[摘 要] 目的：探讨KH型剪切调节蛋白（KHSRP）靶向调控JAK1/STAT3信号轴对食管胃结合部腺癌（AEG）细胞增殖、迁移和侵袭及移植瘤生长与肺转移的影响。方法：收集2017年1月至2018年12月间在淮河医院确诊的64例AEG组织和癌旁组织标本及临床资料，采用免疫组化法观察AEG组织和癌旁组织中KHSRP的表达水平。qPCR法检测AEG细胞OE-19、TE-7、BIC-1、FLO-1、SK-GT-4、BE-3与正常食管上皮细胞Het-1A中KHSRP的表达差异。通过慢病毒载体对KHSRP进行敲减和过表达处理，分别转染OE-19与TE-7细胞、FLO-1与SK-GT-4细胞，实验分为sh-NC组、sh-KHSRP组和Vector组、KHSRP过表达组（KHSRP组）。采用qPCR法检测敲减或过表达效率，CCK-8法、Transwell小室法分别检测敲减或过表达KHSRP对AEG细胞增殖、迁移和侵袭的影响。构建小鼠异种移植瘤和肺转移模型，观察KHSRP对移植瘤体内生长和转移的作用。WB法验证KHSRP靶向JAK/STAT信号通路。细胞拯救实验验证KHSRP是否通过调节JAK1/STAT3信号通路促进AEG细胞的恶性进程。结果：与癌旁组织相比，AEG组织中KHSRP表达水平显著增高（P < 0.05或P < 0.01）。细胞功能实验分析显示，KHSRP过表达在体外均显著促进AEG细胞增殖、迁移和侵袭（P < 0.05或P < 0.01）。动物实验结果显示，KHSRP在裸鼠体内具有促进AEG细胞移植瘤生长与肺转移的作用（P < 0.05或P < 0.01）。在敲减KHSRP后，JAK/STAT信号通路中JAK1、STAT3磷酸化水平均明显降低，过表达KHSRP后情况则均反之（P < 0.05或P < 0.01）。细胞拯救实验显示，KHSRP可以逆转敲减JAK1/STAT3对细胞增殖、迁移和侵袭的抑制作用（P < 0.05或P < 0.01）。结论：KHSRP通过激活JAK1/STAT3信号通路调控AEG细胞转移的恶性进程，KHSRP有望成为AEG临床治疗的潜在靶点。

