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 epidemiological characteristics of knee osteoarthritis(KOA)among military personnel in plateau regions and to explore its risk factors.Methods From July 2023 to July 2024,a multi-stage stratified cluster random sampling method was employed to survey the prevalence of KOA and related risk factors among military personnel in the northwest plateau regions of China,covering different altitudes(1500-4500 m)and geographical areas(Gansu,Qinghai,Tibet,and Xinjiang).All study subjects were divided into KOA and non-KOA groups based on the presence or absence of KOA.Variables including age,gender,body mass index(BMI),education level,smoking status,military rank,military branch,service duration,regional altitude,annual average temperature,training duration,perceived training intensity,and history of knee injury were selected for univariate analyses between groups.Variables with P<0.05 in the univariate analyses were included in the binary multifactor logistic regression to identify risk factors for KOA.Results A total of 3000 questionnaires were distributed,and 2854 valid questionnaires were collected,with a response rate of 95.13%.The sample included 2584 males and 270 females,with 510 cases of KOA,resulting in a prevalence rate of 17.9%.Univariate analysis showed that there were statistically significant differences between KOA and non-KOA groups in terms of age,BMI,smoking status,military rank,military branch,service duration,regional altitude,annual average temperature,training duration,perceived training intensity,and history of knee injury(P<0.05).However,no significant differences were found in gender and education level(P>0.05).Binary multivariate logistic regression analysis revealed that older age(OR=1.382,P=0.017),higher BMI(P<0.01),smoking(OR=1.929,P<0.01),higher military rank(OR=1.485,P=0.007),being a member of the Armed Police(P<0.01),longer service duration(P<0.01),higher regional altitude(OR=1.459,P<0.01),lower annual average temperature(OR=1.188,P=0.001),longer training duration(P<0.01),higher perceived training intensity(OR=2.450,P<0.01),and history of knee injury(OR=2.768,P=0.002)were independent risk factors for KOA.Conclusions Older age,overweight/obesity,smoking,higher military rank,being a member of the Armed Police,longer service duration,higher altitude,cold climate,longer training duration,higher training intensity,and history of knee injury are independent risk factors for KOA among military personnel in the northwest plateau regions of China.

Objective:Summarizing and analyzing the rules of access and renewal of drugs in Australia,Japan,South Korea,and Chinese Taiwan,this paper aims to provide experience for the improvement of China's policy on national drug reimbursement list renewal.Methods:Through literature review,expert interviews,and other academic methods,it compares the different experience of drug renewal policy from the perspectives of the type,content,and renewal period.Results:Internationally representative national or regional medical insurance drug renewal policies are broadly categorized into single-drug price-volume agreements,joint price-volume agreements,and efficacy-based risk-sharing agreements.Conclusion:It is recommended that China should introduce new content such as joint measurement for renewal of exclusive drugs,combination consideration of quantity,price,and effectiveness,risk-sharing agreement for renewal of non-exclusive drugs,and placing an upper limit on the rate of reduction for the first renewal in its medical insurance policy.

