Circadian rhythm disorders are associated with dysfunction in inflammatory diseases,and targeted regulation of the circadian rhythm could serve as an intervention strategy.RORα/γ,as core components of circadian cloc...Circadian rhythm disorders are associated with dysfunction in inflammatory diseases,and targeted regulation of the circadian rhythm could serve as an intervention strategy.RORα/γ,as core components of circadian clock genes,positively modulate the key circadian molecule BMAL1.In this study,Gala-SR,a potent small-molecule compound designed to effectively regulate circadian rhythms,was synthesized through a monosaccharide modification prodrug strategy via a hydrolysable conjugation of galactose onto SR1078,an unique synthetic agonist of RORα/γ.Compared with SR1078,Gala-SR exhibited significantly greater aqueous solubility,cytocompatibility,pharmacokinetic characteristics and efficacy in the targeted activation of RORα.Importantly,Gala-SR ameliorated rhythm disorders by enhancing amplitude of the circadian rhythm both in vitro and in vivo.In circadian rhythm disordered mice with periodontitis,Gala-SR restored local circadian rhythm and mitigated inflammation in periodontal tissue in a circadian clock-dependent manner,and alleviated alveolar bone loss.Our study demonstrates that Gala-SR exhibits great promise in restoration of circadian rhythm and could potentially serve as a targeted therapeutic intervention for treating inflammatory diseases arising from disruptions in circadian rhythm.This work provides a feasible paradigm for the development and translational application of small molecule modulators targeting circadian rhythms.展开更多
The circadian clock is an important internal time regulatory system for a range of physiological and behavioral rhythms within living organisms.Testosterone,as one of the most critical sex hormones,is essential for th...The circadian clock is an important internal time regulatory system for a range of physiological and behavioral rhythms within living organisms.Testosterone,as one of the most critical sex hormones,is essential for the development of the reproductive system,maintenance of reproductive function,and the overall health of males.The secretion of testosterone in mammals is characterized by distinct circadian rhythms and is closely associated with the regulation of circadian clock genes.Here we review the central and peripheral regulatory mechanisms underlying the influence of circadian clock genes upon testosterone synthesis.We also examined the specific effects of these genes on the occurrence,development,and treatment of common male diseases,including late-onset hypogonadism,erectile dysfunction,male infertility,and prostate cancer.展开更多
This review explores the pivotal role of circadian rhythm regulators,particularly the PER genes,in Oral Squamous Cell Carcinoma(OSCC).As key constituents of the biological clock,PERs exhibit a downregulated expression...This review explores the pivotal role of circadian rhythm regulators,particularly the PER genes,in Oral Squamous Cell Carcinoma(OSCC).As key constituents of the biological clock,PERs exhibit a downregulated expression pattern in OSCC,and the expression levels of PERs in OSCC patients are correlated with a favorable prognosis.PERs impact the occurrence and development of OSCC through multiple pathways.In the regulation of cell proliferation,they can function not only through cell cycle regultion but also via metabolic pathways.For example,PER1 can interact with receptors for activated C kinase 1(RACK1)and phosphatidylinositol 3-kinase(PI3K)through its PAS domain to inhibit glycolysis and thereby reduce cell proliferation.Regarding the regulation of cell death,PERs mediate various types of cell death in OSCC cells,such as p53-dependent apoptosis,protein kinase B(AKT)/mammalian target of rapamycin(mTOR)dependent autophagy,or hypoxia-inducible factor l-alpha(HIF-1a)mediated ferroptosis.In regulating epithelia-mesenchymal transition(EMT),PERs can lead to the downregulation of EMT related genes,such as zinc finger E-box binding homeobox 1/2(ZEBI/2),twist family BHLH transcription factor 1/2(TWIST1/2),and Vimentin,thereby influencing the migration and invasion capabilities of OSCC cells.In tumor angiogenesis,PERs exert regulatory effects on related factors,such as methionyl aminopeptidase 2(MetAP2)and vascular endothelial growth factor(VEGF).In the tumor immune microenvironment,PERs can inhibit the inhibitor of kappa B kinase(IKK)/nuclear factor kappa B(NF-kB)pathway and programmed cell death ligand 1(PD-L1)expression,thereby enhancing the cytotoxic effect of CD8+T cells on OSCC cells.In-depth studies focusing on elucidating the precise regulatory mechanisms of PERs can facilitate the development of therapeutic strategies targeting PERs,including restoration of PERs expression/activity,targeting PERs-regulated pathways,combination therapies,and chronotherapy.These furnish a theoretical foundation for formulating individualized treatment plans to achieve precise treatment for patients with OSCC.展开更多
The circadian clock is a highly conserved timekeeping system in organisms,which maintains physiological homeostasis by precisely regulating periodic fluctuations in gene expression.Substantial clinical and experimenta...The circadian clock is a highly conserved timekeeping system in organisms,which maintains physiological homeostasis by precisely regulating periodic fluctuations in gene expression.Substantial clinical and experimental evidence has established a close association between circadian rhythm disruption and the development of various malignancies.Research has revealed characteristic alterations in the circadian gene expression profiles in tumor tissues,primarily manifested as a dysfunction of core clock components(particularly circadian locomotor output cycles kaput(CLOCK)and brain and muscle ARNT-like 1(BMAL1))and the widespread dysregulation of their downstream target genes.Notably,CLOCK demonstrates non-canonical oncogenic functions,including epigenetic regulation via histone acetyltransferase activity and the circadian-independent modulation of cancer pathways.This review systematically elaborates on the oncogenic mechanisms mediated by CLOCK/BMAL1,encompassing multidimensional effects such as cell cycle control,DNA damage response,metabolic reprogramming,and tumor microenvironment(TME)remodeling.Regarding the therapeutic strategies,we focus on cutting-edge approaches such as chrononutritional interventions,chronopharmacological modulation,and treatment regimen optimization,along with a discussion of future perspectives.The research breakthroughs highlighted in this work not only deepen our understanding of the crucial role of circadian regulation in cancer biology but also provide novel insights for the development of chronotherapeutic oncology,particularly through targeting the non-canonical functions of circadian proteins to develop innovative anti-cancer strategies.展开更多
The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and,either directly or indirectly,overall body health,encompassing metabolic and cardiovascular well-being.Given th...The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and,either directly or indirectly,overall body health,encompassing metabolic and cardiovascular well-being.Given the heightened metabolic activity of the brain,there exists a considerable demand for nutrients in comparison to other organs.Among these,the branched-chain amino acids,comprising leucine,isoleucine,and valine,display distinctive significance,from their contribution to protein structure to their involvement in overall metabolism,especially in cerebral processes.Among the first amino acids that are released into circulation post-food intake,branched-chain amino acids assume a pivotal role in the regulation of protein synthesis,modulating insulin secretion and the amino acid sensing pathway of target of rapamycin.Branched-chain amino acids are key players in influencing the brain's uptake of monoamine precursors,competing for a shared transporter.Beyond their involvement in protein synthesis,these amino acids contribute to the metabolic cycles ofγ-aminobutyric acid and glutamate,as well as energy metabolism.Notably,they impact GABAergic neurons and the excitation/inhibition balance.The rhythmicity of branchedchain amino acids in plasma concentrations,observed over a 24-hour cycle and conserved in rodent models,is under circadian clock control.The mechanisms underlying those rhythms and the physiological consequences of their disruption are not fully understood.Disturbed sleep,obesity,diabetes,and cardiovascular diseases can elevate branched-chain amino acid concentrations or modify their oscillatory dynamics.The mechanisms driving these effects are currently the focal point of ongoing research efforts,since normalizing branched-chain amino acid levels has the ability to alleviate the severity of these pathologies.In this context,the Drosophila model,though underutilized,holds promise in shedding new light on these mechanisms.Initial findings indicate its potential to introduce novel concepts,particularly in elucidating the intricate connections between the circadian clock,sleep/wake,and metabolism.Consequently,the use and transport of branched-chain amino acids emerge as critical components and orchestrators in the web of interactions across multiple organs throughout the sleep/wake cycle.They could represent one of the so far elusive mechanisms connecting sleep patterns to metabolic and cardiovascular health,paving the way for potential therapeutic interventions.展开更多
