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.

Objective: To investigate the health literacy and its influencing factors among residents in areas out of poverty in Kunming City, so as to provide insights into formulating health education strategies. Methods: A total of 1 916 permanent residents at ages of 15 to 69 years were sampled in three areas out of poverty in Kunming City using the multi-stage stratified random sampling method and probability proportionate to size sampling method from August to October, 2020. Health literacy was investigated using the Questionnaire on the Health Literacy among Chinese Residents, the level of health literacy was analyzed and weighted by the population of the China's Seventh National Population Census. Factors affecting health literacy among residents in areas out of poverty were identified using a multivariable logistic regression model. Results: A total of 1 916 questionnaires were allocated, and 1 908 valid questionnaires were recovered, with an effective recovery rate of 99.58%. The respondents included 997 men (52.25%) and 911 women (47.75%), and had a mean age of (45.58±14.28) years. The level of health literacy was 21.38%. Multivariable logistic regression analysis identified age (15 to 24 years, OR=5.087, 95%CI: 1.573-16.450; 25 to 34 years, OR=6.016, 95%CI: 1.991-18.183; 35 to 44 years, OR=7.526, 95%CI: 2.541-22.289; 45 to 54 years, OR=4.800, 95%CI: 1.640-14.050), educational level (junior high school, OR=5.333, 95%CI: 3.100-9.175; high school/vocational high school/technical secondary school, OR=19.895, 95%CI: 10.418-37.966; college or above, OR=27.580, 95%CI: 12.349-61.597) as factors affecting health literacy among residents in areas out of poverty in Kunming City. Conclusion The level of health literacy is 21.38% among residents in areas out of poverty in Kunming City, and age and educational level are associated factors.

Background::The study aimed to describe the aortic valve morphology in Chinese patients underwent transcatheter aortic valve replacement (TAVR) for symptomatic severe aortic stenosis (AS), and the impact of sizing strategies and related procedural outcomes.Methods::Patients with severe AS who underwent TAVR were consecutively enrolled from 2012 to 2019. The anatomy and morphology of the aortic root were assessed. "Downsize" strategy was preformed when patients had complex morphology. The clinical outcomes of patients who performed downsize strategy were compared with those received annular sizing strategy. The primary outcome was device success rate, and secondary outcomes included Valve Academic Research Consortium-3 clinical outcomes variables based on 1-year follow-up.Results::A total of 293 patients were enrolled. Among them, 95 patients (32.4%) had bicuspid aortic valve. The calcium volume (Hounsfield Unit-850) of aortic root was 449.90 (243.15-782.15) mm 3. Calcium is distributed mostly on the leaflet level. Downsize strategy was performed in 204 patients (69.6%). Compared with the patients who performed annular sizing strategy, those received downsize strategy achieved a similar device success rate (82.0% [73] vs. 83.3% [170], P= 0.79). Aortic valve gradients (downsize strategy group vs. annular sizing group, 11.28 mmHg vs. 11.88 mmHg, P = 0.64) and percentages of patients with moderate or severe paravalvular regurgitation 2.0% (4/204) vs. 4.5% (4/89), P = 0.21) were similar in the two groups at 30 days after TAVR. These echocardiographic results were sustainable for one year. Conclusions::Chinese TAVR patients have more prevalent bicuspid morphology and large calcium volume of aortic root. Calcium is distributed mostly on the leaflet level. Compare with annular sizing strategy, downsize strategy provided a non-inferior device success rate and transcatheter heart valve hemodynamic performance in self-expanding TAVR procedure.

Objective:To investigate the role of TSLP and NF-κB in the pathogenesis of adenomyosis.Methods:Immunohisto-chemistry was employed to detect the expression of TSLP and NF-κB p65 in the endometrial glandular cell and stromal cell of 35 adeno-myosis patients and 20 hysteromyoma patients as control , and analyze the correlation of the two proteins.The concentration of TSLP was measured by specific ELISA in the serum of healthy subjects besides of the patients with adenomyosis and hysteromyoma .Results:TSLP and NF-κB p65 were both positively expressd in the glandular cells and stromal cells of ectopic and eutopic endometrium of patients with adenomyosis , their expression was significantly higher than that of the control group ( P<0.01 ) , and the expression of TSLP and NF-κB p65 in ectopic endometrium was significantly higher than that in eutopic endometrium ( P<0.01 ).There was positive correlation between TSLP and NF-κB p65 in ectopic endometrium.The concentration of TSLP was higher in the serum of patients with adenomyosis.Conclusion:The TSLP is highly expressed in endometrial glandular and stromal cells of patients with adenomyosis , and there is higher level of TSLP in serum , and there is correlation between the expression of TSLP and NF-κB in ectopic endometrium.

