Aim To investigate the regulatory mecha-nisms of donepezil on the expression and enzymatic ac-tivity of cytochrome P450 3A4(CYP3A4),elucidate the synergistic impact of hypoxia on CYP3A4 function,and reveal its potential association with drug-induced cardiotoxicity,particularly QT interval prolongation.Methods Western blot,co-immunoprecipitation,and gene knockdown techniques were employed to evaluate the effects of donepezil and hypoxia on CYP3A4 pro-tein expression.CYP3A4 enzymatic activity was as-sessed using an in vitro incubation system with rat liver microsomes combined with high-performance liquid chromatography(HPLC),and the half-maximal inhib-itory concentration(IC50)was determined.Results Donepezil(10 μmol·L-1)and hypoxia reduced CYP3A4 protein expression to 31.75％and 45.90％of the control levels,respectively.Both interventions activated the gp78-mediated ubiquitin-proteasome path-way,significantly increasing CYP3A4 ubiquitination levels by 2.1-fold compared to the control group,thereby promoting proteasomal degradation.Donepezil inhibited CYP3A4 enzyme activity with an IC50 of 83.4μmol·L-1,and hypoxia synergistically enhanced this inhibitory effect,reducing the IC50 to 20.79 μmol·L-1.Conclusion Donepezil downregulates CYP3A4 function through dual mechanisms involving ubiquitin-mediated proteasomal degradation and direct enzymatic inhibition.Hypoxia potentiates this effect,leading to impaired metabolism of CYP3A4 substrate drugs,ele-vated plasma drug concentrations(1.6-2.3-fold in-crease compared to normal metabolic conditions),and an increased risk of QT interval prolongation and other forms of cardiotoxicity.

Objective:Near-infrared(NIR)spectroscopy technology faces the problem of insufficient model generalization due to individual differences in non-invasive blood glucose testing,in order to solve this problem,to improve data utilization,and to build predictive models with stronger generalization ability,this study introduces a transfer learning method to study the NIR spectroscopy non-invasive glucose testing.Methods:Migration learning is a machine learning technique that aims to improve task performance in the target domain by transferring knowledge from the source domain to the target domain.In this study,we used community population data as the source domain and student population data as the target domain to improve the performance of the noninvasive glucose detection model on the target domain.In order to verify the effectiveness of migration learning,this study compares the performance of the model before and after migration learning.Results:the model's performance on the noninvasive glucose detection task is significantly improved by the migration learning strategy,and the MAPE and MAE of the migrated model decreases by 52.5460％and 6.0805％,respectively,and the RMSE and MSE decreases by 10.7215％and 12.1135％.Conclusions:This study demonstrates the promising application of transfer learning in the field of non-invasive blood glucose detection,which is expected to realize portable and continuous blood glucose monitoring in the future by migrating the features that are difficult to access in the source domain but are related to blood glucose values to the target domain,which will greatly improve the quality of life of diabetic patients.Advances in noninvasive glucose testing technology will not only reduce patients' pain,but also provide a more convenient means of glucose monitoring,which will provide strong support for diabetes management.

Objective:Near-infrared(NIR)spectroscopy technology faces the problem of insufficient model generalization due to individual differences in non-invasive blood glucose testing,in order to solve this problem,to improve data utilization,and to build predictive models with stronger generalization ability,this study introduces a transfer learning method to study the NIR spectroscopy non-invasive glucose testing.Methods:Migration learning is a machine learning technique that aims to improve task performance in the target domain by transferring knowledge from the source domain to the target domain.In this study,we used community population data as the source domain and student population data as the target domain to improve the performance of the noninvasive glucose detection model on the target domain.In order to verify the effectiveness of migration learning,this study compares the performance of the model before and after migration learning.Results:the model's performance on the noninvasive glucose detection task is significantly improved by the migration learning strategy,and the MAPE and MAE of the migrated model decreases by 52.5460％and 6.0805％,respectively,and the RMSE and MSE decreases by 10.7215％and 12.1135％.Conclusions:This study demonstrates the promising application of transfer learning in the field of non-invasive blood glucose detection,which is expected to realize portable and continuous blood glucose monitoring in the future by migrating the features that are difficult to access in the source domain but are related to blood glucose values to the target domain,which will greatly improve the quality of life of diabetic patients.Advances in noninvasive glucose testing technology will not only reduce patients' pain,but also provide a more convenient means of glucose monitoring,which will provide strong support for diabetes management.