Major depressive disorder(MDD)affects people all over the world,and yet,its etiology is complex and remains incompletely understood.In this review,we aim to assess recent advances in understanding depression and its r...Major depressive disorder(MDD)affects people all over the world,and yet,its etiology is complex and remains incompletely understood.In this review,we aim to assess recent advances in understanding depression and its regulation,as well as its interaction with circadian rhythms.Circadian rhythms are internalized representations of the periodic daily light and dark cycles.Accumulating evidence has shown that MDD and the related mental disorders are associated with disrupted circadian rhythms.In particular,depression has often been linked to abnormalities in circadian rhythms because dysregulation of the circadian system increases susceptibility to MDD.The fact that several rhythms are disrupted in depressed patients suggests that these disruptions are not restricted to any one rhythm but rather involve the molecular circadian clock core machinery.The sleep-wake cycle is one rhythm that is often disrupted in depression,which often leads to disturbances in other rhythms.The circadian disruptions manifested in depressed patients and the effectiveness and fast action of chronobiologically based treatments highlight the circadian system as a key therapeutic target in the treatment of depression.This review assesses the evidence on rising depression rates and examines their contributing factors,including circadian misalignment.We discuss key hypotheses underlying depression pathogenesis,potential etiology,and relevant animal models,and underscore potential mechanisms driving depression's growing burden and how understanding these factors is critical for improving prevention and treatment strategies.展开更多
Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals an...Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals and prevent the onset of chronic disability and ultimately death.Underlying cellular mechanisms for the onset and development of DM are multi-factorial in origin and involve pathways associated with the production of reactive oxygen species and the generation of oxidative stress as well as the dysfunction of mitochondrial cellular organelles,programmed cell death,and circadian rhythm impairments.These pathways can ultimately involve failure in the glymphatic pathway of the brain that is linked to circadian rhythms disorders during the loss of metabolic homeostasis.New studies incorporate a number of promising techniques to examine patients with metabolic disorders that can include machine learning and artificial intelligence pathways to potentially predict the onset of metabolic dysfunction.展开更多
Objective To investigate the structural changes of rat thoracic aorta and changes in expression levels of Bmal1 and cyclins in thoracic aorta endothelial cells following heat stress.Methods Twenty male SD rats were ra...Objective To investigate the structural changes of rat thoracic aorta and changes in expression levels of Bmal1 and cyclins in thoracic aorta endothelial cells following heat stress.Methods Twenty male SD rats were randomized equally into control group and heat stress group.After exposure to 32℃for 2 weeks in the latter group,the rats were examined for histopathological changes and Bmal1 expression in the thoracic aorta using HE staining and immunohistochemistry.In the cell experiments,cultured rat thoracic aortic endothelial cells(RTAECs)were incubated at 40℃for 12 h with or without prior transfection with a Bmal1-specific small interfering RNA(si-Bmal1)or a negative sequence.In both rat thoracic aorta and RTAECs,the expressions of Bmal1,the cell cycle proteins CDK1,CDK4,CDK6,and cyclin B1,and apoptosis-related proteins Bax and Bcl-2 were detected using Western blotting.TUNEL staining was used to detect cell apoptosis in rat thoracic aorta,and the changes in cell cycle distribution and apoptosis in RTAECs were analyzed with flow cytometry.Results Compared with the control rats,the rats exposed to heat stress showed significantly increased blood pressures and lowered heart rate with elastic fiber disruption and increased expressions of Bmal1,cyclin B1 and CDK1 in the thoracic aorta(P<0.05).In cultured RTAECs,heat stress caused significant increase of Bmal1,cyclin B1 and CDK1 protein expression levels,which were obviously lowered in cells with prior si-Bmal1 transfection.Bmal1 knockdown also inhibited heat stress-induced increase of apoptosis in RTAECs as evidenced by decreased expression of Bax and increased expression of Bcl-2.Conclusion Heat stress upregulates Bmal1 expression and causes alterations in expressions of cyclins to trigger apoptosis of rat thoracic aorta endothelial cells,which can be partly alleviated by suppressing Bmal1 expression.展开更多
The circadian clock is a highly hierarchical network of endogenous pacemakers that primarily maintains and directs oscillations through transcriptional and translational feedback loops,which modulates an approximately...The circadian clock is a highly hierarchical network of endogenous pacemakers that primarily maintains and directs oscillations through transcriptional and translational feedback loops,which modulates an approximately 24-h cycle of endocrine and metabolic rhythms within cells and tissues.While circadian clocks regulate metabolic processes and related physiology,emerging evidence indicates that metabolism and circadian rhythm are intimately intertwined.In this review,we highlight the concept of metabolites,including lipids and other polar metabolites generated from intestinal microbial metabolism and nutrient intake,as time cues that drive changes in circadian rhythms,which in turn influence metabolism and aging.Furthermore,we discuss the roles of functional metabolites as circadian cues,paving a new direction on potential intervention targets of circadian disruption,pathological aging,as well as metabolic diseases that are clinically important.展开更多
Background Lactate is a classical byproduct of glucose metabolism,and the main lactate production pathway depends on glycolysis.Lactate stabilized HIF1αby inhibiting PHD activity,leading to hypoxic stress response an...Background Lactate is a classical byproduct of glucose metabolism,and the main lactate production pathway depends on glycolysis.Lactate stabilized HIF1αby inhibiting PHD activity,leading to hypoxic stress response and exacerbating glycolysis in multiple tissues.However,the redox induction mechanism of lactate in mammary gland has not been understood yet.Herein,we describe a lactate-responsive HIF1α/circadian control mechanism in oxidative stress in the mammary glands of dairy cows.Results The in vivo study showed that dairy cows with high lactate concentrations are associated with reduced milk yield and more ROS accumulation in mammary gland.Western blot results in MAC-T cells showed positive correlation between lactate concentrations,expression of HIF1αand oxidative stress indicators,but not circadian core components.To test how lactate-mediated HIF1αdysfunction leads to cell protection process,we investigated altered expression of circadian core related genes following HIF1αstabilization.We found that stabilized HIF1αby lactate inhibited stimulated expression of circadian core components due to the similarity of HRE and E-box transcription elements.Furthermore,we found that lactate treatment strengthened the binding of HIF1αwith BMAL1,HMOX1 and FOXO3 in MAC-T cells.Moreover,HIF1αknockdown altered expression of circadian rhythm related genes and reduced oxidative stress state.Conclusion In summary,our study highlights the central role of competitive transcriptional element occupancy in lactate-mediated oxidative stress of mammary gland,which is caused by HIF1αstabilization and circadian rhythm dysfunction.Our findings introduce a novel nutritional strategy with potential applications in dairy farming for optimizing milk production and maintaining mammary gland health.展开更多
