ObjectiveTo investigate whether Shixiaosan can improve neurological function and inhibit ferroptosis in rats with cerebral ischemia-reperfusion injury （CIRI） by regulating the nuclear factor E₂-related factor 2 （Nrf2）/solute carrier family 7 member 11 （SLC7A11）/glutathione peroxidase 4 （GPX4） pathway. MethodsA rat model of CIRI was established using the intraluminal filament method. Briefly， cervical blood vessels were separated， branches of the external carotid artery were ligated， and the common carotid artery and internal carotid artery were clamped. A nylon filament was inserted through the opening of the external carotid artery to the origin of the middle cerebral artery to block blood flow and induce cerebral ischemia. After 60-120 min of ischemia， the filament was withdrawn to restore blood flow， and the external carotid artery incision was ligated. The rats were divided into a CIRI group， a Shixiaosan low-dose （-L） group （intragastric administration of 1.26 g·kg^-1 Shixiaosan）， a Shixiaosan high-dose （-H） group （intragastric administration of 2.52 g·kg^-1 Shixiaosan）， a donepezil hydrochloride tablet （DON） group （intragastric administration of 0.45 mg·kg^-1 DON）， and a Shixiaosan -H + Nrf2 inhibitor （ML385） group （intragastric administration of 2.52 g·kg^-1 Shixiaosan combined with intraperitoneal injection of 30 mg·kg^-1 ML385）. An additional 12 rats underwent cervical artery separation followed by incision suturing and served as the control group. Equal volumes of double-distilled water were administered to the CIRI and control groups. Neurological function impairment was assessed using the modified Garcia JH score. Magnetic resonance imaging was used to determine the cerebral infarct volume ratio. Hematoxylin-eosin （HE） staining and Prussian blue staining were performed to observe neuronal injury and iron accumulation in the ischemic penumbra， respectively. Transmission electron microscopy was used to examine the ultrastructure of neuronal mitochondria in the ischemic penumbra. Commercial kits were used to measure ferrous iron （Fe²⁺）， malondialdehyde （MDA）， reduced glutathione （GSH） content， and reactive oxygen species （ROS） activity in the ischemic penumbra. The BODIPY （581/591） C11 fluorescent probe was used to detect intracellular lipid peroxidation levels. Western blot was performed to detect protein expression levels of Nrf2， SLC7A11， GPX4， transferrin receptor 1 （TFRC）， ferritin heavy chain （FHC）， and ferritin light chain （FLC） in the ischemic penumbra. ResultsCompared with the control group， the CIRI group exhibited neuronal injury in the ischemic penumbra， characterized by reduced neuron numbers， nucleolar shrinkage， and interstitial edema. Marked iron accumulation was observed in the tissue. Neuronal mitochondria showed atrophy and rupture， with reduced mitochondrial cristae and increased membrane density. The cerebral infarct volume ratio， Fe²⁺ content， MDA content， ROS activity， and lipid peroxidation levels were increased， whereas the modified Garcia JH score， GSH content， and protein expression levels of Nrf2， SLC7A11， GPX4， FHC， and FLC were decreased， and TFRC protein expression was increased （P<0.05）. Compared with the CIRI group， the Shixiaosan -L group， Shixiaosan -H group， and DON group showed attenuated neuronal injury in the ischemic penumbra， reduced iron accumulation， alleviated mitochondrial damage， decreased cerebral infarct volume ratio， Fe²⁺ and MDA contents， ROS activity， and lipid peroxidation levels， as well as increased modified Garcia JH scores， GSH content， and protein expression levels of Nrf2， SLC7A11， GPX4， FHC， and FLC， while TFRC protein expression was decreased （P<0.05）. The magnitude of changes in all indicators was greater in the Shixiaosan -H group than in the Shixiaosan -L group （P<0.05）. Compared with the Shixiaosan -H group， all measured indicators in the Shixiaosan -H + ML385 group showed opposite trends （P<0.05）. ConclusionShixiaosan may inhibit ferroptosis and restore neurological function in rats with CIRI by activating the Nrf2/SLC7A11/GPX4 pathway.

