BACKGROUND:Total flavonoids from Sophora flavescens have a variety of pharmacological effects,including anti-inflammatory,immunomodulatory,antioxidant,and anti-hepatic injury,but the therapeutic effects and mechanisms in non-alcoholic fatty liver disease are not clear.OBJECTIVE:To reveal the mechanism of total flavonoids from Sophora flavescens in the treatment of non-alcoholic fatty liver disease using bioinformatics,network pharmacology and zebrafish experimental validation.METHODS:A zebrafish model of non-alcoholic fatty liver disease was constructed to observe lipid accumulation,pathomorphologic changes,and expression of inflammatory genes in the liver of zebrafish after treatment with total flavonoids from Sophora flavescens.The active ingredients of total flavonoids from Sophora flavescens and non-alcoholic fatty liver disease-related targets were obtained from TCMSP,Swiss Target Prediction,and Bat-man databases.STRING was used to perform protein-protein interaction network analysis,GO functional enrichment and KEGG pathway enrichment analysis.Based on the GSE33814 dataset,the differentially expressed genes of total flavonoids from Sophora flavescens and non-alcoholic fatty liver disease intersection targets were screened out.Correlation analysis and receiver operating characteristic curve were performed using R4.3.2 software.Core genes were verified by the validation set GSE89632.RT-qPCR and western blot assays were performed to verify the expression of core pathway-related genes and proteins.RESULTS AND CONCLUSION:(1)Total flavonoids from Sophora flavescens could improve lipid accumulation in the liver of zebrafish with non-alcoholic fatty liver disease,significantly inhibited the elevation of lipid and aminotransferase levels in zebrafish(P<0.05),and regulated the expression of genes related to inflammation and lipid metabolism.(2)A total of 168 common targets were obtained using the network pharmacology,and top 10 core genes,identified by Cytoscape topology analysis,were HSP90AA1,STAT3,PIK3R1,MAPK1,AKT1,RXRA,PIK3CA,EGFR,JAK2,and ESR1.GO and KEGG analysis pathways mainly included insulin resistance,lipids,and atherosclerosis.There were a total of 59 differentially expressed genes after intersection of total flavonoids from Sophora flavescens and non-alcoholic fatty liver disease targets.The receiver operating characteristic curve and validation set analyses yielded six core targets that were significantly different between healthy individuals and patients with non-alcoholic fatty liver disease(P<0.01).(3)RT-PCR and western blot results verified that total flavonoids from Sophora flavescens inhibited the activation of the JAK2/STAT3 signaling pathway in zebrafish.To conclude,total flavonoids from Sophora flavescens may alleviate the inflammatory response through the JAK2/STAT3 signaling pathway,thus inhibiting lipid accumulation and improving non-alcoholic fatty liver disease.

Objective:To investigate the clinical characteristics and associated factors of comorbid obstructive sleep apnea (OSA) coexisting with restless legs syndrome (RLS).Methods:A retrospective case-control study was conducted, enrolling hospitalized patients diagnosed with OSA or RLS at Peking University Sixth Hospital from June 2015 to May 2023. Participants were divided into three groups: OSA with RLS (comorbid group, n=26), OSA alone ( n=60, RLS-excluding), and RLS alone ( n=45, OSA-excluding). Demographic characteristics, clinical data, laboratory indicators (i.e., hemoglobin, ferritin, serum iron, folate, vitamin B 12, calcium, phosphorus, magnesium, fasting glucose), and polysomnography (PSG) parameters were collected. Group differences were analyzed using ANOVA, chi-square tests, and non-parametric tests. Multivariate logistic regression was performed to identify factors associated with OSA comorbid RLS. Results:Laboratory analyses revealed that patients in the comorbid group had significantly lower hemoglobin ( P=0.046) and ferritin levels ( P=0.024) than the OSA-alone group. Conversely, serum phosphorus was markedly elevated in the comorbid group compared to both control groups ( F=2.23, P<0.01). Polysomnography test found significantly higher periodic limb movement during sleep index (PLMSI) in the comorbid group vs. OSA-alone group (Dunn-Bonferroni correction P=0.001), reduced minimum oxygen saturation in the comorbid group vs. RLS-alone group (Dunn-Bonferroni correction P<0.001), and increased respiratory-related microarousals in the comorbid group vs. RLS-alone group (Dunn-Bonferroni correction P<0.001). Multivariate analysis adjusted for covariates confirmed that periodic limb movement during sleep index (PLMSI) ( OR=1.04, 95% CI=1.02-1.07, P=0.001) and serum phosphorus ( OR=6.51, 95% CI=1.86-27.40, P=0.003) independently contributed to OSA-RLS comorbidity. Conclusion:The coexistence of OSA and RLS manifests as dual dysregulation in iron-phosphorus metabolism and synchronized respiratory-motor dysfunction. Mechanistically, hypoxia-induced systemic inflammation may serve as a nexus linking metabolic perturbations and sleep fragmentation in this clinical subpopulation, highlighting potential biomarkers for targeted management.

