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.
Humans ; ARNTL Transcription Factors/physiology* ; Neoplasms/therapy* ; CLOCK Proteins/physiology* ; Circadian Clocks/genetics* ; Animals ; Circadian Rhythm/genetics* ; Tumor Microenvironment ; Epigenesis, Genetic ; Gene Expression Regulation, Neoplastic

Objective To investigate the effects and mechanisms of Huatan Quyu Decoction on learning and memory abilities in rats with vascular dementia(VD).Methods Totally 112 male SD rats were randomly selected with 16 rats as the sham-operation group,the remaining rats were used to prepare VD models by segmental ligation of the common carotid artery.The successfully modeled rats were randomly divided into model group,Huatan Quyu Decoction low-,medium-and high-dosage groups(6.1,12.1,24.2 g/kg),donepezil hydrochloride group(0.5 mg/kg)and combination group(Huatan Quyu Decoction 12.1 g/kg+donepezil hydrochloride 0.5 mg/kg),with 16 rats in each group.Each group was given the corresponding treatment measures for 4 weeks.The Morris water maze test was used to assess learning and memory abilities,neurological function was evaluated using Garcia score,HE staining was used to observe the morphology of the hippocampal tissue,ELISA was employed to detect the serum content of Aβ,immunohistochemistry was utilized to observe the β-catenin,LRP6 and GSK-3β protein expression in brain tissue.Results Compared with the sham-operation group,the escape latency of the model group rats was prolonged(P<0.01),the number of crossing platforms was reduced(P<0.01),and the neurological deficit score was decreased(P<0.01),the arrangement of hippocampal tissue cells was disorderly,and the tissue was severely damaged,the serum Aβ content increased(P<0.01),the expressions of β-catenin and LRP6 protein in brain tissue decreased,and the expression of GSK-3β protein increased(P<0.01).Compared with the model group,the escape latency of rats in each administration group was shortened,the number of crossing platforms increased,the neurological deficit score increased,the number of hippocampal cells was relatively more,the arrangement was more orderly,and the structure was relatively complete,the serum Aβ content decreased,the expressions of β-catenin and LRP6 proteins increased,and the expression of GSK-3β protein decreased.Among them,Huatan Quyu Decoction high-dosage group had a significantly better effect than Huatan Quyu Decoction low-and medium-dosage groups(P<0.01),and there was no statistical significance in various indicators compared with the donepezil hydrochloride group(P>0.05).Compared with the donepezil hydrochloride group,the combination group showed significant improvements in learning and memory abilities(P<0.01),the neurological deficit score significantly increased(P<0.01),the number of hippocampal cells significantly increased,arranged neatly,and structurally intact,the serum Aβ content significantly decreased(P<0.01),the expression of β-catenin and LRP6 proteins significantly increased,and the expression of GSK-3β protein significantly decreased(P<0.01).Conclusion Huatan Quyu Decoction can repair cognitive function in VD rats,improve learning and memory abilities,and alleviate VD symptoms by activating the Wnt/β-catenin signaling pathway to reduce serum Aβ content,decrease the apoptosis of nerve cells and alleviate the degree of pathological damage in hippocampal tissue.

