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    Construction and characterization of mice with conditional knockout of Stat3 gene in microglia
    ZHU Xiaochen, XIE Xinyi, ZHAO Xuri, XU Lina, HE Zhiyan, ZHOU Wei
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (6): 689-698.   DOI: 10.3969/j.issn.1674-8115.2023.06.005
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    Objective ·To construct mice with conditional knockout of Stat3 gene in microglia based on the Cre-Loxp system and validate their knockout efficiency. Methods ·Cx3cr1creERT2 and Stat3fl/fl genotypic mice were bred for conditional knockout mice (CKO) and Wild Type mice (WT). The mouse genotypes were determined by extracting DNA from mouse tissues through Polymerase Chain Reaction (PCR) combined with the amplification results of cre and flox primers. Stat3 knockdown was induced by intraperitoneal injection of tamoxifen in the CKO and WT mice at 6 weeks of age. The CKO mice (n=4) and WT mice (n=4) were randomly selected for the detection. After two weeks of observation, microglia cells were sorted out by Magnetic Activated Cell Sorting (MACS). Real-time PCR (RT-PCR) was used to detect gene knockout efficiency at the gene level. The expression of STAT3 in microglia was observed by brain immunofluorescence staining. The expression rate of STAT3 in microglia was detected by flow cytometry. The expression rate of STAT3 in macrophages of the spleen was detected by flow cytometry. The condition of neuronal cells was examined by Nissl staining. The condition of the microglia in the cortex and hippocampus was observed by brain immunofluorescence staining. The phenotype of the microglia was detected by flow cytometry. Results ·The CKO mice and WT mice were successfully bred. MACS boosted the proportion of microglia in brain cells from 10% to 85%. RT-PCR results showed that mRNA levels of Stat3 were down-regulated in microglia of CKO mice, compared with the WT mice (P=0.001). The relative mRNA expression of Stat3 in microglia of the CKO mice was 0.331 7±0.041 4. Immunofluorescence staining of brain tissues showed that the fluorescence intensity of STAT3 in microglia of the CKO mice was weaker than that of the WT mice. Flow cytometry of brain tissues showed that the STAT3-positive cells in microglia of the WT mice was (85.30±5.69)% and the CKO mice was (39.70±3.88)%. STAT3 expression was decreased in microglia of the CKO mice (P=0.001). Flow cytometry of spleen tissues showed that there was no statistical difference in the percentage of STAT3-positive cells in splenic macrophages between the CKO and WT mice (P>0.05). Nissl staining showed that there were no significant differences between the neuronal cells of the CKO mice and WT mice. Immunofluorescencestaining of brain tissues showed that there was no significant difference in the shape of microglia between the CKO mice and WT mice. Flow cytometry showed that the phenotype of microglia in the CKO mice was not remarkably different from that of the WT mice. Conclusion ·We successfully construct the STAT3 gene conditional knockout mice from microglia, which provides the foundation for subsequent related studies.

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    Research progress in biological activities and mechanisms of theabrownin
    WANG Jieyi, ZHENG Dan, ZHENG Xiaojiao, JIA Wei, ZHAO Aihua
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (6): 768-774.   DOI: 10.3969/j.issn.1674-8115.2023.06.014
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    Tea is beneficial to human health, which is rich in tea pigments with important biological activities. Theabrownin, derived from theaflavins and thearubigins by oxidative polymerization, mainly distributes in semi-fermented oolong tea, and completely fermented black tea and dark tea. As a kind of macromolecular substance, theabrownin cannot be directly absorbed by the gut, but it can directly interact with intestinal microbiota to regulate and maintain the homeostasis of intestinal flora. Theabrownin has multiple physiological roles via modulating the gut microbiota, including inhibiting hepatic cholesterol production, promoting the catabolism of cholesterol and triglyceride, and promoting energy metabolism in adipose tissues, thereby improving lipid metabolism. Theabrownin can also directly influence the gut absorption of glucose to improve carbohydrate metabolism and maintain blood glucose homeostasis. Theabrownin plays an anti-tumor role by inducing apoptosis and regulating gene expression in tumor cells. Theabrownin also plays an anti-inflammatory role via participating in the regulation of the immune cell differentiation and the levels of inflammatory factors. This review summarizes the formation process, the extraction procedures, and the chemical structure of theabrownin, and reviews the effects and mechanisms of theabrownin on intestinal microbiota, lipid metabolism, blood glucose homeostasis, cancer and inflammation.

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    Exploratory analysis of gut microbiota differences in childhood asthma with different severity
    WEN Yajin, HE Wen, HAN Xiao, ZHANG Xiaobo
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (6): 655-664.   DOI: 10.3969/j.issn.1674-8115.2023.06.001
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    Objective ·To explore the characteristics and differences of gut microbiota in children with different severity of bronchial asthma, and build a prediction model of gut microbiota in severe asthma. Methods ·In this study, children aged 5 to 14 diagnosed with asthma in the Department of Respiratory Medicine of Children's Hospital of Fudan University from Sep 1, 2020 to Aug 31, 2022 were selected, and children with severe asthma (SA) according to the Recommendations for Standardized Diagnosis and Managementof Bronchial AsthmainChildren (2020) were included. Children with mild to moderate asthma (MMA) and healthy children in the same period were matched according to age and gender. Stool samples collected from the three groups were subjected to 16S rRNA gene sequencing and the gut microbiota diversity, structure, and composition were assessed. The area under the receiver operating characteristic (ROC) curve (AUC) was applied to compare the predictive efficacy for SA. Results ·Fifty children were enrolled in the SA group, 54 children matched by gender and age were in the MMA group and 39 healthy children were in the healthy control group. The α diversity of gut microbiota significantly decreased in the asthma children (P<0.05), compared with that in the healthy control group. The relative abundance of Treponema was the highest in the SA group, followed by the MMA group and healthy control group (P<0.001). The relative abundance of Lactobacillus in the MMA group and SA group was higher than that in the healthy control group (both P<0.05). The SA group had a higher relative abundance of Prevotella, Lactobacillus, Eubacterium_eligens_group, Treponema, and Fusicatenibacter. The MMA group had a higher relative abundance of Barnesiella, Holdemanella, Romboutsia and Turicibacter. The healthy control group had a higher relative abundance of the uncultured and Muribaculaceae. Among them, the relative abundance of Barnesiella decreased in the SA group, and it was found to have the highest sensitivity and specificity in predicting SA (AUC 0.713, 95%CI 0.604?0.815). Conclusion ·The diversity of gut microbiota in asthma children is lower than that in healthy children, and the composition of gut microbiota differs among childhood asthma with different severity. The abundance of Barnesiella decreases in the SA group significantly, suggesting that analysis of gut microbiota may help in the assessment of childhood asthma with different severity.

