ObjectiveTo characterize the changes in the overall chemical profile and key index components during nine-time repeating steaming and sun-drying processing of Rhei Radix et Rhizoma， and to reveal the change law of its material basis. MethodsHigh performance liquid chromatography（HPLC） was used to analyze the changes in the overall chemical profile of Rhei Radix et Rhizoma decoction pieces， and the contents of 15 main active components such as chrysophanol-8-O-β-D-glucoside， chrysophanol and gallic acid in the process of nine-time repeating steaming and sun-drying were determined. Combined with chemometrics， the contents and quantity ratio relationships of the glycosides， aglycones and tannins during the processing of Rhei Radix et Rhizoma were analyzed， and the partial least squares-discriminant analysis（PLS-DA） and cluster analysis of the main components in different steaming times were conducted， the statistically significant differential markers were selected with the variable importance in the projection（VIP） value>1. ResultsIn the nine-time repeating steaming and sun-drying process of Rhei Radix et Rhizoma， there were certain regularity in the number and peak area of characteristic peaks and the steaming and sun-drying times， the anthraquinone glycosides and aglycones could be roughly divided into three stages， including rapid change stage， fluctuation change stage and stable stage， and the total amount of tannins showed a decreasing trend. However， the ratios between the three components mentioned above tended to stabilize after five rounds of steaming and sun-drying. The results of PLS-DA and cluster heatmap showed that the content of each component in Rhei Radix et Rhizoma fluctuated greatly during the 1-4 steaming and sun-drying processes， while the content of each component was relatively close during the 5-9 steaming and sun-drying processes. After screening， it was found that chrysophanol， emodin， chrysophanol-8-O-β-D-glucoside， rhein， physcion and emodin-8-O-β-D-glucoside could be used as the index components for distinguishing the processed products of Rhei Radix et Rhizoma with different steaming and sun-drying times. ConclusionThe changes in the properties and efficacy of Rhei Radix et Rhizoma caused by the processing of nine-time repeating steaming and sun-drying are due to the changes in the composition and ratio of various glycosides and complex tannins in this herb， which is also the key to the formation of its characteristic of "purgation with supplement". This study can provide a basis for the research on the processing mechanism of Rhei Radix et Rhizoma and the establishment of processing specifications.

BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a promising target for sensitizing solid tumors to immune checkpoint blockades. However, the highly polar active sites of PTPN2 hinder drug discovery efforts. Leveraging small interfering RNA (siRNA) technology, we developed a novel glutathione-responsive nano-platform HPssPT (HA/PEIss@siPtpn2) to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma (HCC). HPssPT showed potent transfection and favorable safety profiles. PTPN2 deficiency induced by HPssPT amplified the interferon γ signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1, resulting in enhanced antigen presentation and T cell activation. The nano-platform was also able to promote the M1-like polarization of macrophages in vitro. The unique tropism of HPssPT towards tumor-associated macrophages, facilitated by hyaluronic acid coating and CD44 receptor targeting, allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages, thereby synergistically reshaping tumor microenvironment to an immunostimulatory state. In HCC, colorectal cancer, and melanoma animal models, HPssPT monotherapy provoked robust antitumor immunity, thereby sensitizing tumors to PD-1 blockade, which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.

