Apurinic/apyrimidinic endonuclease 1(APE 1)is a multifunctional protein that plays important roles in DNA repair and regulation of gene expression.Because APE 1 is overexpressed in various cancers,it can serve as a cancer biomarker for aiding clinical diagnosis,guiding therapy,and monitoring prognosis.On this basis,a label-free fluorescent probe was designed based on the primer exchange reaction(PER)strategy for highly sensitive detection of APE 1 activity.In the absence of APE 1,the structure of catalytic hairpin(HP)was stable and could not form G-quadruplex.Therefore,the background fluorescence of this sensing system was very low due to the dissociation of thioflavin T(ThT).In the presence of APE 1,the apurinic/apyrimidinic(AP)site of HP was cleaved by APE 1 and a short nucleic acid fragment that acted as a primer to initiate PER was generated.After PER reaction,a large number of G-quadruplex were produced,which could specifically bind with ThT and resulted in significant increase of fluorescence signal.The combination of low background design of HP and PER amplification made this biosensor had high sensitivity with a detection limit(3σ)of 0.0008 U/mL.Furthermore,the primer sequence was directly generated by the cleavage of APE 1 without additional addition,which not only increased the specificity of the reaction,but also simplified the experiment procedure.Moreover,the use of label-free fluorescence signal reduced the cost of the experiment,and realized rapid detection of APE 1.Finally,this sensor was used to detect APE 1 in human serum samples with spiked recoveries of 91%-104%,proving great potential in study of biological enzyme.

OBJECTIVE To explore the levels of helper T lymphocytes(Th)in patients with hepatitis B virus(HBV)infection who were treated with entecavir and observe the impact on viral clearance.METHODS A total of 149 patients with HBV infection who were treated with entecavir in Yan'an Hospital of Kunming City from Jan.2020 to Jan.2024 were enrolled in the study,82 of whom were chronic hepatitis B(CHB),and 67 were chro-nic hepatitis B virus carriers.The enrolled patients were divided into the clearance group with 64 cases and the no clearance group with 85 cases according to the levels of serum hepatitis B surface antigen(HBsAg)at Week 72 of the treatment.The clinical data were compared between the two groups,and the changes of Th1 and Th2 levels during the treatment were analyzed.Multivariate linear regression analysis was performed for the association be-tween virological change during the treatment and immune level.The risk factors for failed clearance of viruses were analyzed by logistic regression model.RESULTS There were significant differences in the age,the levels of alanine aminotransferase(ALT)and HBV DNA between the baseline and Week 24,the levels of aspartate trans-aminase(AST)at the baseline and Week 12,the HBsAg level at Week 24,and the baseline levels of Th1,Th1/Th2 between the CHBc treatment group and the CHB treatment group(P＜0.05).There were linear correlations between the HBV DNA,HBsAg,hepatitis E antigen(HBeAg)and the Th1,Th2 and Th1/Th2,respectively(P＜0.05).Totally 64 patients were accumulatively eradicated with HBsAg on Week 72,with the eradication rate 42.95％.After the confounding factors were adjusted,multivariate analysis showed that the high levels of Th1,Th2 and Th1/Th2 were the risk factors for the failed clearance of viruses(P＜0.05).CONCLUSIONS Among the patients with HBV infection,there is difference in the immune level between the CHB patients and the CHB virus carriers.The levels of Th1,Th2 and Th1/Th2 are strongly correlated with the HBV DNA,HBsAg,HBeAg and efficiency of viral clearance during the treatment with entecavir.

Polycystic ovary syndrome (PCOS) is the predominant cause of subfertility in reproductive-aged women; however, its pathophysiology remains unknown. Neurotensin (NTS) is a member of the gut-brain peptide family and is involved in ovulation; its relationship with PCOS is unclear. Here, we found that NTS expression in ovarian granulosa cells and follicular fluids was markedly decreased in patients with PCOS. In the in vitro culture of cumulus-oocyte complexes, the neurotensin receptor 1 (NTSR1) antagonist SR48692 blocked cumulus expansion and oocyte meiotic maturation by inhibiting metabolic cooperation and damaging the mitochondrial structure in oocytes and surrounding cumulus cells. Furthermore, the ERK1/2-early growth response 1 pathway was found to be a key downstream mediator of NTS/NTSR1 in the ovulatory process. Animal studies showed that in vivo injection of SR48692 in mice reduced ovulation efficiency and contributed to irregular estrus cycles and polycystic ovary morphology. By contrast, NTS partially ameliorated the ovarian abnormalities in mice with dehydroepiandrosterone-induced PCOS. Our findings highlighted the critical role of NTS reduction and consequent abnormal NTSR1 signaling in the ovulatory dysfunction of PCOS, suggesting a potential strategy for PCOS treatment.
Polycystic Ovary Syndrome/physiopathology* ; Female ; Animals ; Neurotensin/metabolism* ; Receptors, Neurotensin/antagonists & inhibitors* ; Mice ; Ovulation/drug effects* ; Humans ; Granulosa Cells/metabolism* ; Adult ; Oocytes/metabolism* ; MAP Kinase Signaling System ; Signal Transduction ; Follicular Fluid/metabolism* ; Disease Models, Animal ; Gonadotropin-Releasing Hormone/analogs & derivatives*