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    Research progress in the relationship between mitochondrial dysfunction and osteoporosis
    JIN Fangquan, FAN Chenghu, TANG Xiaodong, CHEN Yantong, QI Bingxian
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (6): 761-767.   DOI: 10.3969/j.issn.1674-8115.2023.06.013
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    Osteoporosis (OP) is a chronic senile bone disease characterized by decreased bone mass and increased bone fragility. There are many inducing factors and the pathogenesis is complex. To explore the mechanism of OP and improve clinical efficacy has always been a hot topic in life science. In recent years, it has been found that mitochondria play an important role in the pathogenesis of OP. Functional abnormalities such as mitochondrial energy metabolism, mitochondrial oxidative stress, mitochondrial autophagy, mitochondrial-mediated apoptosis and mitochondrial dynamics can interfere with the differentiation of bone marrow mesenchymal stem cells through different signal pathways, cytokines and protein expression to regulate osteoblast activity, proliferation and differentiation, and start the process of osteoclast apoptosis. Therefore, taking mitochondria as the target, regulating the functions of mitochondrial energy metabolism, oxidative stress, autophagy and kinetics, inducing osteogenic differentiation of bone marrow mesenchymal stem cells, promoting osteoblast differentiation and mineralization, and inducing osteoclast apoptosis are potential strategies for the prevention and treatment of OP. In this article, the mechanism of mitochondrial dysfunction in OP was reviewed by referring to relevant literature at home and abroad, in order to lay a foundation for further research.

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    Research progress in autologous regeneration of human corneal endothelial cells
    CHEN Jin, FU Yao
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (6): 775-780.   DOI: 10.3969/j.issn.1674-8115.2023.06.015
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    Human corneal endothelial cells (HCECs) are very important for maintaining corneal transparency, but HCECs remain arrested at the G1 phase after embryonic development and could not proliferate and regenerate in vivo. The density of HCECs decreases spontaneously with corneal development and aging, while systemic factors and corneal diseases can further cause a massive loss to HCECs, lead to corneal opacity and edema and ultimately induce vision impairment. Therefore, the regeneration of HCECs has always been a heated topic in the field of corneal endothelial research. Currently, function restoration of exogenous corneal endothelium mediated by cell therapy and autologous regeneration of endogenous HCECs have made amazing breakthroughs, with endogenous HCECs autologous regeneration being a more convenient and physiological treatment option. This review summarizes and analyzes the strategies and related techniques that are currently applied to the autologous regeneration of HCECs in aspects of operative treatment, gene therapy and pharmacological treatment.

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    SIRT2 regulates macrophage chemotaxis by de-modifying histone H4K8 lactylation
    SONG Wenting, TAO Yue, PAN Yi, MO Xi, CAO Qing
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (8): 1008-1016.   DOI: 10.3969/j.issn.1674-8115.2023.08.008
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    Objective ·To explore the regulatory role of silent information regulator 2 (SIRT2) in modulating the immune phenotype of macrophages after infection by removing the lactylation at H4K8 site of histone and the corresponding mechanism. Methods ·Human THP-1 leukemia cells were induced by phorbol 12-myristate 13-acetate (PMA) and stimulated by lipopolysaccharide (LPS) to establish a macrophage infection model. Macrophages without LPS treatment (pTHP-1) were set as the control (CTRL) group, and macrophages with LPS treatment were set as the infected (LPS) group. Western blotting was used to detect the level of histone modification and SIRT2 protein in macrophages. RT-qPCR was used to detect the expression level of glycolytic key enzymes [phosphofructokinase liver type (PFKL), lactate dehydrogenase A (LDHA)] and modulators genes hypoxia inducible factor 1α (HIF-1α), and the expression level of Sirtuin genes and HDAC genes between the two groups. Transwell was used to detect the ability of macrophage chemotaxis. Lentivirus packaging and cell infection were used to construct SIRT2 overexpression cell line. The interaction analysis method of RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) was used to analyze the difference and pathway enrichment of the genes specifically bound to H4K8 lactylation (H4K8la). Results ·Compared to the CTRL group, macrophage glycolysis was upregulated and the level of H4K8la was significantly increased in the LPS group (P<0.05), while the level of lactylation in other sites remained unchanged. Among all known enzymes with deacetylation modification function, only SIRT2 showed a significant decrease after LPS treatment (P<0.05), and overexpression of SIRT2 could significantly inhibit the level of H4K8la modification, while the level of H4K8ac remained unchanged (P>0.05). The interactive analysis of ChIP-seq and RNA-seq revealed that chemotaxis-related genes were regulated by H4K8la, and macrophage chemotaxis ability significantly decreased after the overexpression of SIRT2 and downregulation of H4K8la (P<0.05). Conclusion ·SIRT2 can change the expression of target genes related to chemotaxis by removing H4K8la modification, thereby reducing the chemotaxis ability of macrophages. Targeting SIRT2 and H4K8la modification may help control inflammation mediated by macrophages.