Aim To investigate the regulatory mecha-nisms of donepezil on the expression and enzymatic ac-tivity of cytochrome P450 3A4(CYP3A4),elucidate the synergistic impact of hypoxia on CYP3A4 function,and reveal its potential association with drug-induced cardiotoxicity,particularly QT interval prolongation.Methods Western blot,co-immunoprecipitation,and gene knockdown techniques were employed to evaluate the effects of donepezil and hypoxia on CYP3A4 pro-tein expression.CYP3A4 enzymatic activity was as-sessed using an in vitro incubation system with rat liver microsomes combined with high-performance liquid chromatography(HPLC),and the half-maximal inhib-itory concentration(IC50)was determined.Results Donepezil(10 μmol·L-1)and hypoxia reduced CYP3A4 protein expression to 31.75％and 45.90％of the control levels,respectively.Both interventions activated the gp78-mediated ubiquitin-proteasome path-way,significantly increasing CYP3A4 ubiquitination levels by 2.1-fold compared to the control group,thereby promoting proteasomal degradation.Donepezil inhibited CYP3A4 enzyme activity with an IC50 of 83.4μmol·L-1,and hypoxia synergistically enhanced this inhibitory effect,reducing the IC50 to 20.79 μmol·L-1.Conclusion Donepezil downregulates CYP3A4 function through dual mechanisms involving ubiquitin-mediated proteasomal degradation and direct enzymatic inhibition.Hypoxia potentiates this effect,leading to impaired metabolism of CYP3A4 substrate drugs,ele-vated plasma drug concentrations(1.6-2.3-fold in-crease compared to normal metabolic conditions),and an increased risk of QT interval prolongation and other forms of cardiotoxicity.

To investigate the association between obesity-related metabolic indices and the risk of knee osteoarthritis(KOA) in middle-aged and older Chinese adults(≥45 years) using data from the China Health and Retirement Longitudinal Study(CHARLS).

Objective To compare the application value of three image post-processing techniques volume rendering(VR),multiplanar reformation(MPR)and curved planar reformation(CPR)in the identifi-cation of rib fracture malunion.Methods The types and numbers of rib fracture malunion in 75 pa-tients were recorded,and the sensitivity,specificity,accuracy and Youden index of VR,MPR and CPR in the diagnosis of rib fracture malunion were compared.Receiver operator characteristic(ROC)curve was drawn and area under the curve(AUC)was calculated,and the detection rates of three image post-processing techniques for different types of rib fracture malunion were compared.Results A total of 243 rib fractures were malunion in 75 patients.The diagnostic sensitivity of VR,MPR and CPR for rib fracture malunion was 52.67%,79.84%and 91.36%,the specificity was 99.58%,97.89%and 99.15%,the accuracy was 83.66%,91.76%and 96.51%,the Youden index was 0.52,0.78 and 0.91,the AUC was 0.761,0.889 and 0.953,respectively.Compared with VR,there were statistically signifi-cant differences in the number of broken rib end misalignment over 1/3,broken rib end overlap,bro-ken rib end angulation and intercostal bridge detected in MPR(P<0.05).Compared with VR,there was a statistically significant difference in the number of different types of rib fracture malunion de-tected by CPR(P<0.05).Compared with MPR,there were statistically significant differences in the number of broken rib end misalignment over 1/3,broken rib end separation and intercostal bridge de-tected in CPR(P<0.05).Conclusion The three image post-processing techniques are of great signifi-cance for the identification of rib fracture malunion.Especially CPR is highly effective in the diagno-sis of rib fracture malunion,and can be used as the main post-processing technique for forensic clini-cal identification of rib fracture malunion.

