BACKGROUND: The American Heart Association (AHA) introduced the concept of cardiovascular-kidney-metabolic (CKM) health and stage, reflecting the interaction among metabolism, chronic kidney disease (CKD), and the cardiovascular system. However, the association between CKM stage and the long-term risk of cardiovascular disease (CVD) has not been validated. This study aimed to evaluate the long-term CVD risk associated with CKM health metrics and CKM stage using data from a population-based cohort study. METHODS: In total, 5293 CVD-free participants were followed up to around 13 years in the Chinese Multi-provincial Cohort Study (CMCS). Considering the pathophysiologic progression of CKM health metrics abnormalities (comprising obesity, central adiposity, prediabetes, diabetes, hypertriglyceridemia, CKD, and metabolic syndrome), participants were divided into CKM stages 0, 1, and 2. The time-dependent Cox regression models were used to estimate the cardiovascular risk associated with CKM health metrics and stage. Additionally, broader CVD outcomes were examined, with a specific assessment of the impact of stage 3 in 2581 participants from the CMCS-Beijing subcohort. RESULTS: Among participants, 91.2% (4825/5293) had at least one abnormal CKM health metric, 8.8% (468/5293), 13.3% (704/5293), and 77.9% (4121/5293) were in CKM stages 0, 1, and 2, respectively; and 710 incident CVD cases occurred during a median follow-up time of 13.3 years (interquartile range: 12.1 to 13.6 years). Participants with each poor CKM health metric exhibited significantly higher CVD risk. Compared with stage 0, the hazard ratio (HR) (95% confidence interval [CI]) for CVD incidence was 1.31 (0.84-2.04) in stage 1 and 2.27 (1.57-3.28) in stage 2. Significant interactive impacts existed between CKM stage and age or sex, with higher CVD risk related to increased CKM stages in participants aged <60 years or females. CONCLUSION These findings highlight the contribution of CKM health metrics and CKM stage to the long-term risk of CVD, suggesting the importance of multi-component recognition and management of poor CKM health in CVD prevention.
Humans ; Female ; Male ; Cardiovascular Diseases/etiology* ; Middle Aged ; Adult ; Cohort Studies ; Renal Insufficiency, Chronic/metabolism* ; Aged ; Risk Factors ; Metabolic Syndrome/metabolism* ; China ; East Asian People

ObjectiveTo investigate the prevalence and associated factors of malocclusion among preschool children in Fengxian District, Shanghai, and to provide a scientific basis for local medical and public health departments to formulate targeted interventions. MethodsA cross-sectional study was conducted from September to December 2024. A total of 1 172 children aged 3‒5 years were recruited from 10 kindergartens across 5 townships in Fengxian District, using stratified cluster random sampling method. Clinical examinations were conducted to record occlusal parameters such as the relationship of the second deciduous molars, canine teeth relationship, anterior overbite and overjet, anterior and posterior crossbite, and crowded dentition. A questionnaire survey was performed to the parents to collect information on factors influencing malocclusion, including genetic predisposition, poor oral habits, dietary patterns, and sleep-related breathing conditions. Data were statistically analyzed using IBM SPSS Statistics 27 software, with chi-square test for categorical data and binary logistic regression analysis for influencing factors. ResultsThe overall prevalence of malocclusion among 3‒5-year-old children in Fengxian District of Shanghai was 70.73%, with no statistically significant differences between genders (P>0.05). Deep overbite accounted for the highest proportion (49.66%), followed by Angle Class Ⅱ malocclusion of the second deciduous molars (17.83% on the left, 19.11% on the right), midline deviation (13.23%), anterior crossbite (6.74%), and crowding of the maxillary and mandibular anterior teeth (16.38% for the maxillary dentition, 17.58% for the mandibular dentition). Multivariate analyses showed that habitual mouth breathing during the day (OR=0.509, P=0.009) and morning dry mouth upon waking (OR=1.455, P=0.023) were independent influencing factors for malocclusion. ConclusionThe prevalence of malocclusion is relatively high among preschool children in Fengxian District, Shanghai,with deep overbite being the dominant trait. Sleep-related breathing conditions (such as habitual mouth breathing during the day and morning dry mouth) is an important influencing factor for malocclusion. Public health authorities should strengthen oral health education and promote the correction of bad habits to reduce the prevalence of malocclusion and improve children’s oral health.

