Allergic rhinitis (AR), a globally prevalent immune-mediated inflammatory condition, is still an incurable disease. In the present study, we have validated the impact of the Kelch-like ECH associated protein 1 (Keap1)-related oxidative stress and inflammatory response in clinical AR patient peripheral blood and nasal swab samples, emphasizing the biological relevance of Keap1 and AR. Targeting Keap1 -nuclear factor erythroid 2-related factor 2 (Nrf2) related anti-oxidative stress may be effective for AR intervention. Drawing inspiration from the Keap1 homodimerization and the E3 ligase characteristics, we herein present a design of novel bivalent molecules for chemical knockdown of Keap1. For the first time, we characterized ternary complexes of Keap1 dimer and one molecule of bivalent compounds. The best bivalent molecule 8 encompasses robust capacity to degrade Keap1 as a homoPROTAC^KEAP1. It efficaciously suppresses inflammatory cytokines in extensively different cells, including human nasal epithelial cells. Moreover, in an AR mouse model, we confirmed that the chemical degradation induced by homoPROTAC^KEAP1 led to therapeutic benefits in managing AR symptoms, oxidative stress and inflammation. In summary, our findings underscore the efficacy of targeting the Keap1 system through the homoPROTAC-ing technology as an innovative and promising treatment strategy for the incurable allergic disorders.

Naturally derived metabolites are valuable resources for drug research and development, and play an important role in the treatment of diseases. As the "second genome" of the body, gut microbiota is rich in metabolic enzymes, which interacts with external substances such as drugs, thus affecting the progression of diseases. This article summarizes the interaction between gut microbiota-producing enzymes and natural medicines, and focuses on the impact of this interaction on disease progression, hoping to provide new ideas for the development and pharmacological mechanism of natural medicines.

Objective:To explore the quality improvement in the organization structure and management model of the integrated community child health services.Methods:This was a qualitative study, including two parts: cause analysis and service improvement suggestions. In the analysis part the data mining was conducted to identify valuable patterns and relationships in the comprehensive child health services. Semi-structured interviews were conducted with 12 relevant department heads and health workers of the comprehensive child health service team at Gumei Community Health Service Center in December 2023, and the causes of the key problems were explored. In the service improvement part, focus group discussions were held to propose suggestions, then improvement measures were formulated to address the identified problems.Results:Through data mining and semi-structured interviews, the key problems were identified: information isolation among multiple departments and lack of coordination mechanism in the comprehensive child health service team. A team organizational structure based on the "three definite" principle was established. The organizational structure should include the pediatric family doctor team, general practitioner management team and departments of pediatrics, maternal and child health care, immunization and child rehabilitation; the management model should include a cross-department resource and information sharing mechanism, the pediatric family doctor model, optimization and integration of physical space, and enhancement of publicity activities for the comprehensive child health services.Conclusion:Based on the analysis in Gumei health service center, this study identified key problems in community integrated child health services, and proposes the quality improvement measure in the organizational structure and management model of the service team.

