BACKGROUND: Doxorubicin hydrochloride (DOX) is extensively used in the treatment of various tumors. However, its clinical application is limited due to dose-dependent cardiotoxicity. Currently, few effective strategies exist to mitigate or eliminate DOX-induced cardiomyopathy (DIC). Although ferroptosis is implicated in DIC and its inhibition partially alleviates the condition, the direct targets of DOX in the progression of cardiotoxicity remain unclear. This study aimed to discover the direct targets of DOX in ferroptosis-mediated DIC. METHODS: A DOX pulldown assay was performed to identify proteins specifically binding to DOX in murine hearts, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify candidate proteins. A cardiac injury mouse model was established by DOX treatment. Based on this, multiple ferroptosis biomarkers were detected by flow cytometry, quantitative real-time polymerase chain reaction, western blotting, immunochemistry, etc. Besides, specific activator and inhibitor of signaling pathways were applied to illuminate molecular mechanisms. RESULTS: Glutathione S-transferase P1 (GSTP1) was identified as a DOX target. GSTP1 activity was inhibited in DOX-treated cardiomyocytes, while its overexpression significantly alleviated DIC. Moreover, GSTP1 overexpression inhibited acyl-CoA synthetase long-chain family member 4 (ACSL4)-dependent ferroptosis. Mechanistically, GSTP1 overexpression suppressed c-Jun N-terminal kinase (JNK) phosphorylation, thereby reducing reactive oxygen species (ROS) production and inhibiting ferroptosis in DIC. CONCLUSIONS This study identifies the DOX/GSTP1/JNK axis as a critical pathway mediating ACSL4-dependent ferroptosis in DIC. GSTP1 is highlighted as a potential key mediator of ferroptosis and a promising therapeutic target for DIC.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease lacking effective therapy. Metformin, an antidiabetic medication, has shown promising therapeutic properties in preclinical fibrosis models; however, its precise cellular targets and associated mechanisms in fibrosis resolution remain incompletely defined. Most research on metformin's effects has focused on mesenchymal and inflammatory responses with limited attention to epithelial cells. In this study, we utilized Sftpc lineage-traced and Fgfr2b conditional knockout mice, along with BMP2/PPARγ and AMPK inhibitors, to explore metformin's impact on alveolar epithelial cells in a bleomycin-induced pulmonary fibrosis model and cell culture. We found that metformin increased the proliferation and differentiation of alveolar type 2 (AT2) cells, particularly the recently identified injury-activated alveolar progenitors (IAAPs)-a subpopulation characterized by low SFTPC expression but enriched for PD-L1. Single-cell RNA sequencing revealed a reduction in apoptosis among mature AT2 cells. Interestingly, metformin's therapeutic effects were not significantly affected by BMP2 or PPARγ inhibition, which blocked the lipogenic differentiation of myofibroblasts. However, Fgfr2b deletion in Sftpc lineage cells significantly impaired metformin's ability to promote fibrosis resolution, a process linked to AMPK signaling. In conclusion, metformin alleviates fibrosis by directly activating AT2 cells, especially the IAAPs, through a mechanism that involves AMPK and FGFR2b signaling, but is largely independent of BMP2/PPARγ pathways.