BACKGROUND:Total flavonoids from Sophora flavescens have a variety of pharmacological effects,including anti-inflammatory,immunomodulatory,antioxidant,and anti-hepatic injury,but the therapeutic effects and mechanisms in non-alcoholic fatty liver disease are not clear.OBJECTIVE:To reveal the mechanism of total flavonoids from Sophora flavescens in the treatment of non-alcoholic fatty liver disease using bioinformatics,network pharmacology and zebrafish experimental validation.METHODS:A zebrafish model of non-alcoholic fatty liver disease was constructed to observe lipid accumulation,pathomorphologic changes,and expression of inflammatory genes in the liver of zebrafish after treatment with total flavonoids from Sophora flavescens.The active ingredients of total flavonoids from Sophora flavescens and non-alcoholic fatty liver disease-related targets were obtained from TCMSP,Swiss Target Prediction,and Bat-man databases.STRING was used to perform protein-protein interaction network analysis,GO functional enrichment and KEGG pathway enrichment analysis.Based on the GSE33814 dataset,the differentially expressed genes of total flavonoids from Sophora flavescens and non-alcoholic fatty liver disease intersection targets were screened out.Correlation analysis and receiver operating characteristic curve were performed using R4.3.2 software.Core genes were verified by the validation set GSE89632.RT-qPCR and western blot assays were performed to verify the expression of core pathway-related genes and proteins.RESULTS AND CONCLUSION:(1)Total flavonoids from Sophora flavescens could improve lipid accumulation in the liver of zebrafish with non-alcoholic fatty liver disease,significantly inhibited the elevation of lipid and aminotransferase levels in zebrafish(P<0.05),and regulated the expression of genes related to inflammation and lipid metabolism.(2)A total of 168 common targets were obtained using the network pharmacology,and top 10 core genes,identified by Cytoscape topology analysis,were HSP90AA1,STAT3,PIK3R1,MAPK1,AKT1,RXRA,PIK3CA,EGFR,JAK2,and ESR1.GO and KEGG analysis pathways mainly included insulin resistance,lipids,and atherosclerosis.There were a total of 59 differentially expressed genes after intersection of total flavonoids from Sophora flavescens and non-alcoholic fatty liver disease targets.The receiver operating characteristic curve and validation set analyses yielded six core targets that were significantly different between healthy individuals and patients with non-alcoholic fatty liver disease(P<0.01).(3)RT-PCR and western blot results verified that total flavonoids from Sophora flavescens inhibited the activation of the JAK2/STAT3 signaling pathway in zebrafish.To conclude,total flavonoids from Sophora flavescens may alleviate the inflammatory response through the JAK2/STAT3 signaling pathway,thus inhibiting lipid accumulation and improving non-alcoholic fatty liver disease.

