ObjectiveTo explore the mechanism by which Sini San （SNS） inhibits ferroptosis， alleviates inflammation and myocardial injury， and improves myocardial infarction （MI）. MethodsThe active ingredients of SNS were obtained by searching the Traditional Chinese Medicine System Pharmacology Platform （TCMSP） database， its target sites were predicted using the SwissTargetPrediction Database， and the core components were screened out using the CytoNCA plug-in. The targets of MI and ferroptosis were obtained by using GeneCards， Online Mendelian Inheritance in Man （OMIM） database， DrugBank， Therapeutic Target Database （TTD）， FerrDb database and literature review， respectively. The intersection of these targets of SNS-MI-ferroptosis was plotted as a Venn diagram. The protein-protein interaction （PPI） network was constructed using the STRING database， and the visualization graph was prepared using Cytoscape. The core targets were screened out using the CytoNCA plug-in， and the biological functions were clustered by the MCODE plug-in. Gene Ontology （GO） functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis were performed using the David database. Molecular docking was performed using AutoDock and visualized with PyMOL2.5.2. The Kunming mice were randomly divided into the control group， the model group， the SNS group， and the trimetazidine （TMZ） group. The mice were subcutaneously injected with isoprenaline （ISO， 5 mg·kg^-1·d^-1） to establish an MI model. The drug was continuously intervened for 7 days. The ST-segment changes were recorded by electrocardiogram （ECG）， and the tissue morphology changes were observed by hematoxylin-eosin （HE） staining. Cardiomyocyte ferroptosis was investigated by transmission electron microscopy. Serum creatine kinase （CK）， creatine kinase isoenzyme （CK-MB）， lactate dehydrogenase （LDH）， reduced glutathione （GSH）， and malondialdehyde （MDA） levels were detected by biochemical assay. Enzyme-linked immunosorbent assay （ELISA） was used to detect serum levels of interleukin （IL）-6 and 4-hydroxynonenal （4-HNE）. Immunohistochemical staining was employed to detect IL-6 and phosphorylated signal transducer and transcription activator 3 （p-STAT3） in cardiac tissues. Western blot was used to detect STAT3 and p-STAT3 in cardiac tissues. Real-time PCR was used to detect the levels of IL-6， IL-18， solute carrier family 7 member 11 （SLC7A11）， arachidonic acid 15-lipoxygenase （ALOX15）， and glutathione peroxidase 4 （GPx4） in cardiac tissues. ResultsA total of 121 active ingredients of SNS were obtained， and 58 potential targets of SNS in the treatment of MI by regulating ferroptosis were screened. The three protein modules with a score5 were mainly related to the inflammatory response. The GO function was mainly related to inflammation， and KEGG enrichment analysis showed that SNS mainly regulated ferroptosis- and inflammation- related signaling pathways. Molecular docking indicated that the core component had a higher binding force to the target site. Animal experiments confirmed that SNS reduced the level of p-STAT3 （P0.01）， down-regulated the expression of ALOX15 mRNA （P0.01）， up-regulated the level of serum GSH， and the expressions of SLC7A11 and GPx4 mRNA， reduced MDA and 4-HNE levels （P0.05， P0.01）. Additionally， SNS improved the mitochondrial injury induced by cardiomyocyte ferroptosis， reduced the area of MI， alleviated inflammation and myocardial injury， lowered the levels of serum CK， CK-MB， LDH， IL-6， and the mRNA expression levels of IL-16 and IL-18 （P0.05）， and improved ST segment elevation. ConclusionSNS can reduce ISO-induced STAT3 phosphorylation levels， inhibit ferroptosis in cardiomyocytes， alleviate inflammation and myocardial injury， thereby improving MI.

