BACKGROUND:Rheumatoid arthritis is widely prevalent worldwide,with its high incidence and universality that considerably affects patients' quality of life.Previous studies have focused on a few immune cells or cytokines,whereas this study comprehensively provides a more complete view of the immune mechanisms in rheumatoid arthritis.OBJECTIVE:To explore the causal relationship between 731 immune cell phenotypes and rheumatoid arthritis using the Mendelian randomization method,thereby providing evidence of causality.METHODS:The 731 immune cell phenotypes used in this study were sourced from the GWAScatalog database,jointly developed by the National Human Genome Research Institute(NHGRI)and the European Bioinformatics Institute(EBI).The rheumatoid arthritis data were from the Finngen database,developed by the Finnish Institute for Molecular Medicine(FIMM).The inverse variance weighting method was employed as the primary analytical approach.Additionally,multiple analytical methods,including MR-Egger,weighted mode,simple mode,and weighted median,were concurrently utilized to complement the final results.Sensitivity analyses(Cochran's Q test,MR-Egger regression,and MR-presso analysis)were also conducted to verify the stability and feasibility of the data.RESULTS AND CONCLUSION:(1)After excluding results through heterogeneity testing,the inverse variance weighting analysis indicated that 10 absolute cell counts,15 median fluorescence intensities of surface antigen levels,1 morphological characteristic,and 9 relative cell counts had a causal relationship with the occurrence of rheumatoid arthritis.(2)According to cell classification,this study found that seven types of B cells,seven types of classical dendritic cells,six types of mature T cells,four types of monocytes,three types of myeloid cells,three types of TBNK cells(lymphocyte subset T cells,B cells and natural killer cells),and five types of Tregs had a causal association with the occurrence of rheumatoid arthritis.(3)Through comprehensive bidirectional two-sample MR analysis,we demonstrated the complex causal relationships between multiple immune phenotypes and rheumatoid arthritis,highlighting the intricate interaction patterns between the immune system and rheumatoid arthritis.These results provide new biomarkers for the early screening and diagnosis of rheumatoid arthritis in China,and help to improve the diagnostic accuracy and sensitivity.

ObjectiveTo investigate the protective effect of α-ketoglutarate （α-KG） on hepatic lipid deposition in offspring caused by arsenic exposure during pregnancy. Methods8-week-old institute of cancer research （ICR） mice were mated in a ratio of 2∶1 between females and males， and the detection of vaginal plugs confirmed pregnant. A total of 32 pregnant mice were randomly divided into four groups： control group， arsenic group， α-KG group， arsenic+α-KG group. On gestational day 0-16 （GD0-GD16）， the arsenic and arsenic+α-KG groups were exposed to sodium arsenite （NaAsO₂ ，15 mg/L） in drinking water everyday， and the α-KG and arsenic+α-KG groups were gavaged with α-KG （2 g/kg） everyday. On GD16， pregnant mice were euthanized to collect fetal liver， and fetal body weight and crown-rump length were measured. Gene expression differences between the control group and the arsenic group were analyzed by transcriptome. The total triglycerides （TGs） and subtypes in fetal liver were detected by liquid chromatography tandem mass spectrometry （LC-MS/MS）. Oil red O staining was used to observe the histopathological changes in the liver. Quantitative polymerase chain reaction （qPCR） was used to detect the expression level of genes related to lipid synthesis， transport， and degradation， and phosphatidylinositol 3' -kinase/ protein kinase B （PI3K/AKT） in the liver of fetus. ResultsTranscriptomics analysis showed that 2 144 genes were downregulated and 1 675 genes were upregulated in the arsenic exposed fetal liver； body weight and crown-rump length were reduced （P_TuKey<0.05）； the level of hepatic TGs was elevated in arsenic group （P_TuKey<0.05）； oil-red O staining showed a significant increase in lipid droplets in arsenic group （P_TuKey<0.01）； the expression of lipid synthesis-related genes were significantly upregulated （P_TuKey<0.05）； the expression of β-oxidation-related genes and lipid degradation-related genes were downregulated （P_TuKey<0.05）； the expression of PI3K， AKT decreased（P_TuKey<0.05）. Compared with the arsenic group， the body weight and crown-rump length of fetus increased in the arsenic+α-KG group （P_TuKey<0.05）； the level of hepatic TGs decreased in the arsenic+α-KG group （P_TuKey<0.05）； oil red O staining showed lipid droplets significantly decreased （P_TuKey<0.01）； the expression of lipid synthesis-related genes were downregulated （P_TuKey<0.05）， the expression of β-oxidation-related genes and lipid degradation-related genes were upregulated （P_TuKey<0.05）； the expression levels of PI3K and AKT increased （P_TuKey<0.05）. Conclusionα-KG alleviated hepatic lipid deposition in offspring exposed to arsenic during pregnancy through activating PI3K/AKT signaling pathway.