The circadian system of mammals is composed of a hierarchical network of oscillators,including a core clock and peripheral clocks.The core clock receives an external photic signal and transmits it to the peripheral cl...The circadian system of mammals is composed of a hierarchical network of oscillators,including a core clock and peripheral clocks.The core clock receives an external photic signal and transmits it to the peripheral clocks,which,in turn,feed back to the core clock.Aging affects various functions of organisms including the circadian system.Entrainment displays the adaptability of the circadian system to changes in the external environment.However,there is currently no systematic study on the effects of aging on the entrainment capability.To explore the influencing mechanism,we develop a mathematical model of two populations of Goodwin oscillators,which represent the core clock and peripheral clocks.Based on numerical simulations,we conduct a detailed study on the impact of three aging-related factors on the entrainment capability represented by the entrainment range,entrainment time,and entrainment phase.The results indicate that the decrease in the sensitivity of suprachiasmatic nucleus(SCN)to light and the coupling strength from the SCN to the peripheral clocks due to aging increase the phase difference between the core and peripheral clocks,narrow the entrainment range,and prolong the entrainment time.A reduction in the coupling strength within the SCN has little effect on the three aspects mentioned above but increases the entrainment phase.Overall,aging reduces the circadian system's adaptability to the external environment,and the increased entrainment phase may lead to corresponding sleep problems.We also show that modulating the internal coupling strength in the peripheral clocks can mitigate aging effects;this provides an idea for using peripheral clocks to adjust the core clock,while also revealing new insights into the interaction between aging and the elasticity of the circadian system.This mechanism provides theoretical support for treating or alleviating circadian system disorders or sleep problems caused by aging.展开更多
The plant circadian clock temporally drives gene expression throughout the day and coordinates various physiological processes with diurnal environmental changes. It is essential for conferring plant fitness and compe...The plant circadian clock temporally drives gene expression throughout the day and coordinates various physiological processes with diurnal environmental changes. It is essential for conferring plant fitness and competitive advantages to survive and thrive under natural conditions through the circadian control of gene transcription. Chinese cabbage(Brassica rapa ssp. pekinensis) is an economically important vegetable crop worldwide, although there is little information concerning its circadian clock system. Here we found that gene expression patterns are affected bycircadian oscillators at both the transcriptional and post-transcriptional levels in Chinese cabbage. Time-course RNA-seq analyses were conducted on two short-period lines(SPcc-1 and SPcc-2) and two long-period lines(LPcc-1 and LPcc-2) under constant light. The results showed that 32.7–50.5% of the genes were regulated bythe circadian oscillator and the expression peaks of cycling genes appeared earlier in short-period lines than long-period lines. In addition, approximately 250 splicing events exhibited circadian regulation, with intron retention(IR) accounting for a large proportion. Rhythmically spliced genes included the clock genes LATE ELONGATEDHYPOCOTYL(BrLHY), REVEILLE 2(BrRVE2) and EARLY FLOWERING 3(BrELF3). We also found that thecircadian oscillator could notably influence the diurnal expression patterns of genes that are associated with glucose metabolism via photosynthesis, the Calvin cycle and the tricarboxylic acid(TCA) cycle at both the transcriptional andpost-transcriptional levels. The collective results of this study demonstrate that circadian-regulated physiological processes contribute to Chinese cabbage growth and development.展开更多
During the development of diet-induced obesity,the change of energy matebolism is closely related to the function of the circadian clock in mammals.Luteolin(LU),one of the most common natural flavonoids riched in many...During the development of diet-induced obesity,the change of energy matebolism is closely related to the function of the circadian clock in mammals.Luteolin(LU),one of the most common natural flavonoids riched in many edible plants,can ameliorate obesity by activating adipose tissue browning,but its effect on circadian clock in this process remains poorly understood.Here we found that dietary LU improved circadian misalignment of energy expenditure in high-fat diet(HFD)-fed wild-type(WT)mice.Moreover,dietary LU efficiently elevated uncoupling protein 1 levels in adipose tissue during the dark period,which was similar to the LU-increased hepatic PER2 expressions.Hepatic peroxisome proliferators-activated receptorsα(PPARα)/recombinant retinoid X receptorα(RXRα)/fibroblast growth factor 21(FGF21)pathway was rhythmically elevated by dietary LU in HFD-fed WT mice,whereas the promotion was inhibited in Per2^(-/-)mice.Meanwhile,Per2 deletion abolished the effects of dietary LU on adipose tissue browning in HFD-fed mice.Further,LU treatment directly activated PPARα/RXRα/FGF21 signaling in primary cultured hepatocytes from WT mice rather than Per2^(-/-)mice.Taken together,the deletion of the core clock component Per2 impedes LUinduced adipose tissue browning through weakening PPARα/RXRα/FGF21 pathway in mice,providing a new insight into the interplay of energy metabolism and circadian clock for the anti-obesity activity of LU.展开更多
Objective:Circadian rhythm disruption(CRD)is a risk factor that correlates with poor prognosis across multiple tumor types,including hepatocellular carcinoma(HCC).However,its mechanism remains unclear.This study aimed...Objective:Circadian rhythm disruption(CRD)is a risk factor that correlates with poor prognosis across multiple tumor types,including hepatocellular carcinoma(HCC).However,its mechanism remains unclear.This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity.Methods:To quantify CRD,the HCC CRD score(HCCcrds)was developed.Using machine learning algorithms,we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort(n=369),and the robustness of this method was validated.Furthermore,we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes.Results:We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis.The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis,higher pathological grade,and advanced clinical stages,while the CRD-related subtype with low HCCcrds had better clinical outcomes.We also identified novel biomarkers for each subtype,such as nicotinamide nmethyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1.Conclusion:We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers.Within these groups greater HCCcrds was associated with worse prognosis.This approach has the potential to improve prediction of an individual’s prognosis,guide precision treatments,and assist clinical decision making for HCC patients.展开更多
Objective:To analyze the characteristics of ambulatory blood pressure in elderly patients with hypertension and find out the risk factors of abnormal circadian rhythm.Methods:According to the circadian rhythm of patie...Objective:To analyze the characteristics of ambulatory blood pressure in elderly patients with hypertension and find out the risk factors of abnormal circadian rhythm.Methods:According to the circadian rhythm of patients’blood pressure,they were divided into group A,group B,and group C,and all the data of hypertension patients in this study were collected,including age,gender,BMI,smoking,drinking,basic diseases(diabetes,cerebrovascular disease,hyperlipidemia,etc.),fasting blood glucose,ambulatory blood pressure(24-hour mean systolic pressure,24-hour mean diastolic pressure,daytime mean systolic pressure and daytime mean diastolic pressure).Results:There were significant differences in mean systolic blood pressure and mean diastolic blood pressure at night among group A,group B and group C(P<0.05).Age,hyperlipidemia and fasting blood glucose were risk factors for circadian rhythm abnormality(P<0.05),and 24-hour urinary sodium was a protective factor for circadian rhythm abnormality(P<0.05).Conclusion:Age,hyperlipidemia and fasting blood glucose are risk factors for circadian rhythm abnormality(P<0.05),and 24-hour urinary sodium is a protective factor for circadian rhythm abnormality(P<0.05).展开更多
