Xanthine oxidase (XO) is an important therapeutic target for the treatment of hyperuricemia and gout. Based on the previously identified potent XO inhibitor 1, seventeen oxadiazoles and their ring-opening analogues were designed and synthesized via the bioisostere replacement strategy. Among them, compounds 2l, 2n, and 3b showed obvious XO inhibitory activity at the concentration of 10 μmol·L^-1, and compound 3b exhibited an IC₅₀ value of 1.45 μmol·L^-1.

Background Swimming is becoming increasingly popular for its combined leisure and fitness benefits. However, polluted swimming pool water may pose various health risks. Previous studies have indicated that health indicators of swimming venues have lower qualification rates compared to other public places, highlighting the urgent need to optimize hygiene management measures. Objective To assess the overall hygiene status and identify the key factors influencing water quality in Shanghai’s swimming venues from 2010 to 2024, and to provide a scientific basis for optimizing water quality management. Methods Water quality was assessed in three stages (2010—2019, 2020—2022, and 2023—2024) based on the monitoring data of Shanghai’s swimming venues (2010—2024). The influences of monitoring stage, region, season, scale, day of week, and per capita attendance on water quality were analyzed using chi-square tests and logistic regression. Results From 2010 to 2024, water quality was monitored in 1478 swimming venues. The compliance rates of turbidity, pH, urea, oxidation-reduction potential, free residual chlorine, combined residual chlorine, total bacteria, coliforms, and heat-resistant coliforms in swimming pool water, and free residual chlorine in the foot disinfection basin water samples were 99.56%, 94.73%, 73.00%, 47.50%, 56.55%, 54.12%, 97.74%, 99.49%, 99.90%, and 69.19%, respectively. The overall water quality compliance rate was 85.28%. The main non-compliant indicators for swimming pool water were urea, ORP, free residual chlorine, and combined residual chlorine, along with free chlorine residual in the foot disinfection basin water samples. Using the period before the implementation of the new national standard as reference, the results of logistic regression revealed that the qualification rates of urea, ORP, and free residual chlorine in the swimming pool water samples, as well as free residual chlorine in foot disinfection basin water samples, were significantly higher during the two phases after launching the new standard (2020–2022 and 2023–2024), and the associated odds ratios (95%CI) were 1.28 (1.00, 1.64) and 1.48 (1.12, 1.95), 13.35 (7.63, 23.37) and 10.78 (7.00, 16.60), 2.54 (1.81, 3.58) and 3.18 (2.41, 4.20), and 3.14 (2.14, 4.60) and 2.83 (1.89, 4.23), respectively. Compared with the reference group, those sampled in urban pools and in non-summer seasons showed higher qualification rates of urea and ORP; in contrast, the pools with high visitor flow showed lower qualification rates of free residual chlorine in both water samples of swimming pools and foot disinfection basins (P<0.05). Conclusion The implementation of the new national standard has effectively enhanced the management standards and significantly improved overall water quality of swimming venues in Shanghai. However, the compliance rates of free residual chlorine and urea in swimming pool water still need further improvement. The compliance of some indicators is influenced by region, season, scale, and average passenger flow, particularly in small suburban swimming venues. Future efforts should focus on refining water quality management strategies and enhancing public health management.

This study aimed to investigate the effect and underlying mechanisms of Zexie Decoction against liver injury in rats with hyperlipidemic acute pancreatitis(HLAP). The network pharmacology-related databases were used to screen the active components and potential targets of Zexie Decoction, as well as the disease targets of HLAP. A protein-protein interaction(PPI) network of the overlapping targets was constructed. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis and Gene Ontology(GO) functional enrichment analysis were performed on the overlapping targets. Sprague-Dawley(SD) rats were randomly divided into sham group, model group, low-dose Zexie Decoction group, and high-dose Zexie Decoction group. Enzyme-linked immunosorbent assay(ELISA) kits were used to detect serum biochemical indicators. Hematoxylin-eosin(HE) staining was used to observe the pathological morphology of the pancreas and liver tissues, while oil red O staining was employed to assess hepatic steatosis. Immunofluorescence staining was used to detect the expression of IL-1β and NLRP3 in pancreatic tissues. Western blot analysis was conducted to evaluate the expression levels of proteins related to oxidative stress, endoplasmic reticulum stress, the PI3K/AKT signaling pathway, and autophagy. Network pharmacology predictions identified 721 targets of Zexie Decoction and 2 486 targets associated with HLAP, with 279 overlapping targets. GO enrichment analysis yielded 1 112 entries, and KEGG enrichment analysis identified 179 signaling pathways. Experimental results showed that Zexie Decoction could reduce the levels of lipid metabolites, serum enzymes, and inflammatory cytokines in HLAP rats, alleviate pathological damage to the pancreas and liver, decrease hepatic lipid accumulation, and decrease the expression of IL-1β and NLRP3 in pancreatic tissues. In addition, Zexie Decoction significantly upregulated the expression of antioxidant stress-related proteins NRF2 and HO-1, downregulated the expression of endoplasmic reticulum stress-related proteins BiP, xBP1s, p-eIF2α, eIF2α, and ATF4, inhibited the expression of PI3K and phosphorylation of AKT, increased the expression of autophagy-related proteins Beclin1, ATG3, ATG5, and ATG12, and reduced the expression of p62. In conclusion, Zexie Decoction can improve HLAP, and its mechanism may be associated with alleviating oxidative stress and endoplasmic reticulum stress, inhibiting the PI3K/AKT pathway, and inducing autophagy in hepatocytes.
Animals ; Rats, Sprague-Dawley ; Drugs, Chinese Herbal/administration & dosage* ; Network Pharmacology ; Rats ; Pancreatitis/genetics* ; Hyperlipidemias/genetics* ; Male ; Liver/injuries* ; Protein Interaction Maps/drug effects* ; Signal Transduction/drug effects* ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Interleukin-1beta/genetics* ; Humans