BACKGROUND: To date, results on relationship between CYP3A4 gene polymorphism were limited and inconclusive, and no study focused on the influence of CYP3A4 gene-obesity interaction on breast cancer risk, especially in Chinese women. The purpose of this study was to evaluate the impact of four single nucleotide polymorphisms (SNPs) of CYP3A4 gene, the SNP-SNP and gene-environment interactions on the susceptibility to breast cancer in Chinese women. METHODS: Logistic regression was used to explore the relationship between four SNPs of CYP3A4 gene and the risk of breast cancer. Generalized multifactor dimensionality reduction (GMDR) was used to screen the best SNP-SNP and gene-abdominal obesity interaction combinations among four SNPs and abdominal obesity. Haplotype examination among 4 SNPs was conducted using the SHEsis web-based platform. RESULTS: Logistic regression analysis showed that carriers of rs2242480- T allele have significantly higher breast cancer risk, than those with rs2242480- CC genotype, adjusted OR (95%CI) was 1.68 (1.23-2.16) and 2.03 (1.53-2.58) for participants with CT genotype and TT genotype under additive model. We did not find any notable interactions between the four SNPs within the CYP3A4 gene. GMDR model found a significant association in a two-locus model involving rs2242480 and obesity, with a p-value of 0.018. Stratified analysis found that breast cancer risk was the highest in obese participants with rs2242480- CT or TT genotype, compared to those non-obese participants with rs2242480- CC genotype, OR (95%CI) was 3.02 (1.83-4.25). We found that all haplotype combinations were not correlated with breast cancer risk. CONCLUSIONS We found that the T allele of rs2242480 within the CYP3A4 gene and interaction between rs2242480 and obesity were associated with an increased risk of breast cancer. However, the results of this study were only applicable to the Han ethnic group and cannot be generalized to other ethnic groups in China, and more SNPs of CYP3A4 gene should been enrolled in the analysis in the future, to verify the results obtained in this study.
Adult ; Aged ; Female ; Humans ; Middle Aged ; Breast Neoplasms/etiology* ; China/epidemiology* ; Cytochrome P-450 CYP3A/metabolism* ; Gene-Environment Interaction ; Genetic Predisposition to Disease ; Haplotypes ; Obesity/epidemiology* ; Polymorphism, Single Nucleotide ; Risk Factors ; East Asian People

Objective To investigate whether Piceatannol(PIC)improves diabetic retinopathy(DR)mediated by microglial polarization and to elucidate the underlying molecular mechanisms.Methods Network pharmacology and bioinformatics were used to analyze the common targets of DR,PIC,and microglia.Human retinal vascular endothelial cells(HRVECs)were cultured in vitro and randomly divided into the NG-HRVECs group,HG-HRVECs group,and HG+PIC-HRVECs group.Cell viability was assessed by the CCK-8 assay,apoptosis was detected by the TUNEL assay,and the concentrations of tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)were measured using ELISA kits.BV-2 cells were cultured in vitro and randomly divided into the NG-BV-2 group,HG-BV-2 group,HG+PIC-BV-2 group,HG+Si-NC-BV-2 group,HG+Si-CXCR4-BV-2 group,and HG+Ibrutinib-BV-2 group.The levels of arginase-1(Arg-1)and inducible ni-tric oxide synthase(iNOS)were measured using ELISA kits.Furthermore,conditioned medium(CM)from BV-2 cells of each group was collected to treat HRVECs,after which the viability,apoptosis rate,and TNF-α and IL-6 concentrations of the HRVECs were measured.A DR rat model was established and intervened with PIC to investigate the ameliorative effects of PIC on retinal pathology.Results Bioinformatics analysis identified CXCR4 as the key target of this study.Compared with the NG-HRVECs group,the apoptosis rate and the concentrations of TNF-α and IL-6 were increased in the HG-HRVECs group.Compared with the HG-HRVECs group,the HG+PIC-HRVECs group showed a decreased apoptosis rate and reduced concentrations of TNF-α and IL-6(all P＜0.05).Compared with the NG-BV-2 group,the HG-BV-2 group ex-hibited decreased Arg-1 levels and increased iNOS levels.Compared with the HG-BV-2 group,the HG+PIC-BV-2,HG+Si-CXCR4-BV-2,and HG+Ibrutinib-BV-2 groups all showed increased Arg-1 levels and decreased iNOS levels(all P＜0.05).Compared with the NG-BV-2-CM group,the HG-BV-2-CM group led to decreased viability,increased apoptosis rate,and in-creased concentrations of TNF-α and IL-6 in HRVECs.In contrast,the HG+PIC-BV-2-CM,HG+Si-CXCR4-BV-2-CM,and HG+Ibrutinib-BV-2-CM groups reversed the effects induced by HG-BV-2-CM on HRVECs(all P＜0.05).Animal experiment results showed that compared with DR model rats,rats treated with different doses of PIC exhibited significantly ameliora-ted retinal histopathological damage,and the protein expressions of Arg-1,iNOS,CXCR4,and p-BTK were reversed.Con-clusion PIC ameliorates DR progression mediated by microglial polarization by inhibiting the CXCR4/BTK pathway.