BACKGROUND:Rheumatoid arthritis is widely prevalent worldwide,with its high incidence and universality that considerably affects patients' quality of life.Previous studies have focused on a few immune cells or cytokines,whereas this study comprehensively provides a more complete view of the immune mechanisms in rheumatoid arthritis.OBJECTIVE:To explore the causal relationship between 731 immune cell phenotypes and rheumatoid arthritis using the Mendelian randomization method,thereby providing evidence of causality.METHODS:The 731 immune cell phenotypes used in this study were sourced from the GWAScatalog database,jointly developed by the National Human Genome Research Institute(NHGRI)and the European Bioinformatics Institute(EBI).The rheumatoid arthritis data were from the Finngen database,developed by the Finnish Institute for Molecular Medicine(FIMM).The inverse variance weighting method was employed as the primary analytical approach.Additionally,multiple analytical methods,including MR-Egger,weighted mode,simple mode,and weighted median,were concurrently utilized to complement the final results.Sensitivity analyses(Cochran's Q test,MR-Egger regression,and MR-presso analysis)were also conducted to verify the stability and feasibility of the data.RESULTS AND CONCLUSION:(1)After excluding results through heterogeneity testing,the inverse variance weighting analysis indicated that 10 absolute cell counts,15 median fluorescence intensities of surface antigen levels,1 morphological characteristic,and 9 relative cell counts had a causal relationship with the occurrence of rheumatoid arthritis.(2)According to cell classification,this study found that seven types of B cells,seven types of classical dendritic cells,six types of mature T cells,four types of monocytes,three types of myeloid cells,three types of TBNK cells(lymphocyte subset T cells,B cells and natural killer cells),and five types of Tregs had a causal association with the occurrence of rheumatoid arthritis.(3)Through comprehensive bidirectional two-sample MR analysis,we demonstrated the complex causal relationships between multiple immune phenotypes and rheumatoid arthritis,highlighting the intricate interaction patterns between the immune system and rheumatoid arthritis.These results provide new biomarkers for the early screening and diagnosis of rheumatoid arthritis in China,and help to improve the diagnostic accuracy and sensitivity.