Acute liver injury (ALI) serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders. The prevention and treatment of ALI is still a serious global challenge. Given the limited therapeutic options for ALI, exploring novel targeted therapeutic agents becomes imperative. The potential therapeutic efficacy of inhibiting RIPK2 is highlighted, as it may provide significant benefits by attenuating the MAPK pathway and NF-κB signaling. Herein, we propose a CMD-OPT model, a two-stage molecular optimization tool for the rapid discovery of RIPK2 inhibitors with optimal properties. Compound RP20, which targets the ATP binding site, demonstrated excellent kinase specificity, ideal oral pharmacokinetics, and superior therapeutic effects in a model of APAP-induced ALI, positioning RP20 as a promising preclinical candidate. This marks the first application of RIPK2 inhibitors in ALI treatment, opening a novel therapeutic pathway for clinical applications. These results highlight the efficacy of the CMD-OPT model in producing lead compounds from known active molecules, showcasing its significant potential in drug discovery.

[Purpose]To analyze the lifetime risk of developing and dying from lung cancer at global and regional levels.[Methods]Data of lung cancer incidence and mortality were obtained from GLOBOCAN 2022 and the population and all-cause mortality data were obtained from the United Nations.The lifetime risk of developing and dying from lung cancer globally and across different regions was estimated by multiple primary adjustment method.[Results]The global lifetime risk of developing lung cancer was 3.59％[95％confidence interval(CI):3.58％～3.59％],ranking third among all cancer types.There were significant gender and regional differences in lifetime risk values.The risk for male was 4.43％(95％CI:4.42％～4.44％),which was higher than that for female(2.71％,95％CI:2.70％～2.72％),with a male-to-female ratio of 1.63.Among regions with varying human development index(HDI)levels,the risk increased with HDI levels,in very high HDI re-gions risk was 5.36％(95％CI:5.34％～5.37％),while in low HDI regions the risk was 0.34％(95％CI:0.33％～0.34％).Among the 20 global regions,East Asia had the highest lifetime risk of 7.53％(95％CI:7.52％～7.55％),while West Africa had the lowest risk of 0.16％(95％CI:0.16％～0.17％).The global lifetime risk of dying from lung cancer was 2.78％(95％CI:2.78％～2.78％),ranking the first among all cancer types.There were significant sex and regional differ-ences in lifetime death risk values.The risk for male was 3.64％(95％CI:3.63％～3.64％),which was higher than that for female(1.89％,95％CI:1.89％～1.90％),with a male-to-female ratio of 1.93.Among regions with varying HDI levels,the risk increased with HDI levels,in very high HDI re-gions the risk was 3.98％(95％CI:3.97％～3.99％),while in low HDI regions the risk was 0.31％(95％CI:0.31％～0.31％).Among the 20 global regions,the Federated States of Micronesia/Poly-nesia had the highest death risk of 5.80％(95％CI:4.98％～6.62％),while West Africa had the lowest risk of 0.15％(95％CI:0.15％～0.16％).The lifetime risk of developing and dying from lung cancer in China was 7.54％(95％CI:7.52％～7.56％)and 5.88％(95％CI:5.87％～5.90％),respec-tively,both ranking the first among all cancer types.[Conclusion]The lifetime risk of developing and dying from lung cancer remains high globally and across different regions,with a particularly heavy burden in high-HDI areas.In China,both the lifetime risk of developing and dying from lung cancer are higher than the global average.This highlights the need for continued enhance-ment of comprehensive prevention and control measures,including addressing lung cancer-related risk factors,as well as improving screening,early diagnosis,and treatment efforts to reduce the lung cancer burden.