Objective To investigate whether Piceatannol(PIC)improves diabetic retinopathy(DR)mediated by microglial polarization and to elucidate the underlying molecular mechanisms.Methods Network pharmacology and bioinformatics were used to analyze the common targets of DR,PIC,and microglia.Human retinal vascular endothelial cells(HRVECs)were cultured in vitro and randomly divided into the NG-HRVECs group,HG-HRVECs group,and HG+PIC-HRVECs group.Cell viability was assessed by the CCK-8 assay,apoptosis was detected by the TUNEL assay,and the concentrations of tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)were measured using ELISA kits.BV-2 cells were cultured in vitro and randomly divided into the NG-BV-2 group,HG-BV-2 group,HG+PIC-BV-2 group,HG+Si-NC-BV-2 group,HG+Si-CXCR4-BV-2 group,and HG+Ibrutinib-BV-2 group.The levels of arginase-1(Arg-1)and inducible ni-tric oxide synthase(iNOS)were measured using ELISA kits.Furthermore,conditioned medium(CM)from BV-2 cells of each group was collected to treat HRVECs,after which the viability,apoptosis rate,and TNF-α and IL-6 concentrations of the HRVECs were measured.A DR rat model was established and intervened with PIC to investigate the ameliorative effects of PIC on retinal pathology.Results Bioinformatics analysis identified CXCR4 as the key target of this study.Compared with the NG-HRVECs group,the apoptosis rate and the concentrations of TNF-α and IL-6 were increased in the HG-HRVECs group.Compared with the HG-HRVECs group,the HG+PIC-HRVECs group showed a decreased apoptosis rate and reduced concentrations of TNF-α and IL-6(all P＜0.05).Compared with the NG-BV-2 group,the HG-BV-2 group ex-hibited decreased Arg-1 levels and increased iNOS levels.Compared with the HG-BV-2 group,the HG+PIC-BV-2,HG+Si-CXCR4-BV-2,and HG+Ibrutinib-BV-2 groups all showed increased Arg-1 levels and decreased iNOS levels(all P＜0.05).Compared with the NG-BV-2-CM group,the HG-BV-2-CM group led to decreased viability,increased apoptosis rate,and in-creased concentrations of TNF-α and IL-6 in HRVECs.In contrast,the HG+PIC-BV-2-CM,HG+Si-CXCR4-BV-2-CM,and HG+Ibrutinib-BV-2-CM groups reversed the effects induced by HG-BV-2-CM on HRVECs(all P＜0.05).Animal experiment results showed that compared with DR model rats,rats treated with different doses of PIC exhibited significantly ameliora-ted retinal histopathological damage,and the protein expressions of Arg-1,iNOS,CXCR4,and p-BTK were reversed.Con-clusion PIC ameliorates DR progression mediated by microglial polarization by inhibiting the CXCR4/BTK pathway.

OBJECTIVE To explore the levels of helper T lymphocytes(Th)in patients with hepatitis B virus(HBV)infection who were treated with entecavir and observe the impact on viral clearance.METHODS A total of 149 patients with HBV infection who were treated with entecavir in Yan'an Hospital of Kunming City from Jan.2020 to Jan.2024 were enrolled in the study,82 of whom were chronic hepatitis B(CHB),and 67 were chro-nic hepatitis B virus carriers.The enrolled patients were divided into the clearance group with 64 cases and the no clearance group with 85 cases according to the levels of serum hepatitis B surface antigen(HBsAg)at Week 72 of the treatment.The clinical data were compared between the two groups,and the changes of Th1 and Th2 levels during the treatment were analyzed.Multivariate linear regression analysis was performed for the association be-tween virological change during the treatment and immune level.The risk factors for failed clearance of viruses were analyzed by logistic regression model.RESULTS There were significant differences in the age,the levels of alanine aminotransferase(ALT)and HBV DNA between the baseline and Week 24,the levels of aspartate trans-aminase(AST)at the baseline and Week 12,the HBsAg level at Week 24,and the baseline levels of Th1,Th1/Th2 between the CHBc treatment group and the CHB treatment group(P＜0.05).There were linear correlations between the HBV DNA,HBsAg,hepatitis E antigen(HBeAg)and the Th1,Th2 and Th1/Th2,respectively(P＜0.05).Totally 64 patients were accumulatively eradicated with HBsAg on Week 72,with the eradication rate 42.95％.After the confounding factors were adjusted,multivariate analysis showed that the high levels of Th1,Th2 and Th1/Th2 were the risk factors for the failed clearance of viruses(P＜0.05).CONCLUSIONS Among the patients with HBV infection,there is difference in the immune level between the CHB patients and the CHB virus carriers.The levels of Th1,Th2 and Th1/Th2 are strongly correlated with the HBV DNA,HBsAg,HBeAg and efficiency of viral clearance during the treatment with entecavir.