Objective:To investigate the clinical characteristics and associated factors of comorbid obstructive sleep apnea (OSA) coexisting with restless legs syndrome (RLS).Methods:A retrospective case-control study was conducted, enrolling hospitalized patients diagnosed with OSA or RLS at Peking University Sixth Hospital from June 2015 to May 2023. Participants were divided into three groups: OSA with RLS (comorbid group, n=26), OSA alone ( n=60, RLS-excluding), and RLS alone ( n=45, OSA-excluding). Demographic characteristics, clinical data, laboratory indicators (i.e., hemoglobin, ferritin, serum iron, folate, vitamin B 12, calcium, phosphorus, magnesium, fasting glucose), and polysomnography (PSG) parameters were collected. Group differences were analyzed using ANOVA, chi-square tests, and non-parametric tests. Multivariate logistic regression was performed to identify factors associated with OSA comorbid RLS. Results:Laboratory analyses revealed that patients in the comorbid group had significantly lower hemoglobin ( P=0.046) and ferritin levels ( P=0.024) than the OSA-alone group. Conversely, serum phosphorus was markedly elevated in the comorbid group compared to both control groups ( F=2.23, P<0.01). Polysomnography test found significantly higher periodic limb movement during sleep index (PLMSI) in the comorbid group vs. OSA-alone group (Dunn-Bonferroni correction P=0.001), reduced minimum oxygen saturation in the comorbid group vs. RLS-alone group (Dunn-Bonferroni correction P<0.001), and increased respiratory-related microarousals in the comorbid group vs. RLS-alone group (Dunn-Bonferroni correction P<0.001). Multivariate analysis adjusted for covariates confirmed that periodic limb movement during sleep index (PLMSI) ( OR=1.04, 95% CI=1.02-1.07, P=0.001) and serum phosphorus ( OR=6.51, 95% CI=1.86-27.40, P=0.003) independently contributed to OSA-RLS comorbidity. Conclusion:The coexistence of OSA and RLS manifests as dual dysregulation in iron-phosphorus metabolism and synchronized respiratory-motor dysfunction. Mechanistically, hypoxia-induced systemic inflammation may serve as a nexus linking metabolic perturbations and sleep fragmentation in this clinical subpopulation, highlighting potential biomarkers for targeted management.

Purpose To explore the value of dual-layer spectral detector CT(DLSCT)in evaluating preoperative tumor staging in rectal adenocarcinoma(RA).Materials and Methods A total of 78 patients with pathologically confirmed RA in Guangdong Provincial Hospital of Chinese Medicine from May 2021 to March 2022 were involved in this retrospective study.All the patients underwent plain and dual-phase contrast-enhanced scans by DLSCT within one week before surgery.Taking pathological results as the golden standard,the accuracy rates of tumor staging were calculated and compared between the multiple-parameter maps derived from DLSCT and 120 kVp polyenergetic image.The effective atomic number(Z-eff)from plain scan,iodine concentration(IC)from arterial phase(AP)and venous phase(VP)were measured.The normalized iodine concentration(NIC)in AP and VP were calculated.The differences of Z-eff,NICAP and NICVP were compared among the pT1-2,pT3 and pT4 groups.The correlation between the pT stages and above values was assessed and the diagnostic efficiencies were analyzed.Results The overall accuracy rate(88.46%vs.67.95%;χ2=9.628,P=0.002),the pT1-2 staging accuracy rate(80.00%vs.40.00%;χ2=6.667,P=0.01),and the pT3 staging accuracy rate(88.10%vs.69.05%;χ2=4.525,P=0.033)of multiple-parameter maps derived from DLSCT were significantly higher than those of 120 kVp polyenergetic image,respectively.The Z-eff,NICAP and NICVP were significantly different among pT stage groups(F=6.456,11.029,12.698,all P<0.05)and exhibited a positive correlation with pT stages(r=0.371,0.367,0.363,all P<0.01).The areas under the curve of Z-eff,NICAP and NICVP to assess pT3-4 staging RA were 0.77,0.71 and 0.74,respectively.Conclusion The multiple-parameter maps derived from DLSCT can significantly improve the diagnostic accuracy of preoperative tumor staging of RA.Z-eff from plain scan and NIC from dual-phase helps differentiate pT1-2 from pT3-4 staging RA.

Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA, the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis; however, it conferred high cardiovascular risk in clinical trials. Furthermore, romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.