Objective : To pathological changes and inducible nitric oxide synthase(iNOS), phosphorylated insulin receptor substrate 1 serine 307(p-IRS1ser 307), phosphorylated protein kinase B serine 473(p-AKTser 473), glycogen synthase kinase-3β(GSK-3β), and gluconeogenic synthase(GS) proteins were observed in the liver of rats under the condition of chronic intermittent hypoxia-replicated oxygen in control. And to explore the role of iNOS/IRS1/AKT/GSK-3β signaling pathway in chronic intermittent hypoxia-induced insulin resistance. Methods : Forty SD rats were randomly divided into a control group(NC group) and an experimental group(CIH group), with 20 rats in each group. The NC group was placed in a normoxic environment for 12 weeks, while the CIH group was first subjected to intermittent hypoxia for 8 weeks, and then resumed normoxic rearing until the 12th week. Fasting blood glucose(FBG) and fasting insulin(FINS) were measured at baseline, week 8 and week 12, and liver tissues were taken for pathology and measurement of iNOS, p-IRS1ser 307, p-AKTser 473, GSK3β and GS levels, to compare the differences between groups. Results: t baseline, there was no significant difference in liver pathology between the two groups, and the observed indexes were not statistically significant(P>0.05); at 8 weeks, compared with the NC group, liver pathology in the CIH group showed significant disorganization of hepatic blood sinusoids and hepatocyte cords, obvious hepatocyte edema, smaller nuclei, increased lymphocyte infiltration, and a small number of fat vacuoles, significantly higher levels of FBG, FINS, insulin resistance index(HOMA-IR), iNOS mRNA, p-IRS1ser 307 protein, GSK-3β protein levels, and decreased p-AKTser 473 protein and GS protein levels, all of which were statistically significant(allP<0.05). IRS1ser 307 protein, GSK-3β protein levels were increased, p-AKTser 473 protein and GS protein levels were decreased, and the differences were statistically significant(allP<0.05); at 12 weeks, no lymphocyte infiltration was seen in the CIH group compared with that of the NC group and fat vacuoles significantly increased, and there was no improvement in the other pathological damage that had already occurred, and the levels of p-AKTser 473 protein significantly increased. AKTser 473 protein level significantly increased, p-IRS1ser 307 protein and GS protein levels were significantly reduced, all of which were statistically significant(allP<0.05), and the rest of the observational indexes were not statistically significant. Pearson′s correlation analysis showed that HOMA-IR of CIH group was significantly positively correlated with the levels of iNOS mRNA, p-IRS1ser 307 protein, and GSK-3β protein at 8 weeks(r=0.874, 0.817,0.872;allP<0.05), and significantly negatively correlated with the levels of p-AKTser 473 protein and GS protein(r=-0.886,-0.879;allP<0.05). Conclusion Chronic intermittent hypoxia can lead to hepatic pathological damage that cannot be reversed even by reoxygenation interventions and may mediate the development of insulin resistance by upregulating the IRS1/AKT/GSK-3β signaling pathway through the upregulation of iNOS mRNA expression.

Objective To comprehensively understand the dynamic transcriptional landscape during infection through investigating the temporal molecular changes in macrophages RAW 264.7 upon infection with Salmonella typhimurium SL1344.Methods Macrophages RAW 264.7 were infected with Salmonella typhimurium SL1344,and cell samples were collected at 0 h,8 h,and 16 h for RNA-sequencing(RNA-seq).Upstream and downstream analyses of the transcriptome data including differential gene expression,clustering,functional annotation,and mo-lecular network studies were conducted to elucidate the signaling pathways changes in macrophages.Results Infec-ted macrophages exhibited significant morphological and transcriptional changes.Differential gene analysis identified significant upregulation and downregulation patterns.Clustering revealed six gene clusters involving various signaling pathways,such as immune response,membrane transport,and lipid catabolic process.Conclusions Macrophages dynamically respond to Salmonella typhimurium infection,displaying distinct temporal gene expression patterns.The coordinated activation of immune response,membrane transport,and lipid catabolic process pathways implies a multifaceted cellular adaptation to external infections,providing essential insights into the molecular mechanisms of macrophage response to Salmonella typhimurium infection.