ObjectiveTo investigate the protective effect of Rehmanniae Radix iridoid glycosides （RIG） on the kidney tissue of streptozotocin （STZ）-induced diabetic mice and explore the underlying mechanism. MethodsTwelve of 72 male C57BL/6J mice were randomly selected as the normal group， and the remaining 60 mice were fed with a high-fat diet for six weeks combined with injection of 60 mg·kg^-1 STZ for 4 days to model type 2 diabetes mellitus. The successfully modeled mice were randomized into model， metformin （250 mg·kg^-1）， catalpol （100 mg·kg^-1）， low-dose RIG （RIG-L， 200 mg·kg^-1） and high-dose RIG （RIG-H， 400 mg·kg^-1） groups （n=11）. Mice in each group were administrated with corresponding drugs， while those in the normal group and model group were administrated with the same dose of distilled water by gavage once a day. After 8 weeks of intervention， an oral glucose tolerance test （OGTT） was performed， and the area under the curve （AUC） was calculated. After mice were sacrificed， both kidneys were collected. The body weight， kidney weight， and fasting blood glucose （FBG） were measured. Biochemical assays were performed to measure the serum levels of triglycerides （TG）， total cholesterol （TC）， serum creatinine （SCr）， and blood urea nitrogen （BUN）. Enzyme-linked immunosorbent assay （ELISA） was employed to determine the serum level of fasting insulin （FINS）， and the insulin sensitivity index （ISI） and homeostatic model assessment for insulin resistance （HOMA-IR） were calculated. The pathological changes in kidneys of mice were observed by hematoxylin-eosin staining and Masson staining. The immunohistochemical method （IHC） was employed to assess the expression of interleukin-1 （IL-1）， interleukin-6 （IL-6）， tumor necrosis factor-α（TNF-α）， transforming growth factor-β₁ （TGF-β₁）， and collagen-3 （ColⅢ） in the kidney tissue. The protein levels of TGF-β₁， cell signal transduction molecule 3 （Smad3）， matrix metalloproteinase-9 （MMP-9）， and ColⅢ in kidneys of mice were determined by Western blot. ResultsCompared with the normal group， the model group showcased decreased body weight and ISI （P<0.01）， increased kidney weight， FBG， AUC， FINS， HOMA-IR， TC， TG， SCr， and BUN （P<0.01）， glomerular hypertrophy， capsular space narrowing， and collagen deposition in the kidney， up-regulated protein levels of IL-1， IL-6， TNF-α， TGF-β₁， ColⅢ， and Smad3 （P<0.01）， and down-regulated protein level of MMP-9 （P<0.01） in the kidney tissue. Compared with the model group， the treatment groups had no significant difference in the body weight and decreased kidney weight （P<0.05， P<0.01）. The FBG level declined in the RIG-H group after treatment for 4-8 weeks and in the metformin， catalpol， and RIG-L groups after treatment for 6-8 weeks （P<0.01）. The AUC in the RIG-L， RIG-H， and metformin groups decreased （P<0.05， P<0.01）. The levels of TC， SCr， and BUN in the serum of mice in each treatment group became lowered （P<0.05， P<0.01）. The level of TG declined in the RIG-L， RIG-H， and metformin groups （P<0.05， P<0.01）. The serum level of FINS declined in the catalpol， RIG-L， and metformin groups （P<0.01）. Compared with the model group， the treatment groups showed decreased HOMA-IR （P<0.01）， increased ISI （P<0.01）， alleviated pathological changes in the kidney tissue， and down-regulated expression of IL-1 and TGF-β₁. In addition， the protein levels of IL-6， TNF-α， and ColⅢ in the RIG-H and metformin groups and IL-6 and TNF-α in the RIG-L group were down-regulated （P<0.05， P<0.01）， and the protein levels of IL-6， TNF-α， and ColⅢ in the catalpol group and ColⅢ in the RIG-L group showed a decreasing trend without statistical difference. The protein levels of TGF-β₁， Smad3， and ColⅢ in the RIG-H and metformin groups were down-regulated （P<0.01）. Compared with that in the model group， the protein level of MMP-9 was up-regulated in each treatment group （P<0.01）. ConclusionRIG can improve the renal structure and function of diabetic mice by regulating the TGF-β₁/Smads signaling pathway.

OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets

Parkinson's disease (PD), a chronic and common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-synuclein. Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronic insulin resistance and deficiency in insulin secretion. Extensive evidence has confirmed shared pathogenic mechanisms underlying PD and T2DM, such as oxidative stress caused by insulin resistance, mitochondrial dysfunction, inflammation, and disorders of energy metabolism. Conventional drugs for treating T2DM, such as metformin and glucagon-like peptide-1 receptor agonists, affect nerve repair. Even drugs for treating PD, such as levodopa, can affect insulin secretion. This review summarizes the relationship between PD and T2DM and related therapeutic drugs from the perspective of insulin signaling pathways in the brain.
Humans ; Parkinson Disease/drug therapy* ; Diabetes Mellitus, Type 2/pathology* ; Signal Transduction/physiology* ; Receptor, Insulin/metabolism* ; Animals ; Insulin Resistance/physiology* ; Insulin/metabolism*

Cardiotoxicity is a critical issue in drug development that poses serious health risks, including potentially fatal arrhythmias. The human ether-à-go-go related gene (hERG) potassium channel, as one of the primary targets of cardiotoxicity, has garnered widespread attention. Traditional cardiotoxicity testing methods are expensive and time-consuming, making computational virtual screening a suitable alternative. In this study, we employed machine learning techniques utilizing molecular fingerprints and descriptors to predict the cardiotoxicity of compounds, with the aim of improving prediction accuracy and efficiency. We used four types of molecular fingerprints and descriptors combined with machine learning and deep learning algorithms, including Gaussian naive Bayes (NB), random forest (RF), support vector machine (SVM), K-nearest neighbors (KNN), eXtreme gradient boosting (XGBoost), and Transformer models, to build predictive models. Our models demonstrated advanced predictive performance. The best machine learning model, XGBoost Morgan, achieved an accuracy (ACC) value of 0.84, and the deep learning model, Transformer_Morgan, achieved the best ACC value of 0.85, showing a high ability to distinguish between toxic and non-toxic compounds. On an external independent validation set, it achieved the best area under the curve (AUC) value of 0.93, surpassing ADMETlab3.0, Cardpred, and CardioDPi. In addition, we explored the integration of molecular descriptors and fingerprints to enhance model performance and found that ensemble methods, such as voting and stacking, provided slight improvements in model stability. Furthermore, the SHapley Additive exPlanations (SHAP) explanations revealed the relationship between benzene rings, fluorine-containing groups, NH groups, oxygen in ether groups, and cardiotoxicity, highlighting the importance of these features. This study not only improved the predictive accuracy of cardiotoxicity models but also promoted a more reliable and scientifically interpretable method for drug safety assessment. Using computational methods, this study facilitates a more efficient drug development process, reduces costs, and improves the safety of new drug candidates, ultimately benefiting medical and public health.

