) mice. A lack of circadian rhythms in adult Cry1 -/-/Cry2 -/- mice is most likely due to developmentally disorganized cellular coupling of oscillating neurons in the SCN. On the other hand, neonatal rats exposed to constant light (LL) developed a tenable circadian system under prolonged LL which was known to fragment circadian behavioral rhythms. In the present study, Cry1 -/-/Cry2 -/- mice were raised under LL from postnatal day 1 for 7 weeks and subsequently exposed to DD for 3 weeks. Spontaneous movement was monitored continuously after weaning and PER2::LUC was measured in the cultured SCN obtained from mice under prolonged DD. Surprisingly, Chi square periodogram analysis revealed significant circadian rhythms of spontaneous movement in the LL-raised Cry1 -/-/Cry2 -/- mice, but failed to detect the rhythms in Cry1 -/-/Cry2 -/- mice raised under light-dark cycles (LD). By contrast, prolonged LL in adulthood did not rescue the circadian behavioral rhythms in the LD raised Cry1 -/-/Cry2 -/- mice. Visual inspection disclosed two distinct activity components with different periods in behavioral rhythms of the LL-raised Cry1-/-/Cry2-/- mice under DD: one was shorter and the other was longer than 24 hours. The two components repeatedly merged and separated. The patterns resembled the split behavioral rhythms of wild type mice under prolonged LL. In addition, circadian rhythms in PER2::LUC were detected in some of the LL-raised Cry1-/-/Cry2-/- mice under DD. These results indicate that neonatal exposure to LL compensates the CRY double deficiency for the disruption of circadian behavioral rhythms under DD in adulthood.

Circadian rhythm, as a homeostatic tool of biological life, plays a vital role in regulating human physiology, metabolism, endocrinology, and emotional and cognitive behaviour. A disrupted circadian rhythm, marked by age-related alterations such as decreased variation in sleep-wake patterns and instability in the timing of these patterns, can worsen age-related problems such as increased oxidative stress and inflammation. Advancing age is associated with anomalies in the redox balance, gradual alterations in physiological functions and deregulation of various metabolic pathways. The mutual interaction between circadian rhythm and ageing may potentially contribute to the development of neurodegenerative disorders. Consistent alterations in circadian rhythms could lead to various degenerative disorders and aggravate age-related ailments. Therefore, understanding and unravelling the intricate interplay between circadian rhythm and ageing holds immense potential for developing therapeutic interventions and promoting healthy ageing strategies. In this review article, we discuss the role of circadian rhythms in physiology and their age-related changes that impact health. We focus on how disruptions in circadian rhythms, common with ageing, may increase risks for neurodegenerative disorders. Understanding this interaction holds promise for developing therapeutic approaches to support healthy ageing.

Background Shift work is associated with behavioral, psychosocial, and physiological consequences in the body that may cause cardiovascular disease (CVD) risk. Therefore, in this study we tried to demonstrate the disruption in circadian rhythm of blood pressure by ambulatory blood pressure monitor in shift working nurses. Methods A total of 50 nurses, 25 night shift working nurses (NSWN), and 25 day shift working nurses (DSWN) underwent ambulatory blood pressure monitoring (ABPM) for a period of 24 hours. Along with measurements of inflammatory markers (hs-CRP and IL-6) the risk factors for cardiovascular disease between NSWN and DSWN and their possible relationship with disrupted circadian rhythm were measured by circadian rhythm questionnaire. Results The mean systolic and diastolic pressure for a period of 24 hours and mean diastolic blood pressure analysis throughout the sleep time was found greater in the NSWN than the DSWN (118 mm Hg vs. 112 mm Hg, p < 0.05: 72 mm Hg vs. 68 mm Hg, p < 0.05: 62 mm Hg vs. 59 mm Hg, p < 0.05). High mean blood pressure readings were found to be more frequent in the NSWN (p < 0.05) than in DSWN. No significant differences were found in IL-6 and hs-CRP levels. However, a significant difference in circadian rhythm abnormality was found in NSWN than in DSWN. Conclusion The 7 day/24 hours ambulatory blood pressure monitoring (ABPM) in NSWN showed a reduced circadian rhythm variation in blood pressure along with abnormality in circadian rhythm itself as compared with DSWN. Work schedules and the consequent rest–activity schedules affect circadian rhythms, with likely long-term impact on health. Therefore, working in critical care unit during night hours leads to abnormal blood pressure in NSWN, suggesting that this type of work, in which sleep is disturbed, leading to mental stress, could be a direct risk factor in cardiovascular diseases.

