Circadian rhythm is ubiquitous in nature.Circadian clock genes such as Bmal1 and Clock form a multi-level transcription-translation feedback network,and regulate a variety of physiological and pathological processes,i...Circadian rhythm is ubiquitous in nature.Circadian clock genes such as Bmal1 and Clock form a multi-level transcription-translation feedback network,and regulate a variety of physiological and pathological processes,including bone and cartilage metabolism.Deletion of the core clock gene Bmal1 leads to pathological bone alterations,while the phenotypes are not consistent.Studies have shown that multiple signaling pathways are involved in the process of Bmal1 regulating bone and cartilage metabolism,but the exact regulatory mechanisms remain unclear.This paper reviews the signaling pathways by which Bmal1 regulates bone/cartilage metabolism,the upstream regulatory factors that control Bmal1,and the current Bmal1 knockout mouse models for research.We hope to provide new insights for the prevention and treatment of bone/cartilage diseases related to circadian rhythms.展开更多
Approximately 20%to 30%of the global workforce is engaged in shift work.As a significant cause of circadian disruption,shift work is closely associated with an increased risk for periodontitis.Nevertheless,how shift w...Approximately 20%to 30%of the global workforce is engaged in shift work.As a significant cause of circadian disruption,shift work is closely associated with an increased risk for periodontitis.Nevertheless,how shift work-related circadian disruption functions in periodontitis remains unknown.Herein,we employed a simulated shift work model constructed by controlling the environmental light-dark cycles and revealed that shift work-related circadian disruption exacerbated the progression of experimental periodontitis.RNA sequencing and in vitro experiments indicated that downregulation of the core circadian protein brain and muscle ARNT-like protein 1(BMAL1)and activation of the Gasdermin D(GSDMD)-mediated pyroptosis were involved in the pathogenesis of that.Mechanically,BMAL1 regulated GSDMD-mediated pyroptosis by suppressing NOD-like receptor protein 3(NLRP3)inflammasome signaling through modulating nuclear receptor subfamily 1 group D member 1(NR1D1),and inhibiting Gsdmd transcription via directly binding to the E-box elements in its promoter.GSDMD-mediated pyroptosis accelerated periodontitis progression,whereas downregulated BMAL1 under circadian disruption further aggravated periodontal destruction by increasing GSDMD activity.And restoring the level of BMAL1 by circadian recovery and SR8278 injection alleviated simulated shift work-exacerbated periodontitis via lessening GSDMD-mediated pyroptosis.These findings provide new evidence and potential interventional targets for circadian disruption-accelerated periodontitis.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 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
基金National Natural Science Foundation of China(82171003 and 82171002)Research and Develop Program of West China Hospital of Stomatology Sichuan University(NO.LCYJ-2022-YY-1)。
文摘Circadian rhythm is ubiquitous in nature.Circadian clock genes such as Bmal1 and Clock form a multi-level transcription-translation feedback network,and regulate a variety of physiological and pathological processes,including bone and cartilage metabolism.Deletion of the core clock gene Bmal1 leads to pathological bone alterations,while the phenotypes are not consistent.Studies have shown that multiple signaling pathways are involved in the process of Bmal1 regulating bone and cartilage metabolism,but the exact regulatory mechanisms remain unclear.This paper reviews the signaling pathways by which Bmal1 regulates bone/cartilage metabolism,the upstream regulatory factors that control Bmal1,and the current Bmal1 knockout mouse models for research.We hope to provide new insights for the prevention and treatment of bone/cartilage diseases related to circadian rhythms.
基金supported by the National Natural Science Foundation of China(Nos.82170955,82101064)the Xinfei Program funded by Fourth Military Medical University。
文摘Approximately 20%to 30%of the global workforce is engaged in shift work.As a significant cause of circadian disruption,shift work is closely associated with an increased risk for periodontitis.Nevertheless,how shift work-related circadian disruption functions in periodontitis remains unknown.Herein,we employed a simulated shift work model constructed by controlling the environmental light-dark cycles and revealed that shift work-related circadian disruption exacerbated the progression of experimental periodontitis.RNA sequencing and in vitro experiments indicated that downregulation of the core circadian protein brain and muscle ARNT-like protein 1(BMAL1)and activation of the Gasdermin D(GSDMD)-mediated pyroptosis were involved in the pathogenesis of that.Mechanically,BMAL1 regulated GSDMD-mediated pyroptosis by suppressing NOD-like receptor protein 3(NLRP3)inflammasome signaling through modulating nuclear receptor subfamily 1 group D member 1(NR1D1),and inhibiting Gsdmd transcription via directly binding to the E-box elements in its promoter.GSDMD-mediated pyroptosis accelerated periodontitis progression,whereas downregulated BMAL1 under circadian disruption further aggravated periodontal destruction by increasing GSDMD activity.And restoring the level of BMAL1 by circadian recovery and SR8278 injection alleviated simulated shift work-exacerbated periodontitis via lessening GSDMD-mediated pyroptosis.These findings provide new evidence and potential interventional targets for circadian disruption-accelerated periodontitis.
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 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.