BACKGROUND:In the preparation of injectable extracellular matrix materials,most of the materials require pepsin digestion followed by combination with other matrix components like hydrogels for pulp tissue regeneration,which also means the destruction of the microenvironment retained by natural extracellular matrix materials.OBJECTIVE:To investigate the effect of injectable dental pulp extracellular matrix prepared by grinding treatment on the regeneration of dental pulp tissue.METHODS:(1)The dental pulp tissue from pig teeth was prepared into acellular dental pulp matrix materials after acellular treatment.After freezing in liquid nitrogen and high-speed grinding,the injectable dental pulp extracellular matrix was prepared.Then,the differences in cell adhesion efficiency and microstructure between the injectable dental pulp extracellular matrix and natural dental pulp extracellular matrix were compared.Immunohistochemical analysis was used to analyze extracellular matrix protein components in injectable dental pulp extracellular matrix.(2)Injectable dental pulp extracellular matrix material inoculated with dental pulp stem cells was injected into the dental pulp cavity constructed from the dentin matrix material.The samples were obtained after 1,3,and 5 weeks of subcutaneous implantation in nude mice to observe the in vivo conversion rate of injectable dental pulp extracellular matrix materials and the regeneration ability of ectopic dental pulp tissue under the skin of nude mice.RESULTS AND CONCLUSION:(1)Compared with the dental pulp extracellular matrix,the injectable dental pulp extracellular matrix significantly improved the cell adhesion rate and retained the porous collagen structure similar to that of natural dental pulp extracellular matrix.(2)Compared with the natural dental pulp extracellular matrix,immunohistochemical staining showed that there was no significant difference in the expression of fibronectin,collagen type Ⅰ,and integrin β1 in the injectable dental pulp extracellular matrix,while the expression of fibronectin was significantly decreased.(3)In vivo experiments show that the injectable dental pulp extracellular matrix has excellent angiogenesis ability and promotes the formation of pulp-like tissues.The results exhibit that the milled injectable dental pulp extracellular matrix can still be used as an effective scaffold for the regeneration of dental pulp.

Objective:To investigate the consistency and sensitivity of minimal residual disease (MRD) detected by multicolor flow cytometry (FCM) and real-time quantitative polymerase chain reaction (RQ-PCR) in patients with acute myeloid leukemia (AML) accompanied by monocytic differentiation after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:A retrospective case series study was conducted. A total of 218 patients diagnosed with AML accompanied by monocytic differentiation who underwent allo-HSCT in Peking University People's Hospital between January 2017 and December 2021 were included. MRD was detected by using bone marrow FCM and RQ-PCR at predefined intervals (at 1-, 2-, 3-, 4.5-, 6-, 9-, and 12-month before and after transplantation). Patients were grouped based on AML-related specific genes, and dynamic changes in MRD results detected by FCM and RQ-PCR after transplantation were analyzed to evaluate the correlation with post-transplant relapse.Results:A total of 218 enrolled patients included 114 males and 106 females, with the median age of 32 years (1-65 years). The median follow-up duration was 218 d (21-1 541 d). Hematologic relapse occurred in 26 patients (12.7%), with a median relapse time of 272 d (83-934 d); 35 patients (15.9%) died, including 15 (6.9%) due to leukemia relapse and 20 (9.2%) due to transplant-related mortality. Predictive markers for relapse included once WT1 positive (WT1+once), twice WT1 positive (WT1+twice), CBFβ::MYH11 fusion genes positive, mixed-lineage leukemia (MLL)-related fusion genes positive, AML1::ETO fusion genes positive, and once FCM positive (FCM+once), twice FCM positive (FCM+twice). The overall consistency rate between FCM and RQ-PCR for MRD detection in AML patients accompanied by monocytic differentiation after transplantation was 75.7% (165/218). The consistency rate of MRD detection results in WT1+once, WT1+ twice, MLL-related fusion gene positive, and NPM1 gene mutation positive with FCM was higher than the average value (>75.7%), while the consistency rate of MRD detection results in AML1::ETO and CBFβ::MYH11 fusion gene positive with FCM was lower than the average value (<75.7%). Notably, persistent low-level positivity without relapse after transplantation occurred in cases with WT1 (15 patients), NPM1 (2 patients), CBFβ::MYH11 (11 patients), or AML1::ETO (2 patients); in contrast, MLL-related fusion genes (particularly MLL::AF6 and MLL::AF9) positive after transplantation indicated relapse in patients. The sensitivity and specificity of RQ-PCR for MRD monitoring varied by genetic markers: WT1+once and WT1+twice (sensitivity: 66.7%, 50.0%; specificity: 84.5%, 91.1%, respectively), AML1::ETO (sensitivity: 100.0%; specificity: 50.0%), CBFβ::MYH11 (sensitivity: 100.0%; specificity: 58.6%), MLL-related fusion genes (sensitivity: 75.0%; specificity: 96.4%), and NPM1 (sensitivity: 75.0%; specificity: 91.7%).Conclusions:The sensitivity and specificity of AML-related genetic markers for recurrence prediction show differences. Discrepancies between RQ-PCR and FCM in MRD detection are notable in AML with monocytic differentiation after transplantation. FCM exhibits relatively lower sensitivity for MRD monitoring in this subtype, while RQ-PCR based on AML-related genes may compensate for FCM limitations.

