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2024 Vol. 54, No. 8 Published: 2024-08-25   603 NSUN2 mediates the activation of CD4+T cells in systemic lupus erythematosus through m5C modification CHEN Wenwen, ZHANG Min, FANG Su, GUO Gangqiang, XUE Xiangyang, MAO Sunzhong. DOI: 10.3969/j.issn.2095-9400.2024.08.001 Objective: To investigate the effect of mRNA m5C methyltransferase NSUN2 on CD4+ T cell activation in patients with systemic lupus erythematosus (SLE). Methods: The NSUN2-stable knockout Jurkat cell monoclonal strain was constructed by lentivirus infection and limited dilution method, and the knockout effectiveness of NSUN2 in Jurkat cells was detected by Western blot and immunofluorescence. Dot blot analysis was made of m5C modification level after NSUN2 knockout. Jurkat cells were activated with anti-human CD3/CD28 antibodies, and the expression levels of Jurkat cell activation markers CD69 and CD25 were detected by flow cytometry at 24 h and 48 h, respectively. The transcription levels of IL-2 and TNF-α after Jurkat cell activation were detected by RT-qPCR. A mouse model of NSUN2+/- was established, CD4+ T cells were isolated by magnetic beads, and the effect of NSUN2 knockdown on CD4+ T cell activation was further evaluated by inducing cell activation in vitro. Arraystar mRNA epigenome chip was used to detect the m5C modification and gene expression level in Jurkat cells after NSUN2 knockout, and m5C modified target genes regulated by NSUN2 were obtained.Combined with the m5C modified gene set of differences in CD4+ T cells of SLE patients set that differs in CD4+T cells of SLE patients, target genes regulated by NSUN2 and associated with SLE disease were screened, and then GO and KEGG enrichment was further used to analyze the potential pathway of NSUN2 regulating CD4+ T cell function in SLE. Results: The NSUN2-knockout Jurkat cell monoclonal strain was successfully obtained using CRISPR-Cas9 technology. Compared with the NSUN2-NC group, the m5C modification level was downregulated in the NSUN2-KO group, while the expression levels of Jurkat cell activation markers CD69 and CD25 were up-regulated. The expression levels of activation-related cytokines IL-2 and TNF-α were up-regulated (P<0.05). Compared with wild-type mice, the expression level of CD69, an activation marker of Naive CD4+ T cells in NSUN2+/- mice, was up-regulated. It was found that NSUN2-regulated gene sets existed in Jurkat cells,and GO and KEGG enrichment showed that these genes were related to T cell activation. Combined with the m5C modified gene set that differs in CD4+ T cells of SLE patients, the target gene set regulated by NSUN2 and associated with SLE disease was screened. GO and KEGG enrichment analysis confirmed that these gene sets were associated with CD4+ T cell function. Conclusion: NSUN2 knockdown promotes the activation of Jurkat cells and Naive CD4+ T cells in mice, and the potential signaling pathway of NSUN2 regulation of CD4+ T cell activation in SLE patients are preliminary screened. 2024 Vol. 54 (8): 603-613 [Abstract] ( 120 ) HTML (1 KB)  PDF (2331 KB)  ( 399 ) 614 Design and activity evaluation of FGF19 mutant based on FGFR asymmetric dimerization model ZHAO Jing, CAO Yu, ZHOU Chuanren, WU Jiamin DOI: 10.3969/j.issn.2095-9400.2024.08.002 Objective: To explore the non-tumorigenic mutant of fibroblast growth factor 19 (FGF19) based on the asymmetric dimerization model of fibroblast growth factor receptor (FGFR) and to evaluate its proliferative and metabolic activities with a view to make it a potential drug for the treatment of cholestasis. Methods: Pymol software was used to analyze the protein crystal structure and design the FGF19 mutant; the modified FGF19 mutant (FGF19F159A) and wild-type FGF19 (FGF19WT) plasmids were transformed into E. coli competent cells,and then the protein with the correct conformation was obtained through induction expression, denaturation, and renaturation. The target protein was purified by nickel column affinity chromatography and molecular exclusion chromatography; Proximity Ligation Assay technique was used to compare the receptor dimerization abilities induced by FGF19WT and FGF19F159A; Cell proliferation activity was measured by MTT method; Western