ObjectiveTo explore the vascular endothelial injury in male mice caused by exposure to polystyrene microplastics （PS-MPs） and the intervention effect of luteolin on vascular remodeling. Additionally， to investigate the mechanism through the oxidative system and metabolomics. MethodsThirty-two C57BL/6 mice （6-8 weeks old） were randomly divided into the saline group （saline group）， the 0.1 mg/kg PS-MPs exposure group （0.1PS-MPs group）， the 1 mg/kg PS-MPs exposure group （1PS-MPs group）， and the 1 mg/kg PS-MPs + luteolin treatment group （1PS-MPs + Lut group）， with 8 mice in each group. After 8 weeks of intervention， the body weight， blood pressure， aortic organ coefficient， and aortic histopathological changes of mice in each group were detected； the total cholesterol （TC）， triglyceride （TG）， and high-density lipoprotein cholesterol （HDL-C） lipid metabolism-related indicators in the aorta of mice were detected； the reactive oxygen species （ROS）， glutathione （GSH）， and malondialdehyde （MDA） oxidative stress-related indicators were detected； the endothelin （ET-1）， nitric oxide （NO）， vascular endothelial growth factor A （VEGF-A）， vascular cell adhesion molecule-1 （VCAM-1/CD106）， and intercellular adhesion molecule-1 （ICAM-1/CD54） endothelial function-related indicators and serum metabolomics were detected. ResultsCompared to the saline group， exposure to PS-MPs resulted in pathological thickening of the mouse aorta， increased aortic organ coefficient， and elevated blood pressure. Lipid metabolism-related indicators， including TC and TG， were elevated， while HDL-C was reduced， indicating lipid metabolism disorder in mice. Oxidative stress markers such as ROS and MDA increased， whereas GSH decreased， demonstrating oxidative damage. Vascular endothelial inflammation and injury markers， including ET-1， VEGF-A， VCAM-1， and ICAM-1， were upregulated， while the vasodilatory substance NO was downregulated， confirming endothelial injury. Furthermore， serum metabolomics results revealed that PS-MPs exposure induced endothelial damage by disrupting metabolic pathways such as the citrate cycle. Compared to the PS-MPs group， luteolin significantly reversed these effects， attenuating oxidative stress and lipid metabolism disorders， and effectively repairing endothelial injury. ConclusionPS-MPs induce vascular toxicity through oxidative stress and lipid metabolism. Luteolin effectively alleviates endothelial damage and vascular remodeling.

Objective To investigate the risk factors for postoperative recurrence and metastasis in patients with T1 stageⅢ/Ⅳ clear cell renal cell carcinoma(ccRCC), and to analyze the influence of surgical methods on prognosis, so as to provide prognostic evaluation and treatment guidance for clinical practice. Methods A retrospective analysis was conducted on 398 patients diagnosed with T1 stage Ⅲ/Ⅳ ccRCC who underwent either partial nephrectomy(PN)or radical nephrectomy(RN)at Jiangsu Province Hospital during Jan. 2008 and Sep. 2022. The patients were divided into recurrence group(n=49)and non-recurrence group(n=349)according to whether the tumor recurred during the follow-up period. The general, clinical data and prognosis were compared between the two groups. Univariate and multivariate Cox regression analyses were used to explore the factors influencing disease-free survival(DFS)and overall survival(OS)after surgery. Subgroup analysis using Kaplan-Meier curves was performed for T1a and T1b patients. Results During the median follow-up of 67(42, 98)months, the recurrence group was characterized by older age, larger tumor diameter, higher proportion of T1b stage, and more complex tumor anatomy. Univariate and multivariate Cox regression analyses showed that age ≥55 years and R.E.N.A.L. score ≥7 were independent risk factors for poorer DFS and OS(P＜0.05). Subgroup analysis revealed that PN or RN did not significantly affect DFS or OS in T1a patients and OS in T1b patients, while RN significantly improved DFS in T1b patients(P＜0.05). Conclusion Age ≥55 years and R.E.N.A.L. score ≥7 are independent risk factors for poor DFS and OS in highgrade T1 ccRCC patients. For T1b patients, RN may improve DFS.