Objective:To investigate the value of soluble interleukin-6 (IL-6) receptor (sIL-6R) level in predicting ultrafiltration insufficiency in peritoneal dialysis (PD) patients.Methods:It was a prospective cohort study. The patients who received continuous ambulatory PD and regular follow-up between November 2016 and July 2018 in the PD Center of Renji Hospital, School of Medicine, Shanghai Jiao Tong University were enrolled. Enzyme-linked immunosorbent assay was used to determine dialysate sIL-6R and its appearance rate (AR) was calculated. Patients were divided into high sIL-6R AR group and low sIL-6R AR group according to median value of sIL-6R AR and prospectively followed up until death, PD cessation, or the end of the study (December 31, 2022). Multiple linear regression was used to analyze the related factors of sIL-6R AR. Kaplan-Meier method and log-rank test were used to compare the survival rate difference of ultrafiltration insufficiency between high sIL-6R AR group and low sIL-6R AR group. Multivariate Cox regression and multivariate competing risk models were used to assess the risk factors associated with occurrence of ultrafiltration insufficiency.Results:A total of 198 PD patients were enrolled, including 115 (58.1%) males, with age of (54.9±13.7) years old and PD duration of 22.5 (6.6, 65.0) months. The sIL-6R AR of the cohort was 2 094.7 (1 672.4, 2 920.9) pg/min. Compared with low sIL-6R AR（<2 094.7 pg/min）group, high sIL-6R AR（>2 094.7 pg/min）group had older age ( t=-3.269, P=0.001), higher body mass index ( t=-3.248, P=0.001), proportion of combined diabetes mellitus ( χ2=8.890, P=0.003), 24 h glucose exposure ( Z=-2.257, P=0.024), 24 h ultrafiltration capacity ( Z=-2.515, P=0.012), 4 h dialysate creatinine to serum creatinine ratio ( t=-2.609, P=0.010), mass transfer area coefficient of creatinine ( Z=-2.308, P=0.021), IL-6 AR ( Z=-3.533, P<0.001) and solute glycoprotein 130 AR ( Z=-8.670, P<0.001), and lower serum albumin ( t=2.595, P=0.010) and residual renal function ( t=2.133, P=0.033). Multiple linear regression analysis showed that body mass index ( β=0.194, P=0.005), serum albumin ( β=-0.215, P=0.002) and dialysate lg[IL-6 AR] ( β=0.197, P=0.011) were independently correlated with sIL-6R AR. By the end of the study, 57 (28.8%) patients developed ultrafiltration insufficiency. Kaplan-Meier analysis showed that high sIL-6R AR group had a significantly inferior ultrafiltration insufficiency-free survival rate than that in low sIL-6R AR group (log-rank χ 2=5.375, P=0.020). Multivariate Cox regression analysis and multivariate competing risk models showed that high dialysate sIL-6R AR (>2 094.7 pg/min) was an independent influencing factor of ultrafiltration insufficiency ( HR=2.286 , 95% CI 1.254-4.165 , P=0.007 ; SHR=2.074, 95% CI 1.124-3.828, P=0.020) in PD patients. Conclusions:Dialysate sIL-6R level was associated with body mass index, serum albumin and dialysate IL-6 level. Dialysate sIL-6R may be a predictive factor of ultrafiltration insufficiency in PD patients.

Objective:To investigate the early and mid-term outcomes of aortic endovascular remodeling device (AERD) for Stanford type A aortic dissection (TAAD) in type Ⅱhybrid surgery, and to evaluate its clinical efficacy.Methods:46 patients with TAAD, including 14 females and 32 males, participated in the single-center clinical trial of West China Hospital of Sichuan University and underwent type II hybrid surgery (Bentall / ascending aorta replacement + AERD implantation) from February 2021 to October 2023. The safety and efficacy of AERD in type Ⅱ hybrid surgery for TAAD were estimated by clinical indicators (postoperative mortality, cardiovascular and cerebrovascular accidents, paraplegia, ischemia), and blood flow condition (volume of the true and false lumen, and suprachial branches).Results:Three patients (6.52%) died during the follow-up period, and the operation-related mortality was 4.35% (2/46). The remaining 43 patients were followed up for an average of (25.53±9.60) months. There were two cases (4.35%) of stroke after the operation, and paraplegia, acute renal insufficiency, and other severe complications were not noticed. The blood flow of the superior branch of the aortic arch was unobstructed, and there was no significant difference in the blood flow of the branch before the operation and at each follow-up time point. Compared to the pre-operation, the true lumen volume of the stent part increased by 59.0% and the false lumen volume decreased by 82.4%.Conclusion:AERD is a safe and effective alternative in type II hybrid surgery for acute TAAD, which is helpful in improving perioperative and short- and long-term survival rates and clinical outcomes.

