Objective To investigate the potential therapeutic effects,targets,and pathways of wogonoside in hypertension-induced renal injury using the Gene Expression Omnibus(GEO)database and network pharmacology,and to validate the effects of wogonoside intervention on the renal tissues of spontaneously hypertensive rats(SHR),angiotensin Ⅱ(Ang Ⅱ)-stimulated NRK-52E cell apoptosis,and the regulation of relevant pathways through in vivo and in vitro experiments.Methods GEO dataset and network pharmacology analyses were performed to investigate the key therapeutic targets of wogonoside for hypertensive nephropathy.The STRING database was used to analyze protein-protein interactions.Biological functions were annotated via Gene Ontology(GO),and the potential signaling pathways were enriched using the Kyoto Encyclopedia of Genes and Genomes(KEGG).SHR were randomly divided into groups and given low,medium,or high doses of wogonoside(0.075,0.75,and 7.5 mg/kg)via gastric gavage for 10 weeks.Morphological changes in the kidney tissue were assessed by hematoxylin-eosin(HE)staining.Serum levels of inflammatory cytokines,including tumor necrosis factor α(TNF-α),interleukin(IL)-1 β,and IL-6,were measured using ELISA.Apoptosis rates were evaluated by TUNEL staining,and Western blot was performed to determine the expression of Bax,Bcl-2,cleaved caspase-3,and caspase-3,and the expression of phosphorylated and total extracellular signal-regulated kinases(ERK)and p38 mitogen-activated protein kinase(MAPK)proteins.An in vitro model of Ang Ⅱ-stimulated NRK-52E cells was constructed and was treated with wogonoside at different concentrations(25,50,or 100 μmol/L)for 24 h.The apoptosis rates were then assessed by Annexin V staining,and Western blot was performed to validate the expression of apoptosis-related and pathway-associated proteins.Results Analysis of dataset GSE41453 revealed 11673 upregulated and 5902 downregulated genes in the renal tissues of SHR compared to the Wistar Kyoto(WKY)rats,or the WKY control group.Through the analysis of multiple databases,371 potential targets of wogonoside were identified,resulting in 98 overlapping targets.From these,45 core therapeutic targets were identified through further analysis,including TNF,CASP3,etc.GO analysis significantly enriched processes such as the negative regulation of apoptosis.KEGG pathway enrichment analysis highlighted the apoptosis pathway,IL-17 signaling pathway,and MAPK signaling pathway as being significantly enriched.Wogonoside treatment effectively mitigated pathological damage in SHR kidney tissues and significantly inhibited the expression of inflammatory cytokines,including TNF-α,IL-1 β,and IL-6(P＜0.05).It also decreased cell apoptosis rates in SHR kidney tissues and Ang Ⅱ-stimulated NRK-52E cells,downregulated the expression of Bax and cleaved caspase-3,and upregulated Bcl-2 expression(P＜0.05).Furthermore,wogonoside treatment inhibited the phosphorylation of ERK and p38 MAPK in SHR kidney tissues and Ang Ⅱ-stimulated NRK-52E cells(P＜0.05).Conclusion Wogonoside may exert its protective effects against hypertension-induced renal injury by suppressing the inflammatory response and cell apoptosis,potentially through the regulation of the MAPK signaling pathway.