OBJECTIVE: The study aimed to estimate the benchmark dose (BMD) of coke oven emissions (COEs) exposure based on mitochondrial damage with the mitochondrial DNA copy number (mtDNAcn) as a biomarker. METHODS: A total of 782 subjects were recruited, including 238 controls and 544 exposed workers. The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction. Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95% confidence lower limit (BMDL). RESULTS: The mtDNAcn of the exposure group was lower than that of the control group (0.60 ± 0.29 vs. 1.03 ± 0.31; P < 0.001). A dose-response relationship was shown between the mtDNAcn damage and COEs. Using the Benchmark Dose Software, the occupational exposure limits (OELs) for COEs exposure in males was 0.00190 mg/m ³. The OELs for COEs exposure using the BBMD were 0.00170 mg/m ³ for the total population, 0.00158 mg/m ³ for males, and 0.00174 mg/m ³ for females. In possible risk obtained from animal studies (PROAST), the OELs of the total population, males, and females were 0.00184, 0.00178, and 0.00192 mg/m ³, respectively. CONCLUSION Based on our conservative estimate, the BMDL of mitochondrial damage caused by COEs is 0.002 mg/m ³. This value will provide a benchmark for determining possible OELs.
Male ; Female ; Animals ; Coke ; Polycyclic Aromatic Hydrocarbons ; DNA Copy Number Variations ; Benchmarking ; Occupational Exposure/analysis* ; DNA, Mitochondrial/genetics* ; DNA Damage

Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis* ; Death, Sudden/etiology*

OBJECTIVE To investigate the mechanism of Xiaoai Jiedu Recipe in promoting ferroptosis of tumor cells and inhibi-ting the growth of transplanted tumors in hepatocellular carcinoma mice by proteomics method.METHODS C57BL/6J mice were randomly divided into,model group,low-and high-dose groups of Xiaoai Jiedu Recipe,Xiaoai Jiedu Recipe combined with ferropto-sis inhibitor group,ferroptosis inhibitor group and cisplatin group.The H22 mouse transplantation tumor model was constructed and the drug administration interventions were as follows:the low-and high-dose groups of Xiaoai Jiedu Recipe were given Xiaoai Jiedu Reci-pe by gavage at the doses of 10 and 20 g·kg-1·d-1;the ferroptosis inhibitor group was given Liproxstatin-1 by intraperitoneal injec-tion at the dose of 10 mg·kg-1·d-1;the cisplatin group was given cisplatin by intraperitoneal injection at the dose of 10 mg·kg-1·d-1;the Xiaoai Jiedu Recipe combined with ferroptosis inhibitor group was given a gavage dose of 20 g·kg-1·d-1of Xiaoai Jiedu Recipe and an intraperitoneal injection of 10 mg·kg-1·d-1 of the ferroptosis inhibitor Liproxstatin-1;the model group was given an equal amount of saline by gavage.The drugs were administered for 11 d continuously.The tumors were stripped to calcu-late tumor inhibition rate.Pathological changes were observed by hematoxylin-eosin(HE).Mitochondrial structural changes were ob-served by transmission electron microscopy.Reactive oxygen species(ROS)levels were detected by flow cytometry.Serum was pre-pared and analysed by TMT peptide labelling combined with LC-MS/MS to find differential protein expression profiles,applying IPA software.Serum iron ions,glutathione(GSH)and malondialdehyde(MDA)levels were measured biochemically.Protein expression levels of nuclear factor E2-related factor 2(Nrf2),heme oxygenase-1(HMOX1),cystine/glutamate reverse transporter protein(SLC7A11)and glutathione peroxidase 4(GPX4)were measured by protein Western blot.RESULTS The tumor growth was inhibi-ted in the low-and high-dose groups and the cisplatin group,with inhibition rates of 36.12%,51.63%and 57.43%,respectively,while the tumor growth was promoted in the ferroptosis inhibitor group,with an inhibition rate of-45.56%,and the tumor size was re-duced in the Xiaoai Jiedu Recipe combined with ferroptosis inhibitor group compared with the ferroptosis inhibitor group,with an inhi-bition rate of 18.11%.HE staining showed that apoptotic cells and a large number of vacuoles accumulated in the tumor tissues of the high-dose group and the cisplatin group.Transmission electron microscopy showed that the mitochondrial atrophy and membrane densi-ty increased to a certain extent in the low and high-dose groups of Xiaoai Jiedu Recipe.Flow cytometry results showed that ROS levels were significantly increased after the intervention of Xiaoai Jiedu Recipe(P<0.01).Proteomic tests showed that there were 129 differ-ential proteins,including 62 down-regulated proteins and 67 up-regulated proteins,in the high-dose group of Xiaoai Jiedu Recipe compared with the model group,and these differential expressions were involved in lipid metabolism,et al.The results of biochemical tests showed that the intervention of Xiaoai Jiedu Recipe increased the serum iron and MDA levels,and decreased the GSH level in mice.Western blot results showed that the protein expression levels of Nrf2 and HMOX1 increased,and those of SLC7A11 and GPX4 decreased after the intervention of the high-dose group of Xiaoai Jiedu Recipe(P<0.01).CONCLUSION Xiaoai Jiedu Recipe pro-motes ferroptosis in hepatocellular carcinoma cells by inducing the Nrf2/HMOX1 signaling pathway,regulating oxidative stress and ele-vating the level of lipid peroxidation,which may be one of its mechanisms of action in inhibiting the growth of transplanted tumors.