OBJECTIVE: To verify the effect of Buyang Huanwu Decoction (BHD) in ameliorating erectile dysfunction (ED) after radical prostatectomy (RP). METHODS: The composition of BHD was verified by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) analysis. Bilateral cavernous nerve crush injury (BCNI) in rats was used to mimic the neurovascular injury occurring after RP. By the envelope method, forty rats were randomly divided into 4 groups as follows: sham (cavernous nerves exposed only), model (BCNI), low-dosage BHD [LBHD, 12.8 g/(kg·d)], and high-dosage BHD [HBHD, 51.2 g/(kg·d)] groups, 10 rats in each group, feeding for 3 weeks respectively. Erectile function was evaluated by measuring intracavernosal pressure (ICP). Changes in the histopathology of corpus cavernosum (CC) were examined by hematoxylin-eosin staining. Meanwhile, the fibrosis of CC was measured by Masson's trichrome staining and Western blot was used to detect the expressions of collagen I, transforming growth factor beta 1 (TGF- β 1) and α-smooth muscle actin (α-SMA). Apoptosis index was detected by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) and Western blot for determining the expressions of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax). The oxidative stress in the CC were assessed by the superoxide dismutase (SOD), malondialdehyde (MDA) and reactive oxygen species (ROS) levels. The proteins expression of c-Jun N-terminal kinase (JNK) and c-Jun were detected by Western blot. In addition, the expression of α-SMA and p-c-Jun in the CC was observed by double immunofluorescence staining. RESULTS: The UPLC-QTOF-MS/MS analysis showed that BHD contained calycosin-7-O- β -D-glucoside, ononin, calycosin and formononetin. Compared with the model group, LBHD and HBHD treatment improved the ICP and the circumference, area, and weight of CC (P<0.05 or P<0.01). Furthermore, LBHD and HBHD treatments increased CC smooth muscle content and decreased apoptosis index (P<0.05 or P<0.01). LBHD and HBHD also elevated SOD and expression level of α -SMA and Bcl-2, and reduced MDA and ROS levels, as well as expression of TGF- β 1, collagen I, Bax, p-c-JNK, p-JNK in the CC compared with the model group (P<0.05 or P<0.01). The double immunofluorescence staining showed that the fluorescence degree of p-c-Jun in both LBHD and HBHD treatment groups was significantly reduced, whereas the α -SMA expression increased (P<0.05 or P<0.01). CONCLUSIONS BHD can improve ED of rats with BCNI, which is related to inhibiting fibrosis, apoptosis, and oxidative stress of CC. The ROS/JNK/c-Jun signaling pathway may play an important role in the process.
Male ; Humans ; Rats ; Animals ; Reactive Oxygen Species ; Tandem Mass Spectrometry ; bcl-2-Associated X Protein ; Rats, Sprague-Dawley ; Erectile Dysfunction/drug therapy* ; Collagen ; Fibrosis ; Disease Models, Animal

BACKGROUND: The molecular mechanisms of heart failure (HF) are still poorly understood. Circular RNA (circRNA) has been discovered in the heart in increasing numbers of studies. The goal of this research is to learn more about the potential roles of circRNAs in HF. METHODS & RESULTS: We used RNA sequencing data to identify the characteristics of circRNAs expressed in the heart and discovered that the majority of circRNAs screened were less than 2000 nt. Additionally, chromosomes One and Y had the most and least number of circRNAs, respectively. After excluding duplicate host genes and intergenic circRNAs, a total of 238 differentially expressed circRNAs (DECs) and 203 host genes were discovered. However, only four of the 203 host genes of DECs were examined in HF differentially expressed genes. Another study used Gene Oncology analysis of DECs host genes to elucidate the underlying pathogenesis of HF, and it found that binding and catalytic activity accounted for a large portion of DECs. Immune system, metabolism, and signal transduction pathways were significantly enriched. Furthermore, 1052 potentially regulated miRNAs from the top 40 DECs were collected to build a circRNA-miRNA network, and it was discovered that 470 miRNAs can be regulated by multiple circRNAs, while others are regulated by a single circRNA. In addition, a comparison of the top 10 mRNAs in HF and their targeted miRNAs revealed that DDX3Y and UTY were regulated by the most and least circRNA, respectively. CONCLUSION These findings demonstrated circRNAs have species and tissue specific expression patterns; while circRNA expression is independent on host genes, the same types of genes in DECs and DEGs worked in HF. Our findings would contribute to a better understanding of the critical roles of circRNAs and lay the groundwork for future studies of HF molecular functions.

OBJECTIVES: To study the clinical efficacy of ultrasound-guided endoscopic retrograde appendicitis therapy in children with appendix-related chronic abdominal pain. METHODS: A retrospective analysis was performed on the medical data of 30 children with the chief complaint of chronic abdominal pain who were admitted from August 2019 to May 2021. All the children were found to have inflammation of the appendix or intracavitary stool and fecalith by ultrasound and underwent ultrasound-guided endoscopic retrograde appendicitis therapy. The medical data for analysis included clinical manifestations, endoscopic findings, white blood cell count, neutrophil percentage, length of hospital stay, and cure rate. RESULTS: Among the 30 children with chronic abdominal pain, there were 13 boys (43%) and 17 girls (57%), with a mean age of (9±3) years (range 3-15 years) at diagnosis. The median duration of the disease was 12 months, and the median length of hospital stay was 3 days. The children had a median white blood cell count of 6.7×10⁹/L and a neutrophil percentage of 50%±13%. Fecalith and a large amount of feces were flushed out of the appendix cavity for 21 children (70%) during surgery. The follow-up rate was 97% (29/30), and the median follow-up time was 11 months (range 5-26 months). Of the 29 children, abdominal pain completely disappeared in 27 children (93%). CONCLUSIONS Ultrasound-guided endoscopic retrograde appendicitis therapy is effective in children with chronic abdominal pain caused by feces or fecalith in the appendix cavity.
Abdominal Pain/etiology* ; Adolescent ; Appendicitis/surgery* ; Appendix/surgery* ; Child ; Child, Preschool ; Fecal Impaction ; Female ; Humans ; Male ; Retrospective Studies ; Ultrasonography, Interventional