ObjectiveTo explore the mechanism by which Sini San （SNS） inhibits ferroptosis， alleviates inflammation and myocardial injury， and improves myocardial infarction （MI）. MethodsThe active ingredients of SNS were obtained by searching the Traditional Chinese Medicine System Pharmacology Platform （TCMSP） database， its target sites were predicted using the SwissTargetPrediction Database， and the core components were screened out using the CytoNCA plug-in. The targets of MI and ferroptosis were obtained by using GeneCards， Online Mendelian Inheritance in Man （OMIM） database， DrugBank， Therapeutic Target Database （TTD）， FerrDb database and literature review， respectively. The intersection of these targets of SNS-MI-ferroptosis was plotted as a Venn diagram. The protein-protein interaction （PPI） network was constructed using the STRING database， and the visualization graph was prepared using Cytoscape. The core targets were screened out using the CytoNCA plug-in， and the biological functions were clustered by the MCODE plug-in. Gene Ontology （GO） functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis were performed using the David database. Molecular docking was performed using AutoDock and visualized with PyMOL2.5.2. The Kunming mice were randomly divided into the control group， the model group， the SNS group， and the trimetazidine （TMZ） group. The mice were subcutaneously injected with isoprenaline （ISO， 5 mg·kg^-1·d^-1） to establish an MI model. The drug was continuously intervened for 7 days. The ST-segment changes were recorded by electrocardiogram （ECG）， and the tissue morphology changes were observed by hematoxylin-eosin （HE） staining. Cardiomyocyte ferroptosis was investigated by transmission electron microscopy. Serum creatine kinase （CK）， creatine kinase isoenzyme （CK-MB）， lactate dehydrogenase （LDH）， reduced glutathione （GSH）， and malondialdehyde （MDA） levels were detected by biochemical assay. Enzyme-linked immunosorbent assay （ELISA） was used to detect serum levels of interleukin （IL）-6 and 4-hydroxynonenal （4-HNE）. Immunohistochemical staining was employed to detect IL-6 and phosphorylated signal transducer and transcription activator 3 （p-STAT3） in cardiac tissues. Western blot was used to detect STAT3 and p-STAT3 in cardiac tissues. Real-time PCR was used to detect the levels of IL-6， IL-18， solute carrier family 7 member 11 （SLC7A11）， arachidonic acid 15-lipoxygenase （ALOX15）， and glutathione peroxidase 4 （GPx4） in cardiac tissues. ResultsA total of 121 active ingredients of SNS were obtained， and 58 potential targets of SNS in the treatment of MI by regulating ferroptosis were screened. The three protein modules with a score5 were mainly related to the inflammatory response. The GO function was mainly related to inflammation， and KEGG enrichment analysis showed that SNS mainly regulated ferroptosis- and inflammation- related signaling pathways. Molecular docking indicated that the core component had a higher binding force to the target site. Animal experiments confirmed that SNS reduced the level of p-STAT3 （P0.01）， down-regulated the expression of ALOX15 mRNA （P0.01）， up-regulated the level of serum GSH， and the expressions of SLC7A11 and GPx4 mRNA， reduced MDA and 4-HNE levels （P0.05， P0.01）. Additionally， SNS improved the mitochondrial injury induced by cardiomyocyte ferroptosis， reduced the area of MI， alleviated inflammation and myocardial injury， lowered the levels of serum CK， CK-MB， LDH， IL-6， and the mRNA expression levels of IL-16 and IL-18 （P0.05）， and improved ST segment elevation. ConclusionSNS can reduce ISO-induced STAT3 phosphorylation levels， inhibit ferroptosis in cardiomyocytes， alleviate inflammation and myocardial injury， thereby improving MI.

Renal lymphatic vessel density is clinically relevant in kidney disease but is still assessed by slow, subjective visual estimation. We evaluated a weakly supervised, attention-based multiple-instance learning framework for automated detection and quantification of renal lymphatic vessel density on D2-40-stained whole-slide images (WSIs). Methods: Two independent internal datasets from Tongji Hospital were collected, including 198 cases of chronic kidney disease (CKD) and 50 cases of hypertensive nephropathy (HTN). All biopsies were immunohistochemically stained for D2-40 and digitized as WSIs. Pathologists provided only slide-level labels (D2-40 high vs. D2-40 low). Tissue regions were automatically segmented, tiled into patches, and encoded using a pretrained convolutional neural network. Patch embeddings were then analyzed with a clustering-constrained attention multiple-instance learning (CLAM) model. Unlike conventional multiple-instance learning (MIL) methods that only weight instances, CLAM jointly performs attention-based instance selection and instance-level clustering to distinguish positive from negative evidence within each slide, yielding more discriminative slide-level features and interpretable attention maps. Performance was compared with a classic MIL model trained on the same features. Results: CLAM achieved area under the receiver operating characteristic curves of 0.942 and 0.858 on the CKD and HTN datasets, respectively, outperforming classic MIL (0.866 and 0.801). Attention maps highlighted lymphatic-rich regions consistent with renal pathologists’ assessments. Conclusions: This clustering-constrained, attention-based weakly supervised framework enables fully automated, reproducible quantification of renal lymphatic vessel density from WSIs, providing renal pathologists with rapid visual and numerical support for diagnosis and risk stratification in CKD and HTN.