Objective To investigate the effects of chronic intermittent hypoxia(CIH)and reoxygenation on insulin resistance(IR)and expressions of miR-27a-3p/PPARγ/IRS1/PI3K/AKT in rat skeletal muscle.Methods GEO database was used for screening the differentially expressed miRNAs in CIH,and their target genes were subjected to GO and KEGG enrichment analysis followed by construction of the miRNA-mRNA-pathway regulatory network using Cytoscape.In the animal experiment,48 male SD rats were randomly divided into normoxia group and CIH group(8 weeks of CIH followed by 4 weeks of normoxic recovery).Blood and skeletal muscle samples were collected at baseline,8 weeks,and 12 weeks to evaluate the changes in fasting blood glucose(FBG)and fasting insulin(FINS)levels and muscular pathology.RT-qPCR and Western blotting were used to detect the changes in the expressions of miR-27a-3p,PPARγ,GLUT4,IRS1,p-IRS1,PI3K,p-AKT and AKT in the muscular tissues.Results No muscular miRNA datasets for CIH were available in GEO database,from which only a kidney-related dataset(GSE202480)was obtained,based on which a total of 165 differentially expressed miRNAs were identified.GO/KEGG analysis suggested that these miRNAs were involved in muscular regulation and insulin signaling.The miRNA-mRNA-pathway network highlighted miR-27a-3p as a crucial regulator in the PPAR and PI3K/AKT pathway.In the animal experiment,the rats subjected to CIH for 8 weeks showed significantly increased FBG,FINS,HOMA-IR,and PPARγ levels,loose muscle fiber arrangement,decreased cross-sectional area of the muscle fibers,and lowered expressions of miR-27a-3p,p-IRS1/IRS1,PI3K,and p-AKT/AKT in the skeletal muscles.Conclusion CIH increases IR,causes skeletal muscle pathology,downregulates miR-27a-3p expression,upregulates PPARγ expression,and inhibits IRS1/PI3K/AKT insulin signaling in the skeletal muscles of rats,and these changes can be reversed by reoxygenation.MiR-27a-3p may participate in CIH-induced IR by modulating the PPAR γ/IRS1/PI3K/AKT signaling pathway.

Objective:To analyze the temporal trends of the incidence rate of tuberculosis (TB) in Shaanxi Province and provide a reference for WHO to control the prevalence of TB effectively.Methods:Joinpoint regression was used to analyze the trend of the incidence rate of TB in Shaanxi Province from 2004 to 2022, and the seasonal autoregressive moving average model was used to forecast the incidence rate of TB in Shaanxi Province to 2030.Results:The incidence rate of TB in Shaanxi Province decreased from 90.896/100 000 in 2004 to 35.364/100 000 in 2022, showing a general downward trend (AAPC=-7.72%, P<0.001). From 2014 to 2019, the reduction trend slowed down (APC=-0.69%, P=0.814), of which the largest decline occurred from 2019 to 2022 (APC=-13.26%, P=0.010). The predicted incidence rate of TB in Shaanxi Province from 2020 to 2022 was higher than the reported incidence rate, with the expected incidence rate of 51.342/100 000 in 2022 and 43.468/100 000 in 2030. Conclusion:The incidence rate of TB in Shaanxi Province shows a downward trend from 2004 to 2022, but the decline has shrunk in recent years. It is predicted that the downward trend will continue to slow down by 2030.