Objective:To detect the pharmacokinetic(PK)parameters of coagulation factor Ⅷ(FⅧ)in adult patients with severe hemophilia A,identify the potential factors influencing FⅧ PK,and optimize the use of FⅧ in individual prophylaxis regimens.Methods:PK characteristics of FⅧ were studied in a total of 23 severe hemophilia A adults.The correlation of patients'characteristics including age,von Willebrand factor antigen(vWF:Ag),blood group,weight,body mass index(BMI)and FⅧ genotype,with FⅧ PK were evaluated.Individual prophylaxis regimens were given based on FⅧ PK parameters.Results:The mean terminal half-life(t1/2)of FⅧ was 20.6±9.3 h,ranged from 11.47 h to 30.12 h.The age(r=0.580)and vWF:Ag(r=0.814)were significantly positively correlated with t1/2 of FⅧ.The mean area under the plasma concentration curve(AUC)of FⅧ was 913±399(328-1 878)IU h/dl,and the AUC of FⅧ was positively correlated with age(r=0.557)and vWF:Ag(r=0.784).The mean residence time(MRT)of FⅧ was 24.7±12.4(13.2-62.2)h,and the MRT of FⅧ was positively correlated with age(r=0.664)and vWF:Ag(r=0.868).The mean in vivo recovery(IVR)of FⅧ was 2.59±0.888(1.5-4.29)IU/dl per IU/kg,the mean clearance(CL)of FⅧ was 3±1.58(0.97-7.18)ml/(kg·h),and there was no significant correlation of IVR and CL with age and vWF:Ag.According to the individual PK parameters,ultra low-dose,low-dose and moderate-dose FⅧ were applied to 15,6,2 adults patients with severe hemophilia A for prophylaxis,respectively.Conclusion:There are significant individual differences in the FⅧ half-life of adult patients with severe hemophilia A.The older the patient,the higher the vWF:Ag level,and the longer the FⅧ half-life.Individual administration is required based on the FⅧ PK parameters to optimize prophylaxis treatment.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective:To observe the anti-inflammatory and glycometabolic effects of glutathione(GSH)on macrophages in collagen induced arthritis(CIA)mice.Methods:①CIA model establishment and groups:A total of 14 female DBA/1J mice were ran-domly divided into:CIA+PBS group and CIA+GSH group.The mice were sacrificed on the 50th day,collecting serum and isolating bone marrow derived macrophages(BMDM),which were marked as BMDM1.②Trained immunity model establishment and groups:BMDM were isolated from normal DBA/1J mice,and were pretreated with histone H3K27 demethylases inhibitor(GSKJ1)or PBS for 2 h.Then,serum from CIA model mice in vivo was incubated for 24 h,and the samples were grouped as follows:(CIA+GSH)+PBS group,(CIA+GSH)+GSKJ1 group,(CIA+PBS)+PBS group,(CIA+PBS)+GSKJ1 group.Lipopolysaccharide(LPS)was adopted to stimulated cells on the 6th day,which were marked as BMDM2.③RNA sequencing was used to detect differentially expressed genes(DEGs)and their function in BMDM1 and BMDM2.q-PCR was adopted to estimate the mRNA levels of PFK and Idh3g.The culture supernatants were used to measure the protein levels of TNF-α and IL-6 by ELISA.Results:①Compared with CIA+PBS group,the mice in CIA+GSH group showed lighter of joint swelling(P<0.05),less arthritis index(P<0.05),HE staining suggested less inflam-matory cell infiltration,Safranin O-fast green staining showed more chondrocytes,TRAP staining indicated reduced osteoclasts.②In BMDM1,GO analysis showed that DEGs were mainly involved in glutathione derivative metabolic process,IL-6 production,inflammatory response,innate immune response,regulation of primary metabolic process and glycolipid binding,compared with CIA+GSH and CIA+PBS group.In CIA+GSH group,the mRNA level of PFK was significantly decreased(P<0.05),while Idh3g was also significantly up-regulated(P<0.05),and the expression of TNF-α,IL-6 were both reduced(P<0.05)compared with CIA+PBS group.③In BMDM2,GO analysis showed that DEGs were also involved in inflammatory response,activation of innate immune response,regulation of tumor necrosis factor production,positive regulation of IL-6 production,regulation of glycolytic process and 1,3-β-D-glucan binding between CIA+GSH and CIA+PBS group.Furthermore,in(CIA+GSH)+PBS group,PFK was decreased(P<0.05),Idh3g was up-regulated(P<0.05),and IL-6 was also significantly down-regulated(P<0.05)compared with(CIA+PBS)+PBS group.However,there was no significant difference in the expression of Idh3g and PFK,moreover,TNF-α and IL-6 were significantly up-regulated compared with(CIA+GSH)+GSKJ1 group and(CIA+GSH)+PBS group.Conclusion:GSH can regulate glycometabolism and inflammatory response of macrophages via demethylation of histone H3K27,and it can also alleviate CIA in mice.

