Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

BACKGROUND: Valvular heart disease (VHD) has become increasingly common with the aging in China. This study aimed to evaluate regional differences in the clinical features, management strategies, and outcomes of patients with VHD across different regions in China. METHODS: Data were collected from the China-VHD Study. From April 2018 to June 2018, 12,347 patients who presented with moderate or severe native VHD with a median of 2 years of follow-up from 46 centers at certified tertiary hospitals across 31 provinces, autonomous regions, and municipalities in Chinese mainland were included in this study. According to the locations of the research centers, patients were divided into five regional groups: eastern, southern, western, northern, and central China. The clinical features of VHD patients were compared among the five geographical regions. The primary outcome was all-cause mortality or rehospitalization for heart failure. Kaplan-Meier survival analysis was used to compare the cumulative incidence rate. RESULTS: Among the enrolled patients (mean age, 61.96 years; 6877 [55.70%] male), multiple VHD was the most frequent type (4042, 32.74%), which was mainly found in eastern China, followed by isolated mitral regurgitation (3044, 24.65%), which was mainly found in northern China. The etiology of VHD varied significantly across different regions of China. The overall rate of valve interventions was 32.67% (4008/12,268), with the highest rate in southern China at 48.46% (205/423). In terms of procedure, the proportion of transcatheter valve intervention was relatively low compared to that of surgical treatment. Patients with VHD in western China had the highest incidence of all-cause mortality or rehospitalization for heart failure. Valve intervention significantly improved the outcome of patients with VHD in all five regions (all P  <0.05). CONCLUSIONS: This study revealed that patients with VHD in China are characterized by significant geographic disparities in clinical features, treatment, and clinical outcomes. Targeted efforts are needed to improve the management and prognosis of patients with VHD in China according to differences in geographical characteristics. REGISTRATION ClinicalTrials.gov , NCT03484806.
Aged ; Female ; Humans ; Male ; Middle Aged ; China/epidemiology* ; Heart Valve Diseases/therapy* ; Kaplan-Meier Estimate ; Tertiary Care Centers ; Treatment Outcome

Objective:To explore the application effect of woven mesh unit method in teaching nursing students in clinical internship.Methods:The 300 nursing interns in Chongqing University Jiangjin Hospital who interned in 2022 were included in the traditional group, and the 300 nursing interns who interned in 2023 were included in the reform group. The traditional group received traditional teaching, while the reform group received woven mesh unit teaching. The two groups of nursing students were compared for the assessment scores (theoretical assessment scores and practical operation scores), emergency response abilities (warning ability, emergency response ability, and recovery and summary ability), and evaluation of clinical teaching quality. The t-tests, chi-square test, and rank-sum test were conducted using SPSS 26.0. Results:The theoretical assessment scores and practical operation scores of the reform group were significantly higher than those of the traditional group [(79.15±9.27) vs. (74.58±9.16), (81.25±8.35) vs. (76.04±8.25)]. The scores and total scores of the early warning ability, emergency response ability, and recovery and summary ability of the reform group were significantly higher than those of the traditional group [(15.28±2.36) vs. (12.91±2.42), (38.76±7.37) vs. (34.15±7.29), (21.25±5.14) vs. (18.73±5.07), (75.29±9.86) vs. (65.79±9.76)]. The clinical teaching quality grade of teachers in the reform group was significantly higher than that of the traditional group [high quality (88.67% vs. 79.00%)/medium quality (11.33% vs. 16.67%)/low quality (0.00% vs. 4.33%)].Conclusions:The application of woven mesh unit method in teaching nursing students in clinical internship can effectively improve their theoretical assessment scores, practical operation level, and emergency response ability, as well as the quality of clinical teaching.

Objective Evaluation of the effect and mechanism research of Qi-Shen-Yi-Zhi formula on improving learning and memory ability in mice injected with Aβ1-42 in hippocampus.Methods Alzheimer's disease model mice were constructed by injecting β amyloid peptide 1-42 into hippocampus and treated with water extracts of Qi-Shen-Yi-Zhi formula.The cognitive abilities of mice were assessed using Morris water maze and Y maze tests,which measure learning and memory capabilities.HE staining was used to observe the damage and TUNEL method was used to determine apoptosis of hippocampus.Detection of the expression of oxidative factors,inflammatory factors,and related antioxidant proteins and apoptotic proteins in the hippocampal tissue of a mouse model of dementia.Results Both high-dose and low-dose groups of Qi-Shen-Yi-Zhi formula significantly improved cognitive dysfunction in mice injected with Aβ1-42 in hippocampus,and attenuated the damage and apoptosis of the hippocampus.It also inhibited oxidative stress and downregulated the expressions of inflammatory factors IL-6,IL-1β and TNF-a,increased the expression of antioxidant proteins Nrf2 and HO-1,and regulated the expressions of apoptotic proteins Caspase-9,Caspase-3,Bax and Bcl-2.Conclusion Qi-Shen-Yi-Zhi formula improves the learning and memory abilities of mice injected with Aβ1-42 in hippocampus,which might be related to the attenuation of oxidative stress and neuronal inflammation of hippocampus.