Objective:To analyze the characteristics of ambulatory blood pressure in elderly patients with hypertension and find out the risk factors of abnormal circadian rhythm.Methods:According to the circadian rhythm of patie...Objective:To analyze the characteristics of ambulatory blood pressure in elderly patients with hypertension and find out the risk factors of abnormal circadian rhythm.Methods:According to the circadian rhythm of patients'blood pressure,they were divided into Group A,Group B and Group C,and all the data of hypertension patients in this study were collected,including age,gender,BMI,smoking,drinking,basic diseases(diabetes,cerebrovascular disease,hyperlipidemia,etc.),fasting blood glucose,ambulatory blood pressure(24-hour mean systolic pressure,24-hour mean diastolic pressure,daytime mean systolic pressure and daytime mean diastolic pressure).Results:There were significant differences in mean systolic blood pressure and mean diastolic blood pressure at night among Group A,Group B and Group C(P<0.05).Age,hyperlipidemia and fasting blood glucose were risk factors for circadian rhythm abnormality(P<0.05),and 24-hour urinary sodium was a protective factor for circadian rhythm abnormality(P<0.05).Conclusion:Age,hyperlipidemia and fasting blood glucose are risk factors for circadian rhythm abnormality(P<0.05),and 24-hour urinary sodium is a protective factor for circadian rhythm abnormality(P<0.05).展开更多
Background:The prevalence of circadian misalignment,particularly social jetlag(SJL),contributes significantly to the epidemic of metabolic disorders.However,the precise impact of SJL on the liver has remained poorly e...Background:The prevalence of circadian misalignment,particularly social jetlag(SJL),contributes significantly to the epidemic of metabolic disorders.However,the precise impact of SJL on the liver has remained poorly elucidated.Methods:The rhythmicity of circulating prolactin(PRL)was evaluated in subjects with SJL and mice under SJL.The causative mechanism of SJL on fatty liver was explored using jetlag model in wild-type and PrI^(-/-) mice.Luciferase reporter assay,electrophoretic mobility shift assay,and chromatin immunoprecipitation analysis were used to study the transcriptional mechanism of retinoic acid receptor-related orphan receptor α on PRL.RNA-sequencing(RNA-seq)on human and mice liver as well as circadian analysis were used to study the mechanism of SJL-associated desynchronized PRL on hepatic lipid metabolism.The therapeutic effect of PRL intervention on SJL-induced mice at different time points was compared.Results:SJL increases the risk of metabolic dysfunction-associated steatotic liver disease(MASLD),mediated by the disruption of the rhythmicity of serum PRL.In particular,SJL inhibits the rhythmic transcription of PRL in the pituitary,leading to desynchronized PRL levels in circulation.Under jetlag conditions,the rhythmicity of the hepatic PRL signaling pathway was significantly dampened,which resulted in increased lipogenesis via inhibited hepatic mitogen-activated protein kinase/cyclin D1 expressions.Notably,PRL treatment at PRL nadir in jetlagged mice decreased hepatic lipid content and liver injury markers to a greater extent compared with conventional PRL administration.Conclusions:Reprogrammed hepatic PRL signaling pathway with concomitant dysregulated lipid metabolism homeostasis was the causative mechanism of fatty liver under SJL,which was mediated through derailed serum PRL rhythm.Restoration of PRL rhythm could effectively alleviate SJL-induced fatty liver,providing new insight into treating MASLD.展开更多
Circadian rhythm is a self-sustaining endogenous oscillation that serves as an internal timekeeping mechanism adapted to the Earth’s 24-h rotational schedule.It exists ubiquitously in nearly all organisms,from prokar...Circadian rhythm is a self-sustaining endogenous oscillation that serves as an internal timekeeping mechanism adapted to the Earth’s 24-h rotational schedule.It exists ubiquitously in nearly all organisms,from prokaryotes to mammals,and regulates diverse physiological and behavioral processes by synchronizing them with environmental fluctuations[1].Previous reports indicated that circadian rhythms exist in biological individuals and cells cultured in vitro[2].The mammalian circadian rhythm system consists of a central pacemaker located in the suprachiasmatic nucleus(SCN)of the hypothalamus,which coordinates peripheral rhythms through the sympathetic and parasympathetic nervous systems[3].This hierarchical mechanism uses neural populations as optimal models for circadian rhythm research.展开更多
Parkinson’s disease(PD)is the second most common neurodegenerative disease,which manifests with both motor and non-motor symptoms.Circadian rhythm dysregulation,as one of the most challenging non-motor features of PD...Parkinson’s disease(PD)is the second most common neurodegenerative disease,which manifests with both motor and non-motor symptoms.Circadian rhythm dysregulation,as one of the most challenging non-motor features of PD,usually appears long before obvious motor symptoms.Moreover,the dysregulated circadian rhythm has recently been reported to play pivotal roles in PD pathogenesis,and it has emerged as a hot topic in PD research.In this review,we briefly introduce the circadian rhythm and circadian rhythm-related genes,and then summarize recent research progress on the altered circadian rhythm in PD,ranging from clinical features to the possible causes of PD-related circadian disorders.We believe that future comprehensive studies on the topic may not only help us to explore the mechanisms of PD,but also shed light on the better management of PD.展开更多
Mammalian bone is constantly metabolized from the embryonic stage,and the maintenance of bone health depends on the dynamic balance between bone resorption and bone formation,mediated by osteoclasts and osteoblasts.It...Mammalian bone is constantly metabolized from the embryonic stage,and the maintenance of bone health depends on the dynamic balance between bone resorption and bone formation,mediated by osteoclasts and osteoblasts.It is widely recognized that circadian clock genes can regulate bone metabolism.In recent years,the regulation of bone metabolism by non-coding RNAs has become a hotspot of research.MicroRNAs can participate in bone catabolism and anabolism by targeting key factors related to bone metabolism,including circadian clock genes.However,research in this field has been conducted only in recent years and the mechanisms involved are not yet well established.Recent studies have focused on how to target circadian clock genes to treat some diseases,such as autoimmune diseases,but few have focused on the co-regulation of circadian clock genes and microRNAs in bone metabolic diseases.Therefore,in this paper we review the progress of research on the co-regulation of bone metabolism by circadian clock genes and microRNAs,aiming to provide new ideas for the prevention and treatment of bone metabolic diseases such as osteoporosis.展开更多
基金supported in part by grants from the National Key R&D Program of China(2021YFC2400400/04 to L.L.C.)the National Natural Science Foundation of China for Key Program Projects(82030070 to L.L.C.)+2 种基金the National Natural Science Foundation of China for Distinguished Young Scholars(22025102 to Q.W.)the National Natural Science Foundation of China(82271036 to Y.F.W.,22277033 to J.Z.,22177034 to L.K.M.)the Young Elite Scientist Sponsorship Program by CAST(2022QNRC001 to Y.F.W.)。
文摘Circadian rhythm disorders are associated with dysfunction in inflammatory diseases,and targeted regulation of the circadian rhythm could serve as an intervention strategy.RORα/γ,as core components of circadian clock genes,positively modulate the key circadian molecule BMAL1.In this study,Gala-SR,a potent small-molecule compound designed to effectively regulate circadian rhythms,was synthesized through a monosaccharide modification prodrug strategy via a hydrolysable conjugation of galactose onto SR1078,an unique synthetic agonist of RORα/γ.Compared with SR1078,Gala-SR exhibited significantly greater aqueous solubility,cytocompatibility,pharmacokinetic characteristics and efficacy in the targeted activation of RORα.Importantly,Gala-SR ameliorated rhythm disorders by enhancing amplitude of the circadian rhythm both in vitro and in vivo.In circadian rhythm disordered mice with periodontitis,Gala-SR restored local circadian rhythm and mitigated inflammation in periodontal tissue in a circadian clock-dependent manner,and alleviated alveolar bone loss.Our study demonstrates that Gala-SR exhibits great promise in restoration of circadian rhythm and could potentially serve as a targeted therapeutic intervention for treating inflammatory diseases arising from disruptions in circadian rhythm.This work provides a feasible paradigm for the development and translational application of small molecule modulators targeting circadian rhythms.