Inflammaging is a process of cellular dysfunction associated with chronic inflammation, which plays a significant role in the onset and progression of liver diseases. Research on its mechanisms has become a hotspot. In viral hepatitis, inflammaging primarily involve oxidative stress, cell apoptosis and necrosis, as well as gut microbiota dysbiosis. In non-alcoholic fatty liver disease, inflammaging is more complex, involving insulin resistance, fat deposition, lipid metabolism disorders, gut microbiota dysbiosis, and abnormalities in NAD⁺ metabolism. In liver tumors, inflammaging is characterized by weakening of tumor suppressive mechanisms, remodeling of the liver microenvironment, metabolic reprogramming, and enhanced immune evasion. Therapeutic strategies targeting inflammaging have been developing recently, and antioxidant therapy, metabolic disorder improvement, and immunotherapy are emerging as important interventions for liver diseases. This review focuses on the mechanisms of inflammaging in liver diseases, aiming to provide novel insights for the prevention and treatment of liver diseases.
Humans ; Liver Diseases/pathology* ; Inflammation ; Oxidative Stress ; Non-alcoholic Fatty Liver Disease ; Liver Neoplasms ; Gastrointestinal Microbiome

Over the past few decades, tumor immunotherapy has revolutionized the landscape of cancer clinical treatment. There is a flourishing development of combination strategies to improve the anti-tumor efficacy of mono-immunotherapy. However, instead of a straightforward combination of multiple therapeutics, it is more preferable to pursue a synergistic effect by designing rational combinations as well as administration strategies, which are based on a comprehensive understanding of the physiological and pathological features. In this case, the timing and spatial distribution of the combination drugs become essential factors in achieving improved therapeutic outcomes. Therefore, the concept of Sequential Drug Delivery System (SDDS) is proposed to define the spatiotemporally programmed drug delivery/release through triggers of internal conditions and/or external interventions, thus complying with the dynamic disease evolution and the human immunity. This review summarizes the recent advancements in biomaterial-based SDDSs used for spatiotemporally-tuned combination tumor immunotherapy. Furthermore, the rationales behind various engineering strategies are discussed. Finally, an overview of potential synergistic mechanisms as well as their prospects for combination immunotherapy is presented.

Asthma is a chronic inflammatory respiratory disease involving multiple cells and cellular components， characterized by recurrent episodes of wheezing， shortness of breath， chest tightness， and coughing， significantly impacting patients' quality of life. The phosphatidylinositol 3-kinase/protein kinase B（PI3K/Akt） signaling pathway， as a crucial hub in intracellular signaling， is widely involved in the regulation of cell growth， proliferation， survival， metabolism， and a series of pathophysiological processes. Its regulatory role in the pathological progression of asthma is particularly significant， specifically in promoting airway inflammation， mediating epithelial mesenchymal transition， accelerating airway remodeling， regulating cell autophagy， inducing mucus hypersecretion， and influencing immune response balance. This study analyzed potential molecular targets of the PI3K/Akt pathway， including activators such as cysteine proteinase inhibitor 1（CST1）， found in inflammatory zone 1（FIZZ1） and free fatty acid receptor 1（FFAR1）， and inhibitors such as human β-defensin-3（hBD-3）， disintegrins， metalloproteinase 33（ADAM33） and interleukin-27（IL-27）， and initially revealed the potential molecular mechanisms of traditional Chinese medicine（TCM） in asthma intervention. Based on this， the authors systematically summarized the efficacy and specific mechanisms of TCM monomers， compounds， and external treatments for asthma by regulating the PI3K/Akt signaling pathway through literature review and analysis， aiming at establishing a robust foundation for the wide application and advanced development of TCM in asthma treatment， offering innovative insights for clinical research and drug development of asthma.