Objective To investigate the potential therapeutic effects of trifolin on hypertension-induced renal injury,as well as the key targets and pathways involved.Methods The mRNA transcriptional profiles of peripheral blood clinical samples from hypertensive patients were analyzed using Gene Expression Omnibus(GEO),a high-throughput gene expression database.The network pharmacology method was employed to screen key targets of trifolin in treating hypertension-induced renal injury.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were conducted.NRK-52E cells,a rat renal proximal tubular cell line,were used to construct an angiotensin Ⅱ(Ang Ⅱ)-stimulated cell model.Flow cytometry was performed to assess cell apoptosis rates and Western blotting was performed to determine the expression levels of apoptosis-related proteins,including Bax,Bcl-2,cleaved caspase-3,and caspase-3,and the phosphorylation and total protein levels of the key MAPK pathway proteins,including ERK,p38 MAPK,and JNK.Results Analysis of the dataset GSE75360 revealed that,compared with healthy controls,3 331 genes were upregulated and 3 197 genes were downregulated in peripheral blood mononuclear cells of hypertensive patients.According to network pharmacology analysis,472 potential targets of trifolin were identified,including CASP3 and MAPK1.Protein-protein interaction network analysis showed that these targets were closely associated with apoptosis regulatory signaling pathways.GO and KEGG pathway enrichment analyses indicated that trifolin was significantly enriched in pathways associated with negative regulation of apoptosis,apoptotic signaling pathways,and the MAPK signaling pathway.The in vitro experiments confirmed that,compared with the Ang Ⅱ group,trifolin intervention inhibited apoptosis in Ang Ⅱ-stimulated NRK-52E cells,suppressed the expression of Bax and cleaved caspase-3,promoted Bcl-2 expression,and inhibited the phosphorylation of p38 MAPK,ERK,and JNK(P<0.05).Conclusion Trifolin may exert its protective effect against hypertension-induced renal injury by inhibiting Ang Ⅱ-induced NRK-52E cell apoptosis and regulating the MAPK signaling pathway,representing an important mechanism underlying its therapeutic action.

BACKGROUND: Spicy food consumption has been reported to be inversely associated with mortality from multiple diseases. However, the effect of spicy food intake on the incidence of vascular diseases in the Chinese population remains unclear. This study was conducted to explore this association. METHODS: This study was performed using the large-scale China Kadoorie Biobank (CKB) prospective cohort of 486,335 participants. The primary outcomes were vascular disease, ischemic heart disease (IHD), major coronary events (MCEs), cerebrovascular disease, stroke, and non-stroke cerebrovascular disease. A Cox proportional hazards regression model was used to assess the association between spicy food consumption and incident vascular diseases. Subgroup analysis was also performed to evaluate the heterogeneity of the association between spicy food consumption and the risk of vascular disease stratified by several basic characteristics. In addition, the joint effects of spicy food consumption and the healthy lifestyle score on the risk of vascular disease were also evaluated, and sensitivity analyses were performed to assess the reliability of the association results. RESULTS: During a median follow-up time of 12.1 years, a total of 136,125 patients with vascular disease, 46,689 patients with IHD, 10,097 patients with MCEs, 80,114 patients with cerebrovascular disease, 56,726 patients with stroke, and 40,098 patients with non-stroke cerebrovascular disease were identified. Participants who consumed spicy food 1-2 days/week (hazard ratio [HR] = 0.95, 95% confidence interval [95% CI] = [0.93, 0.97], P <0.001), 3-5 days/week (HR = 0.96, 95% CI = [0.94, 0.99], P = 0.003), and 6-7 days/week (HR = 0.97, 95% CI = [0.95, 0.99], P = 0.002) had a significantly lower risk of vascular disease than those who consumed spicy food less than once a week ( Ptrend <0.001), especially in those who were younger and living in rural areas. Notably, the disease-based subgroup analysis indicated that the inverse associations remained in IHD ( Ptrend = 0.011) and MCEs ( Ptrend = 0.002) risk. Intriguingly, there was an interaction effect between spicy food consumption and the healthy lifestyle score on the risk of IHD ( Pinteraction = 0.037). CONCLUSIONS Our findings support an inverse association between spicy food consumption and vascular disease in the Chinese population, which may provide additional dietary guidance for the prevention of vascular diseases.
Humans ; Male ; Female ; Prospective Studies ; Middle Aged ; Aged ; Vascular Diseases/etiology* ; Risk Factors ; China/epidemiology* ; Adult ; Proportional Hazards Models ; Cerebrovascular Disorders/epidemiology* ; East Asian People