blot assay was used to detect protein expression levels of phospho-fibroblast growth factor receptor substrate 2 (PFRS2),phospho-extracellular regulated protein kinase (P-ERK), and cholesterol 7alpha-hydroxylase (Cyp7A1);Immunohistochemistry was used to detect the expression levels of proliferation indicators, Ki67 and proliferating cell nuclear antigen (PCNA); RT-qPCR was implemented to determine the relative mRNA levels of tumor indicators, such as alpha-fetoprotein (AFP), cyclin A2 (CCNA2) and epidermal growth factor receptor (EGFR);Mass spectrometry was used to determine the content of cholic acid (CA), deoxycholic acid (DCA), ursodeoxycholic acid (UDCA), chenodeoxycholic acid (CDCA) in the liver; after db/db mice were injected with FGF19WT and FGF19F159A for one month, their blood glucose level was monitored and compared and the ability to improve glucose tolerance was tested through glucose tolerance experiments. Results: Based on the structural design,FGF19F159A was successfully constructed, and protein with high purity was obtained through expression and purification; PLA experiments showed that FGF19F159A significantly reduced the degree of receptor dimerization compared with the FGF19WT group (P<0.01); MTT experiments showed that the proliferative activity of FGF19F159A was significantly reduced compared to the FGF19WT group (P<0.05); Western blot experiments showed that FGF19F159A significantly decreased the expression level of P-FRS2 and P-ERK, compared with the FGF19WT group (P<0.05); Immunohistochemical analysis showed that FGF19F159A significantly declined the expression level of proliferation markers such as Ki67 and PCNA in the liver (P<0.01), compared with the FGF19WT group; FGF19F159A prominently suppressed the relative mRNA levels of AFP, CCNA2 and EGFR in the liver, compared with the FGF19WT group (P<0.01); There was no significant difference in the protein expression level of Cyp7A1 and the content of CA, DCA, UDCA and CDCA in the liver of the FGF19F159A group compared to the FGF19WT group (P>0.05); There was basically no difference between FGF19F159A and FGF19WT in the ability to lower blood glucose and improve glucose tolerance (P>0.05). Conclusion: The FGF19F159A designed based on the asymmetric dimerization model of FGFR significantly reduces proliferative activity while retaining its metabolic activity, which is expected to become a potential drug for cholestasis. 2024 Vol. 54 (8): 614-622 [Abstract] ( 76 ) HTML (1 KB)  PDF (2079 KB)  ( 209 ) 623 Crebanine inhibits pancreatic cancer cell growth through DUSP5/ERK signaling pathway LIN Chengyin,XIANG Shixuan, CHEN Letaotao, DENG Jie DOI: 10.3969/j.issn.2095-9400.2024.08.003 Objective: To explore the effect of crebanine on the proliferation and apoptosis of pancreatic cancer cells and its potential mechanism. Methods: CCK8, clone formation assay and EdU staining were used to detect the effect of crebanine on the proliferation of human pancreatic cancer cells Panc-1 and Patu-8988. The effect of crebanine on apoptosis was detected by flow cytometry and TUNEL staining. Western blot assay was conducted to determine the effects of crebanine on DUSP5 protein, proliferation-related protein Ki67, apoptosisrelated proteins Bcl-2 and Bax, and p-ERK1/2. Results: After 24 h treatment with crebanine, the proliferation ability of pancreatic cancer cells decreased (P<0.05), while the apoptosis rate increased significantly (P<0.05).Meanwhile, the expression of DUSP5 was markedly upregulated (P<0.05), and the expression of p-ERK1/2 was downregulated (P<0.05). Knockdown of DUSP5 effectively reversed the anti-proliferation and pro-apoptotic abilities of crebanine in pancreatic cancer cells (all P<0.05), and partially restored the p-ERK1/2 protein reduced by crebanine (P<0.05). Conclusion: Crebanine inhibits the proliferation and promotes apoptosis of pancreatic cancer cells by upregulating DUSP5 expression and subsequently inactivating ERK1/2 signaling. 