Objective To observe the value of 18F-D3FSP PET/CT machine learning(ML)models for evaluating subjective cognitive decline(SCD).Methods Thirty-two SCD patients(SCD group)and 16 healthy volunteers(control group)who received 18F-D3FSP PET/CT were selected from Sino Longitudinal Study on Cognitive Decline(SILCODE)and divided into training set(n=34)and test set(n=14)at a ratio of 7∶3.Support vector machine(SVM),random forest(RF)and logistic regression(LR)models were constructed based on Hamilton anxiety scale(HAMA)and standard uptake value ratio(SUVR)of brain regions being significantly different between groups to evaluate SCD.Then PET/CT data were amplified by format conversion and divided into training set(including 8 775 CT images and 1 833 PET images)and test set(including 2 025 CT images and 423 PET images)at the ratio of 8∶2.VGG16 models were constructed based on CT and PET images to evaluate SCD,respectively.Results The area under the receiver operating characteristic curve(AUC)of SVM,RF and LR model for evaluating SCD in training set was all 1.000,while was 0.863,0.872 and 1.000 in test set,respectively.LR model was overfitting,and RF model had better performance.The accuracy of VGG16 model for evaluating SCD based on CT and PET images tended to be stable after the 175th and 150th iterations,with the highest accuracy of 67.11％ and 65.35％ in training set,which tended to be stable after the 165th and 145th iterations,with the highest accuracy of 62.43％ and 59.16％ in test set,respectively.Conclusion 18F-D3FSP PET/CT ML models could be used to evaluate SCD.

Objective To explore the experiences of children with Crohn's disease and their parents regarding the exclusion diet,and to provide a basis for formulating personalized dietary guidance programs.Methods A total of 12 children with Crohn's disease and their parents,hospitalized in the Department of Gastroenterology at a tertiary children's hospital in Guangzhou from June to December 2023,were selected as research subjects using objective sampling.Semi-structured interviews were conducted,and the data were analyzed and refined using Colaizzi's seven-step analysis method.Results Totally 3 themes and 14 sub-themes were extracted.①Lack of cognition and trust in Crohn's disease exclusion diet(unfamiliarity with the contents of the diet,misunderstanding of the diet's preparation,inadequate response to daily exclusion diet practices,parents' distrust in the exclusion diet).②The practical challenges of the Crohn's disease exclusion diet(the challenge of personal dietary preferences,the challenge of family meal preparation,the challenge of school feeding,food intolerance,feelings of monotony and weariness following the exclusion diet).③Innovations in practicing the Crohn's disease exclusion diet(managing taste fatigue,managing visual fatigue,innovative cooking methods,prioritizing exclusive enteral nutrition followed by the exclusion diet,overcoming the desire for universal food).Conclusion Children with Crohn's disease and their parents exhibit insufficient cognition and trust in the exclusion diet and face various challenges in practice.Clinical medical staff should adopt personalized coping strategies tailored to the specific circumstances of each child.

BACKGROUND:In previous studies,the equivalent structure of three-dimensional cell reconstruction of tissue engineering oral mucosa is similar to normal oral mucosa,including epithelial-like structure,lamina propria-like structure,and vascular lumen-like structure,and has initially achieved the establishment of vascular equivalent,but its vascularization characteristics are not very clear.OBJECTIVE:Vascular-like structures of vascularized oral mucosa equivalent were obtained by targeting vascular endothelial cells specific marker expression profiles correlated with laser capture microdissection system,and their vascularization ability was evaluated to reveal their vascularization characteristics.METHODS:Human gingival epithelial cells were cultured from human gingival epithelium and human gingival fibroblasts,human gingival mesenchymal stem cells were cultured from human gingival lamina propria.Human gingival mesenchymal stem cells were induced to differentiate into vascular endothelial-like cells after monoclonal expansion culture.Human gingival epithelial cells,human gingival fibroblasts,and vascular endothelial-like cells were loaded with acellular vascular matrix-0.25%human-like collagen type Ⅰ scaffold to construct the vascularized oral mucosa equivalent.The layered structure of oral mucosa equivalent(experimental group)and the acellular vascular matrix-0.25%human-like collagen type Ⅰ scaffold(control group)were implanted subcutaneously into the back of nude mice,respectively.14 days later,the incision surface of the two groups was coated with biogel.The biogel surface of the experimental group was inoculated with human gingival epithelial cells,while the control group was not inoculated with cells.The samples were collected after 14 days of feeding.The layered structure of oral mucosa equivalent was observed by morphology.The neovascular-like structures in oral mucosa equivalents were labeled by immunohistochemistry and immunofluorescence with a more comprehensive expression profile of vascular endothelial cells,and the vascularization characteristics were analyzed.A laser capture microdissection system was used to capture the neovascularization structures in the oral mucosa equivalents specifically labeled by immunohistochemistry and analyze their vascularization characteristics.RESULTS AND CONCLUSION:(1)The morphology showed that the cell level of oral mucosa equivalent was clear,and the structure was similar to that of normal oral mucosa,that is,there were epithelioid structures,lamina-like structures,and vascular cavelike structures,and there were scattered erythrocytes in the vascular cavelike structures.(2)The results of EdU Apollo tracer seed cells in the oral mucosa equivalent group showed that human gingival epithelial cells labeled with EdU Apollo 488 showed green fluorescence expression.DAPI labeled human gingival fibroblasts showed blue fluorescence expression and formed lamina-like structures in vivo.EdU Apollo 567 labeled vascular endothelial-like cells showed red fluorescence expression and formed a vascular-like structure in vivo.(3)Vascular endothelial cell specific marker expression profile immunofluorescence labeling of vascular structure showed that compared with normal oral mucosa,the expressions of CD31,CD51,CD54,CD105,Tie-2,VWF,vascular endothelial growth factor receptor 1,and vascular endothelial growth factor receptor 2 in oral mucosa equivalents were increased(P<0.000 1).There were no significant changes in CD34 expression(P>0.05).(4)Compared with the specifically labeled oral mucosal vascular structures,the expression levels of CD51,CD54,CD105,Tie-2,VWF,vascular endothelial growth factor receptor 1,and vascular endothelial growth factor receptor 2 of the oral mucosa equivalents targeted by the laser capture microdissection system were increased(P<0.000 1).There were no significant changes in expression of CD31 and CD34(P>0.05).(5)The results showed that the oral mucosa equivalent reconstructed by three-dimensional cell stratification could achieve good vascularization,and its vascularization characteristics were consistent with the immunological function and characteristics of neovascularization.Vascularization helps three-dimensional cell layer reconstruction of oral mucosa equivalent regeneration.