The objective of this study was to observe the effect of Astragalus membranaceus on high sugar-induced Caenorhabditis elegans, and to explore its mechanism of action. UPLC-MS method was used to identify the components of Astragalus membranaceus. A high glucose model was established by using Caenorhabditis elegans as a model organism, and the effects of Astragalus membranaceus on body length, body bending, swallowing frequency, and reactive oxygen species (ROS) of the nematode were determined; the effects of Astragalus membranaceus on the expression of mRNA of genes related to the protein skinhead-1 (SKN-1) signaling pathway were examined by using the real-time fluorescence quantitative polymerase chain reaction (PCR). The results showed that compared with the normal group, the nematode body length, body bending, and swallowing frequency expression were significantly reduced and the ROS content in the body was significantly increased in the high glucose state; after the administration of Astragalus membranaceus, the body length, body bending, and swallowing frequency expression were significantly increased, and the ROS content was significantly reduced (P < 0.01). Compared with the normal group, SKN-1, superoxide dismutas-3 (SOD-3), glutathione S-transferase 4 (GST-4), and glutathione S-transferase 7 (GST-7) expression were significantly decreased in Caenorhabditis elegans in the high glucose condition; SKN-1, SOD-3, GST-4, and GST-7 expression were significantly increased after administration of Astragalus membranaceus (P < 0.01). In the present study, we demonstrated that Astragalus membranaceus has an effect on high glucose-induced Caenorhabditis elegans nematodes, and its mechanism of action may be through the modulation of the SKN-1 signaling pathwaym in order to ameliorate the oxidative stress response induced by high glucose.

Qualitative analysis of the ingredients absorbed into blood and their metabolites of Xihuang pill (XHP) were conducted using high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS/MS) technology. Network pharmacology was used to explore the potential anticancer mechanisms of the ingredients against glioma, and their specific mechanisms were validated through molecular docking and experimental verification. SD rats were intragastrically administered with XHP, and rat serum samples were collected. Ingredients absorbed into blood and their metabolites were identified based on the retention time of chromatographic peaks, accurate molecular mass, characteristic fragment ions, and comparisons with reference substances and literature data. PharmMapper and SwissTarget Prediction databases were used to obtain the targets of the XHP-medicated serum, while GeneCards, OMIM, PharmGKB, TTD, and DrugBank databases were used to obtain glioma disease targets. The "component-target" network relationship diagram was constructed using Cytoscape 3.9.1 software. The protein-protein interaction (PPI) network diagram was constructed using the STRING database, and the targets were analyzed using GO and KEGG analyses. Molecular docking was used to verify the binding ability of core targets with their corresponding compounds in XHP-medicated serum. The potential mechanism of the anti-glioma effect of 11-keto-β-boswellic acid (KBA), a representative component of XHP-medicated serum, was verified using CCK-8 and Western blot assays. A total of 40 compounds were identified in the XHP-medicated serum, including 28 prototype components and 12 metabolites. The network pharmacology results showed that elemonic acid, 3-acetyl-β-boswellic acid, KBA, α-boswellic acid, and other 5 compounds might be the active ingredients of XHP-medicated serum in the treatment of glioma. Glutathione reductase (GSR), glucose-6-phosphate dehydrogenase (G6PD), ATP-citrate lyase (ACLY), aldo-keto reductase family 1 member B1 (AKR1B1) and glutaredoxin (GLRX) were identified as key targets, involving pathways such as glutathione metabolism and the pentose phosphate pathway. Further cell experiments showed that KBA significantly inhibited the proliferation of T98G cells with an IC₅₀ of 30.96 μmol·L^-1, and KBA (30 μmol·L^-1) significantly downregulated the protein expression levels of GSR in T98G cells. In summary, XHP-medicated serum may exert its anti-glioma effect by regulating GSR and G6PD-targeted pathways involved in glutathione metabolism. These results provide valuable evidence for further investigating the mechanism of XHP in treating glioma. The animal welfare and experimental procedures were approved by the Ethical Committee of Laboratory Animals at Nanjing University of Chinese Medicine (approval No. ACU221001).