OBJECTIVE: To explore the feasibility of incorporating simple bedside indicators into death predictive model for elderly critically ill patients based on interpretability machine learning algorithms, providing a new scheme for clinical disease assessment. METHODS: Elderly critically ill patients aged ≥ 65 years who were hospitalized in the intensive care unit (ICU) of Tacheng People's Hospital of Ili Kazak Autonomous Prefecture from June 2017 to May 2020 were retrospectively selected. Basic parameters including demographic characteristics, basic vital signs and fluid intake and output within 24 hours after admission, as well acute physiology and chronic health evaluation II (APACHE II), Glasgow coma score (GCS) and sequential organ failure assessment (SOFA) were also collected. According to outcomes in hospital, patients were divided into survival group and death group. Four datasets were constructed respectively, namely baseline dataset (B), including age, body temperature, heart rate, pulse oxygen saturation, respiratory rate, mean arterial pressure, urine output volume, infusion volume, and crystal solution volume; B+APACHE II dataset (BA), B+GCS dataset (BG), and B+SOFA dataset (BS). Then three machine learning algorithms, Logistic regression (LR), extreme gradient boosting (XGboost) and gradient boosting decision tree (GBDT) were used to develop the corresponding mortality predictive models within four datasets. The feature importance histogram of each prediction model was drawn by SHapley additive explanation (SHAP) method. The area under curve (AUC), accuracy and F1 score of each model were compared to determine the optimal prediction model and then illuminate the nomogram. RESULTS: A total of 392 patients were collected, including 341 in the survival group and 51 in the death group. There were statistically significant differences in heart rate, pulse oxygen saturation, mean arterial pressure, infusion volume, crystal solution volume, and etiological distribution between the two groups. The top three causes of death were shock, cerebral hemorrhage, and chronic obstructive pulmonary disease. Among the 12 prognostic models trained by three machine learning algorithms, overall performance of prognostic models based on B dataset was behind, whereas the LR model trained by BA dataset achieved the best performance than others with AUC of 0.767 [95% confidence interval (95%CI) was 0.692-0.836], accuracy of 0.875 (95%CI was 0.837-0.903) and F1 score of 0.190. The top 3 variables in this model were crystal solution volume with first 24 hours, heart rate and mean arterial pressure. The nomogram of the model showed that the total score between 150 and 230 were advisable. CONCLUSION The interpretable machine learning model including simple bedside parameters combined with APACHE II score could effectively identify the risk of death in elderly patients with critically illness.
Humans ; Critical Illness ; Machine Learning ; Aged ; Algorithms ; Intensive Care Units ; Retrospective Studies ; APACHE ; Prognosis ; Organ Dysfunction Scores ; Hospital Mortality ; Male ; Female

OBJECTIVES: This study aimed to explore the active components, potential targets, and mechanism of Cnidii Fructus in the treatment of periodontitis with osteoprosis through network pharmacology, molecular docking, and molecular dynamics simulation technology. METHODS: The main chemical constituents and targets of Cnidii Fructus were screened using the TCMSP and SwissTargetPrediction databases, as well as literature reports. Targets of periodontitis and osteoporosis were predicted using different databases. The intersection targets of Cnidii Fructus, periodontitis, and osteoporosis were obtained using Venny 2.1. The protein-protein interaction network was formed on the STRING platform. Cytoscape 3.9.1 was used to construct the active component-intersection target interaction network, perform the topological analysis, and screen key targets and core active components. Furthermore, the Metascape database was used to perform gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis on the intersection targets. The top five key targets and core active components were selected as receptor proteins and ligand small molecules. Discovery Studio 2019 was used to dock ligands and receptors and visualize the docking results. Molecular dynamics simulation was conducted using Gromacs2022.3 to assess the stability of the interactions between the core active components and the main targets. RESULTS: A total of 20 potential active ingredients of Cnidii Fructus were screened, and 116 targets of Cnidii Fructus were obtained for treating periodontitis and osteoporosis. GO and KEGG analyses of the 116 targets showed that Cnidii Fructus may play a therapeutic role through the phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) and advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) signaling pathways. Molecular docking showed that the core constituents were well bound to the main targets. Molecular dynamics simulations confirmed the stability of the Diosmetin-AKT1 complex system. CONCLUSIONS The preliminary discovery of the potential molecular pharmacological mechanism of Cnidii Fructus extract in the targeted treatment of periodontitis with osteoporosis through a multi-component, multitarget, and multi-pathway approach can serve as a theoretical foundation for future drug-development research and clinical application.
Molecular Docking Simulation ; Molecular Dynamics Simulation ; Network Pharmacology ; Periodontitis/complications* ; Drugs, Chinese Herbal/chemistry* ; Osteoporosis/complications* ; Humans ; Protein Interaction Maps ; Cnidium/chemistry*