ObjectiveTo explore the ameliorative effect of the endoplasmic reticulum stress inhibitor 4-phenylbutyric acid （4-PBA） on bile acid metabolism disorders induced by bacterial lipopolysaccharide （LPS） in late-pregnant mice， and to clarify the regulatory mechanism of endoplasmic reticulum stress （ERS） in intrahepatic cholestasis of pregnancy （ICP）. MethodsTwenty-four pregnant mice were divided into control group， LPS group， 4-PBA group， and LPS+4-PBA group. On the 16th day of pregnancy， the LPS group received intraperitoneal injection of LPS （200 μg/kg） and the 4-PBA group received injection of 4-PBA （150 mg/kg）. In the LPS+4-PBA group， 4-PBA was intraperitoneally injected first， followed by LPS administration 1 h later. Serum total bile acid （TBA）， liver injury markers， bile acid profiles， and the expression of key genes and proteins were detected 6 h after LPS treatment. ResultsLPS exposure increased serum TBA levels in pregnant mice（P<0.05）， activated ERS markers and inflammatory factors， and downregulated bile acid transporters and the expression of the rate limiting enzyme CYP7A1（all P<0.05）. 4-PBA intervention effectively inhibited ERS， reduced TBA levels（P<0.05）， and upregulated Ntcp， Bsep， Mdr3， and Mrp3 gene expression（all P<0.05）. ConclusionERS plays an important role in LPS interference with the homeostasis of bile acid metabolism during pregnancy. Inhibiting ERS can improve bile stasis by regulating bile acid transporters， providing a theoretical basis for targeted therapy of ICP.

Objective To investigate the correlations of resting electrocardiogram ST-T abnormality and stress hyperglycemia ratio(SHR)with short-term prognosis of acute left heart failure(ALHF).Methods The clinical data of 125 patients with ALHF were analyzed.According to the prognosis within 30 days after onset,the patients were divided into good prognosis group(n=59),poor prognosis group(n=42)and death group(n=24).The resting electrocardiogram indications,admission blood glucose and glycosylated hemoglobin at fasting on the next day were collected,and SHR was calculated for exploring the correlations of resting electrocardiogram ST-T abnormality and SHR with short-term prognosis of ALHF.Results and conclusion The differences in gender,blood pressure and other general data among 3 groups were trivial(P>0.05),but death group was at an older age as compared with good prognosis group(P<0.05).The resting electrocardiogram ST-T abnormality rate,QRS wave duration and QTc interval were lower/shorter in good prognosis group than in the other two group(P<0.05),and the above indicators were lower/shorter in poor prognosis group than in death group(P<0.05).Good prognosis group had the lowest SHR,followed by poor prognosis group and death group(P<0.05).Multivariate Logistic regression analysis revealed that ST-T abnormality,prolonged QRS wave duration,prolonged QTc interval and high SHR were independent risk factors for poor prognosis in ALHF patients(P<0.05).Resting electrocardiogram ST-T abnormality and SHR were significantly and positively correlated with ALHF short-term prognosis.

Objective To evaluate the clinical efficacy and safety of the daratumumab-based regimens,including daratumumab,dexamethasone,and lenalidomide(DRd),as well as daratumumab,dexamethasone,and bortezomib(DVd),in the treatment of patients with relapsed or refractory multiple myeloma(RRMM)at our center.Methods Eighty patients with RRMM were assigned to either the DRd group(42 cases)or the DVd group(38 cases)based on their treatment regimens.Both groups received a baseline treatment of daratumumab combined with dexamethasone(Dd regimen).In the DVd group,1.3 mg/m2 of bortezomib was administered subcutaneously on days 1,4,8,and 11 of each cycle,followed by a 10 day drug-free interval(days 12～21),repeated every 3 weeks until disease progression.In the DRd group,25 mg of lenalidomide was orally administered daily from day 1 to day 21 of each cycle,in addition to the Dd regimen,continuing until disease progression.The two groups were compared in terms of laboratory parameters,tumor markers,clinical efficacy,safety profiles,and long-term prognostic outcomes.Results After treatment,the overall response rate(ORR)of the DRd group and the DVd group was 78.57%(33 out of 42 cases)and 52.63%(20 out of 38 cases),respectively.The serum creatinine(SCr)levels were(92.54±14.33)and(102.07±15.41)μmol/L,respectively;the M protein contents were(19.62±2.04)and(21.08±2.23)g/L,respectively;the β2-microglobulin(β2-MG)levels were(3.49±1.12)and(4.16±1.25)mg/L,respectively;and the progression-free survival rates were 42.86%(18 out of 42 cases)and 26.32%(10 out of 38 cases),respectively.All these indicators showed statistically significant differences between the DRd group and the DVd group(all P<0.05).The incidence rates of adverse reactions in the observation group and the control group were 14.29%(6 out of 42 cases)and 13.16%(5 out of 38 cases),respectively,and the difference was not statistically significant(P>0.05).Conclusion The DRd regimen demonstrates superior efficacy compared to the DVd regimen in treating patients with RRMM,leading to improved patient prognosis with a favorable safety profile.