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    Research progress of exercise therapy for depressive disorder
    ZHANG Shuoyuan, LI Chunbo
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (7): 916-922.   DOI: 10.3969/j.issn.1674-8115.2023.07.014
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    Depressive disorder, as one of the major diseases in the world, has always received much attention for its prevention and treatment. As an emerging treatment, exercise therapy has optimistic application prospect with the advantages such as lower cost, fewer side effects and easier implementation, compared to conventional treatments such as drug therapy and physical therapy. Relevant studies have explored the mechanism of exercise in the treatment of depressive disorder, but the mechanism is not clear yet, which may involve improving the levels of neurobiochemical molecules, inhibiting inflammatory response, regulating neuroendocrine system, improving neuroplasticity, and other aspects. Exercise therapy has been proved to have similar biological effects with antidepressants, and may have overlapping effects with other treatments. Early intervention can benefit both non- diseased and already diseased populations to a certain extent. At present, there is still a gap in the clinical field related to exercise therapy for depressive disorder, and there are few high-quality studies. The design of exercise therapy plans is still in the exploratory stage, and there is no consensus on the design of exercise therapy plans. Additionally, there is a lack of relevant exercise therapy guidelines for clinicians to refer to. This review systematically introduces the biological mechanism of exercise therapy for depressive disorder, summarizes the clinical research results in this field carried out at home and abroad, and analyzes the current program and advantages and disadvantages of exercise therapy, in order to provide reference for the in-depth development of the exercise therapy researches.

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    Study on factors influencing social network service addiction among junior college students based on problem behavior theory
    WANG Suping, TANG Hua, ZHOU Dong, CAI Yong, GONG Ruijie
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (8): 955-962.   DOI: 10.3969/j.issn.1674-8115.2023.08.002
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    Objective ·To construct a structural equation model based on problem behavior theory to conduct a study on social network addiction among junior college students. Methods ·A cross-sectional questionnaire survey was conducted in a college in Shanghai. Logistic regression analysis was used to analyze the effects of gender, grade, study pressure, self-esteem, loneliness, depression, entrapment, defeat, interpersonal needs, perceived social support, smoking, alcohol, exercise, and academic achievement on social network service addiction. Based on the problem behavior theory, the structural equation model was used to construct a theoretical framework model of social network service addiction of junior college students. Results ·60.31% of the total 980 participants had social network service addiction. The univariate Logistic regression results showed that depression, self-esteem, loneliness, frustration, drowsiness, social support, interpersonal needs, exercise, and academic performance had a significant impact on social network addiction. The structural equation model fitted well [S-Bχ2/df=8.03, goodness-of-fit index (GFI)=0.924, comparative fit index (CFI)=0.909, Tucker-Lewis index (TLI)=0.872, root mean square error of approximation (RMSEA)=0.096, standardized root mean square residual (SRMR)=0.070], suggesting the mutual influence between the personality system and the perceived environment system, between the personality system and the behavioral system, and between the perceived environment system and the behavior system interact (β=1.018, P=0.000; β=0.218, P=0.003; β=0.268, P=0.000). The influence of personality system and behavior system on social network service addiction was not statistically significant, while the perceived environment system had a significant positive impact on social network service addiction (β=0.481, P=0.001). Conclusion ·Personality system and behavior system indirectly affect social network service addiction by influencing perceived environment system, and perceived environment system directly affects social network service addiction. For the problem of social network addiction among lower grade college students, it is necessary to fully respect the characteristics of college students, and work together from three levels of the system to reduce the risk of social network addiction among college students.

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    Construction of Shanghai Diabetes Clinical Database and real-world study
    XUE Yanbin, QI Jiying, ZHANG Zizheng, JING Renjie, SUN Wen, YAO Huayan, HE Ping, CUI Bin, NING Guang
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (9): 1145-1152.   DOI: 10.3969/j.issn.1674-8115.2023.09.008
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    Objective ·To construct a clinical database of diabetes in Shanghai, mine the value of clinical data, and carry out real-world study. Methods ·The data were extracted from Shanghai Link Healthcare Database. All original clinical data have undergone standard processes such as desensitization, encryption, cleaning, standardization, information extraction and structuring, and clinical data were analyzed by the method of medical statistics or machine learning according to different research contents. Results ·The database has imported the clinical data of 150 million visits and treatment records of 2.12 million diabetic patients in 37 municipal hospitals over a ten-year period from 2013 to 2022. The overall analysis showed the basic characteristics and development trends of all aspects of diabetes disease in real-world settings, the potential risks of diabetes are discovered by constructing retrospective cohort, and the inherent patterns of the disease are revealed by using machine learning methods such as cluster analysis and network analysis. Conclusion ·The establishment of Shanghai Diabetes Clinical Database can not only summarize and show the clinical status of diabetes, but also obtain more scientific achievements with realistic clinical value by real-world clinical data study.