Objective:To evaluate the influencing factors of carotid-femoral pulse wave velocity (CF-PWV) and its value to predict outcomes in peritoneal dialysis (PD) patients.Methods:Eligible patients undergoing PD in Renji Hospital of Shanghai Jiao Tong University between August 2016 and July 2018 were recruited and prospectively followed up until death, PD cessation, or to the end of the study. CF-PWV was measured by an arterial pulse wave velocity meter to assess arterial stiffness (July 31, 2020). Overhydration was measured by bioimpedance spectroscopy. The patients were divided into CF-PWV≤10 m/s group and CF-PWV>10 m/s group according to the measured value of CF-PWV. The influencing factors of elevated CF-PWV were analyzed by multivariate logistic regression. Survival curves were generated using the Kaplan-Meier method and multivariate Cox proportional hazards models were used to analyze the difference for all-cause mortality and cardiovascular disease (CVD) mortality between the two groups.Results:A total of 224 PD patients were enrolled, including 133 males (59.4%). The age was (55.2±13.4) years old, and median PD vintage was 22.3(6.5, 59.3) months. Among them, 47(21.0%) patients were comorbid with diabetes, and 37(16.5%) patients had CVD history. The median CF-PWV was 9.6(8.4, 11.4) m/s for the cohort, and 105(46.9%) participants had CF-PWV over 10 m/s. Compared with CF-PWV≤10 m/s group, CF-PWV>10 m/s group patients had older age, increased percentage of diabetes and CVD (all P<0.05). Multivariate logistic analysis showed that increased age ( OR=1.070, 95% CI 1.043-1.099, P<0.001), diabetes ( OR=3.693, 95% CI 1.646-8.287, P=0.002) and higher overhydration ( OR=1.238, 95% CI 1.034-1.483, P=0.020) were independent influencing factors for elevated CF-PWV in PD patients. After followed up for 37.4(25.6, 41.7) months, 24 patients died, including 19 cases of CVD-related deaths. Kaplan-Meier survival analysis showed that all-cause mortality and CVD mortality were significantly higher in the CF-PWV>10 m/s group than those in CF-PWV≤10 m/s group (Log-rank χ2=6.423, P=0.011; Log-rank χ2=6.243, P=0.012, respectively). Multivariate Cox proportional hazards models showed that increased age was an independent influencing factor for both all-cause mortality and CVD mortality ( HR=1.057, 95% CI 1.010-1.107, P=0.018; HR=1.062, 95% CI 1.009-1.118, P=0.022). Conclusions:Increased arterial stiffness is relatively common in PD patients. Higher CF-PWV in PD patients is associated with increased age, diabetes and higher overhydration, and it is probably a valuable predictor of outcome in PD patients.

The historical evolution， fermentation technology and key links of Sojae Semen Praeparatum （SSP） were sorted out by consulting ancient books and modern literature， and the influencing factors and control methods of quality were analyzed and summarized in order to provide reference for the quality control of SSP. After analysis， it was found that in the fermentation process of SSP， fermentation strains， miscellaneous bacteria， temperature and humidity were all important factors affecting the quality of SSP. The condition control of "post fermentation" process has been paid more attention to in the past dynasties. In addition， the delicious SSP recognized in ancient times should be made from mold fermentation， and the breeding and application of fermented mold may be the key point to solve the quality problem of SSP. Therefore， based on the evaluation indexes of SSP in the past dynasties， it is of great significance to study and optimize the technological conditions such as strain， temperature and humidity in depth to improve the quality of SSP.