Objective·To explore the predictive value of diuretic renal scintigraphy parameters such as 20-minute residual rate(R20)for pyeloplasty in children with congenital unilateral ureteropelvic junction obstruction(UPJO).Methods·The clinical data and diuretic renal scintigraphy results of 110 children with congenital unilateral UPJO who were first treated at the Department of Nuclear Medicine,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine from August 2018 to August 2023 were retrospectively analyzed.The imaging results and the progress of hydronephrosis were followed up after the first diuretic renal scintigraphy.According to the outcome event of pyeloplasty due to the progression of hydronephrosis,the children were divided into operation group and non-operation group.Age,gender,side of hydronephrosis,and baseline diuretic renal scintigraphy parameters including blood perfusion rate(BPR),differential renal function(DRF),time to peak(Tmax),time to half(T1/2)and R20 were compared between the two groups.Logistic regression was used to analyze the effect of various parameters on the progression of hydronephrosis.The receiver operating characteristic(ROC)curve was used to analyze the predictive value of diuretic renal scintigraphy parameters for surgical intervention.Wilcoxon test was used to compare the examination parameters of two diuretic renal dynamic imaging.Results·During the follow-up,60 children underwent pyeloplasty after progression,and the other 50 children did not progress.The differences in DRF,Tmax,T1/2 and R20 between the two groups of children at baseline were statistically significant(all P<0.05).Univariate and multivariate Logistic regression analysis showed that only R20 was an independent predictor of pyeloplasty(OR=4.730,95%CI 1.009-1.178,P=0.030).R20 predicted pyeloplasty with a sensitivity of 88.3%,specificity of 56%,the area under the ROC curve of 0.758(95%CI 0.667-0.850,P=0.000),and the cut-off value of 90.08%.During the follow-up,38 children underwent the second diuretic renal scintigraphy,and the DRF was lower than before.The difference between the two DRFs was statistically significant(Z=-2.589,P=0.010),especially in children with R20≥90.08%(Z=-2.166,P=0.030).R20 in the non-operation group decreased significantly compared with the baseline(Z=-2.062,P=0.039).However,R20 in the operation group was higher than baseline,but the difference was not statistically significant(P>0.05).Conclusion·R20 plays an important role in the prediction of pyeloplasty in children with congenital unilateral UPJO.For children with R20≥90.08%,pyeloplasty should be performed as soon as possible to prevent further deterioration of renal function.

Objective:To investigate serum vitamin A and vitamin D status in children aged 2-<7 years in 20 cities in China.Methods:A cross-sectional study was conducted. A total of 2 924 healthy children aged 2-<7 years were recruited from September 2018 to September 2019 from 20 cities in China, categorized by age groups of 2-<3 years, 3-<5 years, and 5-<7 years. The demographic and economic characteristics and health-related information of the enrolled children were investigated. Body weight and height were measured by professional staff members. The serum vitamin A and vitamin D levels were detected by high-performance liquid chromatography-tandem mass spectrometry. Chi-square test and Logistic regression were applied to analyze the association between vitamin A and vitamin D deficiency and insufficiency as well as their underlying impact factors.Results:The age of the 2 924 enrolled children was 4.33 (3.42, 5.17) years. There were 1 726 males (59.03%) and 1 198 females (40.97%). The prevalences of vitamin A and vitamin D deficiency in enrolled children were 2.19% (64/2 924) and 3.52% (103/2 924), respectively, and the insufficiency rates were 29.27% (856/2 924) and 22.20% (649/2 924), respectively. Children with both vitamin A and vitamin D deficiencies or insufficiencies were found in 10.50% (307/2 924) of cases. Both vitamin A ( χ2=7.91 and 8.06, both P=0.005) and vitamin D ( χ2=71.35 and 115.10, both P<0.001) insufficiency rates were higher in children aged 3-<5 and 5-<7 years than those in children aged 2-<3 years. Vitamin A and vitamin D supplementation in the last 3 months was a protective factor for vitamin A and D deficiency and insufficiency, respectively ( OR=0.68 and 0.22, 95% CI 0.49-0.95 and 0.13-0.40, both P<0.05). The rates of vitamin A and D insufficiency was higher in children with annual household incomes <60 000 RMB than in those with annual household incomes ≥60 000 RMB ( χ2=34.11 and 10.43, both P<0.01). Northwest and Southwest had the highest rates of vitamin A and vitamin D insufficiency in children aged 2-<7 yeas, respectively ( χ2=93.22 and 202.54, both P<0.001). Conclusions:Among 20 cities in China, children aged 2-<7 years experience high rates of vitamin A and vitamin D insufficiency, which are affected by age, family economic level, vitamin A and vitamin D supplementation, and regional economic level. The current results suggest that high level of attention should be paid to vitamin A and vitamin D nutritional status of preschool children.