Objective To establish an optimized diagnostic model for hepatocellular carcinoma(HCC),designated as G-GADA,in chronic hepatitis B(CHB)patients based on the parameters of age,sex,alpha-fetoprotein(AFP),des-γ-carboxy prothrombin(DCP),and Golgi protein 73(GP73),to address the problems of low sensitivity and specificity in the early diagnosis of hepatitis B virus(HBV)-related liver cancer,and to assess the value of this model in the diagnosis of HCC.Methods A retrospective analysis was performed for 201 CHB patients(CHB group),137 patients with HBV-related liver cirrhosis(LC group),and 111 treatment-na?ve patients with newly diagnosed HCC(HCC group)who were admitted to Mengchao Hepatobiliary Hospital of Fujian Medical University from June 2015 to June 2020.Serological markers(AFP,DCP,alpha-fetoprotein L3%[AFP-L3%],and GP73)were compared between groups and were analyzed in terms of their differences from the clinical and tumor characteristics of HCC patients,and the Spearman correlation analysis was used to assess the correlation between different markers.A Logistic regression analysis was used to establish a diagnostic model for liver cancer,and the receiver operating characteristic(ROC)curve was used to assess the diagnostic performance of each marker.Results Comparison of clinical features between CHB,LC,and HCC patients showed that HCC patients had significantly higher age,proportion of male patients,and serum levels of DCP,AFP,GP73,and AFP-L3%(all P<0.05).In HCC patients,DCP levels are associated with tumor size and microvascular invasion;AFP levels are related to patient age,tumor size,tumor number,distant metastasis,and microvascular invasion;AFP-L3%levels are associated with patient age,tumor size,tumor number,distant metastasis,Milan staging,and microvascular invasion;GP73 levels are linked to tumor number,distant metastasis,and microvascular invasion(all P<0.05).The correlation analysis of the serum markers showed a strong positive correlation between AFP and AFP-L3%(r=0.71,P<0.05)and a moderate positive correlation between AFP and GP73(r=0.33,P<0.05)and between AFP-L3%and GP73(r=0.41,P<0.05).Based on the features of age,sex,DCP,AFP,and GP73,the multivariate Logistic regression analysis was used to establish a G-GADA diagnostic model for HCC,and for all patients,the G-GADA model had an area under the ROC curve(AUC)of 0.915(95%confidence interval[CI]:0.875-0.945)in the derivation cohort and 0.913(95%CI:0.862-0.950)in the validation cohort for the diagnosis of HCC.In the AFP-negative patients,the G-GADA model achieved an AUC of 0.884(95%CI:0.833-0.924)in the derivation cohort and 0.851(95%CI:0.779-0.907)in the validation cohort,and in the patients with liver cirrhosis,the G-GADA model achieved an AUC of 0.901(95%CI:0.841-0.944)in the derivation cohort and 0.885(95%CI:0.806-0.940)in the validation cohort.Conclusion The G-GADA diagnostic model based on multiple variables significantly improves the detection rate of HCC,and demonstrates superior diagnostic performance in patients with low AFP expression and those with liver cirrhosis.The G-GADA model has a better clinical application value in the noninvasive diagnosis of HCC.