Liposomes serve as critical carriers for drugs and vaccines, with their biological effects influenced by their size. The microfluidic method, renowned for its precise control, reproducibility, and scalability, has been widely employed for liposome preparation. Although some studies have explored factors affecting liposomal size in microfluidic processes, most focus on small-sized liposomes, predominantly through experimental data analysis. However, the production of larger liposomes, which are equally significant, remains underexplored. In this work, we thoroughly investigate multiple variables influencing liposome size during microfluidic preparation and develop a machine learning (ML) model capable of accurately predicting liposomal size. Experimental validation was conducted using a staggered herringbone micromixer (SHM) chip. Our findings reveal that most investigated variables significantly influence liposomal size, often interrelating in complex ways. We evaluated the predictive performance of several widely-used ML algorithms, including ensemble methods, through cross-validation (CV) for both liposome size and polydispersity index (PDI). A standalone dataset was experimentally validated to assess the accuracy of the ML predictions, with results indicating that ensemble algorithms provided the most reliable predictions. Specifically, gradient boosting was selected for size prediction, while random forest was employed for PDI prediction. We successfully produced uniform large (600 nm) and small (100 nm) liposomes using the optimised experimental conditions derived from the ML models. In conclusion, this study presents a robust methodology that enables precise control over liposome size distribution, offering valuable insights for medicinal research applications.

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

The engineering application of microbially induced carbonate precipitation(MICP)is limited by pH-dependent conformational dynamics of urease.Focusing on the α-subunit urease from Sporosarcina pasteurii,this study integrated conductivity experiments and constant-pH molecular dynamics simulations to analyze active site conformational dynamics and catalytic function across pH 3-11.Results showed that under neutral conditions(pH 7-8),key histidine residues(HIS139/HIS249)exhibited minimal dis-placement(＜0.5 ?),the longest hydrogen bond lifetime(＞8 ps),highest conformational stability(root mean square deviation,RMSD:0.15-0.18 nm),and optimal catalytic activity(conductivity change rate:0.03 mS/cm·min-1,CaCO3 precipitation:3.84 g).Extreme pH(pH 3/11)induced structural collapse(displacement up to 1.8 ?)and complete activity loss.Simulations revealed that neutral pH sta-bilizes a protonation-dependent cooperative allosteric network by maintaining active site cavity volume(～120 ?3)and moderate conformational coherence(correlation coefficient～0.8).This work deciphers the molecular mechanism of pH-regulated urease dynamics through protonation states,providing theoreti-cal support for MICP applications in acidic mine tailing remediation and alkaline soil stabilization.