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    Construction of acellular cartilage matrix/silk fibroin scaffold and its cartilage tissue engineering study
    WANG Qianyi, RAN Xinyue, ZHANG Peiling, CI Zheng, LEI Dong, ZHOU Guangdong
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (7): 795-803.   DOI: 10.3969/j.issn.1674-8115.2023.07.001
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    Objective ·To construct a bioactivity tissue engineering scaffold with double network cross-linking for cartilage tissue regeneration using an acellular cartilage matrix (ACM) with a natural silk fibroin (SF) biomaterial. Methods ·The cell-associated immunogenic components were removed by nuclease digestion, and the extracellular matrix-associated glycoproteins and collagen structures were retained, The efficiency of cartilage tissue decellularization was measured by spectrophotometry by using DNA, histoglycosaminoglycan and collagen quantification kits. ACM and SF were configured into a mixed solution, and the nucleophilic cross-linking reaction with the hydroxyl and carboxyl groups contained in both was carried out by adding ethylene glycol diglycidyl ether. Then it was freeze-dried to make porous bionic scaffolds (n=5). At the same time, porous scaffolds containing only ACM or SF were prepared by the same method (n=5). The microstructure of the scaffolds was observed by scanning electron microscopy (SEM), and the mechanical strength, elastic modulus and resilience of different groups of scaffolds were evaluated by mechanical tests. The internal and external nutrient exchange capacity of the scaffolds was reacted by water absorption rate. Chondrocytes from rabbit ears were isolated, cultured, and seeded on ACM-SF scaffolds. After 1, 4, and 7 days of culture, the adhesion, distribution, and matrix secretion of the cells on the scaffolds were observed by SEM, and the viability status of the cells was determined by double-staining of live and dead cells. CCK-8 method was used to determine the cytotoxicity of the scaffolds. The cells were implanted subcutaneously in nude mice, cultured in vivo for 4 and 8 weeks, and finally removed for histological testing. Differences between groups were tested by One-Way ANOVA. Statistical significance was accepted at a value of P<0.05. Results ·After enzymatic digestion, almost no cells remained in the acellular matrix, and the active components of the extracellular matrix were retained. The composite scaffold prepared by ACM-SF has interconnected microporous structure and good elasticity, and could recover its original shape after repeated compression in the wet state. The water absorption rate of ACM-SF reached nearly 20 times, which provided an effective material exchange condition for the cell adhesion environment. Histological tests showed that the ACM-SF scaffold regenerated homogeneous, typical cartilage tissue in vivo. Conclusion ·ACM-SF composite porous scaffold has a good bionic microenvironment and can be applied to tissue engineering cartilage regeneration.

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    Research progress in neuroimmune disorders in atopic dermatitis
    XUAN Zhenquan, CHEN Xuanyi, YAO Zhirong
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (8): 1049-1055.   DOI: 10.3969/j.issn.1674-8115.2023.08.014
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    Atopic dermatitis (AD) is a chronic inflammatory skin disease with the highest incidence in the world. The main clinical manifestations are eczema-like skin lesions, pruritus and xeroderma. Recent studies have revealed that sensory neurons in the skin lesions of AD patients can interact abnormally with keratinocytes (KC) and immune cells, leading to neuroimmune disorders. Among them, there are two types of sensory neurons involved in neuroimmune disorders, including histaminergic and non-histaminergic sensory neurons. In neuroimmune disorders, KC and immune cells activate sensory neurons to induce pruritus by secreting proinflammatory cytokines such as interleukin-4 (IL-4), IL-13, IL-31, IL-33, and thymic stromal lymphopoietin, as well as chemokines such as C-X-C motif chemokine ligand 12 (CXCL12) and CXCL10. In addition, neuropeptides such as nerve growth factor, brain-derived neurotrophic factor and artemin secreted by KC and immune cells can induce overgrowth of sensory neurons, thereby promoting neuroimmune disorders. At the same time, the excessive release of neuropeptides such as calcitonin gene-related peptide and substance P by sensory neurons can act on KC and immune cells, thereby aggravating skin inflammation. In recent years, many drugs targeting neuroimmune disorders are in preclinical studies, clinical trials and other stages, or have been marketed for the treatment of AD. Among them, our research group has found that lidocaine, a local anesthetic, can target neuroimmune disorders and relieve pruritus and skin inflammation in AD patients. At present, the role of neuroimmune disorders in AD has not been systematically discussed. Based on this, this article reviews the types of sensory neurons involved in neuroimmune disorders, the role of KC, immune cells and sensory neurons in neuroimmune disorders, as well as the therapeutic strategies targeting neuroimmune disorders.

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    RBX1 regulates uveal melanoma immune-related genes via STAT1
    ZHOU Xiaowen, LI Qian, ZHANG Zhe, SHEN Jianfeng, FAN Xianqun
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (6): 709-717.   DOI: 10.3969/j.issn.1674-8115.2023.06.007
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    Objective ·To investigate the role of RBX1 (ring-box protein 1) in the regulation of immune-related genes in uveal melanoma (UVM) tumor cells. Methods ·The Cancer Genome Atlas (TCGA) was searched to analyze the expression levels of RBX1 in tumors and the correlation with clinical stages and survival prognosis. RBX1 was transiently knocked down in the UVM cell lines, i.e., 92.1, OMM2.3 and MEL290 by using small interfering RNAs (siRNAs) targeting RBX1. RNA sequencing was performed on the 92.1 cells with transient knockdown of RBX1, and the differentially expressed genes between the siRBX1-transfected cells and control cells were analyzed by gene set enrichment analysis (GSEA) to investigate the relationship between RBX1 and tumor immune-related genes. Based on the results of the analysis, signal transducer and activator of transcription 1 (STAT1) and its downstream CXC chemokine ligand 9 (CXCL9) and CXCL10 mRNA expression levels were detected by real-time fluorescence quantitative PCR (qPCR) in 92.1, OMM2.3 and MEL290 cells with transient knockdown of RBX1, respectively. The protein expression levels of STAT1 and p-STAT1 in 92.1 cells were detected by Western blotting. The cell lines OMM2.3 and MEL290, in which RBX1 was transiently knocked down, were treated with 5 nmol/L or 10 nmol/L STAT1 inhibitor fludarabine for 48 h, and the mRNA expression levels of CXCL9 and CXCL10 were detected by qPCR. Results ·TCGA database analysis showed that RBX1 was highly expressed in a variety of tumors compared to the normal tissues, particularly in adrenocortical carcinoma and UVM. In addition, the patients with late stage of these two kinds of tumors had higher expression level of RBX1, and the patients with higher expression level of RBX1 had shorter overall survival time (P<0.05). RNA sequencing of 92.1 cells with transiently knocked down RBX1 and control cells revealed differential genes, and GSEA showed that RBX1 was involved in the regulation of tumor immune-related pathways. Heat map analysis showed an increase in STAT1 expression after RBX1 knockdown. In the 92.1, OMM2.3 and MEL290 cell lines, qPCR showed increases in STAT1, CXCL9 and CXCL10 mRNA expression after transient knockdown of RBX1, and Western blotting showed that STAT1 and p-STAT1 expression increased after knockdown of RBX1 in 92.1 cell lines. The increases of CXCL9 and CXCL10 mRNA in OMM2.3 and MEL290 cell lines were suppressed by STAT1 inhibitors. Conclusion ·RBX1 may regulate CXCL9 and CXCL10 expression via STAT1 in UVM cells and is involved in tumor immune regulation.