基金supported by grants from the National Natural Science Foundation of China(N0.82474525 and No.82074444)the Hunan Provincial Natural Outstanding Young People Science Foundation(2023JJ10032)the Hunan Province Health and High-Level Talent Medical Academic Leader Training Plan(20240304051).
文摘The circadian clock is an important internal time regulatory system for a range of physiological and behavioral rhythms within living organisms.Testosterone,as one of the most critical sex hormones,is essential for the development of the reproductive system,maintenance of reproductive function,and the overall health of males.The secretion of testosterone in mammals is characterized by distinct circadian rhythms and is closely associated with the regulation of circadian clock genes.Here we review the central and peripheral regulatory mechanisms underlying the influence of circadian clock genes upon testosterone synthesis.We also examined the specific effects of these genes on the occurrence,development,and treatment of common male diseases,including late-onset hypogonadism,erectile dysfunction,male infertility,and prostate cancer.
基金supported by the following funding:National Natural Science Foundations of China(82002888,82272899 and 82370974)Sichuan Science and Technology Program(2022YFS0207 and 2023YFS0127)+1 种基金Scientific Research Foundation,WestChinaHospital of Stomatology SichuanUniversity(RCDWJS2021-8)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-004).
文摘This review explores the pivotal role of circadian rhythm regulators,particularly the PER genes,in Oral Squamous Cell Carcinoma(OSCC).As key constituents of the biological clock,PERs exhibit a downregulated expression pattern in OSCC,and the expression levels of PERs in OSCC patients are correlated with a favorable prognosis.PERs impact the occurrence and development of OSCC through multiple pathways.In the regulation of cell proliferation,they can function not only through cell cycle regultion but also via metabolic pathways.For example,PER1 can interact with receptors for activated C kinase 1(RACK1)and phosphatidylinositol 3-kinase(PI3K)through its PAS domain to inhibit glycolysis and thereby reduce cell proliferation.Regarding the regulation of cell death,PERs mediate various types of cell death in OSCC cells,such as p53-dependent apoptosis,protein kinase B(AKT)/mammalian target of rapamycin(mTOR)dependent autophagy,or hypoxia-inducible factor l-alpha(HIF-1a)mediated ferroptosis.In regulating epithelia-mesenchymal transition(EMT),PERs can lead to the downregulation of EMT related genes,such as zinc finger E-box binding homeobox 1/2(ZEBI/2),twist family BHLH transcription factor 1/2(TWIST1/2),and Vimentin,thereby influencing the migration and invasion capabilities of OSCC cells.In tumor angiogenesis,PERs exert regulatory effects on related factors,such as methionyl aminopeptidase 2(MetAP2)and vascular endothelial growth factor(VEGF).In the tumor immune microenvironment,PERs can inhibit the inhibitor of kappa B kinase(IKK)/nuclear factor kappa B(NF-kB)pathway and programmed cell death ligand 1(PD-L1)expression,thereby enhancing the cytotoxic effect of CD8+T cells on OSCC cells.In-depth studies focusing on elucidating the precise regulatory mechanisms of PERs can facilitate the development of therapeutic strategies targeting PERs,including restoration of PERs expression/activity,targeting PERs-regulated pathways,combination therapies,and chronotherapy.These furnish a theoretical foundation for formulating individualized treatment plans to achieve precise treatment for patients with OSCC.
基金supported by the Ministry of Science and Technology of the People’s Republic of China(Nos.2020YFA0803300 and 2021YFA0805600)the National Natural Science Foundation of China(Nos.92157113,82072630,82173114,82072903,82272872,82002811,82188102,and 82030074)+2 种基金the Zhejiang Natural Science Foundation Key Project(Nos.LD22H160002 and LD21H160003)the Zhejiang Natural Science Foundation Discovery Project(No.LQ22H160023)the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang(No.2019R01001),China.
文摘The circadian clock is a highly conserved timekeeping system in organisms,which maintains physiological homeostasis by precisely regulating periodic fluctuations in gene expression.Substantial clinical and experimental evidence has established a close association between circadian rhythm disruption and the development of various malignancies.Research has revealed characteristic alterations in the circadian gene expression profiles in tumor tissues,primarily manifested as a dysfunction of core clock components(particularly circadian locomotor output cycles kaput(CLOCK)and brain and muscle ARNT-like 1(BMAL1))and the widespread dysregulation of their downstream target genes.Notably,CLOCK demonstrates non-canonical oncogenic functions,including epigenetic regulation via histone acetyltransferase activity and the circadian-independent modulation of cancer pathways.This review systematically elaborates on the oncogenic mechanisms mediated by CLOCK/BMAL1,encompassing multidimensional effects such as cell cycle control,DNA damage response,metabolic reprogramming,and tumor microenvironment(TME)remodeling.Regarding the therapeutic strategies,we focus on cutting-edge approaches such as chrononutritional interventions,chronopharmacological modulation,and treatment regimen optimization,along with a discussion of future perspectives.The research breakthroughs highlighted in this work not only deepen our understanding of the crucial role of circadian regulation in cancer biology but also provide novel insights for the development of chronotherapeutic oncology,particularly through targeting the non-canonical functions of circadian proteins to develop innovative anti-cancer strategies.