Objective To investigate the mechanism by which 4-week high-intensity interval training(HIIT)regulates the mitochondrial unfolded protein response(UPRmt)in skeletal muscle and improves mitochondrial function in a rat model of chronic unpredictable mild stress(CUMS).Methods Male SPF-grade SD rats(6～8 weeks old)were divided randomly into control(C),model(M),HIIT+control(HC),and HIIT+model(HM)groups.Rats in the M and HM groups were subjected to CUMS for 8 weeks to establish a depression model,while rats in the HC and HM groups received HIIT for 5 d a week for 4 weeks.The exercise regimen consisted of 3 min high-speed(85％～90％Smax)combined with 1 min low-speed(50％～55％Smax)uninterrupted repetitive training(Smax is maximum training speed).Behavioral changes were evaluated at weeks 4 and 8.Tissue samples were taken 24 h after the last behavioral test and skeletal muscle mitochondria were examined by transmission electron microscopy.The ATP and reactive oxygen species(ROS)contents were measured by enzyme-linked immunosorbent assays and protein expression levels of activating transcription factor(ATF)4,ATF5,C/EBP homologous protein(CHOP),and heat shock protein 60(HSP60)were detected by Western blot.Results(1)The body mass,number of crossing grids,number of upright positions,sugar-water preference rate,and ATP content were significantly decreased in group M compared with group C(P＜0.01),while the number of damaged mitochondria,ROS content,ATF4,ATF5,CHOP,and HSP60 protein expression were significantly increased(P＜0.01).(2)After 4-weeks of HIIT intervention,the ATP content and ATF4 and ATF5 protein expression levels were significantly increased in the HC group compared with C group(P＜0.05,P＜0.01).The number of crossing grids,number of upright positions,sugar-water preference rate,ATP content,and ATF4 protein expression were significantly increased in the HM group compared with M group(P＜0.01),while the number of damaged mitochondria,ROS content,and ATF5,CHOP,and HSP60 protein expression levels were significantly decreased(P＜0.01).(3)After 4 weeks of HIIT intervention,the number of crossing grids in CUMS rats was significantly positively correlated with ATF4 protein expression,and ROS content was correlated with CHOP protein expression,number of damaged mitochondria,and ATF5 protein expression(|r|＞0.75,P＜0.01;|r|＞0.75,P＜0.05).Upright frequency was significantly negatively correlated with ATF5 and HSP60 protein expression,the number of crossing grids,the sugar-water preference rate,and the expression of CHOP and HSP60 proteins(|r|＜0.75,P＜0.05).Conclusions 4-week HIIT intervention can improve mitochondrial dysfunction and alleviate depressive-like behavior in CUMS rats by regulating skeletal muscle UPRmt.