Hereditary breast cancer(HBC)is one of the important subtypes of breast cancer(BC),primarily characterized by mutations in the BRCA1/2 genes.Accurate identification of BRCA1/2 mutation carriers remains a significant clinical challenge.Traditional genetic testing methods for BRCA1/2 mutations are often expensive and complex.In recent years,advancements in radiomics and artificial intelligence(AI)have opened new avenues for non-invasive prediction of BRCA1/2 mutations.This review summarized the current research progresses in utilizing radiomics and AI for screening and predicting of BRCA1/2-related HBC.

Andrographolide sulfonate (AS) is a sulfonated derivative of andrographolide extracted from Andrographis paniculata (Burm.f.) Nees, and has been approved for several decades in China. The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis. Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling, improved body weights, and attenuated pathological changes in joints of rats with adjuvant-induced arthritis. Additionally, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β in the serum and ankle joints were reduced. Bioinformatics analysis, along with the spleen index and measurements of IL-17 and IL-10 levels, suggested a potential relationship between AS and Th17 cells under arthritic conditions. In vitro, AS was shown to block Th17 cell differentiation, as evidenced by the reduced percentages of CD4⁺ IL-17A⁺ T cells and decreased expression levels of RORγt, IL-17A, IL-17F, IL-21, and IL-22, without affecting the cell viability and apoptosis. This effect was attributed to the limited glycolysis, as indicated by metabolomics analysis, reduced glucose uptake, and pH measurements. Further investigation revealed that AS might bind to hexokinase2 (HK2) to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or pyruvate kinase M2 (PKM2), and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation. Furthermore, AS impaired the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signals in vivo and in vitro, which was abolished by the addition of lactate. In conclusion, AS significantly improved adjuvant-induced arthritis (AIA) in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.
Animals ; Th17 Cells/immunology* ; Diterpenes/pharmacology* ; Arthritis, Rheumatoid/metabolism* ; Proto-Oncogene Proteins c-akt/immunology* ; Glycolysis/drug effects* ; Cell Differentiation/drug effects* ; Phosphatidylinositol 3-Kinases/genetics* ; Rats ; Male ; Rats, Sprague-Dawley ; Humans ; Andrographis paniculata/chemistry* ; Arthritis, Experimental/drug therapy* ; Interleukin-17/immunology* ; Signal Transduction/drug effects*

Breast milk is the optimal natural food for newborns. However， some newborns cannot receive maternal breast milk due to reasons such as mother-infant separation or insufficient lactation. The establishment of human milk banks （HMB） can effectively address these issues， thereby increasing the breastfeeding rate among hospitalized newborns and improving their quality of survival. However， HMB in China is still in the development and improvement stage. Its implementation involves a series of ethical issues， such as informed consent， privacy protection， economic incentives， quality and safety， and fair resource distribution， which hinder HMB’s widespread promotion. Therefore， discussing the ethical dilemmas faced by the widespread establishment of HMB in China’s hospitals and analyzing coping strategies are crucial for improving the breastfeeding rate of newborns. This paper deeply analyzed and sorted out the ethical issues and challenges currently faced by HMB in China， and proposed corresponding strategies， including “ensuring informed consent and voluntary participation of both donors and recipients，” “protecting the privacy of donors and recipients，” “establishing an ethics-based moral incentive and social support system，” “strictly controlling quality and safety issues”， and “developing fair and rational policies，” aiming to provide a reference solution for addressing ethical concerns in the establishment and operation of HMB.