Aim To explore the mechanism of the syn-ergistic effect of the ferroptosis inducer erastin com-bined with shikonin in promoting ferroptosis in human hypertrophic scar fibroblasts(HSFBs).Methods Hypertrophic scar tissues provided by the General Hos-pital of Ningxia Medical University were collected,and HSFBs were extracted.HSFBs were identified by HE staining and immunofluorescence.The inhibitory rates of Era and SHK on HSFBs at different concentrations were detected by CCK-8 assay,and the IC50 value was calculated.CompuSyn software was used to calculate the co-use index(CI).Control group,Erastin(Era)group,shikonin(SHK)group and Era+SHK group were set up,and the number and morphological chan-ges of cells were observed after 24 hours of interven-tion.The ability of cell migration and invasion was de-tected by scratch test and Transwell test.The changes of malondialdehyde(MDA),total iron ion and reactive oxygen species(ROS)were detected by corresponding biochemical kits.The expressions of collagen I,α-SMA and GOT1,SLC7A11,GPX4 and FTH1 were detected by Western blot.Results The IC50 value of Era and SHK of primary HSFBs was 2.22 μmol·L-1 and 3.94μmol·L-1 respectively,which was used as the single drug concentration for subsequent experiments.The CompuSyn software was employed to calculate the CI value when the two drugs were used in combination,and the concentrations corresponding to CI=0.39597(Era:1.2 μmol·L-1+SHK:1.5 μmol·L-1)were selected as subsequent combination concentrations(Because when CI was equal to 0.395 97,the concen-tration of each drug was lower than the concentration of single drug,and the inhibition rate of combined drug was greater than 50％).Compared with the monother-apy group,the number of HSFBs in the SHK+Era group was significantly reduced,cell membrane showed breakage and vesiculation,cell wrinkling became smal-ler,and cytoplasm was concentrated.The migration and invasion ability of HSFBs in the SHK+Era group were obviously weakened(P＜0.05),and the expres-sion of fibrosis-related proteins collagen Ⅰ and α-SMA was reduced(P＜0.05);the contents of MDA,total i-ron ions,and ROS in HSFBs of the SHK+Era group increased(P＜0.05),and the protein expression lev-els of SLC7A11,GOT1,GPX4,and FTH1 further de-creased(P＜0.05).Conclusions Erastin in combi-nation with shikonin can synergistically inhibit the pro-liferation,migration and fibrosis levels of HSFBs.The mechanism may be that erastin enhances the inhibition of shikotin on GOT1,increases the levels of cellular i-ron ions,ROS,and lipid peroxides,thereby promoting ferroptosis in HSFBs.

Liposomes serve as critical carriers for drugs and vaccines,with their biological effects influenced by their size.The microfluidic method,renowned for its precise control,reproducibility,and scalability,has been widely employed for liposome preparation.Although some studies have explored factors affecting liposomal size in microfluidic processes,most focus on small-sized liposomes,predominantly through experimental data analysis.However,the production of larger liposomes,which are equally significant,remains underexplored.In this work,we thoroughly investigate multiple variables influencing liposome size during microfluidic preparation and develop a machine learning(ML)model capable of accurately predicting liposomal size.Experimental validation was conducted using a staggered herringbone micromixer(SHM)chip.Our findings reveal that most investigated variables significantly influence liposomal size,often interrelating in complex ways.We evaluated the predictive performance of several widely-used ML algorithms,including ensemble methods,through cross-validation(CV)for both lipo-some size and polydispersity index(PDI).A standalone dataset was experimentally validated to assess the accuracy of the ML predictions,with results indicating that ensemble algorithms provided the most reliable predictions.Specifically,gradient boosting was selected for size prediction,while random forest was employed for PDI prediction.We successfully produced uniform large(600 nm)and small(100 nm)liposomes using the optimised experimental conditions derived from the ML models.In conclusion,this study presents a robust methodology that enables precise control over liposome size distribution,of-fering valuable insights for medicinal research applications.

Objective To propose a low-dose CT image denoising method based on an improved Corediff model to recover the detailed features of the image and enhance the image quality.Methods An RS-Corediff model was established by modifying the key component U-Net network of the Corediff model.Firstly,the residual module was introduced in the network input stage for feature extraction;secondly,a new downsampling module was designed in the U-Net network encoder,which learned the semantic information of the feature map by convolution and maintained the learning state during the downsampling process so as to fully extract the image features;thirdly,the feature splicing processing was used to further enhance the learning effect during the upsampling process of the U-Net network decoder;finally,the convolutional kernel size was modified to adjust the sensory field during the convolutional process of the whole U-Net network structure so as to obtain rich features.The RS-Corediff model was compared with the residual encoder-decoder convolutional neural network(RED-CNN)model and the Corediff model on the public dataset AAPM 2016 in order to verify its effectiveness for low-dose CT image denoising.Results The RS-Corediff model gained advantages over the RED-CNN and Corediff models with a peak signal-to-noise ratio(PSNR)of 41.269 8,structural similarity(SSIM)of 0.953 4 and root mean square error(RMSE)of 17.568 7.Conclusion The proposed method effectively preserves the texture and details of low-dose CT images during the denoising process to improve the overall quality of the images.[Chinese Medical Equipment Journal,2025,46(5):9-13]