Objective:To observe the efficacy and safety of adrenocorticotropic hormone (ACTH) therapy in children with steroid dependent nephrotic syndrome (SDNS)/frequently relapsed nephrotic syndrome (FRNS).Methods:The clinical data of children with SDNS/FRNS who received treatment with prednisone acetate tablets were retrospectively collected from June 2019 to June 2023 in the Nephrology Department of Xi′an Children′s Hospital. The children were divided into glucocorticoid+ACTH group and glucocorticoid group, according to whether ACTH was used or not. The differences in cortisol, total cholesterol and 24 hour urinary protein quantity between 2 groups of children at baseline and follow-up endpoints were compared, and the effectiveness (the proportion of no recurrence and discontinuation of glucocorticoid) and occurrence of adverse reactions were evaluated.Results:A total of 39 patients with SDNS/FRNS were included in this study, with 21 cases in the glucocorticoid+ACTH group and 18 cases in the glucocorticoid group. Among the 39 children, there were 33 cases of SDNS and 6 cases of FRNS, respectively. The proportion of baseline low cortisol levels was 76.9% (30/39). The proportion of cortisol levels returning to normal after ACTH treatment in the glucocorticoid+ACTH group was 76.2% (16/21). The baseline and follow-up endpoint for cortisol levels in the glucocorticoid+ACTH group were 28.0(19.8, 51.5) μg/L and 79.9(58.9, 113.0) μg/L, respectively. The baseline and follow-up endpoint for cortisol levels in the glucocorticoid group were 21.0(15.8, 37.4) μg/L and 25.3(18.2, 51.4) μg/L, respectively. In the 2 groups of cortisol levels, there was statistically significant difference in the interaction effect between time and group ( Wald χ2=11.595, P=0.001), there was a statistically significant difference at the follow-up endpoint between the 2 groups ( Wald χ2=19.462, P<0.001), and the difference was statistically significant in the time effect of the glucocorticoid+ACTH group ( Wald χ2=21.100, P<0.001). The baseline and follow-up endpoint for total cholesterol in the glucocorticoid+ACTH group were 4.95(4.23, 5.26) mmol/L and 4.38(4.04, 5.24) mmol/L, respectively. The baseline and follow-up endpoint for total cholesterol in the glucocorticoid group were 4.80 (4.17, 5.28) mmol/L and 5.74 (5.04, 6.88) mmol/L, respectively. In the 2 groups of total cholesterol, there was statistically significant difference in the interaction effect between time and group ( Wald χ 2=9.842, P=0.002), there was statistically significant difference at the follow-up endpoint between the 2 groups ( Wald χ 2=12.187, P<0.001), the difference was statistically significant between the 2 groups in the time effect at baseline and the follow-up endpoint (glucocorticoid+ACTH group: Wald χ 2=6.488, glucocorticoid group: Wald χ2=7.112; all P<0.05). The baseline and follow-up endpoint for 24 hour urinary protein quantity in the glucocorticoid+ACTH group were 115 (105, 128) mg/d and 121 (113, 128) mg/d, respectively. The baseline and follow-up endpoint for 24 hour urinary protein quantity in the glucocorticoid group were 118 (113, 125) mg/d and 138 (119, 2 100) mg/d, respectively. In the 2 groups of 24 hour urinary protein quantity, there was statistically significant difference in the interaction effect between time and group ( Wald χ2=7.743, P=0.005), there was statistically significant difference at the follow-up endpoint between the 2 groups ( Wald χ2=7.779, P=0.005), and the difference was statistically significant in the time effect of the glucocorticoid group ( Wald χ2=13.331, P<0.001). The proportion of no recurrence (17/21) and discontinuation of oral glucocorticoid (16/21) in the glucocorticoid+ACTH group were higher than those in the glucocorticoid group (the proportion were both 6/18), and the differences between the 2 groups were statistically significant (the chi square values were 9.084 and 7.240, respectively; all P<0.01). No adverse reactions occurred in the glucocorticoid group. The incidence of adverse reactions in the glucocorticoid+ACTH group was 14.3% (3/21), of which 2 cases developed generalized urticaria and 1 case developed hypertension. Conclusions:ACTH has a good efficacy and safety in children with SDNS/FRNS. The results of this study need to be further validated by increasing the sample size and conducting multicenter studies.