2024 Vol. 54 (8): 623-630 [Abstract] ( 115 ) HTML (1 KB)  PDF (2201 KB)  ( 201 ) 631 FR-PVT: A feature-refined pyramid vision transformer for accurate image segmentation NIE Yingwang,WANG Lei, MEI Chenyang, CHEN Hao DOI: 10.3969/j.issn.2095-9400.2024.08.004 Objective: To accurately extract target regions in medical images used for morphological assessment and clinical disease monitoring, a hybrid network combining Convolutional Neural Network (CNN) and Transformer was explored to simultaneously learn local and global information in images. Methods: ①A novel feature-refined segmentation network (referred to as FR-PVT) was developed by introducing a CNN-based decoder and integrating it with the pyramid vision transformer (PVT). The decoder was used to refine multiscale global features captured by the PVT, consisting of the feature refinement module (FRM), context attention module (CAM), and similarity aggregation module (SAM). ②To validate FR-PVT, it was used to segment polyps from five public colonoscopy image datasets (ClinicDB, ColonDB, EndoScene, ETIS, and KvasirSEG) and palpebral fissures from frame images in the eye videography dataset provided by the Eye Hospital of Wenzhou Medical University. ③The performance of FR-PVT was evaluated by four different metrics, including Dice coefficient, IOU, Matthews correlation coefficient (MCC), and Hausdorff distance (Hdf). The same segmentation tasks were compared between FR-PVT and the networks available (Polyp-PVT, U-Net, and its multiple variants).Results: ①The FR-PVT was able to handle colonoscopy images acquired under various imaging conditions and achieved average Dice coefficients of 0.937, 0.819, 0.892, 0.800, and 0.909, respectively, for the five different testing subsets from ClinicDB, ColonDB, EndoScene, ETIS, and KvasirSEG datasets. ②Experimental results on frame images from the eye videography dataset showed that the FR-PVT obtainedaverage Dice, IOU, MCC,and Hdf of 0.966, 0.943, 0.957, and 4.706, respectively. ③The segmentation performance on five polyp datasets showed that the FR-PVT obtained average Dice and IOU of 0.840 and 0.764, outperforming Polyp-PVT (0.834 and 0.760), U-Net (0.561 and 0.493), U-Net++ (0.546 and 0.476), SFA (0.476 and 0.367), PraNet (0.741 and 0.675). Performance differences on frame images from the eye videography dataset showed that the FR-PVT obtains average Dice and IOU of 0.840 and 0.764. Conclusion: The FR-PVT achieves better segmentation performance than Polyp-PVT and several CNN-based networks available (such as U-Net and its variants). 2024 Vol. 54 (8): 631-640 [Abstract] ( 80 ) HTML (1 KB)  PDF (2333 KB)  ( 283 ) 641 Bone marrow mesenchymal stem cell-derived exosomes reverse high glucose-induced osteogenic dysfunction of bone marrow mesenchymal stem cells via PI3K/AKT signaling pathway TAO Endong,XIA Weijie, WANG Fulin, WANG Xianyu, CAI Leyi, FENG Yongzeng. DOI: 10.3969/j.issn.2095-9400.2024.08.005 Objective: To investigate the therapeutic effect of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-EXOs) on high glucose-induced osteogenic dysfunction of bone marrow mesenchymal stem cells (BMSCs) and its mechanism. Metheds: Exosomes were extracted from BMSCs by ultracentrifugation, and their characteristics were evaluated by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. High glucose medium was used to simulate the high glucose microenvironment, and the effect of BMSCs-EXOs on the oxidative stress level, osteogenic differentiation, and mineralization ability of high glucose-induced BMSCs were studied by DCFH-DA fluorescent probe, Western blot, cell immunofluorescence (IF), alkaline phosphatase staining (ALP), and alizarin red staining (ARS). In addition, the PI3K pathway blocker (LY294002) was used to inhibit the phosphorylation of PI3K to study whether BMSCs-EXOs affect the osteogenic differentiation and mineralization ability of BMSCs by activating the PI3K/AKT signaling pathway. Results:The successfully extracted exosomes from BMSCs were evaluated by TEM, NTA and Western blot. Compared with the control group, the oxidative stress level was significantly increased in the HG group (P<0.05) and the protein expression levels of HO-1 and NQO-1 significantly decreased (P<0.05); the activities of ALP and ARS were significantly decreased (P<0.05), and the protein expression levels of COL1A1, RUNX2, BMP2, p-PI3K and p-AKT were significantly decreased (P<0.05). Compared with the HG group, the oxidative stress level was significantly decreased (P<0.05) and the protein expression levels of