OBJECTIVE To evaluate the effect of Qishen Yizhi formula on improving learning and memory ability in D-galactose subcutaneous injection induced subacute aging mice.METHODS Subacute aging mice model mice were developed by D-galactose subcutaneous injection and then treated with positive drug donepezil(2 mg·kg-1·d-1)and Qishen Yizhi formula water extracts in low(1.33 g·kg-1·d-1)and high dose group(2.67 g·kg-1·d-1).The learning and memory abilities of mice were evaluated using Morris water maze and Y maze tests;HE staining was used to examine hippocampal damage in model mice;TUNEL was used to detect apoptosis of mouse hippocampal tissue;ELISA was used to detect the expression levels of oxidative stress factors and inflammatory fac-tors in the mouse hippocampus tissue;Western blot was used to detect the expression of signaling pathway proteins related to apoptosis,oxidative stress and inflammatory stress in the hippocampus of mice.RESULTS The water extract of Qishen Yizhi formula signifi-cantly shortened the latency and distance of model mice for reaching the platform in the water maze test(P<0.01),and significantly increased the number of crossing the platform(P<0.01);increased the exploration time and number of the Y maze new arm in model mice(P<0.05);inhibited the TUNEL fluorescence expression in the hippocampus of model mice(P<0.01);upregulated the activity of the oxidative stress factor superoxide dismutase(SOD)(P<0.05)and glutathione(GSH)content(P<0.05),and downregulated malondialdehyde(MDA)content(P<0.05);reduced interleukin(IL)-1β,IL-6 and tumor necrosis factor(TNF-α)expression levels(P<0.05,P<0.01);decreased the expression of apoptosis signaling pathway proteins Cleaved Caspase-3 and Caspase-3(P<0.05),upregulated the expression of oxidative stress signaling pathway proteins Nrf2 and HO-1(P<0.05),and downregulated the expression of inflammatory stress signaling pathway proteins p-NF-κB and NF-κB(P<0.05).CONCLUSION Qishen Yizhi for-mula can improve the learning and memory ability of subacute aging model mice injected with D-galactose,which may be related to its inhibitory effect on hippocampal oxidative stress and inflammatory stress.

Objective:To explore the application effect of woven mesh unit method in teaching nursing students in clinical internship.Methods:The 300 nursing interns in Chongqing University Jiangjin Hospital who interned in 2022 were included in the traditional group, and the 300 nursing interns who interned in 2023 were included in the reform group. The traditional group received traditional teaching, while the reform group received woven mesh unit teaching. The two groups of nursing students were compared for the assessment scores (theoretical assessment scores and practical operation scores), emergency response abilities (warning ability, emergency response ability, and recovery and summary ability), and evaluation of clinical teaching quality. The t-tests, chi-square test, and rank-sum test were conducted using SPSS 26.0. Results:The theoretical assessment scores and practical operation scores of the reform group were significantly higher than those of the traditional group [(79.15±9.27) vs. (74.58±9.16), (81.25±8.35) vs. (76.04±8.25)]. The scores and total scores of the early warning ability, emergency response ability, and recovery and summary ability of the reform group were significantly higher than those of the traditional group [(15.28±2.36) vs. (12.91±2.42), (38.76±7.37) vs. (34.15±7.29), (21.25±5.14) vs. (18.73±5.07), (75.29±9.86) vs. (65.79±9.76)]. The clinical teaching quality grade of teachers in the reform group was significantly higher than that of the traditional group [high quality (88.67% vs. 79.00%)/medium quality (11.33% vs. 16.67%)/low quality (0.00% vs. 4.33%)].Conclusions:The application of woven mesh unit method in teaching nursing students in clinical internship can effectively improve their theoretical assessment scores, practical operation level, and emergency response ability, as well as the quality of clinical teaching.