Objective A finite element simulation analysis of a bracketless orthodontic appliance was carried out to determine the correction amount under different working conditions.A design scheme for the bracketless orthodontic appliance was also formulated to create an orthodontic appliance formed by the fused deposition process with a personalized orthodontic effect.Methods Combined with the computed tomography data of the patient,a tooth model was reversely reconstructed.The correction amount of the tooth under tilting,twisting,and translation working conditions was established using the finite element method.Materials with different elastic moduli were chosen to make three-dimensional(3D)shaped bracketless orthodonitc appliance,and the orthodontic force was measured.Results Different correction amounts could be designed according to different working conditions so that the orthodontic appliance had a personalized treatment effect.The orthodontic force of the bracketless orthodontic appliance increased with elastic modulus and thickness.Under the given working conditions,the orthodontic force was minimal(90 mN)when the orthodontic material was at the minimum(90 mN).The orthodontic force reached its maximum value when the orthodontic material was at the maximum(61.66 N).Conclusions According to the patient's tooth condition and the size of the orthodontic force required for each step of correction in the whole correction process,the design should consider bracketless orthodontics with different elastic moduli and thicknesses to treat deformed teeth to realize the effect of staged orthodontic correction.

Objective To evaluate the efficacy and safety of brexpiprazole in treating acute schizophrenia.Methods Patients with schizophrenia were randomly divided into treatment group and control group.The treatment group was given brexpiprozole 2-4 mg·d-1 orally and the control group was given aripiprazole 10-20 mg·d-1orally,both were treated for 6 weeks.Clinical efficacy of the two groups,the response rate at endpoint,the changes from baseline to endpoint of Positive and Negative Syndrome Scale(PANSS),Clinical Global Impression-Improvement(CGI-S),Personal and Social Performance scale(PSP),PANSS Positive syndrome subscale,PANSS negative syndrome subscale were compared.The incidence of treatment-related adverse events in two groups were compared.Results There were 184 patients in treatment group and 186 patients in control group.After treatment,the response rates of treatment group and control group were 79.50％(140 cases/184 cases)and 82.40％(150 cases/186 cases),the scores of CGI-I of treatment group and control group were(2.00±1.20)and(1.90±1.01),with no significant difference(all P＞0.05).From baseline to Week 6,the mean change of PANSS total score wese(-30.70±16.96)points in treatment group and(-32.20±17.00)points in control group,with no significant difference(P＞0.05).The changes of CGI-S scores in treatment group and control group were(-2.00±1.27)and(-1.90±1.22)points,PSP scores were(18.80±14.77)and(19.20±14.55)points,PANSS positive syndrome scores were(-10.30±5.93)and(-10.80±5.81)points,PANSS negative syndrome scores were(-6.80±5.98)and(-7.30±5.15)points,with no significant difference(P＞0.05).There was no significant difference in the incidence of treatment-related adverse events between the two group(69.00％vs.64.50％,P＞0.05).Conclusion The non-inferiority of Brexpiprazole to aripiprazole was established,with comparable efficacy and acceptability.

From the perspectives of traditional Chinese medicine （TCM） information knowledge base and assisted decision-making knowledge base， the construction status， quality evaluation status and existing problems of current TCM knowledge bases have been sorted out. And based on the quality evaluation strategies and dimensions of know-ledge bases in other disciplines， the evaluation indexes for TCM knowledge base is discussed， and the evaluation framework is initially formed， providing ideas for the improvement of the TCM knowledge base evaluation system. In terms of the evaluation indexes， there are basic evaluation dimensions which include data sources， data collection， and data application. The specific evaluation dimension of the information-based knowledge base is data quality， while that of the assisted decision-making knowledge base is data matching. Except for the data application dimension which counts the valid data items in the database for calculation， other indexes are scored based on the qualitative evaluation of "yes"， "no" or "unknown". The basic evaluation score and the specific evaluation score are added to obtain the total score. The knowledge base is graded according to the score， and the results are presented in the form of grade plus number.