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*

Background Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants widely distributed in the environment. Epidemiological studies have shown that PFAS exposure is closely associated with liver dysfunction and an increased risk of liver cancer. Some animal and cell experiments have also revealed its hepatotoxicity and potential carcinogenicity; however, the related carcinogenic mechanism has not yet been fully elucidated. Objective To explore the potential molecular mechanism of PFAS-induced liver cancer, identify the key causal genes, and specifically evaluate the causal association and expression changes of KMT2C in this process, as well as the binding stability between KMT2C and PFAS, and to provid a theoretical basis for mechanistic studies and molecular target discovery in PFAS-related liver cancer. Methods Toxicity prediction was performed on six representative PFAS. Potential target genes of PFAS were identified by integrating results from SwissTargetPrediction, STITCH, and TargetNet databases. Liver cancer-related genes were retrieved from GeneCards, Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Database (TTD). The intersection of PFAS targets and liver cancer-related genes was used to obtain core genes. A compound-gene-disease regulatory network was constructed, and a protein–protein interaction network was established using STRING database. A core gene network was visualized based on node degree values. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore biological functions and enriched signaling pathways. Subsequently, two-sample Mendelian randomization was employed to assess potential causal relationships between candidate genes and hepatocellular carcinoma, enabling the identification of key genes. Molecular docking analysis using AutoDock was conducted to evaluate the binding stability between KMT2C and PFAS, and TCGA data were used to validate the differential expression of KMT2C between hepatocellular carcinoma and adjacent normal tissues. Results PFAS exhibited multisystem toxicity and posed significant risks of liver injury and carcinogenesis. A total of 266 PFAS target genes and 2923 liver cancer-related genes were identified, with 61 intersecting genes obtained. The enrichment analysis revealed that these intersecting genes were primarily involved in epigenetic regulation, nuclear receptor signaling pathways, and apoptosis-related pathways including TGF-β FoxO and Notch, suggesting their roles in diverse tumor-related biological processes. The two-sample Mendelian randomization results showed a significant negative causal association between KMT2C and hepatocellular carcinoma (OR=0.68, P <0.05). The molecular docking results demonstrated that all tested PFAS exhibited favorable binding to the KMT2C protein, with binding energies below –5.0 kcal·mol⁻¹. KMT2C was significantly upregulated in hepatocellular carcinoma tissues (unpaired P=0.025; paired P=8.38 × 10⁻⁴). Conclusion The KMT2C protein is found to stably bind with all six PFAS, exhibiting strong structural affinity. A causal relationship is identified between KMT2C and the development of hepatocellular carcinoma. TCGA data indicate that KMT2C is significantly upregulated in hepatocellular carcinoma tissues, and it may serve as a key regulatory target in PFAS-related liver cancer.

The level of urinary albumin is a critical indicator for the early diagnosis and management of chronic kidney disease (CKD). However, existing methods for detecting albumin are not conducive to point-of-care testing due to the complexity of reagent addition and incubation processes. This study presents a smartphone-integrated handheld automated biochemical analyzer (sHABA) designed for point-of-care testing of urinary albumin. The sHABA features a pre-loaded, disposable reagent cassette with reagents for the albumin assay arranged in the order of their addition within a hose. The smartphone-integrated analyzer can drive the reagents following a preset program, to enable automatic sequential addition. The sHABA has a detection limit for albumin of 5.9 mg/L and a linear detection range from 7 to 450 mg/L. The consistency of albumin level detection in 931 urine samples using sHABA with clinical tests indicates good sensitivity (95.78%) and specificity (90.16%). This research advances the field by providing an automated detection method for albumin in a portable device, allowing even untrained individuals to monitor CKD in real time at the patient's bedside. In the context of promoting tiered diagnosis and treatment, the sHABA has the potential to become an essential tool for the early diagnosis and comprehensive management of CKD and other chronic conditions.

To investigate the association between obesity-related metabolic indices and the risk of knee osteoarthritis(KOA) in middle-aged and older Chinese adults(≥45 years) using data from the China Health and Retirement Longitudinal Study(CHARLS).

The level of urinary albumin is a critical indicator for the early diagnosis and management of chronic kidney disease(CKD).However,existing methods for detecting albumin are not conducive to point-of-care testing due to the complexity of reagent addition and incubation processes.This study presents a smartphone-integrated handheld automated biochemical analyzer(sHABA)designed for point-of-care testing of urinary albumin.The sHABA features a pre-loaded,disposable reagent cassette with re-agents for the albumin assay arranged in the order of their addition within a hose.The smartphone-integrated analyzer can drive the reagents following a preset program,to enable automatic sequential addition.The sHABA has a detection limit for albumin of 5.9 mg/L and a linear detection range from 7 to 450 mg/L.The consistency of albumin level detection in 931 urine samples using sHABA with clinical tests indicates good sensitivity(95.78％)and specificity(90.16％).This research advances the field by providing an automated detection method for albumin in a portable device,allowing even untrained individuals to monitor CKD in real time at the patient's bedside.In the context of promoting tiered diagnosis and treatment,the sHABA has the potential to become an essential tool for the early diagnosis and comprehensive management of CKD and other chronic conditions.