This study aimed to explore the mechanisms and molecular targets of total flavones of Abelmoschus manihot(TFA) plus empagliflozin(EM) in attenuating diabetic tubulopathy(DT) by targeting mitochondrial homeostasis and pyroptosis-apoptosis-necroptosis(PANoptosis). In the in vivo study, the authors established the DT rat models through a combination of uninephrectomy, administration of streptozotocin via intraperitoneal injections, and exposure to a high-fat diet. Following modeling successfully, the DT rat models received either TFA, EM, TFA+EM, or saline(as a vehicle) by gavage for eight weeks, respectively. In the in vitro study, the authors subjected the NRK52E cells with or without knock-down Z-DNA binding protein 1(ZBP1) to a high-glucose(HG) environment and various treatments including TFA, EM, and TFA+EM. In the in vivo and in vitro studies, The authors investigated the relative characteristics of renal tubular injury and renal tubular epithelial cells damage induced by reactive oxygen species(ROS), analyzed the relative characteristics of renal tubular PANoptosis and ZBP1-mediatted PANoptosis in renal tubular epithelial cells, and compared the relative characteristics of the protein expression levels of marked molecules of mitochondrial fission in the kidneys and mitochondrial homeostasis in renal tubular epithelial cells, respectively. Furthermore, in the network pharmacology study, the authors predicted and screened targets of TFA and EM using HERB and SwissTargetPrediction databases; The screened chemical constituents and targets of TFA and EM were constructed the relative network using Cytoscape 3.7.2 network graphics software; The relative targets of DT were integrated using OMIM and GeneCards databases; The intersecting targets of TFA, EM, and DT were enriched and analyzed signaling pathways by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG) software using DAVID database. In vivo study results showed that TFA+EM could improve renal tubular injury, the protein expression levels and characteristics of key signaling molecules in PANoptosis pathway in the kidneys, and the protein expression levels of marked molecules of mitochondrial fission in the kidneys. And that, the ameliorative effects in vivo of TFA+EM were both superior to TFA or EM. Network pharmacology study results showed that TFA+EM treated DT by regulating the PANoptosis signaling pathway. In vitro study results showed that TFA+EM could improve ROS-induced cell injury, ZBP1-mediatted PANoptosis, and mitochondrial homeostasis in renal tubular epithelial cells under a state of HG, including the protein expression levels of marked molecules of mitochondrial fission, mitochondrial ultrastructure, and membrane potential level. And that, the ameliorative effects in vitro of TFA+EM were both superior to TFA or EM. More importantly, using the NRK52E cells with knock-down ZBP1, the authors found that, indeed, ZBP1 was mediated PANoptosis in renal tubular epithelial cells as an upstream factor. In addition, TFA+EM could regulate the protein expression levels of marked signaling molecules of PANoptosis by targeting ZBP1. In summary, this study clarified that TFA+EM, different from TFA or EM, could attenuate DT with multiple targets by ameliorating mitochondrial homeostasis and inhibiting ZBP1-mediated PANoptosis. These findings provide the clear pharmacological evidence for the clinical treatment of DT with a novel strategy of TFA+EM, which is named "coordinated traditional Chinese and western medicine".
Animals ; Rats ; Mitochondria/metabolism* ; Benzhydryl Compounds/administration & dosage* ; Glucosides/administration & dosage* ; Abelmoschus/chemistry* ; Male ; Homeostasis/drug effects* ; Flavones/administration & dosage* ; Rats, Sprague-Dawley ; Diabetic Nephropathies/physiopathology* ; Drugs, Chinese Herbal/administration & dosage* ; DNA-Binding Proteins/genetics* ; Humans ; Apoptosis/drug effects*