OBJECTIVE To investigate the current status of hospital-associated infections,distribution of infection cases in departments,infection sites and pathogens so as to achieve the rational allocation of resources and provide data support for continuous improvement of medical quality.METHODS From 2019 to 2023,the relevant data in-cluding the departments of hospitalized patients with the infections,time of infections,infection sites and patho-gens were collected from all of the infection patients of Hohhot First Hospital by Xinglin nosocomial infection teal-time monitoring system and were statistically analyzed.RESULTS There were 1802 cases of hospital-associated infec-tions in total from 2019 to 2023,and the average incidence rate of infection was 1.18％.The average incidence of hospi-tal-associated infections exceeded 3％in 6 of 36 departments from 2019 to 2023(584 cases in total,accounting for 32.41％among all the cases),and the incidence of hospital-associated infections showed an upward trend in intensive care unit(ICU)(x2=4.125,P=0.042).The 3 major infection sites of the patients with hospital-associated infections were as follow:the patients with respiratory system infection accourted for 66.35％,the patients with urinary system infec-tions accounted for 19.39％,the patients with blood system infections 3.33％.Klebsiella pneumoniae,Escherichia coli and Acinetobacter baumannii ranked the top 3 species of pathogens causing the hospital-associated infection,accounting for 17.68％,12.25％and 11.33％,respectively.CONCLUSIONS The incidence of hospital-associated infections shows an upward trend in recent years.It is necessary to strengthen the comprehensive and meticulous management of the infec-tions and take full advantage of information surveillance data so as to further improve the medical quality and safety.

OBJECTIVE To investigate the current status of hospital-associated infections,distribution of infection cases in departments,infection sites and pathogens so as to achieve the rational allocation of resources and provide data support for continuous improvement of medical quality.METHODS From 2019 to 2023,the relevant data in-cluding the departments of hospitalized patients with the infections,time of infections,infection sites and patho-gens were collected from all of the infection patients of Hohhot First Hospital by Xinglin nosocomial infection teal-time monitoring system and were statistically analyzed.RESULTS There were 1802 cases of hospital-associated infec-tions in total from 2019 to 2023,and the average incidence rate of infection was 1.18％.The average incidence of hospi-tal-associated infections exceeded 3％in 6 of 36 departments from 2019 to 2023(584 cases in total,accounting for 32.41％among all the cases),and the incidence of hospital-associated infections showed an upward trend in intensive care unit(ICU)(x2=4.125,P=0.042).The 3 major infection sites of the patients with hospital-associated infections were as follow:the patients with respiratory system infection accourted for 66.35％,the patients with urinary system infec-tions accounted for 19.39％,the patients with blood system infections 3.33％.Klebsiella pneumoniae,Escherichia coli and Acinetobacter baumannii ranked the top 3 species of pathogens causing the hospital-associated infection,accounting for 17.68％,12.25％and 11.33％,respectively.CONCLUSIONS The incidence of hospital-associated infections shows an upward trend in recent years.It is necessary to strengthen the comprehensive and meticulous management of the infec-tions and take full advantage of information surveillance data so as to further improve the medical quality and safety.