Objective To investigate the predictive value of combined radiomic features derived from chest CT scans with clinical characteristics for epidermal growth factor receptor(EGFR)gene mutations in non-small cell lung cancer(NSCLC).Methods A multi-center case-control study was conducted on the clinical data and CT images of 1 070 NSCLC patients from the radiology departments of the 3 medical institutions between January 2013 and October 2023.The 719 NSCLC patients from the First Affiliated Hospital of Army Medical University were randomly divided into a training set and an internal validation set in a ratio of 7∶3;The 173 patients in the Eastern Theatre General Hospital and the 178 patients in Army Medical Centre of PLA were assigned into the external validation set 1 and 2,respectively.Least absolute shrinkage and selection operator(LASSO)regression was employed to identify the optimal radiomic features,which were subsequently used to construct a radiomics model.Univariate and multivariate logistic regression analyses were applied to identify clinical features associated with EGFR mutation,thereby developing a clinical model.The radiomic and clinical features were subsequently combined to develop a comprehensive model.All the 3 classification models were built using random forest(RF)machine learning.The area under curve(AUC),accuracy,sensitivity and specificity were utilized to evaluate the predictive performance of the models.Calibration curve was plotted to assess the goodness of fit of the comprehensive model,while decision curve analysis was performed to assess the clinical utility of the model.Results The AUC value of the radiomics model was 0.762 4(95%CI:0.692 4～0.825 1),0.745 4(95%CI:0.671 1～0.814 3),and 0.724 7(95%CI:0.639 7～0.801 6),respectively,in the internal validation set,external validation set 1,and external validation set 2;The AUC value of the clinical prediction model was 0.691 7(95%CI:0.627 9～0.757 6),0.652 5(95%CI:0.576 7～0.729 1),and 0.779 2(95%CI:0.712 5～0.847 3),respectively in the above sets in turn;The comprehensive model constructed based on clinical features and radiomic features showed the best predictive efficacy,with an AUC value of 0.818 0(95%CI:0.757 7～0.874 3),0.782 4(95%CI:0.703 1～0.848 2),and 0.796 6(95%CI:0.718 1～0.868 6),respectively in the above sets.Calibration curve analysis indicated that the comprehensive model had a good fit,while decision curve analysis revealed that the model provided a favorable net benefit.Conclusion Our comprehensive model constructed based on chest CT radiomic features and clinical characteristics shows superior predictive performance for EGFR gene mutations in NSCLC across multiple center datasets,which may be helpful for clinical decision-making for treatment strategies.

Objective To evaluate the predictive value of deep learning features from chest CT images combined with clinical and radiomics features for epidermal growth factor receptor(EGFR)mutations in non-small cell lung cancer(NSCLC).Methods This case-control study retrospectively analyzed clinical and imaging data of 1 070 NSCLC patients from radiology departments at three hospitals(January 2013 to October 2023).Patients were divided into:a training set(n=502)and internal validation set(n=217)via 7∶3 randomization of 719 cases from the First Affiliated Hospital of Army Medical University;external validation set 1(n=173)from General Hospital of Eastern Theater Command;external validation set 2(n=178)from Daping Hospital of Army Medical University.Deep learning features were extracted using a 2.5D convolutional neural network(CNN)with ResNet101 backbone,radiomics features were derived from CT images,and clinical risk factors were identified to construct models.An integrated model combined deep learning,clinical,and radiomics features.All four models were developed using random forest(RF)classifiers.Calibration curves assessed goodness-of-fit,and decision curve analysis(DCA)evaluated clinical utility.Results The deep learning model achieved AUCs of 0.833 7(95%CI:0.770 6～0.884 7),0.815 1(0.741 6～0.882 8),and 0.810 1(0.745 2～0.873 6)in the internal and two external validation sets,respectively.Clinical models yielded AUCs of 0.731 0(0.660 2～0.802 1),0.746 0(0.666 4～0.824 9),and 0.813 4(0.743 1～0.883 6);radiomics models showed AUCs of 0.762 4(0.692 4～0.825 1),0.745 4(0.671 1～0.814 3),and 0.724 7(0.639 7～0.801 6).The integrated model demonstrated optimal performance with AUCs of 0.905 5(0.857 0～0.945 4),0.832 7(0.763 3～0.896 4),and 0.889 0(0.834 4～0.934 3).DCA indicated significant net benefit for EGFR prediction at threshold probabilities of 0.15～0.85 using the integrated model.Conclusion Deep learning features from CT images effectively predict EGFR mutation status in NSCLC.The integrated model combining deep learning,clinical,and radiomics features further enhances predictive performance.