HO-1 and NQO-1 were significantly upregulated (P<0.05); the activities of ALP and ARS were significantly increased (P<0.05), and the protein expression levels of COL1A1, RUNX2, BMP2, p-PI3K and p-AKT were significantly up-regulated (P<0.05).When LY294002 was added, the phosphorylation expression of the PI3K/AKT signaling pathway was significantly inhibited, and the osteogenic effect of BMSCs-EXOs was also significantly weakened (P<0.05). Conclusion:BMSCs-EXOs partially restored osteogenic differentiation and mineralization by reducing high glucose-induced oxidative stress levels, and this osteogenic effect of BMSCs-EXOs was demonstrated to be achieved through the PI3K/AKT signaling pathway. 2024 Vol. 54 (8): 641-649 [Abstract] ( 207 ) HTML (1 KB)  PDF (2329 KB)  ( 294 ) 650 Network target prediction and mechanism confirmation of ginsenoside Rg1 in treating multiple myeloma LIN Li, LU Ying, LI Kongfei, WANG Tiantian, YU Zhuruohan. DOI: 10.3969/j.issn.2095-9400.2024.08.006 Objective: To explore the mechanism of ginsenoside Rg1 in the treatment of multiple myeloma (MM) by using network pharmacology and in vitro cell experiments. Methods: TTD, DisGeNet, GeneCards,PharmGKB, PubChem, Super-PRED and PharmMapper were used to predict the MM target. Ginsenoside Rg1 target was predicted by CTD and SymMap database. Protein-protein interaction network of MM and Rg1 intersection targets was constructed by STRING database. Gene Ontology (GO) and KEGG-pathway database were used to enrich the main biological functions and signal pathways of Rg1 in treating MM. Molecular docking was used to verify the binding activity of the core target with Rg1. CCK-8, flow cytometry and Western blot experiments were used to detect the cell activity, apoptosis rate, ROS level and the relative expression of core action targets Caspase3, Bax, Bcl-2 and NF-κB p65 in RPMI 8226 cell at different doses of ginsenoside Rg1 (5,10 and 20 μmol/L). Results: A total of 215 Rg1-MM targets were screened. The enrichment analysis of GO and KEGG pathway suggested that the mechanism of Rg1 in treating MM might involve oxidative stress, apoptosis and inflammation-related signaling pathways. Molecular docking suggested that Rg1 might play a role by regulating NFKB1, STAT3, AKT1, MAPK3, CASP3, BCL2 and other targets. In vitro experiments, compared with the control group, Rg1 (5, 10 and 20 μmol/L) significantly inhibited the proliferation (P<0.01) of RPMI 8226 cell,promoted apoptosis (P<0.01) and ROS production (P<0.01), and inhibited the activation of NF-κB signaling pathway (P<0.05). Conclusion: Ginsenoside Rg1 has a potential therapeutic effect on MM, which can regulate oxidative stress, apoptosis and proliferation of RPMI 8226 cell, and its mechanism involves the regulation of NF-κB signaling pathway. 2024 Vol. 54 (8): 650-656，663 [Abstract] ( 119 ) HTML (1 KB)  PDF (2417 KB)  ( 243 ) 657 Association between ceramide and risk of new-onset atrial fibrillation in acute myocardial infarction GUAN Fanlu, JIANG Wenbing DOI: 10.3969/j.issn.2095-9400.2024.08.007 Objective: To analyze the clinical features of new-onset atrial fibrillation in patients with acute myocardial infarction, and to explore the association between ceramides and the risk of new-onset atrial fibrillation.Methods: From January 2020 to March 2024, a total of 815 patients with acute myocardial infarction in Wenzhou people’s hospital were enrolled. Among them, 85 patients developed new-onset atrial fibrillation within 24 hours of admission. Demographics, comorbidities, laboratory tests, and ceramide (C16, C24, C24:1) were collected at admission and compared between the two groups (atrial fibrillation vs non-atrial fibrillation). Multivariate Logistic regression was used to adjust for different variables, and then the association between ceramide and the risk of new-onset atrial fibrillation in patients with myocardial infarction and the potential mechanism were analyzed.Results: Compared with non-atrial fibrillation, the patients with new-onset atrial fibrillation were mainly male,significantly older, and had more comorbidities. After adjustment for baseline characteristics, ceramides were associated with the risk of atrial fibrillation in patients with MI (C16: OR=1.99, 95%CI=1.15-3.46, P=0.014;C24: OR=0.87, 95%CI=0.78-0.97, P=0.013; C24:1: OR=1.33, 95%CI=1.05-1.69, P=0.016), the association was attenuated after the adjustment of CRP and NT-proBNP. Conclusion: Ceramides were associated with newonset atrial fibrillation in patients with myocardial infarction, with increased C16 and C24:1 associated with an increased risk of atrial fibrillation, while increased C24 was associated with a reduced risk of atrial fibrillation. 