BACKGROUND:In the preparation of injectable extracellular matrix materials,most of the materials require pepsin digestion followed by combination with other matrix components like hydrogels for pulp tissue regeneration,which also means the destruction of the microenvironment retained by natural extracellular matrix materials.OBJECTIVE:To investigate the effect of injectable dental pulp extracellular matrix prepared by grinding treatment on the regeneration of dental pulp tissue.METHODS:(1)The dental pulp tissue from pig teeth was prepared into acellular dental pulp matrix materials after acellular treatment.After freezing in liquid nitrogen and high-speed grinding,the injectable dental pulp extracellular matrix was prepared.Then,the differences in cell adhesion efficiency and microstructure between the injectable dental pulp extracellular matrix and natural dental pulp extracellular matrix were compared.Immunohistochemical analysis was used to analyze extracellular matrix protein components in injectable dental pulp extracellular matrix.(2)Injectable dental pulp extracellular matrix material inoculated with dental pulp stem cells was injected into the dental pulp cavity constructed from the dentin matrix material.The samples were obtained after 1,3,and 5 weeks of subcutaneous implantation in nude mice to observe the in vivo conversion rate of injectable dental pulp extracellular matrix materials and the regeneration ability of ectopic dental pulp tissue under the skin of nude mice.RESULTS AND CONCLUSION:(1)Compared with the dental pulp extracellular matrix,the injectable dental pulp extracellular matrix significantly improved the cell adhesion rate and retained the porous collagen structure similar to that of natural dental pulp extracellular matrix.(2)Compared with the natural dental pulp extracellular matrix,immunohistochemical staining showed that there was no significant difference in the expression of fibronectin,collagen type Ⅰ,and integrin β1 in the injectable dental pulp extracellular matrix,while the expression of fibronectin was significantly decreased.(3)In vivo experiments show that the injectable dental pulp extracellular matrix has excellent angiogenesis ability and promotes the formation of pulp-like tissues.The results exhibit that the milled injectable dental pulp extracellular matrix can still be used as an effective scaffold for the regeneration of dental pulp.

Objective To investigate the effects and mechanisms of Huatan Quyu Decoction on learning and memory abilities in rats with vascular dementia(VD).Methods Totally 112 male SD rats were randomly selected with 16 rats as the sham-operation group,the remaining rats were used to prepare VD models by segmental ligation of the common carotid artery.The successfully modeled rats were randomly divided into model group,Huatan Quyu Decoction low-,medium-and high-dosage groups(6.1,12.1,24.2 g/kg),donepezil hydrochloride group(0.5 mg/kg)and combination group(Huatan Quyu Decoction 12.1 g/kg+donepezil hydrochloride 0.5 mg/kg),with 16 rats in each group.Each group was given the corresponding treatment measures for 4 weeks.The Morris water maze test was used to assess learning and memory abilities,neurological function was evaluated using Garcia score,HE staining was used to observe the morphology of the hippocampal tissue,ELISA was employed to detect the serum content of Aβ,immunohistochemistry was utilized to observe the β-catenin,LRP6 and GSK-3β protein expression in brain tissue.Results Compared with the sham-operation group,the escape latency of the model group rats was prolonged(P<0.01),the number of crossing platforms was reduced(P<0.01),and the neurological deficit score was decreased(P<0.01),the arrangement of hippocampal tissue cells was disorderly,and the tissue was severely damaged,the serum Aβ content increased(P<0.01),the expressions of β-catenin and LRP6 protein in brain tissue decreased,and the expression of GSK-3β protein increased(P<0.01).Compared with the model group,the escape latency of rats in each administration group was shortened,the number of crossing platforms increased,the neurological deficit score increased,the number of hippocampal cells was relatively more,the arrangement was more orderly,and the structure was relatively complete,the serum Aβ content decreased,the expressions of β-catenin and LRP6 proteins increased,and the expression of GSK-3β protein decreased.Among them,Huatan Quyu Decoction high-dosage group had a significantly better effect than Huatan Quyu Decoction low-and medium-dosage groups(P<0.01),and there was no statistical significance in various indicators compared with the donepezil hydrochloride group(P>0.05).Compared with the donepezil hydrochloride group,the combination group showed significant improvements in learning and memory abilities(P<0.01),the neurological deficit score significantly increased(P<0.01),the number of hippocampal cells significantly increased,arranged neatly,and structurally intact,the serum Aβ content significantly decreased(P<0.01),the expression of β-catenin and LRP6 proteins significantly increased,and the expression of GSK-3β protein significantly decreased(P<0.01).Conclusion Huatan Quyu Decoction can repair cognitive function in VD rats,improve learning and memory abilities,and alleviate VD symptoms by activating the Wnt/β-catenin signaling pathway to reduce serum Aβ content,decrease the apoptosis of nerve cells and alleviate the degree of pathological damage in hippocampal tissue.