基金supported by a grant from the French Society of Sleep Research and Medicine(to LS)The China Scholarship Council(to HL)The CNRS,INSERM,Claude Bernard University Lyon1(to LS)。
文摘The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and,either directly or indirectly,overall body health,encompassing metabolic and cardiovascular well-being.Given the heightened metabolic activity of the brain,there exists a considerable demand for nutrients in comparison to other organs.Among these,the branched-chain amino acids,comprising leucine,isoleucine,and valine,display distinctive significance,from their contribution to protein structure to their involvement in overall metabolism,especially in cerebral processes.Among the first amino acids that are released into circulation post-food intake,branched-chain amino acids assume a pivotal role in the regulation of protein synthesis,modulating insulin secretion and the amino acid sensing pathway of target of rapamycin.Branched-chain amino acids are key players in influencing the brain's uptake of monoamine precursors,competing for a shared transporter.Beyond their involvement in protein synthesis,these amino acids contribute to the metabolic cycles ofγ-aminobutyric acid and glutamate,as well as energy metabolism.Notably,they impact GABAergic neurons and the excitation/inhibition balance.The rhythmicity of branchedchain amino acids in plasma concentrations,observed over a 24-hour cycle and conserved in rodent models,is under circadian clock control.The mechanisms underlying those rhythms and the physiological consequences of their disruption are not fully understood.Disturbed sleep,obesity,diabetes,and cardiovascular diseases can elevate branched-chain amino acid concentrations or modify their oscillatory dynamics.The mechanisms driving these effects are currently the focal point of ongoing research efforts,since normalizing branched-chain amino acid levels has the ability to alleviate the severity of these pathologies.In this context,the Drosophila model,though underutilized,holds promise in shedding new light on these mechanisms.Initial findings indicate its potential to introduce novel concepts,particularly in elucidating the intricate connections between the circadian clock,sleep/wake,and metabolism.Consequently,the use and transport of branched-chain amino acids emerge as critical components and orchestrators in the web of interactions across multiple organs throughout the sleep/wake cycle.They could represent one of the so far elusive mechanisms connecting sleep patterns to metabolic and cardiovascular health,paving the way for potential therapeutic interventions.
基金supported by the National Natural Science Foundation of China(No.81701347,31961133026,81570171,31871187,and 81070455)the National Key R&D Program of China(No.2019YFA0802400)the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions。
文摘Major depressive disorder(MDD)affects people all over the world,and yet,its etiology is complex and remains incompletely understood.In this review,we aim to assess recent advances in understanding depression and its regulation,as well as its interaction with circadian rhythms.Circadian rhythms are internalized representations of the periodic daily light and dark cycles.Accumulating evidence has shown that MDD and the related mental disorders are associated with disrupted circadian rhythms.In particular,depression has often been linked to abnormalities in circadian rhythms because dysregulation of the circadian system increases susceptibility to MDD.The fact that several rhythms are disrupted in depressed patients suggests that these disruptions are not restricted to any one rhythm but rather involve the molecular circadian clock core machinery.The sleep-wake cycle is one rhythm that is often disrupted in depression,which often leads to disturbances in other rhythms.The circadian disruptions manifested in depressed patients and the effectiveness and fast action of chronobiologically based treatments highlight the circadian system as a key therapeutic target in the treatment of depression.This review assesses the evidence on rising depression rates and examines their contributing factors,including circadian misalignment.We discuss key hypotheses underlying depression pathogenesis,potential etiology,and relevant animal models,and underscore potential mechanisms driving depression's growing burden and how understanding these factors is critical for improving prevention and treatment strategies.
基金Supported by American Diabetes AssociationAmerican Heart Association+3 种基金NIH NIEHSNIH NIANIH NINDSand NIH ARRA.
文摘Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals and prevent the onset of chronic disability and ultimately death.Underlying cellular mechanisms for the onset and development of DM are multi-factorial in origin and involve pathways associated with the production of reactive oxygen species and the generation of oxidative stress as well as the dysfunction of mitochondrial cellular organelles,programmed cell death,and circadian rhythm impairments.These pathways can ultimately involve failure in the glymphatic pathway of the brain that is linked to circadian rhythms disorders during the loss of metabolic homeostasis.New studies incorporate a number of promising techniques to examine patients with metabolic disorders that can include machine learning and artificial intelligence pathways to potentially predict the onset of metabolic dysfunction.
文摘Objective To investigate the structural changes of rat thoracic aorta and changes in expression levels of Bmal1 and cyclins in thoracic aorta endothelial cells following heat stress.Methods Twenty male SD rats were randomized equally into control group and heat stress group.After exposure to 32℃for 2 weeks in the latter group,the rats were examined for histopathological changes and Bmal1 expression in the thoracic aorta using HE staining and immunohistochemistry.In the cell experiments,cultured rat thoracic aortic endothelial cells(RTAECs)were incubated at 40℃for 12 h with or without prior transfection with a Bmal1-specific small interfering RNA(si-Bmal1)or a negative sequence.In both rat thoracic aorta and RTAECs,the expressions of Bmal1,the cell cycle proteins CDK1,CDK4,CDK6,and cyclin B1,and apoptosis-related proteins Bax and Bcl-2 were detected using Western blotting.TUNEL staining was used to detect cell apoptosis in rat thoracic aorta,and the changes in cell cycle distribution and apoptosis in RTAECs were analyzed with flow cytometry.Results Compared with the control rats,the rats exposed to heat stress showed significantly increased blood pressures and lowered heart rate with elastic fiber disruption and increased expressions of Bmal1,cyclin B1 and CDK1 in the thoracic aorta(P<0.05).In cultured RTAECs,heat stress caused significant increase of Bmal1,cyclin B1 and CDK1 protein expression levels,which were obviously lowered in cells with prior si-Bmal1 transfection.Bmal1 knockdown also inhibited heat stress-induced increase of apoptosis in RTAECs as evidenced by decreased expression of Bax and increased expression of Bcl-2.Conclusion Heat stress upregulates Bmal1 expression and causes alterations in expressions of cyclins to trigger apoptosis of rat thoracic aorta endothelial cells,which can be partly alleviated by suppressing Bmal1 expression.
基金supported by grants from the Chinese Academy of Sciences(XDB39050800)the Major Project of Guangzhou National Laboratory(GZNL2024A03013)the National Natural Science Foundation of China(92357308 and 32321004)。
文摘The circadian clock is a highly hierarchical network of endogenous pacemakers that primarily maintains and directs oscillations through transcriptional and translational feedback loops,which modulates an approximately 24-h cycle of endocrine and metabolic rhythms within cells and tissues.While circadian clocks regulate metabolic processes and related physiology,emerging evidence indicates that metabolism and circadian rhythm are intimately intertwined.In this review,we highlight the concept of metabolites,including lipids and other polar metabolites generated from intestinal microbial metabolism and nutrient intake,as time cues that drive changes in circadian rhythms,which in turn influence metabolism and aging.Furthermore,we discuss the roles of functional metabolites as circadian cues,paving a new direction on potential intervention targets of circadian disruption,pathological aging,as well as metabolic diseases that are clinically important.
基金supported by National Nature Science Foundation of China(32102552 and 32172741).
文摘Background Lactate is a classical byproduct of glucose metabolism,and the main lactate production pathway depends on glycolysis.Lactate stabilized HIF1αby inhibiting PHD activity,leading to hypoxic stress response and exacerbating glycolysis in multiple tissues.However,the redox induction mechanism of lactate in mammary gland has not been understood yet.Herein,we describe a lactate-responsive HIF1α/circadian control mechanism in oxidative stress in the mammary glands of dairy cows.Results The in vivo study showed that dairy cows with high lactate concentrations are associated with reduced milk yield and more ROS accumulation in mammary gland.Western blot results in MAC-T cells showed positive correlation between lactate concentrations,expression of HIF1αand oxidative stress indicators,but not circadian core components.To test how lactate-mediated HIF1αdysfunction leads to cell protection process,we investigated altered expression of circadian core related genes following HIF1αstabilization.We found that stabilized HIF1αby lactate inhibited stimulated expression of circadian core components due to the similarity of HRE and E-box transcription elements.Furthermore,we found that lactate treatment strengthened the binding of HIF1αwith BMAL1,HMOX1 and FOXO3 in MAC-T cells.Moreover,HIF1αknockdown altered expression of circadian rhythm related genes and reduced oxidative stress state.Conclusion In summary,our study highlights the central role of competitive transcriptional element occupancy in lactate-mediated oxidative stress of mammary gland,which is caused by HIF1αstabilization and circadian rhythm dysfunction.Our findings introduce a novel nutritional strategy with potential applications in dairy farming for optimizing milk production and maintaining mammary gland health.