Objectives:To evaluate the performance of AVEIR VR single chamber leadless pacemaker(AVEIR VR)in the real world in China and the predictive factors of pacing threshold to assess the feasibility of AVEIRTM VR implantation in the domestic population.Methods:All patients who underwent AVEIR VR implantation by experienced operators from Peking University People's Hospital in multiple domestic hospitals from June 2024 to October 2024 were consecutively included,and their baseline characteristics,procedural data(including pacemaker electrical measurements at various stages),and follow-up results were observed,recorded,and statistically analyzed.Results:This study included 20 patients who met the indication for pacemaker implantation and underwent AVEIR VR implantation.Their mean age was(71.40±13.37)years,body mass index(BMI)was(23.05±3.71)kg/m2,body surface area(BSA)was(1.70±0.16)m2,all 20 patients were successfully implanted with pacemakers,there were no major complications(newly occurred pericardial effusion during the perioperative period,cardiac tamponade,poor pacemaker function,pacemaker dislocation/perforation,tricuspid valve injury,myocardial infarction,stroke,pulmonary embolism,and clinical death).One patient developed new frequent ventricular premature contractions after pacemaker release.The pacing threshold(PCT)at one week after implantation was correlated with PCT in tether mode(r=0.650,P=0.009)and PCT in release phase(r=0.596,P=0.019),but not with the sensing and impedance in each phase.Conclusions:This preliminary exploration study show that AVEIRTM VR implantation demonstrates satisfactory performance among real world patients in China,especially in elderly and low weight populations,confirming its safety.

Objective:To evaluate the clinical feasibility of subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation following transvenous lead extraction (TLE).Methods:This was a retrospective study. Consecutive patients who underwent S-ICD implantation at Peking University People′s Hospital between June 2015 and October 2023 were enrolled. Patients were divided into the TLE group and the newly implanted group based on whether they received TLE prior to S-ICD implantation. Baseline characteristics, S-ICD indication, defibrillation threshold test results, complications, and postoperative follow-up data were collected and compared between the two groups.Results:A total of 27 patients were included, aged (49.2±14.2) years, including 19 males. There were 12 patients in the TLE group and 15 in the newly implanted group. Compared with the TLE group, patients in the newly implanted group were younger ((43.3±13.7) years vs. (55.6±12.0) years, P=0.013). The main S-ICD indication in the TLE group was high infection risk (9/12), whereas in the newly implanted group it was younger age (11/15). All patients underwent successful S-ICD implantation, with 18 patients completing defibrillation threshold testing (all successful). Additionally, the TLE group had longer follow-up duration than the newly implanted group (42 (19, 60) months vs. 12 (3, 28) months, P=0.001). No complications or deaths occurred during follow-up, with normal device function in both groups. A total of 17 ventricular tachycardia or fibrillation events were recorded, of which 7 met defibrillation criteria and all received effective therapy. Conclusion:S-ICD demonstrates safety and efficacy as a therapeutic option for patients after TLE, with comparable device functionality and follow-up outcomes to patients with newly implanted S-ICD.