Objective　To observe the ER ultrastructures in humn embryonic epithelial cells of colonic mucosa、renal tubule and hepatocytes and also their alterations in embryogenesis.Methods　Transmission electromicroscopy technique.Results　With the embryonic development, the ER increased in amount, became complex in structure and with its characteristic ER structures in different cells. Conclusion　The changes of ER structures are one of the characters during cell differentiation.

Objective To explore the scan technique and image quality of coronary artery imaging with dual-source CT without oral Betaloc preparation.Methods Plain and enhanced dual-source CT coronary artery imaging without oral Betaloc preparation was performed in 215 patients with clinically suspected coronary heart disease or early-stage coronary lesions.Calcium scoring with plain scan images and multi-planar reconstruction(MPR),maximum intensity projection(MIP)and volume rendering technique (VRT)reconstruction with enhanced scan images were made in all cases.The scan technique and post reconstruction experience was summarized.The image quality was classified as three grades,and coronary segments classified according to AHA standards were evaluated.Results The median of calcium score of the 215 cases was 82.2(2.3—1827.9).The average heart rate of the enhanced scan was(80.6?15.3) (57—139)bpm.The post reconstruction methods with which coronary segments could be shown as best as possible consisted of(1)multiphases screening methods,(2)bi-phase or multiple-phase complement method,and(3)premature beat removing or arrhythmia shifting method.Altogether 3026 coronary segments were evaluated,among them 97.5% were evaluated as grade 1 image quality,2.0% were evaluated as grade 2 and 0.5% were evaluated as grade 3.The coronary segments in 91 cases were completely normal, while 112 segments with

Objective To explore the scanning technique and image quality of coronary artery imaging with dual-source CT without oral Betaloc preparation in the patients with high heart rate.Methods 412 cases were undergone coronary imaging with dual-source CT (including plain and enhanced scans) ,among them,there were 30 cases with heart rate more than 100 bpm.Multi-planar reconstruction(MPR),maximum intensity projection(MIP) and volume rendering (VR) were performed using contrast-enhanced images.The image quality was classified into 3 grades, and coronary segments named according to AHA standard were evaluated.Results The average heart rate during enhanced scan in the 30 cases was (115.6?11.8)(101～139)bpm,the average breath hold time was (5.7?1.2) s.The best reconstruction phase was in the systolic phase. Altogether 424 coronary segments were evaluated, among them 93.9%(398/424)belonged to the first grade,5.0%(21/424)belonged to the second grade,and 1.2%(5/424) belonged to the third grade. Conclusion Without oral administration of Betaloc preparation, good coronary artery images can be obtained in the patients with high heart rate by dual-source CT.

A high performance liquid chromatographic assay has been developed for the simultaneous determination of four water soluble vitamins,thia min, ribo-flavin, uiacin and pyridoxine, in cereal products and fresh vegetables. For hydrolyzing sample in 0.4 mol/L HCL, autoclaving at 120℃, 15 psi for 30 minutes, a ?Bondapak column (300mm ? 3.9mm, Waters Co), a mobile phase of methanol-water (30:70) (0.005 mol/L heptanesulfonic acid) and a flow rate of 1.0ml/min gave the most satisfactory separation of the four vitamins. A double channel detector was used: three vitamins (B1, B2 and B5) were detected by UV spectrophotometry (254 nm) first, pyridoxine (B6) was detected by fluorometry (EX 290 nm, EM 390 nm) afterwards. Detection limits were 2, 5, 5 and 2ng, linear ranges were 5-40 ng, 5-50 ng, 5-40 ng and 5-50 ng for B1, B2, B5 and Be, respectively. Recoveries were 91.3%-102% (B1), 103%-105% (B2), 92%-100% (B5) and 99%-100% (B6), comparing with reference method and checking with food composition tables, very satisfactory results were obtained by this method.