Objective:To investigate the predictive value of peritoneal protein clearance (Pcl) for cardiovascular events and cardiovascular mortality in peritoneal dialysis (PD) patients.Methods:Eligible PD patients were prospectively enrolled from January 2014 to April 2015 in the PD Center of Renji Hospital, School of Medicine, Shanghai Jiao Tong University. All patients were followed up until death, withdrawing from PD, transferring to other centers, or the end of study period (October 1, 2018). The patients were divided into high Pcl group and low Pcl group by the median Pcl, and the differences of related indicators between the two groups were compared. A multiple linear regression model was used to analyze the influencing factors of Pcl. The Kaplan-Meier method and Log-rank test were used to compare the cumulative survival rates of patients between the two groups. A multivariate Cox regression model was used to estimate the risk of cardiovascular events and cardiovascular mortality in relation to Pcl in PD patients.Results:A total of 271 patients were enrolled, with 135 males (49.8%), age of (56.92±0.84) years old and a median PD duration of 38.77(19.00, 63.10) months. There were 70 patients (25.8%) comorbiding with diabetes and 81 patients (29.9%) with cardiovascular diseases (CVD). The median Pcl of this cohort was 67.93(52.31, 88.36) ml/d. Compared with the low Pcl group (Pcl<67.93 ml/d), the high Pcl group (Pcl≥67.93 ml/d) had older age, and greater proportion of CVD, body mass index (BMI), pulse pressure, brain natriuretic peptide, mass transfer area coefficient of creatinine (MTACcr), and lower serum albumin (all P<0.05). There was no significant difference in gender, dialysis duration, proportion of diabetes, proportion of angiotensin converting enzyme inhibitor and angiotensin receptor blocker, proportion of continuous ambulatory PD, high sensitivity C reactive protein, fluid removal including 24 h urine volume and 24 h ultrafiltration, and residual renal function between the two groups (all P>0.05). Multiple linear regression analysis showed that serum albumin ( β=-0.388, P<0.001), BMI ( β=0.189, P<0.001), and MTACcr ( β=0.247, P<0.001) were independently related to lg(Pcl). During the study period, 55 patients experienced one or more cardiovascular events and 39 patients had cardiovascular mortality. According to Kaplan-Meier analysis, cardiovascular mortality in the high Pcl group was higher than that of low Pcl group (Log-rank χ2=6.902, P=0.009). Multivariate Cox regression analysis showed that, high lg(Pcl) was an independent influencing factor of cardiovascular events in PD patients ( HR=7.654, 95% CI 1.676-34.945, P=0.009). Conclusions:Serum albumin, BMI and MTACcr are independently associated with Pcl, and Pcl is an independent predictor of cardiovascular events in PD patients.

Objective To develop novel NAE inhibitors with non-nucleoside scaffold by a scaffold hopping strategy and study the in vitro antitumor activities. Methods Disulfonamideindazole 14 was synthesized through 23 steps with a good yield. Its chemical structure was confirmed by ¹H NMR and MS. MTT method was used to determine the in vitro antitumor activities. Results Compound 14 exhibited moderate antitumor activities against various cancer cells and promoted significant UBC12 accumulation in a dose-dependent manner. Conclusion Compound 14 is a potent NAE inhibitor with remarkable apoptosis induction and cell cycle arrest in prostate cancer PANC-1 cells. Our work provides a valuable leading compound for the further design and development of NAE inhibitors.

Objective: To improve physical activity by assessing pedometer-based physical activity during specific intervals over a week, among junior high school students,and to provide a reference for improving the level of students’ physical activity. Methods: Students (n=675) of grades 6-8 from six public junior high schools in Shanghai were recruited and instructed to wear a pedometer for a week, step counts and contents were recorded over a specific period. This period mainly included steps taken on the way to and from school, at school, at home in the evening on weekdays, and in the morning, afternoon, and evening on weekends. Results: The daily step counts recorded were 8 332 steps, with those on weekdays showing significantly higher values than step counts on weekends (9 065 steps vs. 6 392 steps)(t=22.9, P<0.01). Proportionately, the physical activity level at school contributed more to daily step counts (61.3%), followed by those on the commute to and from school(25.5%). Boys were more active than girls. For all intervals on weekdays, the step counts of students in rural districts, with overweight or obese, in grades 6 and 7, were higher than those in urban districts, with normal status, in grade 8 respectively (P<0.05). Low-activity students with physical education were more active than one without physical education(t boy=1.99,t girl=2.45,P<0.05). Conclusion These findings facilitate the implementation of effective, feasible interventions to enhance physical activity over a series of intervals during the day.