Objective:To explore the effect of variable priority cognitive-motor dual-task training in aged cognitive frailty patients with type 2 diabetes mellitus.Methods:From September 2022 to September 2023, a total of 108 aged cognitive frailty patients with type 2 diabetes mellitus were selected in the Department of Endocrinology of North China University of Science and Technology Affiliated Hospital as research subjects.The subjects were divided into three groups in the order of admission, with 36 people in each group.Three groups of patients were intervened for 8 weeks using variable priority cognitive-motor dual-task training (VP group), exercise combined cognitive intervention with sequential task (ST group), and endocrinology routine treatment and nursing (control group), respectively.The scores of mini-mental state examination(MMSE), frailty phenotype(FP) and Berg balance scale(BBS) were compared among the three groups before and after the intervention.Repeated measurement variance analysis was used to compare scale results by SPSS 22.0.Results:(1)The MMSE score of patients before and after intervention had significant interaction effect between time and groups ( F=69.929, P<0.05).The MMSE scores of the VP group and ST group after 8 weeks of intervention were higher than those before intervention and after 4 weeks of intervention, and the MMSE scores of the two groups after 4 weeks of intervention were also higher than those before intervention (all P<0.05).After 4 weeks and 8 weeks of intervention, the MMSE score of the VP group was higher than that of the ST group and the control group, and the MMSE score of the ST group was higher than that of the control group after 8 weeks of intervention(all P<0.05).(2)The FP score of patients before and after intervention had a significant interaction effect between time and groups ( F=46.425, P<0.05).The FP score of the VP group at 8 weeks of intervention (2.64±0.59) was lower than that after 4 weeks of intervention (3.28±0.51) and before intervention (3.56±0.61), and the FP score after 4 weeks of intervention was lower than before intervention (all P<0.05).The FP score of the ST group after 8 weeks of intervention (3.44±0.56) was lower than before the intervention (3.59±0.56) ( P<0.05); After 4 weeks of intervention, the FP score of the VP group was lower than that of the control group (3.36±0.54) ( P<0.05).After 8 weeks of intervention, the FP score of the VP group was lower than that of the ST group and the control group (3.39±0.55) (both P<0.05).(3)The FP score of patients before and after intervention had a significant interaction effect between time and groups ( F=135.791, P<0.05).The BBS scores of the VP group and ST group after 8 weeks of intervention were higher than those before and after 4 weeks of intervention, and the BBS scores after 4 weeks of intervention were also higher than those before intervention (all P<0.05).After 4 weeks of intervention, the BBS score of the VP group was higher than that of the control group ( P<0.05).After 8 weeks of intervention, the BBS score of the VP group was higher than that of the ST group and the control group, and the BBS score of the ST group was also higher than that of the control group (all P<0.05). Conclusion:The variable priority cognitive-motor dual-task training can improve the cognitive function, physical frailty and balance function in aged cognitive frailty patients with type 2 diabetes mellitus, and the intervention effect is better than that of exercise combined cognitive intervention with sequential task and endocrinology routine treatment and nursing.