基金Project supported by the graduate training funds of Shanghai Ocean University in China。
文摘The circadian system of mammals is composed of a hierarchical network of oscillators,including a core clock and peripheral clocks.The core clock receives an external photic signal and transmits it to the peripheral clocks,which,in turn,feed back to the core clock.Aging affects various functions of organisms including the circadian system.Entrainment displays the adaptability of the circadian system to changes in the external environment.However,there is currently no systematic study on the effects of aging on the entrainment capability.To explore the influencing mechanism,we develop a mathematical model of two populations of Goodwin oscillators,which represent the core clock and peripheral clocks.Based on numerical simulations,we conduct a detailed study on the impact of three aging-related factors on the entrainment capability represented by the entrainment range,entrainment time,and entrainment phase.The results indicate that the decrease in the sensitivity of suprachiasmatic nucleus(SCN)to light and the coupling strength from the SCN to the peripheral clocks due to aging increase the phase difference between the core and peripheral clocks,narrow the entrainment range,and prolong the entrainment time.A reduction in the coupling strength within the SCN has little effect on the three aspects mentioned above but increases the entrainment phase.Overall,aging reduces the circadian system's adaptability to the external environment,and the increased entrainment phase may lead to corresponding sleep problems.We also show that modulating the internal coupling strength in the peripheral clocks can mitigate aging effects;this provides an idea for using peripheral clocks to adjust the core clock,while also revealing new insights into the interaction between aging and the elasticity of the circadian system.This mechanism provides theoretical support for treating or alleviating circadian system disorders or sleep problems caused by aging.
基金supported by the Science and Technology Program of Hebei Province, China (236Z2903G)the Innovative Research Group Project of Hebei Natural Science Foundation, China (C2024204246)+1 种基金the Hebei International Joint Research Center of Vegetable Functional Genomicsthe International Joint R&D Center of Hebei Province in Modern Agricultural Biotechnology for supporting this work。
文摘The plant circadian clock temporally drives gene expression throughout the day and coordinates various physiological processes with diurnal environmental changes. It is essential for conferring plant fitness and competitive advantages to survive and thrive under natural conditions through the circadian control of gene transcription. Chinese cabbage(Brassica rapa ssp. pekinensis) is an economically important vegetable crop worldwide, although there is little information concerning its circadian clock system. Here we found that gene expression patterns are affected bycircadian oscillators at both the transcriptional and post-transcriptional levels in Chinese cabbage. Time-course RNA-seq analyses were conducted on two short-period lines(SPcc-1 and SPcc-2) and two long-period lines(LPcc-1 and LPcc-2) under constant light. The results showed that 32.7–50.5% of the genes were regulated bythe circadian oscillator and the expression peaks of cycling genes appeared earlier in short-period lines than long-period lines. In addition, approximately 250 splicing events exhibited circadian regulation, with intron retention(IR) accounting for a large proportion. Rhythmically spliced genes included the clock genes LATE ELONGATEDHYPOCOTYL(BrLHY), REVEILLE 2(BrRVE2) and EARLY FLOWERING 3(BrELF3). We also found that thecircadian oscillator could notably influence the diurnal expression patterns of genes that are associated with glucose metabolism via photosynthesis, the Calvin cycle and the tricarboxylic acid(TCA) cycle at both the transcriptional andpost-transcriptional levels. The collective results of this study demonstrate that circadian-regulated physiological processes contribute to Chinese cabbage growth and development.
文摘During the development of diet-induced obesity,the change of energy matebolism is closely related to the function of the circadian clock in mammals.Luteolin(LU),one of the most common natural flavonoids riched in many edible plants,can ameliorate obesity by activating adipose tissue browning,but its effect on circadian clock in this process remains poorly understood.Here we found that dietary LU improved circadian misalignment of energy expenditure in high-fat diet(HFD)-fed wild-type(WT)mice.Moreover,dietary LU efficiently elevated uncoupling protein 1 levels in adipose tissue during the dark period,which was similar to the LU-increased hepatic PER2 expressions.Hepatic peroxisome proliferators-activated receptorsα(PPARα)/recombinant retinoid X receptorα(RXRα)/fibroblast growth factor 21(FGF21)pathway was rhythmically elevated by dietary LU in HFD-fed WT mice,whereas the promotion was inhibited in Per2^(-/-)mice.Meanwhile,Per2 deletion abolished the effects of dietary LU on adipose tissue browning in HFD-fed mice.Further,LU treatment directly activated PPARα/RXRα/FGF21 signaling in primary cultured hepatocytes from WT mice rather than Per2^(-/-)mice.Taken together,the deletion of the core clock component Per2 impedes LUinduced adipose tissue browning through weakening PPARα/RXRα/FGF21 pathway in mice,providing a new insight into the interplay of energy metabolism and circadian clock for the anti-obesity activity of LU.
基金supported by Tianjian advanced biomedical laboratory key research and development projectHenan Province Natural Science Foundation(grant number:242300421283)+1 种基金Henan Province Science and Technology Research and Development(grant number:242102311176)Henan Province medical science and technology research project(grant number:SBGJ202403038)。
文摘Objective:Circadian rhythm disruption(CRD)is a risk factor that correlates with poor prognosis across multiple tumor types,including hepatocellular carcinoma(HCC).However,its mechanism remains unclear.This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity.Methods:To quantify CRD,the HCC CRD score(HCCcrds)was developed.Using machine learning algorithms,we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort(n=369),and the robustness of this method was validated.Furthermore,we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes.Results:We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis.The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis,higher pathological grade,and advanced clinical stages,while the CRD-related subtype with low HCCcrds had better clinical outcomes.We also identified novel biomarkers for each subtype,such as nicotinamide nmethyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1.Conclusion:We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers.Within these groups greater HCCcrds was associated with worse prognosis.This approach has the potential to improve prediction of an individual’s prognosis,guide precision treatments,and assist clinical decision making for HCC patients.
文摘Objective:To analyze the characteristics of ambulatory blood pressure in elderly patients with hypertension and find out the risk factors of abnormal circadian rhythm.Methods:According to the circadian rhythm of patients’blood pressure,they were divided into group A,group B,and group C,and all the data of hypertension patients in this study were collected,including age,gender,BMI,smoking,drinking,basic diseases(diabetes,cerebrovascular disease,hyperlipidemia,etc.),fasting blood glucose,ambulatory blood pressure(24-hour mean systolic pressure,24-hour mean diastolic pressure,daytime mean systolic pressure and daytime mean diastolic pressure).Results:There were significant differences in mean systolic blood pressure and mean diastolic blood pressure at night among group A,group B and group C(P<0.05).Age,hyperlipidemia and fasting blood glucose were risk factors for circadian rhythm abnormality(P<0.05),and 24-hour urinary sodium was a protective factor for circadian rhythm abnormality(P<0.05).Conclusion:Age,hyperlipidemia and fasting blood glucose are risk factors for circadian rhythm abnormality(P<0.05),and 24-hour urinary sodium is a protective factor for circadian rhythm abnormality(P<0.05).