ObjectiveSerum metabolomics of acute lung injury（ALI） in rats was conducted using ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry（UPLC-Q-TOF-MS） to explore the similarities and differences in the mechanism of Qingqiao（harvested when the fruits of Forsythiae Fructus were initially ripe and still green in color） and Laoqiao（harvested when the fruits of Forsythiae Fructus were ripe） in the treatment of ALI. MethodA total of 24 SD male rats were acclimatized and fed for 1 week， 6 of them were randomly selected for the blank group and 18 for the experimental group. The ALI model was induced in the experimental group by tracheal intubation with lipopolysaccharide（LPS）. After successfully constructing the ALI model， these rats was randomly divided into model group， Qingqiao group and Laoqiao group， with 6 rats in each group. The Qingqiao and Laoqiao groups were administered orally once a day at a dose of 1.5 g·kg^-1， while the blank and model groups received an equivalent volume of saline for 3 consecutive days. The pathological conditions of rat lung tissues were comprehensively assessed by hematoxylin-eosin（HE） staining， wet-to-dry mass ratio（W/D） of lung tissues， and protein concentration in rat bronchoalveolar lavage fluid（BALF）. The levels of interleukin（IL）-6， IL-1β and tumor necrosis factor（TNF）-α in BALF were quantified using enzyme-linked immunosorbent assay（ELISA）. UPLC-Q-TOF-MS was used to identify and analyze the chemical compositions of Qingqiao and Laoqiao， and serum metabolomics of rats in each group was analyzed， combined with multivariate statistical analysis with variable importance in the projection（VIP） value>1， P<0.05 from t-test， and fold change（FC）≥1.5 or FC≤0.5 to screen the differential metabolites Qingqiao and Laoqiao for the treatment of ALI. The Kyoto Encyclopedia of Genes and Genomes（KEGG） database was used in combination with MetaboAnalyst for the metabolic pathway analysis of the screened differential metabolites. ResultCompared with the blank group， rats in the model group exhibited enlarged alveolar lumen， ruptured alveoli， interstitial hemorrhage， bronchial exudation of a large number of neutrophils and erythrocytes， and a significant increase in the protein concentration in the BALF and the W/D value of the lung tissues（P<0.01）. In contrast， compared with the model group， rats in the Qingqiao group and the Laoqiao group showed reduced bronchial hemorrhage in the lungs， and the protein concentration in the BALF and the W/D value of the lung tissues were significantly decreased（P<0.01）， the lung injury was significantly alleviated， but more obvious in the Qingqiao group. Compared with the blank group， the expression levels of IL-6， IL-1β and TNF-α in the BALF of the model group were significantly higher（P<0.01）. Additionally， compared with the model group， the expression levels of IL-6， IL-1β and TNF-α in the Qingqiao and Laoqiao groups were significantly lower（P<0.01）. The chemical composition analysis of Qingqiao and Laoqiao revealed that 63 components were detected in Qingqiao and 55 components were detected in Laoqiao， with 47 common components， 16 components unique to Qingqiao and 8 components unique to Laoqiao. Characterizing the differences in serum metabolomics in rats， 19 and 12 metabolites were called back by Qingqiao and Laoqiao， respectively. The metabolic pathway enrichment analysis showed that Qingqiao exerted its therapeutic effects by affecting 6 key metabolic pathways， including linoleic acid metabolism， phenylalanine metabolism， phenylalanine， tyrosine and tryptophan biosynthesis， glycerophospholipid metabolism， α-linolenic acid metabolism， and arachidonic acid metabolism， and Laoqiao exerted therapeutic effects by affecting 6 key metabolic pathways， including linoleic acid metabolism， arachidonic acid metabolism， sphingolipid metabolism， phenylalanine metabolism， ascorbate and aldarate metabolism， and glycerophospholipid metabolism. ConclusionQingqiao and Laoqiao have therapeutic effects on ALI， and Qingqiao is more effective. Both of them can play a therapeutic role in ALI by regulating amino acid metabolism and lipid metabolism， but the metabolic pathways affected by them are different.