Asthma is a chronic inflammatory respiratory disease involving multiple cells and cellular components， characterized by recurrent episodes of wheezing， shortness of breath， chest tightness， and coughing， significantly impacting patients' quality of life. The phosphatidylinositol 3-kinase/protein kinase B（PI3K/Akt） signaling pathway， as a crucial hub in intracellular signaling， is widely involved in the regulation of cell growth， proliferation， survival， metabolism， and a series of pathophysiological processes. Its regulatory role in the pathological progression of asthma is particularly significant， specifically in promoting airway inflammation， mediating epithelial mesenchymal transition， accelerating airway remodeling， regulating cell autophagy， inducing mucus hypersecretion， and influencing immune response balance. This study analyzed potential molecular targets of the PI3K/Akt pathway， including activators such as cysteine proteinase inhibitor 1（CST1）， found in inflammatory zone 1（FIZZ1） and free fatty acid receptor 1（FFAR1）， and inhibitors such as human β-defensin-3（hBD-3）， disintegrins， metalloproteinase 33（ADAM33） and interleukin-27（IL-27）， and initially revealed the potential molecular mechanisms of traditional Chinese medicine（TCM） in asthma intervention. Based on this， the authors systematically summarized the efficacy and specific mechanisms of TCM monomers， compounds， and external treatments for asthma by regulating the PI3K/Akt signaling pathway through literature review and analysis， aiming at establishing a robust foundation for the wide application and advanced development of TCM in asthma treatment， offering innovative insights for clinical research and drug development of asthma.

Objective To explore the impact of multi-model adaptive statistical iterative reconstruction (ASiR-V) algorithm on radiation dose and image quality in children’s ultra-low-dose chest CT examination. Methods A total of 72 children who underwent chest CT scans at Qingdao Municipal Hospital with admissions between January 2024 and January 2025 were selected as subjects and divided into two groups using a random number table. In the control group (n = 36), the tube voltage was set at 100 kVp and the conventional filtered back projection algorithm was used. In the observation group (n = 36), the tube voltage was set at 80 kVp and images were reconstructed using 30% ASiR-V (observation group 1), 60% ASiR-V (observation group 2), and 90% ASiR-V (observation group 3), respectively. Radiation doses were recorded for each group, and both subjective and objective evaluations of image quality were conducted. Results Compared with the control group, the observation group demonstrated significantly lower volume CT dose index [(0.86 ± 0.09) mGy], dose length product [(25.90 ± 3.55) mGy·cm], and effective dose [(0.01 ± 0.001) mSv] (P < 0.05). There was no significant difference in subjective evaluation scores of image quality among the four groups (z = −2.206, P = 0.530). Additionally, Fisher’s exact test showed that the proportion of images scoring 4-5 points was higher in observation group 2 than in observation group 3 (P = 0.024). The noise value of the ascending aorta in the mediastinal window and the noise values of the right and left middle lung fields and the right and left upper lung fields in the lung window were lower in observation groups 2 and 3 than in the control group, and these values were lower in observation group 3 than in observation group 2 (P < 0.05). The signal-to-noise ratios of the ascending aorta and liver in observation groups 2 and 3 were higher than those in the control group, and the ratios were higher in observation group 3 than in observation group 2 (P < 0.05). Conclusion Reconstruction using the 60% ASiR-V algorithm for pediatric ultra-low-dose chest CT examination can ensure good image quality while reducing radiation dose and improving examination safety.

Objective: To investigate the willingness to receive the pneumococcal vaccine and its influencing factors among middle-aged and elderly population in Zhejiang Province, so as to provide a basis for increasing the vaccination rate of pueumococcal among middle-aged and elderly population. Methods: From March to May 2024, a multi-stage random sampling method was employed to recruit residents aged ≥50 years from 35 counties (cities or districts) in Zhejiang Province. Data on basic information, knowledge of pneumonia, pneumococcal vaccine, and willingness to receive pneumococcal vaccine were collected through questionnaire surveys. A multivariable logistic regression model was used to analyze influencing factors for the willingness to receive pneumococcal vaccine among middle-aged and elderly population. Results: A total of 10 500 middle-aged and elderly population were surveyed. Among them, there were 5 202 males, accounting for 49.54%, and 5 298 females, accounting for 50.46%. The mean age was (65.11±9.05) years. Of the participants, 7 732 individuals were aware of pneumonia, accounting for 73.64%. A total of 1 724 individuals had received pneumococcal vaccine, corresponding to a vaccination rate of 16.42%. Furthermore, 5 138 participants expressed willingness to receive pneumococcal vaccine, with a willingness rate of 48.93%. The multivariable logistic regression analysis showed that middle-aged and elderly population aged ≥60 years (60-<70 years, OR=1.577, 95%CI: 1.433-1.736; ≥70 years, OR=2.110, 95%CI: 1.918-2.321), those with a history of chronic diseases (OR=1.250, 95%CI: 1.154-1.353), those who were recommended to receive the pneumonia vaccine by doctors (OR=4.896, 95%CI: 4.507-5.318), those who were aware of pneumonia (OR=1.460, 95%CI: 1.338-1.594), those who were aware that the elderly are prone to pneumonia (OR=1.490, 95%CI: 1.375-1.614), those who were aware of the causes of pneumonia (OR=1.559, 95%CI: 1.434-1.694), those who were aware that vaccination can prevent pneumonia (OR=2.196, 95%CI: 2.031-2.375), and those who were aware of the immunization schedule for pneumonia vaccine (OR=1.897, 95%CI: 1.683-2.124) had a higher willingness to receive pneumonia vaccine. Conclusions The willingness of middle-aged and elderly population in Zhejiang Province to receive pneumonia vaccine is related to age, history of chronic diseases, awareness of pneumonia, and awareness of pneumonia vaccine. It is recommended to strengthen health education on pneumonia and pneumonia vaccine for middle-aged and elderly population, in order to increase the willingness to receive the vaccine and vaccination rate.