文摘Objective:To analyze the characteristics of ambulatory blood pressure in elderly patients with hypertension and find out the risk factors of abnormal circadian rhythm.Methods:According to the circadian rhythm of patients'blood pressure,they were divided into Group A,Group B and Group C,and all the data of hypertension patients in this study were collected,including age,gender,BMI,smoking,drinking,basic diseases(diabetes,cerebrovascular disease,hyperlipidemia,etc.),fasting blood glucose,ambulatory blood pressure(24-hour mean systolic pressure,24-hour mean diastolic pressure,daytime mean systolic pressure and daytime mean diastolic pressure).Results:There were significant differences in mean systolic blood pressure and mean diastolic blood pressure at night among Group A,Group B and Group C(P<0.05).Age,hyperlipidemia and fasting blood glucose were risk factors for circadian rhythm abnormality(P<0.05),and 24-hour urinary sodium was a protective factor for circadian rhythm abnormality(P<0.05).Conclusion:Age,hyperlipidemia and fasting blood glucose are risk factors for circadian rhythm abnormality(P<0.05),and 24-hour urinary sodium is a protective factor for circadian rhythm abnormality(P<0.05).
基金supported by the National Natural Science Foundation of China(82030026,81900787,81770819,82300877,and 82450002)the Key Project supported by Medical Science and technology development Foundation,Nanjing Department of Health(YKK24104)+1 种基金the Medical Research Program of Jiangsu Provincial Health Committe(M2024050)the China Postdoctoral Science Foundation(2023M731628).
文摘Background:The prevalence of circadian misalignment,particularly social jetlag(SJL),contributes significantly to the epidemic of metabolic disorders.However,the precise impact of SJL on the liver has remained poorly elucidated.Methods:The rhythmicity of circulating prolactin(PRL)was evaluated in subjects with SJL and mice under SJL.The causative mechanism of SJL on fatty liver was explored using jetlag model in wild-type and PrI^(-/-) mice.Luciferase reporter assay,electrophoretic mobility shift assay,and chromatin immunoprecipitation analysis were used to study the transcriptional mechanism of retinoic acid receptor-related orphan receptor α on PRL.RNA-sequencing(RNA-seq)on human and mice liver as well as circadian analysis were used to study the mechanism of SJL-associated desynchronized PRL on hepatic lipid metabolism.The therapeutic effect of PRL intervention on SJL-induced mice at different time points was compared.Results:SJL increases the risk of metabolic dysfunction-associated steatotic liver disease(MASLD),mediated by the disruption of the rhythmicity of serum PRL.In particular,SJL inhibits the rhythmic transcription of PRL in the pituitary,leading to desynchronized PRL levels in circulation.Under jetlag conditions,the rhythmicity of the hepatic PRL signaling pathway was significantly dampened,which resulted in increased lipogenesis via inhibited hepatic mitogen-activated protein kinase/cyclin D1 expressions.Notably,PRL treatment at PRL nadir in jetlagged mice decreased hepatic lipid content and liver injury markers to a greater extent compared with conventional PRL administration.Conclusions:Reprogrammed hepatic PRL signaling pathway with concomitant dysregulated lipid metabolism homeostasis was the causative mechanism of fatty liver under SJL,which was mediated through derailed serum PRL rhythm.Restoration of PRL rhythm could effectively alleviate SJL-induced fatty liver,providing new insight into treating MASLD.
基金funded by the National Natural Science Foundation of China(no.12275329,Nan Ding,and no.12175289,Jufang Wang)the West Light Foundation of The Chinese Academy of Sciences(xbzglzb2022003,Nan Ding)+2 种基金the Science and Technology Research Project of Gansu Province(no.145RTSA012,Jufang Wang,and no.21JR7RA108,Nan Ding)the Gansu Provincial Science Fund for Distinguished Young Scholars(no.22JR5RA942,Wei Wang)the CuiYing Science and Technology Innovation Program of the Second Hospital of Lanzhou University(CY2023-MS-A03,Wei Wang).
文摘Circadian rhythm is a self-sustaining endogenous oscillation that serves as an internal timekeeping mechanism adapted to the Earth’s 24-h rotational schedule.It exists ubiquitously in nearly all organisms,from prokaryotes to mammals,and regulates diverse physiological and behavioral processes by synchronizing them with environmental fluctuations[1].Previous reports indicated that circadian rhythms exist in biological individuals and cells cultured in vitro[2].The mammalian circadian rhythm system consists of a central pacemaker located in the suprachiasmatic nucleus(SCN)of the hypothalamus,which coordinates peripheral rhythms through the sympathetic and parasympathetic nervous systems[3].This hierarchical mechanism uses neural populations as optimal models for circadian rhythm research.
基金the National Nature Science Foundation of China(81771521)Key Research and Development Plan of Liaoning Science and Technology Department(2018225051)+1 种基金Guangdong Provincial Key R&D Program(2018B030337001)the National Key Research and Development Program of China(2016YFC1306600).
文摘Parkinson’s disease(PD)is the second most common neurodegenerative disease,which manifests with both motor and non-motor symptoms.Circadian rhythm dysregulation,as one of the most challenging non-motor features of PD,usually appears long before obvious motor symptoms.Moreover,the dysregulated circadian rhythm has recently been reported to play pivotal roles in PD pathogenesis,and it has emerged as a hot topic in PD research.In this review,we briefly introduce the circadian rhythm and circadian rhythm-related genes,and then summarize recent research progress on the altered circadian rhythm in PD,ranging from clinical features to the possible causes of PD-related circadian disorders.We believe that future comprehensive studies on the topic may not only help us to explore the mechanisms of PD,but also shed light on the better management of PD.
基金This work was supported by the National Natural Science Foundation of China(Nos.81901430 and 81871835)the Guangdong Provincial Natural Science Foundation of China(No.2022A1515010379)+1 种基金the Innovation Project from Department of Education of Guangdong Province(No.2021KTSCX 055)the Shanghai Frontiers Science Research Base of Exercise and Metabolic Health,and the Shanghai Key Laboratory for Human Athletic Ability Development and Support(Shanghai University of Sport)(No.11DZ2261100),China.
文摘Mammalian bone is constantly metabolized from the embryonic stage,and the maintenance of bone health depends on the dynamic balance between bone resorption and bone formation,mediated by osteoclasts and osteoblasts.It is widely recognized that circadian clock genes can regulate bone metabolism.In recent years,the regulation of bone metabolism by non-coding RNAs has become a hotspot of research.MicroRNAs can participate in bone catabolism and anabolism by targeting key factors related to bone metabolism,including circadian clock genes.However,research in this field has been conducted only in recent years and the mechanisms involved are not yet well established.Recent studies have focused on how to target circadian clock genes to treat some diseases,such as autoimmune diseases,but few have focused on the co-regulation of circadian clock genes and microRNAs in bone metabolic diseases.Therefore,in this paper we review the progress of research on the co-regulation of bone metabolism by circadian clock genes and microRNAs,aiming to provide new ideas for the prevention and treatment of bone metabolic diseases such as osteoporosis.