Objective To explore the risk factors for 28-day mortality of sepsis-associated acute kidney injury(SA-AKI)patients and to develop a nomogram risk prediction model.Methods A retrospective cohort study was conducted,involving 184 patients with SA-AKI admitted to the intensive care unit(ICU)of the 940th Hospital of Joint Logistic Support Force of PLA between January 2017 and December 2022.Patients were categorized into survival(n=135)and non-survival(n=49)groups based on 28-day mortality.Clinical data were collected,and statistically significant risk factors were preliminarily screened.Multivariate stepwise logistic regression analysis was performed to identify independent risk factors for 28-day mortality of SA-AKI patients.A nomogram predictive model was constructed using these factors,and internally validated with the Bootstrap method.The receiver operating characteristic curve(ROC curve)was drawn,and the area under the ROC curve(AUC)was calculated to verify the predictive value and accuracy of the model.Results The 28-day mortality rate among 184 SA-AKI patients was 26.6％(49/184).Multivariate stepwise logistic regression analysis identified multiple organ dysfunction syndrome(MODS)(OR=16.393,95％CI 4.317-62.254,P＜0.001),high acute physiology and chronic health evaluation Ⅱ(APACHE Ⅱ)score(OR=1.097,95％CI 1.036-1.161,P=0.002),low oxygenation index(OR=0.992,95％CI 0.986-0.998,P=0.015),low neutrophil count(OR=0.912,95％CI 0.860-0.968,P=0.002)and low fibrinogen concentration(OR=0.733,95％CI 0.549-0.978,P=0.034)as independent risk factors.The prediction model equation was P=1/1+e-logit(P),logit(P)=-1.626+2.797×MODS+0.092×AP ACHE Ⅱ+(-0.311)×fibrinogen+(-0.092)×neutrophil count+(-0.008)×oxygenation index.Internal validation with 1000 Bootstrap resamples showed high consistency between predicted and actual values.ROC analysis showed an AUC of 0.911(95％CI 0.868-0.955,P＜0.05)for the model,with 93.9％sensitivity and 78.5％specificity at a cut-off of 0.194.The Hosmer-Lemeshow test confirmed good calibration(P=0.62),and decision-making curve analysis demonstrated clinical utility within the high-risk threshold range(0.1-0.9).Conclusions MODS,high APACHE Ⅱ score,low oxygenation index,low neutrophil count,and low fibrinogen concentration are independent risk factors for 28-day mortality in SA-AKI patients.The developed nomogram risk prediction model may provide important guidance for predicting 28-day mortality in SA-AKI patients.

AIM To optimize the extraction process for total polyphenols from Conioselinum vaginatu(Spreng.)Thell.,make component analysis,and evaluate their anti-oxidant,hypoglycemic activities.METHODS The effects of ultrasound,enzymatic hydrolysis,acid hydrolysis,alcohol extraction and hydrolysis processes on the extraction quantity of total polyphenols were investigated,respectively.With extraction temperature,extraction time,ethanol concetration and liquid-solid ratio as influencing factors,extraction quantity of total polyphenols as an evaluation index,the extraction process was optimized by response surface method.HPLC was adopted in the identification of polyphenolic composition and determination of their contents.Subsequently,total polyphenols' scavenging capacities on DPPH,ABTS,OH free radicals,total reducing power and inhibitory capacity on α-glucosidase were determined.RESULTS The highest extraction quantity of total polyphenols was observable when extraction process was employed.The optimal conditions were determined to be 62 ℃ for extraction temperature,54 min for extraction time,69％for ethanol concentration,and 50∶1 for liquid-solid ratio,the extraction quantity of total polyphenols was(9.51±0.2)mg GAE/g.Seven constituents existed in C.vaginatu,among which ferulic acid demonstrated the highest content,followed by that of myricetin,while D-tryptophan content was the lowest.At the concentration of 7.61 mg/L,total polyphenols displayed the scavenging rates on DPPH,ABTS,OH free radicals of 80.70％,85.97％,28.60％,total reducing power of 0.22,and inhibition rate on α-glucosidase of 77.23％,respectively.CONCLUSION This stable and reliable method can be used for the extraction of total polyphenols from C.vaginatum with strong anti-oxidant,hypoglycemic activities.

Objectives:To evaluate the performance of AVEIR VR single chamber leadless pacemaker(AVEIR VR)in the real world in China and the predictive factors of pacing threshold to assess the feasibility of AVEIRTM VR implantation in the domestic population.Methods:All patients who underwent AVEIR VR implantation by experienced operators from Peking University People's Hospital in multiple domestic hospitals from June 2024 to October 2024 were consecutively included,and their baseline characteristics,procedural data(including pacemaker electrical measurements at various stages),and follow-up results were observed,recorded,and statistically analyzed.Results:This study included 20 patients who met the indication for pacemaker implantation and underwent AVEIR VR implantation.Their mean age was(71.40±13.37)years,body mass index(BMI)was(23.05±3.71)kg/m2,body surface area(BSA)was(1.70±0.16)m2,all 20 patients were successfully implanted with pacemakers,there were no major complications(newly occurred pericardial effusion during the perioperative period,cardiac tamponade,poor pacemaker function,pacemaker dislocation/perforation,tricuspid valve injury,myocardial infarction,stroke,pulmonary embolism,and clinical death).One patient developed new frequent ventricular premature contractions after pacemaker release.The pacing threshold(PCT)at one week after implantation was correlated with PCT in tether mode(r=0.650,P=0.009)and PCT in release phase(r=0.596,P=0.019),but not with the sensing and impedance in each phase.Conclusions:This preliminary exploration study show that AVEIRTM VR implantation demonstrates satisfactory performance among real world patients in China,especially in elderly and low weight populations,confirming its safety.