Objective To investigate the effects of dienogest on pain relief and inflammation in endometriosis(EMs),as well as its impact on the brain-derived neurotrophic factor(BDNF)/tropo-myosin receptor kinase B(TrkB)and nuclear factor kappa-B(NF-κB)/NOD-like receptor protein 3(NLRP3)inflammatory pathways.Methods An allograft method was used to establish an EMs rat model.The rats were randomly divided into sham-operated group(n=16),model group(n=16),low-dose dienogest group(n=16),medium-dose dienogest group(n=16)and high-dose dienogest group(n=16).After 7 days of treatment,the implantation volume and writhing response frequency were recorded.Enzyme-linked immunosorbent assay(ELISA),reverse transcription-polymerase chain reaction and Western blotting were employed to measure the expression levels of vascular endothelial growth factor(VEGF),inducible nitric oxide synthase(iNOS),interleukin(IL)-6,IL-1β and tumor necrosis factor(TNF)-α in the EMs rat models.Serum levels of BDNF,TrkB,NF-κB and NLRP3 were detected.Results Compared with model group,dinorgestrel significantly reduced ectopic endo-metrial volume and torsion response of EMs(P＜0.05).Compared with model group,dinorgestrel significantly decreased the expression of VEGF,iNOS,IL6,IL-1 β and TNF-α in EMs model(P＜0.05).In addition,compared with model group,dienogest significantly decreased the expressions of BDNF,TrkB,NF-κB and NLRP3 in ectopic endometrium(P＜0.05).Conclusion Dinorgestrel can relieve EMS-related dysmenorrhea and inflammation,and its mechanism of action may be partly mediated by BDNF/TrkB pathway and NF-κB/NLRP3 pathway.

Objective The potential mechanism of hepatotoxicity induced by rhubarb was preliminarily explored by network pharmacology and verified by cell experiments.Methods Based on network pharmacology,component collection and target prediction are carried out through multiple databases.PPI network construction,GO enrichment analysis and KEGG pathway analysis were combined with software to systematically predict the mechanism of hepatotoxicity induced by rhubarb.The pathway information predicted by network pharmacology was verified by primary hepatocyte experiments and Western blot experiments.Results The results of network pharmacology showed that RH was the main component of hepatotoxicity induced by rhubarb.Seventeen core targets of hepatotoxicity induced by rhubarb were obtained.KEGG results suggested that DNA damage and apoptosis were one of the key mechanisms of hepatotoxicity induced by rhubarb.The results of primary hepatocytes and Western blot showed that RH could inhibit the viability of primary hepatocytes in a time-dose dependent manner.ABT and SFP can significantly reduce the toxicity of RH on primary liver cells in mice,and RFP can increase the toxicity of RH to mouse primary liver cells.Upregulation of γ-H2AX and PARP-1 protein in primary liver cells of mice after treatment with different concentrations of RH.Conclusion RH in rhubarb can significantly inhibit the viability of mouse primary hepatocytes,and its toxicity to mouse primary hepatocytes is mainly caused by the metabolic activation of RH by CYP 2C9.RH can activate PARP-1 protein,phosphorylate H2AX,induce DNA damage and apoptosis in mouse primary hepatocytes.

【Objective】 To explore the safety of transrectal ultrasound-guided transperineal injection of sodium hyaluronate to expand the Dirichlet gap in laparoscopic radical prostatectomy. 【Methods】 A total of 14 healthy male purebred beagle dogs were selected and randomly divided into 2 groups, with 7 in either group.The control group was treated with conventional laparoscopic radical prostatectomy, while the experimental group was treated with laparoscopic radical prostatectomy after 2.5 mL sodium hyaluronate was injected into the Dirichlet gap under the guidance of transrectal ultrasound.The total operation time, prostate separation time, intraoperative blood loss and rectal status of the 2 groups were observed. 【Results】 After the injection of sodium hyaluronate into the Dirichlet gap between the prostate and the rectum, no rectal tissue was found in the prostate, and no obvious damage was found in the posterior rectum in either groups.The postoperative hemoglobin (HGB) was [(118.70±2.56) g/L vs.(122.10±2.19) g/L, P=0.02]; the total operation time was [(141.40±9.80) min vs.(119.10±9.16) min, P<0.05]; the prostate separation time was [(24.99±1.75) min vs.(16.64±2.34) min, P<0.05]; the amount of bleeding was [(47.43±4.32) mL vs.(34.86±5.18) mL, P<0.05] in the control group and experimental group. 【Conclusion】 Laparoscopic radical prostatectomy performed after 2.5 mL of sodium hyaluronate injection into the Dirichlet gap under the guidance of transrectal ultrasound can shorten the total operation time, the separation and resection time of the prostate, and reduce the amount of bleeding, which can improve and reduce the incidence of rectal injury, and prove the feasibility of this approach for prostatic cancer.