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    Mechanism of blood-brain barrier damage caused by the inhibition of Wnt7/β-catenin pathway induced by endoplasmic reticulum stress in cerebrovascular endothelial cells after stroke
    DONG Haiping, XIE Haiyi, MA Xiaoxiao, WANG Zhenhong
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (7): 829-838.   DOI: 10.3969/j.issn.1674-8115.2023.07.005
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    Objective ·To investigate whether the inactivation of Wnt7/β-catenin signaling causes the destruction of the blood-brain barrier (BBB) in cerebrovascular endothelial cells after ischemic stroke, and investigate whether endoplasmic reticulum stress bursts mediates the inhibition of Wnt7/β-catenin pathway. Methods ·The model of middle cerebral artery occlusion (MCAO) in mice was established by a monofilament nylon suture with a round tip, which was used to temporarily occlude the middle cerebral artery for 60 min. MCAO model mice were intraperitoneally injected with the endoplasmic reticulum stress blocker 4-phenylbutyric acid (4-PBA) as 4-PBA+MCAO group. Sham surgery group (Sham group) was set. Twenty-four hours after MCAO, Evans blue (EB) was used to measure the BBB permeability. The brain water content was calculated by dry-wet weight ratio, and the adhesion of cerebrovascular endothelial cells and pericytes in mice was measured by immunofluorescence. Human brain microvascular endothelial cells (HBMECs) were used to establish an oxygen and glucose deprivation (OGD) model for 4 h, and then cultured with 4-PBA for 24 h. Cells were divided into blank control group, OGD group, and OGD+4-PBA group for CCK-8 assay to determine the cell viability. FITC-labeled bovine serum albumin (FITC-BSA) was used to detect the cell permeability. The secretion of platelet-derived growth factor β (PDGF-β) was measured by ELISA. Fluo-3 AM fluorescence probe was used to detect the fluorescence intensity of cells to assess intracellular Ca2+ concentration, and reactive oxygen species (ROS) content was measured by CM-H2DCFDA fluorescence probe to clarify the endoplasmic reticulum stress state. Western blotting was used to examine the expression of connexins, including zonula occludens-1 (ZO-1) and claudin-5, the expression of endoplasmic reticulum stress proteins, including CCAAT/enhancer-binding protein homologous protein (CHOP), glucose-regulated protein 78 (GRP78), and cysteine-containing aspartate-specific proteases-12 (Caspase-12), and the expression of Wnt7/β-catenin in HBMECs. Results ·Compared with the Sham group, the brain water content of the infarction area of mice increased after MCAO, and the exudation of EB increased significantly (both P<0.05). The adhesion between cerebrovascular endothelial cells and pericytes in mice was reduced after the occurrence of MCAO. After intraperitoneal injection of 4-PBA in mice with MCAO, the degree of brain edema and the exudation of EB were reduced (both P<0.05), and the adhesion between cerebrovascular endothelial cells and pericytes increased. Compared with the HBMECs of the blank control group, the viability of HBMECs after OGD decreased, and the permeability of HBMECs increased (both P<0.05). OGD condition also led to decreased expression of connexins (ZO-1 and claudin-5), decreased secretion of PDGF-β in HBMECs, increased expression of endoplasmic reticulum stress proteins (CHOP, GRP78 and Caspase-12), up-regulated intracellular Ca2+ concentration and ROS content, and decreased expression of Wnt7 and β-catenin in HBMECs (all P<0.05). After HBMECs were cultured with 4-PBA, the damage of HBMECs caused by OGD was reduced, and the expression of connexins increased. The permeability of HBMECs was reduced, and the secretion of PDGF-β was promoted (all P<0.05). After 4-PBA treatment, the activity of Wnt7/β-catenin signaling was significantly restored in the OGD model of HBMECs (P<0.05). Conclusion ·Wnt7/β-catenin signaling inactivation caused by endothelial reticulum stress bursts leads to cerebrovascular endothelial cell damage, which is the crucial pathway of BBB destruction after stroke.

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    Advances in the application of 18F-FDG PET/CT radiomics for diagnosis, treatment and prognosis prediction of lymphoma
    CHENG Ran, HU Jiajia, LI Biao
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (6): 781-787.   DOI: 10.3969/j.issn.1674-8115.2023.06.016
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    Lymphoma is a highly heterogeneous hematological malignancy that can affect multiple organs throughout the body, exhibiting significant clinical variations among its subtypes. 18F-fluorodeoxyglucose (18F-FDG) PET/CT plays a crucial role in the clinical diagnosis and treatment of lymphoma by facilitating anatomical localization and quantification of metabolic characteristics of highly aggressive lymphomas. This imaging examination method enables a comprehensive evaluation by comparing the metabolic changes before and after treatment, as well as the metabolic difference between lesions and blood pools. However, the heterogeneity of lymphoma, coupled with the limitations of 18F-FDG PET/CT in differentiation, poses challenges for physicians and adversely impacts the clinical treatment plan and prognosis of patients. With the advancement of computer hardware and image analysis technology, radiomics technology, based on the extraction of imaging features of lesions for analysis and diagnosis, has emerged. Numerous researchers have dedicated their efforts to exploring imageomics in lymphoma assessment by using 18F-FDG PET/CT. By integrating feature data with relevant clinical information, models have been developed to effectively correlate image information, clinical data, pathology, and survival outcomes, thereby enhancing the accuracy and efficiency of imaging diagnosis. Furthermore, the utilization of predictive models for prognosis and treatment efficacy has the potential to mitigate subjective errors arising from disparities in physician experience, thereby contributing to the realization of personalized medicine. This review intends to comprehensively summarize the research progress of 18F-FDG PET/CT radiomics in the diagnosis, treatment and evaluation of lymphoma in recent years, from the aspects of diagnosis and differential diagnosis, prognosis prediction and risk grading, drug efficacy prediction and radiomics analysis algorithm optimization, so as to provide insights for future research in machine learning and the development of medical imaging analysis techniques.