Objective:To investigate the relationship between chronic obstructive pulmonary disease (COPD) and bone mineral density (BMD) in Chinese male and female adults.Methods:Linear regression models were used to analyze the correlations between COPD and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade concerning bone mineral density indices, including broadband ultrasound attenuation, speed of sound, and stiffness index, based on data from the second resurvey of China Kadoorie Biobank.Results:Among 23 876 participants, the prevalence of COPD was 34.3% (3 130/9 125) in males and 23.2% (3 416/14 751) in females. Compared with healthy males and healthy females, broadband ultrasound attenuation, speed of sound, and stiffness index decreased in males and females with COPD, with β values (95% CI) of -0.87 (-1.37- -0.36), -3.42 (-5.42- -1.43) and -1.53 (-2.34- -0.71) in males and -0.66 (-1.09- -0.23), -2.24 (-3.92- -0.55), -1.06 (-1.71- -0.40) in females, respectively. The decrease was greater in males than females (all P for interaction <0.05). The GOLD grade of COPD was inversely correlated with all the three indices in a dose-response manner (all P for trend <0.001). Subgroup analysis showed that patients with COPD had a greater decrease in BMD in males whose ages were ≥ 60 years, males who were less physically active, and participants who were not overweight or obese. Conclusions:COPD was negatively correlated with bone mineral density. More attention should be paid to the bone mineral density of patients with COPD, especially those with older age, less physical activity, or lower BMI.

Objective:To describe the prevalence of daytime nap habit in participants of the China Kadoorie Biobank (CKB) study, across 10 study regions and explore its correlation with prevalence of major chronic diseases.Methods:Participants with a self-reported pre-diagnosis of any cancer at baseline survey were excluded. Logistic regression models were used to analyze the differences in study regions and age distribution of the prevalence daytime nap habit, and its correlation with the prevalence of diabetes, hypertension, coronary heart disease (CHD), stroke, chronic obstructive pulmonary disease (COPD), and chronic liver diseases.Results:Among 510 145 participants, 39.9% had daytime nap habit in summer and 20.8% had daytime nap habit all the year round. Urban-rural differences were observed in the prevalence of summer nap habit and perennial nap habit. Daytime nap in summer was common in rural areas and Suzhou, with prevalence ranged from 32.9% to 73.3%. Haikou and Liuzhou had higher prevalence of perennial nap (60.4% and 63.3%). The proportion of people with daytime nap habit all the year round increased with age ( P for trend <0.001), the proportion was highest in those aged 70- years (31.9%). Daytime nap habit in summer was positively correlated with the prevalence of diabetes, hypertension, CHD and chronic liver disease with OR of 1.10 (95% CI: 1.07-1.14), 1.03 (95% CI:1.02-1.05), 1.07 (95% CI: 1.02-1.12) and 1.07 (95% CI:1.00-1.14), respectively. Daytime nap habit all the year round was positively correlated with the prevalence of diabetes, hypertension, CHD, stroke, COPD and chronic liver disease with OR of 1.33 (95% CI: 1.29-1.37), 1.11 (95% CI: 1.09-1.13), 1.39 (95% CI: 1.33-1.45), 1.33 (95% CI: 1.26-1.41), 1.12 (95% CI: 1.08-1.16) and 1.27 (95% CI:1.18-1.37) respectively. Conclusion:There were regional and age differences in prevalence of daytime nap habit among CKB participants. Daytime nap habit, especially daytime nap habit all the year round, was positively correlated with the prevalence of major chronic diseases.

Objective: To observe the incidence of unreasonable use of high beam at nighttime among motor vehicle drivers, so as to provide the evidence for the prevention and control of road traffic injury. Methods: Four roads into city and five urban roads were selected in Yongkang of Zhejiang Province. An automatic recording system was used to collect the unreasonable use of high beam among motor vehicle drivers on the selected roads from 19:00 to 5:00 on Monday, Wednesday, Friday and Sunday during a week in July 2020. The regression tree model was used to analyze the relationship of the unreasonable use of high beam with road, time and traffic flow. Results: A total of 89 989 motor vehicles were observed, and 2 419 motor vehicle drivers had unreasonable use of high beam, with an incidence rate of 2.69%. The incidence rate of the unreasonable use of high beam was 3.14% in the roads into city, which was higher than 2.30% in the urban roads ( P<0.05 ). The incidence rates of the unreasonable use of high beam in the roads into city and in the urban roads were 5.15% and 2.90% on Wednesday, which were higher than those on Monday ( 2.89% and 2.34% ), Friday ( 2.90% and 1.92% ) and Sunday (2.06% and 2.12%). The highest incidence rate of the unreasonable use of high beam in the roads into city was 6.07% between 4:00 and 5:00, and in the urban roads was 4.50% between 2:00 and 3:00. The results of regression tree classification analysis showed that the highest incidence rate was 8.13% on the roads into city in the east, west and south directions, and on the urban roads in the east and north directions with less than 317 vehicles per hour on Wednesday. Conclusion It is more likely for motor vehicle drivers to use high beams unreasonably at nighttime on the roads into city with less traffic flow.