Objective:To compare the efficacy and safety of crisaborole ointment 2% versus pimecrolimus cream 1% in the treatment of mild to moderate atopic dermatitis in children aged 2 years or older.Methods:A multicenter, randomized, open-label, controlled clinical trial was conducted. A total of 120 pediatric patients aged 2 - 17 years with mild to moderate atopic dermatitis were enrolled from departments of dermatology of 8 hospitals in China between March 2022 and February 2023. The participants were randomly assigned in a 1∶1 ratio to the crisaborole group and the pimecrolimus group, and received the treatment with crisaborole ointment 2% and pimecrolimus cream 1% respectively, twice a day for 4 weeks. Visits were scheduled at baseline/on day 1, as well as on days 8, 15, and 29. The primary efficacy outcome was the percentage of patients achieving the Investigator's Static Global Assessment (ISGA) success (defined as clear [0] or almost clear [1] on the ISGA scale, combined with ≥ 2‐grade improvement from baseline) on day 29. The secondary efficacy outcomes included changes in the Eczema Area and Severity Index (EASI) total scores from baseline to day 29, percentages of patients achieving ISGA improvement (defined as clear [0] or almost clear [1] on the ISGA scale), as well as changes in the Peak Pruritus Numerical Rating Scale (NRS) scores, Dermatology Life Quality Index (DLQI) /Infants' Dermatology Life Quality Index (IDLQI) /Children's Dermatology Life Quality Index (CDLQI) scores, and in the Dermatitis Family Impact (DFI) scores. Drug safety was evaluated according to the incidence of adverse events. Categorical data were compared using the chi-square test. Since measurement data did not follow a normal distribution, the rank sum test was used for comparisons of measurement data between groups.Results:A total of 106 children with mild to moderate atopic dermatitis were included in the per-protocol analysis set, with 52 in the crisaborole group (26 males and 26 females) and 54 in the pimecrolimus group (27 males and 27 females). There were no significant differences in age, disease duration, ISGA and EASI scores at baseline between the two groups (all P > 0.05). On day 29, 22 patients (42.31%) in the crisaborole group and 25 (46.30%) in the pimecrolimus group achieved ISGA success, with no significant difference between the two groups ( χ2 = 0.17, P = 0.68) ; 35 patients (67.31%) in the crisaborole group and 45 (83.33%) in the pimecrolimus group achieved ISGA improvement, also with no significant difference between the two groups ( χ2 = 3.68, P = 0.06) ; additionally, there were no significant differences in the EASI, pruritus NRS, DLQI/IDLQI/CDLQI, or DFI scores between the two groups (all P > 0.05). Adverse reactions to the two topical agents were mainly local reactions such as mild to moderate pain, itching, or worsening of itching, and no obvious systemic adverse reactions occurred. The incidence of drug-related adverse reactions was 46.15% (24 cases) in the crisaborole group and 37.04% (20 cases) in the pimecrolimus group, with no significant difference between the two groups ( χ2 = 0.91, P = 0.34) . Conclusion:The efficacy of crisaborole ointment 2% was comparable to that of pimecrolimus cream 1% in the treatment of mild to moderate atopic dermatitis in children aged ≥ 2 years, and it yielded early and rapid improvement in the quality of life of patients and their families, with good safety and tolerability profiles.