Background and Aims It is common to see that patients with chronic kidney disease CKD are complaint with sleep disorders. The data reveal that lymphocytes are under the regulation of circadian rhythm in the peripheral blood of humans. CKD patients have shown to stay up in a low-grade inflammatory status. And these patients are associated with systemic inflammation and acquired immune deficiency. In this condition, there are disorders of expression of chemokine receptors and function of lymphocytes in patients with CKD. Since the disorders of circadian rhythm have been reported, it is supposed that some proteins regulating circadian rhythm of lymphocytes may involve in sleep disorders. It is reported that circadian clock gene edcoded proteins, nuclear PER and CRY ptochrome (CRY), play an important role in the regulation of circadian rhythm. Therefore, we designed a questionnaire to patients with CKD stages 1-5 and investigated the levels of CRY mRNA and protein in PB lymphocytes. Method This research enrolled 101 patients (52 male and 49 female) with CKD stages 1-5, who were admitted to Xiangya Hospital, Changsha, China from August 2017 to August 2018. CKD was defined as the reduced level of eGFR when they received the Pittsburgh Sleep Quality-Index (PSOI) questionnaire. Patients were screened by strict exclusion criteria. The clinical files included general information of patients and blood biochemical test data. Subjective sleep quality was assessed in all patients using the Pittsburgh Sleep Quality-Index (PSQI). The expression of circadian clock genes PER1 and CRY1 in peripheral blood leukocytes using quantitative RT-PCR and Western blotting. Results Sleep questionnaires were obtained from the 101 patients from CKD stage 1 to 5. There were significant differences between the group of PSQI ≤ 5 and PSQI > 5 in aging, Hb, HCT, Alb, ALT and CRP (Table1). The six valuables were chosen with Scr, eGFR, Ca, P, Hb and Anxiety/Depression score with logistic anlaysis. It was found that the values of Aging and Scr were significantly increased in high PSQI (Table 2). It also found that the PSQI score was negative correlated with the stage of CKD (Table 3). The higher level of PER1 and CRY1 in PBMC of CKD stage 1 patients was confirmed by Western blot and qRT-PCR. It was also found that the expression of PER1 and CRY1 significantly down regulated in the PBMC of CKD stage 5 patients. However, the expression of PER1 and CRY1 was no obviously differences of in the patients with CKD stage 2 to CKD stage 4 (Figure 1 and Figure 2). Conclusion It was found that the progress of CKD was associated with the degree of sleep disorders in our research. The score of PSQI was negativly correlated with the lower eGFR. It indicated that there is association between sleep quality and eGFR. It also found that Hb, HCT, Alb and ALT were significantly better in the group whose PSQI score was lower than 5. CRP is a hallmark of inflammations a close relation with sleep disorders. There is correlation between decreased sleep quality and elevated CRP level. It also found that the more aging and CRP, the higher PSQI score with logistical analysis in our research. It suggested that there is a chronic inflammation are associated with the sleep of the patients with CKD. PBMCs are invloved in status of inflammation. It indicated that the PBMCs of patients with CKD may be affected by the sleep disorders. The circadian rhythm can be also shown in human’s PBMCs. The proteins of Per and CRY were two of period circadian clock proteins. In our research, we test that the expression of PER1 and CRY1 in PBMCs of patients with CKD. It found that PER1 and CRY1 were higher expressed in patients with CKD stage 1 and lowest in patients with CKD stage 5. It suggested that the circadian rhythm of PBMCs was associated with the stage of CKD. It was said that the function of PBMCs also are affected in CKD, such as the regulation of cellular calcium homeostasis, which can influence the circadian rhythm.

IntroductionUnderstanding the intricate relationship between circadian rhythms and depression is crucial for developing effective interventions and treatments for individuals affected by depression. Circadian rhythms regulate various physiological and behavioral processes, while depression manifests as persistent feelings of sadness and disturbances in sleep, appetite, and energy levels. Emerging research suggests a significant interplay between circadian rhythm disruption and depression, highlighting the need for comprehensive analysis in this area.MethodologyA bibliometric and visual analysis of literature on circadian rhythms in depression from 2004 to 2024 was conducted using the Web of Science Core Collection. Data were analyzed using bibliometric tools including VOSviewer, CiteSpace, and Bibliometrix to identify publication trends, geographical distribution, authorship patterns, institutional collaborations, journal preferences, keyword co-occurrence, and highly cited references.ResultsAnalysis revealed a steady increase in publications and citations related to circadian rhythms in depression. The United States emerged as the leading contributor, with strong global collaborations. Key journals included Chronobiology International and Journal of Affective Disorders. Top keywords included circadian rhythm, depression, sleep, melatonin, and bipolar disorder. The most cited article is a review titled “Practice parameters for the indications for polysomnography and related procedures: An update for 2005”.ConclusionsThis study offers a comprehensive overview of research on circadian rhythms in depression, highlighting key trends, contributors, and interdisciplinary intersections.