Objective: To investigate the genetic and genomic profiling of juvenile myelomonocytic leukemia (JMML) and factors affecting its survival rate. Methods: Clinical characteristics, cytogenetics, molecular biology results and survival status of children with 27 JMML cases admitted to the Hematology Department of Children's Hospital, Capital Institute of Pediatrics from December 2012 to December 2021 were analyzed retrospectively, and the outcomes of the children were followed up. Kaplan-Meier method was used for survival analysis. Univariate analysis was used for analyzing factors affecting the overall survival (OS) rates of patients who received hematopoietic stem cell transplantation (HSCT). Log-Rank test was used for comparison of survival curves. Results: Among 27 JMML cases, there were 11 males and 16 females. The age of disease onset was 28 (11,52) months. There are 20 cases of normal karyotype, 4 cases of monosomy 7, 1 case of trisomy 8,1 case of 11q23 rearrangement and 1 case of complex karyotype. A total of 39 somatic mutations were detected.Those involved in RAS signal pathway were the highest (64%(25/39)), among which PTPN11 mutation was the most frequent (44% (11/25)). A total of 17 cases (63%) received HSCT, 8 cases (30%) did not receive HSCT, and 2 cases (7%) lost follow-up. For children receiving transplantation, the follow-up time after transplantation was 47 (11,57) months. The 1-year OS rate of high-risk transplantation group (17 cases) and high-risk non transplantation group (6 cases) was (88±8)% and (50±20)% respectively, with a statistically significant difference (χ²=5.01, P=0.025). The 5-year OS rate of the high-risk transplantation group was (75±11)%. The survival time of those who relapsed or progressed to acute myeloid leukemia after transplantation was significantly shorter than that of those who did not relapse (χ²=6.80, P=0.009). The OS rate of patients with or without PTPN11 mutation was (81±12) % and (67±19)% respectively (χ²=0.85, P=0.356). Conclusions: The main pathogenesis involved in JMML is gene mutation related to RAS signaling pathway, and the most common driver gene of mutation is PTPN11. Allogeneic HSCT can significantly improve the survival rate of high-risk JMML patients. The recurrence or progression after transplantation was related to poor prognosis.
Male ; Female ; Child ; Humans ; Child, Preschool ; Leukemia, Myelomonocytic, Juvenile/therapy* ; Retrospective Studies ; Survival Analysis ; Mutation ; Hematopoietic Stem Cell Transplantation