2024 Vol. 54 (8): 657-663 [Abstract] ( 89 ) HTML (1 KB)  PDF (1281 KB)  ( 195 ) 664 The relationship between cognitive function impairment and 25 (OH) D3 levels in children with obstructive sleep apnea-hypopnea syndrome CAI Weini, YU Chenyi, ZHONG Peipei, CAI Xiaohong DOI: 10.3969/j.issn.2095-9400.2024.08.008 Objective: To analyze the relationship between cognitive function and 25-hydroxyvitamin D3 [25(OH)D3] levels in children with obstructive sleep apnea-hypopnea syndrome (OSAHS) and explore the mechanism of cognitive function impairment in children with OSAHS. Methods: From January 2022 to January 2023, 100 children admitted to the Department of Pediatric Sleep Medicine of the Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University due to “snoring” were selected. According to the results of overnight polysomnography monitoring, 50 children in the OSAHS group and 50 children in the simple snoring group. And 30 healthy children who underwent physical examinations in the same period were selected as healthy group. The sleep monitoring data, cognitive function, and serum 25(OH)D3 levels of children in the healthy group, simple snoring group, and OSAHS group were compared. Results: Compared with the healthy group and the simple snoring group, children with OSAHS had decreased sleep effficiency (SE), reduced deep sleep time (SWM sleep), increased light sleep time (I+II sleep), statistically significant differences in minimum oxygen saturation (L-SpO2) and obstructive apnea hypopnea index (OAHI) among the three groups (P<0.05).The serum 25(OH)D3 levels in children with OSAHS were decreased significantly (P<0.05). The planned level and attention level of children in OSAHS group decreased (P<0.05), with no statistically significant differences in simultaneous processing and sequential processing levels among the three groups (P>0.05). Pearson correlation analysis showed that the serum 25(OH)D3 levels of OSAHS children were positively correlated with L-SpO2 (r=0.793, P<0.001), and negatively correlated with OAHI (r=-0.559, P<0.001). 25(OH)D3 level was positively correlated with the planning level (r=0.615, P<0.001) and attention level (r=0.558, P<0.001). The OAHI in OSAHS children was negatively correlated with the planned level (r=-0.630, P<0.001) and attention level (r=-0.538, P<0.001). L-SpO2 of children with OSAHS was positively correlated with the planned level (r=0.841,P<0.001) and attention level (r=0.477, P<0.001) in OSAHS children. Conclusion: The level of serum 25(OH)D3 in children is associated with OSAHS, the severity of OSAHS is negatively correlated with the level of 25(OH)D3.The cognitive function impairment of children with OSAHS is positively correlated with the 25(OH)D3 level,and the severity of OSAHS is positively related to cognitive function impairment. Hence, the decrease in serum 25(OH)D3 levels may exacerbate the cognitive impairment in children with OSAHS. 2024 Vol. 54 (8): 664-669 [Abstract] ( 77 ) HTML (1 KB)  PDF (1453 KB)  ( 256 ) 672 The prenatal diagnosis and genetic background of fetal growth restriction CHEN Yangping, HUANG Hailong DOI: 10.3969/j.issn.2095-9400.2024.08.010 Fetal growth restriction (FGR) is one of the most formidable challenges in prenatal period,which could cause not only fetal death in the third trimester in utero, but also adult metabolic syndrome such as metabolic diseases, diabetes and hypertension. There is no obviously effective treatment in utero. Its etiology is complex, with fetal genetics as one of the important reasons. Prenatal identification of the genetic etiology of FGR is crucial to the prognosis of FGR. Chromosome microarray analysis can detect about an extra 10% of copy number variation in addition to chromosome karyotype analysis, but there are many reasons unknown yet.Postnatal application of