Objective To determine the acetylation level of nucleophosmin(NPM)in female breast cancer and to discuss its function through mutation of modified lysine sites.To construct positive and negative NPM mutants on its acetylated lysine sites and to express them in breast cancer cells.Methods Acetylation level and acetylated lysine sites of NPM in three breast cancer tissues and para-carcinoma tissues were detected by acetylome technology;NPM mutants were constructed by site-directed mutagenesis PCR,specific PCR products were digested by DpnI and transformed into Escherichia coli(E.coli)to obtain specific plasmids for mutants;The accuracy of mutants were verified by double restriction enzyme digestion and sequencing;The mutants were expressed in BT-549 cells by transient transfection and verified by RT-PCR method.Protein expression and acetylation level of NPM were validated by Western blotting;Function of NPM acetylation was analyzed by proteomic detection and bioinformatic analysis.Results The 27th and 32nd lysine of NPM were highly acetylated in breast cancer tissues,which were 2.76 and 2.22 times higher than those in adjacent normal tissues,respectively;The NPM mutants showed the same molecular weight as that of wild type NPM and contained expected mutation sites;Corresponding NPM mRNA levels of BT-549 cells transfected with NPM mutants were significantly increased.With the increase of wild type NPM expression level,NPM acetylation level increased,while decreased after 27th lysine underwent negative mutation.NPM acetylation can significantly change the expression levels of 101 proteins in BT-549 cells,which are enriched in regulation of cellular macromolecule biosynthesis,DNA-template transcription,RNA biosynthesis and RNA metabolism process.Conclusion NPM is highly acetylated in breast cancer and can play a key role in cellular macromolecule biosynthesis,DNA-templated transcription,RNA biosynthesis and RNA metabolism process.

Background: Intrahepatic cholangiocarcinoma (ICC) is a highly desmoplastic tumor with poor prognosis even after curative resection. We investigated the associations between the composition of the ICC stroma and immune cell infiltration and aimed to develop a stromal-immune signature to predict prognosis in surgically treated ICC. Patients and methods: We recruited 359 ICC patients and performed immunohistochemistry to detect α-smooth muscle actin (α-SMA), CD3, CD4, CD8, Foxp3, CD68, and CD66b. Aniline was used to stain collagen deposition. Survival analyses were performed to detect prognostic values of these markers. Recursive partitioning for a discrete-time survival tree was applied to define a stromal-immune signature with distinct prognostic value. We delineated an integrated stromal-immune signature based on immune cell subpopulations and stromal composition to distinguish subgroups with different recurrence-free survival (RFS) and overall survival (OS) time. Results: We defined four major patterns of ICC stroma composition according to the distributions of α-SMA and collagen: dormant (α-SMAlow/collagenhigh), fibrogenic (α-SMAhigh/collagenhigh), inert (α-SMAlow/collagenlow), and fibrolytic (α-SMAhigh/collagenlow). The stroma types were characterized by distinct patterns of infiltration by immune cells. We divided patients into six classes. Class I, characterized by high CD8 expression and dormant stroma, displayed the longest RFS and OS, whereas Class VI, characterized by low CD8 expression and high CD66b expression, displayed the shortest RFS and OS. The integrated stromal-immune signature was consolidated in a validation cohort. Conclusion We developed and validated a stromal-immune signature to predict prognosis in surgically treated ICC. These findings provide new insights into the stromal-immune response to ICC.

Tumor microenvironment (TME) is composed of endothelial cells, pericytes, immune cells, cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs), extracellular matrix (ECM) and other components of the complex biological environment. TME interacts with the tumor cells through a large amount of signaling pathways, participates in the process of tumor progression, invasion, and metastasis. Hence, TME has become a potential therapeutic target for cancer treatment, exhibiting excellent therapeutic potential and research value in the field of cancer treatment. Currently, the novel nanotechnology has been widely applied in anticancer therapy, and nanotechnology-mediated drug delivery system is being explored to apply in TME modulation to inhibit tumor progression. Nanotechnology-mediated drug delivery has many advantages over traditional therapeutic modalities, including longer circulation times, improved bioavailability, and reduced toxicity. This review summarized the research of targeted nano-drug delivery based on TME regulation, including regulation strategies based on CSCs, CAFs, immune cells, ECM, tumor vascularization, exosomes, and microbiota. In addition, we summarized the advantages, opportunities, and challenges of TME regulation strategy compared with traditional treatment strategy, which provides a reference for the application of nano-drug delivery system based on TME regulation strategy in tumor precision therapy.