Objective:To investigate the association between hyperuricemia and the risk for stroke occurrence, as well as the mediating effect of hypertension on this association.Methods:In this study, the China Chronic Diseases and Nutrition Surveillance system in 2015 was used as baseline data. We identified hospital admissions for stroke using the electronic homepage of inpatient medical records from 2013-2020, and death data were obtained from the 2015-2020 National Mortality Surveillance System. A retrospective cohort was established after matching and linking the database. The Cox proportional hazard regression model was used to analyze the relationship between hyperuricemia and the risk of stroke and its subtypes. Restricted cubic spline analysis was conducted to examine the dose-response relationship between serum uric acid levels and the risk for stroke. Mediation analysis was performed to investigate the mediating effect of hypertension on the association between hyperuricemia and the risk for stroke and its subtypes. Subgroup analyses were conducted based on gender and age groups.Results:A total of 124 352 study subjects were included, with an accumulative follow-up time of 612 911.36 person-years. During the follow-up period, 4 638 cases of stroke were found, including 3 919 cases of ischemic stroke and 689 cases of hemorrhagic stroke. The incidence density of stroke was 756.72 per 100 000 person-years, 641.37 per 100 000 person-years for ischemic stroke, and 114.60 per 100 000 person-years for hemorrhagic stroke. Multivariable Cox proportional hazards regression models showed that after adjusting for covariates, compared to those without hyperuricemia, individuals with hyperuricemia had a 16% higher risk for stroke [hazard ratio ( HR)=1.16, 95% CI: 1.06-1.27], a 12% higher risk of ischemic stroke ( HR=1.12, 95% CI: 1.01-1.24), and a 39% higher risk of hemorrhagic stroke ( HR=1.39, 95% CI: 1.11-1.75). Mediation analysis showed that hypertension partially mediated the associations between hyperuricemia and the risk for stroke, ischemic stroke, and hemorrhagic stroke, with mediation proportions of 36.07%, 39.98%, and 25.34%, respectively. The mediating effect is pronounced in the male population and individuals below 65. Conclusion:Hyperuricemia is a risk factor for stroke, and hypertension partially mediates the effect of hyperuricemia on stroke.

Objective:To explore the predictive value of the prognostic nutritional index (PNI) in concurrently infected patients with acute-on-chronic liver failure (ACLF).Methods:220 cases with ACLF diagnosed and treated at the First Affiliated Hospital of Xi'an Jiaotong University from January 2011 to December 2016 were selected. Patients were divided into an infection and non-infection group according to whether they had co-infections during the course of the disease. Clinical data differences were compared between the two groups of patients. Binary logistic regression analysis was used to screen out influencing factors related to co-infection. The receiver operating characteristic curve was used to evaluate the predictive value of PNI for ACLF co-infection. The measurement data between groups were compared using the independent sample t-test and the Mann-Whitney U rank sum test. The enumeration data were analyzed using the Fisher exact probability test or the Pearson χ2 test. The Pearson method was performed for correlation analysis. The independent risk factors for liver failure associated with co-infection were analyzed by multivariate logistic analysis. Results:There were statistically significant differences in ascites, hepatorenal syndrome, PNI score, and albumin between the infection and the non-infection group ( P ?