Objective The occurrence of chickenpox in rapidly developing areas poses substantial seasonal risk to children.However,certain factors influencing local chickenpox outbreaks have not been studied.Here,we examined the relationship between spatial clustering,heterogeneity of chickenpox outbreaks,and socioeconomic factors in Southern China. Methods We assessed chickenpox outbreak data from Southern China between 2006 and 2021,comprising both relatively fast-growing parts and slower sub-regions,and provides a representative sample of many developing regions.We analyzed the spatial clustering attributes associated with chickenpox outbreaks using Moran's I and local indicators of spatial association and quantified their socioeconomic determinants using Geodetector q statistics. Results There were significant spatial heterogeneity in the risk of chickenpox outbreaks,with strong correlations between chickenpox risk and various factors,particularly demographics and living environment.Furthermore,interactive effects among specific are factors,such as population density and per capita residential building area,percentage of households with toilets,percentage of rental housing,exhibited q statistics of 0.28,0.25,and 0.24,respectively. Conclusion This study provides valuable insights into the spatial dynamics of chickenpox outbreaks in rapidly developing regions,revealing the socioeconomic factors affecting disease transmission.These implications extend the formulation of effective public health strategies and interventions to prevent and control chickenpox outbreaks in similar global contexts.

Objective We aimed to observe the effect of the traditional Chinese medicine(TCM)-based"tertiary hospital-community integrated"treatment program in patients with diabetic kidney disease.Methods A total of 126 patients from the Jiangtai and Cuigezhuang Communities in Chaoyang District were randomly divided into the experimental group and the control group(n=63 patients per group).In the experimental group,the"tertiary hospital-community integrated"treatment program was implemented(including TCM differentiated health preservation,chronic disease management,comprehensive diagnosis and treatment program of integrated Chinese and Western medicine),while in the control group,the existing chronic disease diagnosis,treatment,and management program in the community was implemented(including chronic disease management with regular follow-ups,diagnosis and treatment program of Western medicine).The observation period was 6 months,with 3 months as a course of treatment.The 24 h urine total protein level(24 hUTP),the serum level of creatinine(Scr),and the estimated glomerular filtration rate(eGFR)were compared between the two groups,as well as the effective rates of 24 hUTP,Scr,and eGFR,the rate of achieving standard glucose levels and normal lipid metabolism,including low-density lipoprotein-cholesterol(LDL-C),triglyceride(TG),and glycosylated hemoglobin(GHB),the level of patients'self-management,and the medical service in utilization.Results There were 120 patients included for analysis(60 in the experimental group and 60 in the control group).The difference in 24 hUTP was significantly different(P＜0.05),while Scr and eGFR were not statistically different between the experimental and control groups after 3 months of treatment.The differences in 24 hUTP,Scr,and eGFR were statistically significant after 6 months(P＜0.05).After 6 months of treatment in both groups,the effective rates of 24 hUTP,Scr,and eGFR were higher in the experimental group than in the control group(78.3％,48.3％,and 50.0％in the experimental group and 35.0％,18.3％,and 15.0％in the control group,respectively)(P＜0.05);after 6 months,the LDL-C,TG,and GHB qualified rates were higher in the experimental group than in the control group(75.0％,83.3％,and 71.7％in the experimental group and 56.7％,63.3％,and 46.7％in the control group,respectively;P＜0.05);comparing the self-management levels of the two groups after 3 and 6 months of treatment,the total self-management score and the total self-efficacy score were both higher in the experimental group than in the control group(P＜0.05);comparing the time of hospitalization and hospitalization costs of the two groups 6 months after enrollment,the time of hospitalization and hospitalization costs were lower in the experimental group(P＜0.05).Conclusion The"tertiary hospital-community integrated"TCM-based treatment program improves renal function,glucose and lipid metabolism,and patients'self-management;it can reduce the economic burden of families,save medical resources,and improve the utilization of medical services.