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    Causal relationship between atrial fibrillation and cognitive impairment: a Mendelian randomization study
    GAO Xiong, ZHANG Qiuxia, YANG Miaomiao, LUO Wei, WANG Yuegang, XIU Jiancheng
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (11): 1359-1365.   DOI: 10.3969/j.issn.1674-8115.2023.11.003
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    Objective ·To investigate the causal relationship between atrial fibrillation (AF) and cognitive impairment. Methods ·A two-sample Mendelian randomization (TSMR) analysis was used to assess the potential causality of AF on cognitive dysfunction. Single nucleotide polymorphisms (SNPs) strongly associated with AF were extracted as instrumental variables by using a dataset of a large-scale genome-wide association study (GWAS) on AF. The associations of SNPs with Alzheimer′s disease dementia, Parkinson′s disease dementia, vascular dementia, Lewy body dementia, frontotemporal dementia, undefined dementia, and overall cognitive function assessment were extracted separately from publicly available GWAS data on cognitive dysfunction. The inverse variance-weighted (IVW) method was used for the main analysis, and sensitivity analyses were conducted by using Cochran′s Q test, MR-Egger regression, and leave-one-out method. To verify the robustness of the results, replicate analyses and meta-analyses were performed by using different GWAS data. Results ·In the initial analysis, 101 SNPs were extracted as instrumental variables from a meta-analysis of a genome-wide association study involving up to 1 030 836 individuals. The IVW analysis showed no evidence for causal associations between AF and dementia [dementia (OR=1.032; 95%CI 0.973?1.094; P=0.290), Parkinson′s disease dementia (OR=1.004; 95%CI 0.780?1.291; P=0.977), vascular dementia (OR=1.123; 95%CI 0.969?1.301; P=0.125), or unspecified dementia (OR=1.013; 95%CI 0.910?1.129; P=0.807)]. In the replication analysis, 27 SNPs were extracted as instrumental variables from the FinnGen AF GWAS data, and the IVW analysis were consistent with the initial analysis [cognitive function (OR=0.999; 95%CI 0.982?1.016; P=0.874), Alzheimer′s disease dementia (OR=0.977; 95%CI 0.943?1.012; P=0.193), Lewy body dementia (OR=1.014; 95%CI 0.898?1.145; P=0.826), or frontotemporal dementia (OR=0.996; 95%CI 0.745?1.333; P=0.980)]. Both Mendelian randomization analyses and meta-analyses showed no evidence of an association between genetically predicted AF and different types of dementia or overall cognitive function assessment. MR-Egger regression suggested no horizontal pleiotropy and leave-one-out analysis showed stable results after individually removing each SNP. Conclusion ·No evidence of a causal relationship between AF and cognitive impairment was found. The associations observed in observational studies can be partially attributed to confounding factors such as shared biology or co-morbidities.

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    Behavioral and eye movement study of attention bias to alcohol-related cues in male alcohol-dependent patients and correlation analysis of psychological factors
    SI Yuqi, LUO Ruyan, CHEN Tianzhen, WANG Lihui, ZHONG Na, JIANG Haifeng, ZHAO Min
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (6): 738-746.   DOI: 10.3969/j.issn.1674-8115.2023.06.010
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    Objective ·To investigate if male alcohol-dependent patients have attention bias to alcohol-related pictures, show the behavioral and eye movement characteristics of attention bias, and explore the correlation between attention bias and sleep, anxiety, depression, impulsion and other psychological factors. Methods ·Twenty-nine subjects in the case group (alcohol-dependent patients who were hospitalized in Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, from August 2021 to February 2022) and 29 healthy subjects in the healthy control group participated in the study. The experimental design was a mixed experimental design of three-factor hybrid. The cue types were alcohol-related and emotion pictures. The probe was on the same side or on the opposite side of the alcohol or emotional picture. The characteristics of subjects' attentional bias to alcohol cues were investigated by using the classical dot detection paradigm and eye movement monitoring technique. Groups were inter-group variables, and clue types and relative locations of probe points were intra-group variables. The behavioral and eye movement data were collected while the study subjects viewed pairs of alcohol-related and neutral pictures, or pairs of emotional and neutral pictures in a dot-probe paradigm. Dependent variables included behavioral indicators and eye movement indicators. Pittsburgh Sleep Quality Index (PSQI), 7-tiem Generalized Anxiety Disorder Scale (GAD-7), Patien Health Questionnaire (PHQ-9), and Barratt Impulsiveness Scale (BIS-11) scales were used to assess psychosomatic conditions such as sleep, anxiety, depression, and impulsivity, respectively. Behavioral and eye movement characteristics of attention bias in the alcohol-dependent group were analyzed. In addition, the correlation with behavioral and eye movement characteristics of attention bias and scale scores was analyzed. Results ·The behavioral results showed that the reaction time of the alcohol-dependent group was significantly longer than that of the healthy control group (P=0.006). The eye movement results showed that when the type of cue was alcohol-related picture, the alcohol-dependent group had slower attention detection (P=0.031) and longer attention maintenance (P=0.005) on alcohol-related cues. Moreover, the pupil size during the viewing of alcohol-related cues (P=0.001) and emotional cues (P=0.008) were significantly smaller than those of the healthy control group. It was also found that, there was a negative correlation between the correct rate of the alcohol-dependent group and the BIS-11 scale score (r=-0.437, P=0.032), and a positive correlation between reaction time and GAD-7 score (r=0.407, P=0.033). The time of the first visual fixation entry was positively correlated with GAD-7 score (r=0.414, P=0.045), and the PSQI score was positively correlated with PHQ-9 score (r=0.422, P=0.041) in the case group. Conclusion ·Alcohol-dependent patients have attention bias towards alcohol-related cues according to the behavioral and eye movement result. Compared with the traditional behavioral regression of attention bias based on correct rate and reaction time results, eye movement provides more direct and multi indicator evidence for the evaluation of attention bias in alcohol-dependent patients.

