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
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.