Objective:To retrieve, evaluate and integrate the evidence related to the preparation process for initiating extracorporeal cardiopulmonary resuscitation in hospital, so as to provide reference for clinical implementation of extracorporeal cardiopulmonary resuscitation.Methods:According to the evidence-based nursing method and the 6S evidence model, guidelines, clinical decisions, expert consensus, systematic review and other literatures related to the preparation process for initiating extracorporeal cardiopulmonary resuscitation in hospital were searched from National Guideline Clearinghouse, Scottish Intercollegiate Guidelines Network, National Institute for Health and Care Excellence, and other websites, UpToDate, The Cochrane Library, PubMed, Embase, CNKI, Wanfang and other databases. The retrieval date limit was from the establishment of the database to May 20, 2023. Researchers assessed the quality of the included articles, and extracted and summarized the evidence that met the quality standards.Results:A total of 11 articles were included, including 2 guidelines, 6 expert consensuses, 1 systematic review and 2 quasi-experimental studies. A total of 18 pieces of evidences were summarized from 6 aspects, including medical conditions, team building, materials management, operation mechanism, pre-initiating treatment and initiating judgment.Conclusions:This study summarizes the evidence of preparation process for initiating extracorporeal cardiopulmonary resuscitation in hospital, which can provide reference for promoting the implementation of extracorporeal cardiopulmonary resuscitation. Future studies still need to focus on team building, personnel training and assessment, and optimisation of the management system, so as to improve the efficiency and readiness of treatment.

BACKGROUND:At present,measurement osteotomy technique and gap balance technique are the two main surgical methods in total knee arthroplasty.Both methods have their advantages and disadvantages.By adjusting the osteotomy angle,the gap balance technique can reduce the release of soft tissue and obtain a more balanced flexion and extension space.The clinical efficacy of gap balance technique is superior,but this surgical method lacks tools and is easily influenced by the surgeon's surgical experience and subjective judgment,with more errors.Measurement osteotomy technique has a short learning curve,but it relies on anatomic markers and is prone to many complications due to inaccurate positioning.In recent years,many instrument companies have successively developed and launched tools that can improve the quality of surgery.However,there are still few reports about the tool. OBJECTIVE:To compare the clinical efficacy of gap balance technique and measurement osteotomy technique under Offset Repo-Tensor in total knee arthroplasty,and explore the value of Offset Repo-Tensor in total knee arthroplasty. METHODS:The medical records of 85 patients with total knee arthroplasty were collected and divided into two groups according to the operation method.Group A consisted of 44 patients who underwent total knee arthroplasty using a gap balance technique combined with Offset Repo-Tensor.Group B consisted of 41 patients who underwent total knee arthroplasty using measurement osteotomy technique.Surgical time,American Knee Society Score,knee range of motion,changes in lower limb alignment,and postoperative complications were compared between the two groups to evaluate the clinical efficacy of gap balance technique combined with Offset Repo-Tensors in total knee arthroplasty. RESULTS AND CONCLUSION:(1)All 85 patients were followed up.(2)Postoperative knee range of motion in both groups was higher than that before surgery(P<0.05),and the improvement in group A was more significant than that in group B(P<0.05).(3)American Knee Society Score in both groups after surgery was higher than that before surgery(P<0.05),and the American Knee Society Score in group A was higher than that in group B at 2 weeks,1,3 months,and the last follow-up(P<0.05).(4)The operation time of group A was slightly shorter than that of group B,but the difference was not significant(P>0.05).(5)The lower limb alignment in both groups was improved after operation,but there was no significant difference between the two groups(P>0.05).(6)The complication rate of group A(2%)was lower than that of group B(7%),but there was no significant difference between the two groups(P>0.05).(7)It is indicated that compared with the measurement osteotomy technique,the combination of Offset Repo-Tensor and gap balance technique can elevate the clinical effect and improve the function and motion range of the knee joint.