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    Epidemiological characteristics and risk factors of severe asthma in children: a single-center prospective cohort study
    WANG Yingwen, LI Xiaoling, DAI Jiajia, LIU Fang, HUANG Jianfeng, WANG Libo, ZHANG Xiaobo, FENG Rui
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (6): 665-672.   DOI: 10.3969/j.issn.1674-8115.2023.06.002
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    Objective ·To explore the epidemiological characteristics of severe asthma in children and analyze the risk factors. Methods ·A single-center prospective cohort study was conducted. Six hundred and seventy four children with difficult-to-treat asthma who visited the Children′s Hospital of Fudan University from January 1 to December 31, 2021 were included to establish a dynamic cohort. Basic information (including gender, age, gestational age at birth, birth weight, etc.) and comorbidity of the cohort members were collected. The asthma control status, drug inhalation technique level, medication compliance, pulmonary function parameters [forced expiratory volume in one second (FEV1) as a percent-age of the predicted value (FEV1%pred), FEV1/ forced vital capacity (FVC), and the rate of estimated values of forced expiratory flow at 50% of FVC exhaled (FEF50), FEF75, and FEF25-75 in percent-predicted value, respectively], airway inflammation index [fraction exhaled nitric oxide (FeNO)], and allergy status parameters [eosinophil (EOS) and immunoglobulin E (IgE)] of all cohort members were evaluated. All cohort members underwent re-evaluation respectively at the specialist asthma clinic of the hospital at 3, 6, 9, and 12 months. Results ·At the endpoint of the cohort, 52 children were diagnosed with severe asthma, accounting for 7.7%. A high proportion of severe asthma was found in children who were exposed to secondhand smoke, used air conditioning at home all year round, or had coexisting rhinitis/nasosinusitis, FEV1%pred<80%, FEV1/FVC<80%, small airway dysfunction, EOS>300/μL, IgE>200 IU/L, or FeNO>20/25 ppb [FeNO>20 ppb (≤12 years old) or >25 ppb (>12 years old), 1 ppb=1×10-9 mol/L]. A high proportion of non-severe asthma was found in children who were breastfed for 6 months or longer, or had good medication compliance. The differences were statistically significant (all P<0.05). There were more males in children with severe asthma aged 6?11 years, and more females in children with severe asthma aged 12?17 years, with statistical significance (both P<0.05). Multiple-factor Logistic regression analysis showed that only small airway dysfunction was an independent risk factor for severe asthma [OR=5.158 (95%CI 2.516?10.572)]. Conclusion ·The proportion of children with severe asthma has a significantly decrease after one year of standardized management in children with difficult-to-treat asthma. Small airway dysfunction is an independent risk factor for the progression to severe asthma.

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    Research progress of the role of non-canonical Wnt signaling pathway in ovarian cancer and its potential therapeutic implications
    ZHOU Wanzhen, TENG Yincheng
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (8): 1056-1063.   DOI: 10.3969/j.issn.1674-8115.2023.08.015
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    Ovarian cancer is a malignant tumor of the female reproductive system with the highest mortality, and involves the aberrant regulation of multiple molecular signaling pathways. As a highly conserved molecular pathway, Wnt signaling pathway plays an important role in embryonic development, tissue homeostasis, and tumorigenesis. Wnt signaling pathway includes canonical Wnt/β-catenin pathway and non-canonical pathway, and the latter mainly includes Wnt/planar cell polarity (Wnt/PCP) pathway and Wnt/Ca2+ pathway. Previous studies have mainly focused on the relationship between the canonical Wnt pathway and tumor progression. Recently, the non-canonical Wnt pathway has gradually received attention, and related researches have enriched the understanding of the non-canonical Wnt pathway in physiological and pathological processes such as tissue development and tumorigenesis. The existing studies suggest that the nonclassical Wnt pathway is abnormally regulated in ovarian cancer and is closely related to the staging and prognosis of ovarian cancer. Non-classical Wnt pathway plays an important role in many biological processes such as proliferation, migration and invasion of ovarian cancer cells, and the changes of this pathway are also related to chemotherapy resistance of ovarian cancer. This article reviews the role of the non-canonical Wnt pathway in ovarian cancer, and discusses the research progress of targeted therapy based on the non-canonical Wnt pathway, aiming to provide new ideas for the development of novel targeted drugs.