Urinary incontinence is a common complication following robot-assisted radical prostatectomy (RARP). Urethral length has been identified as a factor affecting postoperative continence recovery. In this meta-analysis, we examined the association between use of the maximal urethral length preservation (MULP) technique and postoperative urinary continence in patients undergoing RARP. We conducted a comprehensive search of PubMed, Web of Science, Embase, and the Cochrane Library up to December 31, 2023. The quality of the literature was assessed using the Newcastle-Ottawa Scale. A random-effects meta-analysis was performed to synthesize data and calculate the odds ratio (OR) from eligible studies on continence and MULP. Six studies involving 1869 patients met the eligibility criteria. MULP was positively associated with both early continence (1 month after RARP; Z = 3.62, P = 0.003, OR = 3.10, 95% confidence interval [CI]: 1.68-5.73) and late continence (12 months after RARP; Z = 2.34, P = 0.019, OR = 2.10, 95% CI: 1.13-3.90). Oncological outcomes indicated that MULP did not increase the overall positive surgical margin rate or the positive surgical margin status at the prostate apex (both P > 0.05). In conclusion, the use of the MULP technique in RARP significantly improved both early and late postoperative continence outcomes without compromising oncological outcomes.
Humans ; Prostatectomy/adverse effects* ; Robotic Surgical Procedures/methods* ; Male ; Urethra/surgery* ; Urinary Incontinence/prevention & control* ; Postoperative Complications/etiology* ; Prostatic Neoplasms/surgery* ; Organ Sparing Treatments/methods*

Stroke, a major cerebrovascular disease, has high morbidity and mortality. Effective methods to reduce the risk and improve the prognosis are lacking. Currently, uric acid (UA) is associated with the pathological mechanism, prognosis, and therapy of stroke. UA plays pro/anti-oxidative and pro-inflammatory roles in vivo. The specific role of UA in stroke, which may have both neuroprotective and damaging effects, remains unclear. There is a U-shaped association between serum uric acid (SUA) levels and ischemic stroke (IS). UA therapy provides neuroprotection during reperfusion therapy for acute ischemic stroke (AIS). Urate-lowering therapy (ULT) plays a protective role in IS with hyperuricemia or gout. SUA levels are associated with the cerebrovascular injury mechanism, risk, and outcomes of hemorrhagic stroke. In this review, we summarize the current research on the role of UA in stroke, providing potential targets for its prediction and treatment.
Humans ; Uric Acid/metabolism* ; Stroke/drug therapy* ; Animals ; Hyperuricemia/drug therapy* ; Ischemic Stroke/blood* ; Biomarkers/blood*