OBJECTIVE: To study and compare the effect of indwelling drainage tube and extubation time on occult hemorrhage and functional recovery after total hip arthroplasty(THA). METHODS: From July 2017 to June 2018, 123 patients who underwent THA in our hospital for the first time were selected as the subjects of study. According to whether the drainage tube was retained or not and the time of extubation, they were divided into three groups:in group A, 41 patients (24 males, 17 females, age 53 to 77 years) did not put drainage tube after THA;in group B, 41 patients were removed 24 hours after THA, 26 males and 15 females, aged 55 to 74 years;in group C, 41 patients were removed 48 hours after THA, 25 males and 16 females, aged 52 to 75 years. The VAS score of pain 72 hours after THA, the total and recessive blood loss, the time of starting functional exercise, and the incidence of postoperative limb swelling were recorded. All the patients were followed up for one year after discharge. Harris hip score was used to evaluate the degree of hip function recovery one year after operation. RESULTS: The occult blood loss of group A, B and C were(513.6±25.3), (521.7±33.4), (519.3±29.8) ml, respectively, with no significant difference(>0.05). There was no significant difference in blood loss in operation among the three groups(>0.05). In group B and C, the postoperative apparent blood loss was more than that in group A (<0.05). There was no significant difference in VAS scores of the three groups before and 72 hours after operation (>0.05). The time of getting out of bed in group A was shorter than that in group B and C (<0.05), and that in group B was shorter than that in group C(<0.05). The Harris hip score at 1 year after operationof the three groups was significantly higher than that of before operation (<0.05). There was no significant difference in Harris hip score before and after operation among three groups (>0.05). There was no significant difference in the incidence of complications among three groups (>0.05). CONCLUSION Whether the drainage tube is left or not and the time of extubation have no significant effect on the latent blood loss and functional recovery after THA, but without drainage tube after THA can reduce the apparent blood loss, patients can get out of bed at 6 hours after THA, which is more conducive to the recovery and nursing of patients.
Aged ; Airway Extubation ; Arthroplasty, Replacement, Hip ; Drainage ; Female ; Humans ; Male ; Middle Aged ; Recovery of Function ; Treatment Outcome