whole exome sequencing can detect additional monogenic diseases. With the development of whole exome sequencing technology followed with reduced cost, it is expected to become the first-tier prenatal detection method for FGR. 2024 Vol. 54 (8): 672-677 [Abstract] ( 109 ) HTML (1 KB)  PDF (1245 KB)  ( 185 ) 678 Faculty structure model on the teaching effect of Medical Statistics course in medical undergraduates YU Qiuyan, XU Yixi, MAO Guangyun, YANG Xinjun. DOI: 10.3969/j.issn.2095-9400.2024.08.011 Objective: To examine the effect of faculty structure model on the teaching effect of Medical Statistics in medical undergraduates. Methods: The undergraduates who take Medical Statistics course in Wenzhou Medical University were selected as the subjects of investigation. The course evaluation through self-designed questionnaire was collected, and the students’ grades and lecturers were linked through the academic information system. The mixed effect model was employed to evaluate the effect of faculty structure on the teaching results.Results: A total of 1 964 participants completed the questionnaire. The number of undergraduates and median value of total grade was 1 186(60.4%) and 81 in the “Professor-Lecturer” pattern, 251(12.78%) and 86 in the “Professor-Associated Professor” pattern, 286(14.56%) and 80 in the “Associated Professor-Lecturer” pattern, and 241(12.27%) and 80 in the “Lecturer-Lecturer” pattern. There was 30% of undergraduates whose experimental course were given by teachers from the Office of Epidemiology and Health Statistics (the E&HS office). A total of 785(40%) undergraduates agreed that they acquired the related knowledge and skills through this course. From the results of mixed effect model, the final grade of undergraduates whose theoretical course given by the professor and associate professor were significantly higher than those given by the professor and lecturer (β=5.036,95%CI=0.065-9.524, P<0.001), and the interaction effect existed between the theoretical pattern and the experimental pattern of faculty structure. The undergraduates whose theoretical course were given by the “Associated Professor-Lecturer” pattern (β=0.165, 95%CI=0.002-0.322, P=0.049) and the “Lecturer-Lecturer” pattern (β=0.231, 95%CI=0.065-0.410, P=0.014) achieved higher self-evaluated scores in the acquired knowledge and skills than the “Professor-Lecturer” pattern. Conclusion: In teaching theoretical courses, it is appropriate to increase the proportion of the “Professor-Associated Professor” pattern and encourage the lecturers to take multiple measures to enrich their own teaching styles. Under the same teaching guide of experimental course and classroom exercises, it is not necessary to prioritize the teachers from the E&HS office to give experimental courses. 2024 Vol. 54 (8): 678-683,封三 [Abstract] ( 120 ) HTML (1 KB)  PDF (1333 KB)  ( 192 ) 684 Dilemmas of college students evaluation and its optimization strategies under the background of highquality development: A case study of Wenzhou Medical University JIN Sufan, Wang Chaojie, ZHU Xuebo DOI: 10.3969/j.issn.2095-9400.2024.08.012 On the basis of analyzing the role and value of student evaluation in universities, this article proposes four dilemmas in current student evaluation: deviation of evaluation objects, psychological deviation,improper approaches, and lack of result feedback. The specific causes of these dilemmas are analyzed and explained from the perspective of the relationship between students, teachers, and managers. Through a detailed introduction and analysis of Wenzhou Medical University’s practice in improving the quality of student evaluation,it is proposed that under the background of high-quality development, student evaluation work should be improved from five aspects: developing a positive attitude towards teaching quality, enhancing the awareness of teachers and students for evaluation, establishing a quality assurance system that runs through the entire process,improving the application of evaluation results, and forming a two-way linkage between teaching evaluation and teacher development. 2024 Vol. 54 (8): 684-688，封三 [Abstract] ( 98 ) HTML (1 KB)  PDF (1418 KB)  ( 224 )

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