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    CXCL9 expression in breast cancer and its correlation with the characteristics of tumor immunoinfiltration
    DU Shaoqian, TAO Mengyu, CAO Yuan, WANG Hongxia, HU Xiaoqu, FAN Guangjian, ZANG Lijuan
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (7): 860-872.   DOI: 10.3969/j.issn.1674-8115.2023.07.008
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    Objective ·To explore the effect of C-X-C motif chemokine ligand 9 (CXCL9) expression on the prognosis of breast cancer patients and its correlation with tumor-infiltrating immune cells (TIICs). Methods ·Transcriptome data of 1 100 breast tumor tissues and 112 adjacent tissues were obtained from The Cancer Genome Atlas (TCGA) database. CIBERSORT deconvolution algorithm was used to analyze the proportion of TIIC subgroups in breast cancer immune microenvironment and its effect on the prognosis of patients. Differentially expressed genes, immune-related genes and breast cancer prognostic-related genes were downloaded from TCGA database, ImmPort database and GEPIA2 data platform, respectively. The intersection relationships of the three gene sets were analyzed by using R language, and the target genes were screened. Based on the downloaded transcriptome data, CXCL9 positive-related genes, the difference of CXCL9 mRNA expression in breast cancer tissues and adjacent tissues and its effect on the prognosis of patients were analyzed. STRING data platform was used to analyze the protein-protein interaction (PPI) network of CXCL9. Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis were performed on CXCL9 positive correlation genes and the genes corresponding to the interacting proteins obtained from the PPI network by using R language. Spearman correlation coefficient was used to analyze the correlation between CXCL9 mRNA expression and TIIC subgroups and immune checkpoint-related genes. Paraffin tissue samples of 60 clinical breast cancer patients were collected and made into tissue chips. The correlation between CXCL9 expression and CD8+ T cells infiltration in the tissue chips was detected by immunohistochemical staining (IHC). The types of CXCL9+ cells in breast cancer interstitium were analyzed by multiplex immunohistochemistry staining (mIHC). Kaplan-Meier (KM) survival curve was used to analyze the effect of CXCL9 mRNA expression and CD8+ T cell infiltration on the prognosis of breast cancer patients. Results ·CIBERSORT algorithm analysis showed that the distribution proportion of TIIC subgroups in breast cancer immune microenvironment varied greatly, and their effect on patients′ prognosis was also different. The Venn diagram of three types of gene sets was drawn, and CXCL9 was screened out. The top 150 positive correlation genes with CXCL9 were obtained. CXCL9 mRNA expression levels in four molecular types of breast cancer were higher than those in adjacent tissues (all P=0.000), and their high expressions were significantly associated with good prognosis of patients (P=0.013). A total of 41 interacting proteins were obtained through PPI network analysis. GO and KEGG analysis showed that CXCL9 and its related genes were mainly enriched in biological functions and pathways related to immune regulation. Spearman correlation coefficient analysis showed that the expression level of CXCL9 mRNA was positively correlated with CD8+ T cells infiltration ratio, negatively correlated with M2-type macrophages infiltration ratio, and positively correlated with most immune checkpoint genes expression (all P<0.05). IHC experiments showed that CXCL9 was highly expressed in breast cancer tissues compared with adjacent tissues, accompanied by an increased percentage of CD8+ T cells infiltration (P=0.000). mIHC results showed that CXCL9 was expressed in some CD68+ tumor-associated macrophages (TAMs) and CD11c+ dendritic cells (DCs) in the stroma of breast cancer. KM survival curve showed that when CXCL9 was highly expressed, CD8+ T cells high infiltration could prolong the survival of breast cancer patients. Conclusion ·CXCL9 can be used as a biomarker for good prognosis of breast cancer patients. The high expression of CXCL9 in the microenvironment of breast cancer is positively correlated with the infiltration ratio of CD8+ T cells and may activate its anti-tumor effect. The expression of CXCL9 may be closely related to the recruitment of lymphocytes into the tumor microenvironment for anti-tumor immune response.

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    Effect of hydrogel stiffness on nucleus pulposus cell phenotypes in vitro and its repairment of intervertebral disc in vivo
    CHEN Zehao, LÜ Zhendong, ZHANG Zhen, CUI Wenguo, ZHANG Yuhui
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (7): 804-813.   DOI: 10.3969/j.issn.1674-8115.2023.07.002
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    Objective ·To investigate the effect of hydrogel stiffness on nucleus pulposus cell phenotype and its function in repairing intervertebral disc degeneration in rats. Methods ·Methacrylate gelatin (GelMA) hydrogels with different concentrations were constructed. The stiffness of the hydrogels was investigated by using rheological analysis and uniaxial compression test. The microstructure and morphology of the hydrogels were observed by scanning electron microscopy (SEM). Nucleus pulposus cells with normal phenotype were inoculated on the surface of GelMA hydrogels. The biocompatibility of the hydrogel was evaluated by live-dead cell staining and the growth pattern of nucleus pulposus cells on hydrogels with different stiffness was observed with phalloidin staining under microscope. Immunofluorescence staining was performed to examine the nuclear localization of Yes-associated protein (YAP) and real-time quantitative reverse transcription PCR (qRT-PCR) was used to detect the expression levels of nucleus pulposus cell-associated genes [neural cell adhesion molecule 1 (Ncam-1), aggrecan (Acan), sex-determing region of Y chromosome (SRY)-box transcription factor 9 (Sox9)]. A rat caudal acupuncture intervertebral disc degeneration model was established. Nucleus pulposus cells cultured on different hydrogels were harvested and injected into the degenerated discs separately. Four weeks after surgery, magnetic resonance imaging (MRI) was performed to analyze the water content of the intervertebral discs in each group. Histological tests were performed to examine the disc structure and proteoglycan levels. Results ·The elastic modulus of the hydrogels was 1 kPa and 200 kPa when the concentration of GelMA prepolymerisation solution was at 4% and 15% respectively. SEM observation revealed that the hydrogels showed a loose and porous microstructure, and the porosity of hydrogels decreased significantly with the decrease of their stiffness. In vitro experiments demonstrated that both GelMA hydrogel mediums showed good biocompatibility and the ability to support cell proliferation. Nucleus pulposus cells cultured on the soft matrix (4%GelMA) had a lower elongation and spreading area than those cultured on the stiff matrix (15%GelMA), showing a tendency of YAP concentration in the cytoplasm. The gene expression of nucleus pulposus cells was examined and the levels of Sox9, Acan and Ncam-1 in the soft matrix hydrogel group were 23.7, 6.6 and 12.7 times of those in the control group respectively. In vivo experiments on rat disc degeneration showed that the soft hydrogel matrix group had higher disc water content and structural integrity than the stiff hydrogel matrix group. Conclusion ·Compared to stiff GelMA hydrogels, hydrogels with low stiffness better maintain the growth phenotypes in the nucleus pulposus cells and have better therapeutic effect on disc degeneration in vivo.

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