G protein-coupled receptor (GPR) 40, as one of GPRs family, plays a potential role in regulating glucose and lipid metabolism. To study the effect of GPR40 novel agonist SZZ15-11 on hyperglycemia and hyperlipidemia and its potential mechanism, spontaneous type 2 diabetic KKA^y mice, human hepatocellular carcinoma HepG2 cells and murine mature adipocyte 3T3-L1 cells were used. KKA^y mice were divided into four groups, vehicle group, TAK group, SZZ (50 mg·kg^-1) group and SZZ (100 mg·kg^-1) group, with oral gavage of 0.5% sodium carboxymethylcellulose (CMC), 50 mg·kg^-1 TAK875, 50 and 100 mg·kg^-1 SZZ15-11 respectively for 45 days. Fasting blood glucose, blood triglyceride (TG) and total cholesterol (TC), non-fasting blood glucose were tested. Oral glucose tolerance test and insulin tolerance test were executed. Blood insulin and glucagon were measured via enzyme-linked immunosorbent assay (ELISA). After mice′s execution, liver tissue was harvested to test TG and TC content. Then pathological morphology of liver was observed through hematoxylin-eosin (HE) staining, and the lipid metabolism relative signal pathway was analyzed by Western blot and RT-PCR. The experiments were approved by the Institutional Animal Care and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. At the same time, Akt phosphorylation level in HepG2 cells and adiponectin in 3T3-L1 cells treated with TNFα were measured with Western blot. The results show that SZZ15-11 not only decreased blood glucose and lipid, improved insulin sensitivity, but also increased fasting blood glucagon and promoted insulin secretion after glucose loading in KKA^y mice. Additionally, SZZ15-11 alleviated hepatic steatosis and liver dysfunction in KKA^y mice. In liver tissue, SZZ15-11 increased AMPKα phosphorylation level and cholesterol metabolism relative gene Abcg8 transcription. In HepG2 cells, SZZ15-11 increased Akt phosphorylation level. In adipocyte 3T3-L1, SZZ15-11 recovered the decreased adiponectin expression by TNFα. This study proved that GPR40 agonist SZZ15-11 could be a candidate compound for regulating glucolipid metabolic disorder.

The incidence of intrahepatic cholangiocarcinoma (ICC) continues to rise, and there are no effective drugs to treat it. The immune microenvironment plays an important role in the development of ICC and is currently a research hotspot. Icaritin (ICA) is an innovative traditional Chinese medicine for the treatment of advanced hepatocellular carcinoma. It is considered to have potential immunoregulatory and anti-tumor effects, which is potentially consistent with the understanding of "Fuzheng" in the treatment of tumor in traditional Chinese medicine. However, whether ICA can be used to treat ICC has not been reported. Therefore, in this study, sgp19/kRas, an in situ ICC mouse model with intact immune system, was selected to evaluate the efficacy of ICA in the treatment of ICC in vivo for the first time, and the effects of ICA on the tumor immune microenvironment of ICC mice were analyzed by flow cytometry. This experiment was approved by the Experimental Animal Ethics Committee of Capital Medical University (approval number: AEEI-2023-138). In this study, sgp19/kRas ICC mouse model was treated with oral gavage of 100 mg·kg^-1 ICA. We found that ICA significantly inhibited tumor growth and tumor cell proliferation in the sgp19/kRas ICC mouse model after 3 weeks of treatment. Flow cytometry analysis indicated that ICA treatment markedly reduced the proportion of M2 macrophages and increased the number of CD3⁺CD4⁺ T cells. In vitro experiments demonstrated that ICA promoted macrophage polarization towards the M1 phenotype while inhibiting polarization towards the M2 phenotype. Furthermore, transcriptomic analysis suggested that ICA enhanced Toll-like receptor 9 (TLR9) expression, influencing macrophage nitric oxide metabolism synthesis pathways and receptor-related activities, thereby regulating macrophage polarization. In summary, this study demonstrates that ICA treatment significantly delays tumor progression in sgp19/kRas ICC mouse models. Mechanistically, ICA may achieve its anti-ICC effects by upregulating TLR9 receptor expression levels, promoting macrophage polarization towards the M1 phenotype, and altering the tumor immune microenvironment.

Objective To build the early predictive model for chronic kidney disease(CKD)in hypertension and diabetes patients in the community.Methods The CKD patients were recruited from 4 health care centers in 4 urban areas in Kunming.The control group was residents without hypertension and diabetes(n = 1267).The disease group was residents with hypertension and/or diabetes(n = 566).The questionnaire survey,physical examination,laboratory testing,and 5 SNPs gene types in the PVT1 gene.The risk factors,which were filtered with logistics regression,were used to build predictive models.Four machine learning algorithms were built:support vector machine(SVM),random forest(RF),Na?ve Bayes(NB),and artificial neural network(ANN)models.Results Thirteen indicators included in the final diagnostic model:age,disease type,ethnicity,blood urea nitrogen,creatinine,eGFR from MDRD,ACR,eGFR from EPI2009,PAM13 score,sleep quality survey,staying-up late,PVT1 SNP rs11993333 and rs2720659.The accuracy,specificity,Kappa value,AUC of ROC,and PRC of ANN are greater than those of the other 3 models.The sensitivity of RF is the highest among 4 types of machine learning.Conclusions The ANN predictive model has a good ability of efficiency and classification to predict CKD with hypertension and/or diabetes patients in the community.