OBJECTIVE: To observe the effect of electroacupuncture (EA) combined with lifestyle control on hepatic fat status, hepatic enzymology, glycolipid metabolism and anthropological parameters in patients with obese nonalcoholic fatty liver disease(NAFLD). METHODS: A total of 90 patients with obese NAFLD were randomized into an observation group (45 cases, 4 cases dropped off) and a control group (45 cases, 1 case dropped off). Lifestyle control was implemented in the control group. On the basis of the treatment in the control group, acupuncture was applied at Zhongwan (CV 12), Quchi (LI 11), Shuifen (CV 9), Huaroumen (ST 24), Daheng (SP 15), Guanyuan (CV 4), Qihai (CV 6), etc. EA was provided at Huaroumen (ST 24) and Daheng (SP 15) with dilatational wave, 2 Hz/100 Hz in frequency, 30 min each time, once every other day, 3 times a week. The treatment for 12 weeks was required in both of the two groups. Hepatic fat status [controlled attenuation parameter (CAP) and liver stiffness measurement (LSM)], hepatic enzymology [alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyl transferase (GGT)], glycolipid metabolism and insulin sensitivity [fasting plasma glucose (FPG), fasting serum lisulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C)] and anthropological parameters [body weight (BW), body mass index (BMI), fat percentage (FP), waist circumference (WC), hip circumference (HC) and waist-to-hip ratio (WHR)] in the two groups were observed before and after treatment. RESULTS: ①Compared before treatment, hepatic CAP, LSM, serum ALT, AST and GGT after treatment were obviously reduced in the two groups (<0.05, <0.01). After treatment, CAP and ALT in the observation group were lower than the control group (<0.05). ②Compared before treatment, FINS, HOMA-IR, LDL-C, TC and TG after treatment were obviously reduced in the two groups (<0.05, <0.01),while the levels of HDL-C were increased (<0.05). Compared before treatment, FPG after treatment in the observation group was reduced (<0.05). Compared with the control group, FINS, HOMA-IR, TC and TG in the observation group were lower than those in the control group after treatment (<0.05). ③Compared before treatment, BW BMI, FP, WC, HC, WHR after treatment were obviously reduced in the two groups (<0.01). After treatment, WC and WHR in the observation group were lower than the control group (<0.05). CONCLUSION Electroacupuncture combined with lifestyle control can effectively treat obese nonalcoholic fatty liver disease, and present better therapeutic effect on hepatic fat status, glycolipid metabolism, insulin resistance, WC and WHR.

Total knee arthroplasty(TKA) has been the final clinical treatment of knee osteoarthritis at the final stage, postoperative limb and prosthesis alignment restoration directly affect clinical effect. In recent years, computer-assisted surgery has been used in TKA and obtained satisfied results. There paper has investigated that the use of computer-assisted systems could improve soft tissue balance after TKA, improve accuracy of installation of prosthesis, recover limb alignment and decrease intro-blood loss, postoperative fat embolism. Although computer-assisted navigation is not mainstream, with the continuous improvement of technology and innovation, the computer-assisted surgery could exert a more important role in TKA, and considerably beneficial effect on improvement of postoperative clinical effects.
Arthroplasty, Replacement, Knee ; Humans ; Knee Joint ; Osteoarthritis, Knee ; Postoperative Period ; Surgery, Computer-Assisted

Objective To explore the clinical factors that can be used to predict the early weight loss after laparoscopic sleeve gastrectomy(LSG).Methods The clinical data of 64 obese patients undergoing LSG in Peking Union Medical College Hospital from August 2015 to January 2018 were retrospectively analyzed.We analyzed the relationship between different clinical factors and early weight loss,determined the independent predictors based on models,and estimated their test power by using the receiver operating characteristic(ROC)curves.Results Correlation analysis indicated that preoperative body mass index(=0.000,=0.000,=0.000),waist circumference(WC)(=0.000,=0.000,=0.000),whole body fat volume(=0.000,=0.006,=0.003),homeostatic model assessment for insulin resistance(HOMA-IR)(=0.000,=0.000,=0.002),and hypersensitive C-reactive protein(hsCRP)(=0.004,=0.002,=0.025)were negatively correlated with excess weight loss percentage(EWL %) after 3,6 and 12 months.Also,hsCRP after 6 months showed negative correlation with EWL % after 1 year(=0.029).Binary Logistic regression analysis showed that WC was an independent predictor of early weight loss(=0.018).ROC analysis showed that when the optimal cutoff value is 142.5 cm for WC, index was highest,with a sensitivity of 80% and a specificity of 87%.Patients were further divided into low WC group and high WC group based on this optimal cutoff value.The low WC group had significantly higher EWL% than the high WC group 3 months(=6.677,=0.000),6 months(=6.157,=0.000),and 1 year(=4.006,=0.000)after surgery.The low WC group also had significantly lower hsCRP than high WC group 6 months after surgery(=-3.510,=0.000).HOMA-IR showed no significant difference between these two groups(=-0.821,=0.412).Conclusions WC is an independent predictor of weight loss early after LSG.The patients with low WC have better weight loss effectiveness.
Body Mass Index ; C-Reactive Protein ; analysis ; Gastrectomy ; Humans ; Insulin Resistance ; Laparoscopy ; Obesity, Morbid ; surgery ; Retrospective Studies ; Treatment Outcome ; Waist Circumference ; Weight Loss