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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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    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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    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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    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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    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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    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 on the neural circuit of pain emotion mediated by amygdala
    MA CUI, YE Yujuan, YAN Xingke
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1304-1310.   DOI: 10.3969/j.issn.1674-8115.2023.10.012
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    The occurrence of pain emotion is closely related to the functional and structural changes of specific central nervous circuit. When pain is accompanied by depression, anxiety, pain aversion memory and other emotional states, it activates or inhibits different neural circuits. The amygdala (AMY) of the limbic system participates in the regulation of pain, anxiety, depression, aversive memory and other emotions, and has extensive connections with brain nuclei related to pain and emotion, jointly regulating pain, anxiety, depression, aversive memory and other responses. This article summarizes the main circuits related to pain emotions mediated by AMY. It is concluded that the neural circuits related to depression include central amygdala → parafascicular nucleus of thalamus (CeA GABA → PF Glu), dorsal raphe nucleus → central amygdala (DRN 5-HT → CeA SOM), central amygdala → ventrolateral periaqueductal gray (CeA GABA → vlPAG GABA). Nerve circuits related to anxiety include ventral tegmental area → central amygdala (VTA→CeADA), locus coeruleus → basolateral amygdala (LCNE→BLA). The neural circuit related to pain aversion memory is lateral parabrachial nucleus → central amygdala (lPBN CGRP→CeA CGRP). Among them, activating the CeA GABA→PF Glu circuit can lead to depression accompanied by pain, activating the CeA GABA→vlPAG GABA circuit can alleviate pain sensitivity caused by depression, and activating the DRN 5-HT→CeA SOM circuit can alleviate pain perception and depressive emotions; activating the VTA→CeA DA loop can alleviate pain sensitivity and anxiety like behavior, inhibiting LC NE→BLA loop can alleviate anxiety caused by pain; activating the lPBN CGRP→CeA CGRP loop can generate pain aversion memory.

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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 in the role of gut microbiota in the pathogenesis and treatment of IgA nephropathy
    LI Junru, OUYANG Yan, XIE Jingyuan
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (8): 1044-1048.   DOI: 10.3969/j.issn.1674-8115.2023.08.013
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    As the most common form of glomerulonephritis worldwide, IgA nephropathy (IgAN) is characterized by the diffuse deposition of immune complexes formed by glycosylation-deficient IgA1 (Gd-IgA1) and its specific antibodies (Gd-IgA1-IgG) in the glomerular mesangium. Although the mechanisms of Gd-IgA1 production are still unknown, there is accumulating evidence that Gd-IgA1-producing plasma cells are primarily derived from gut-associated lymphoid tissue, giving rise to the "gut-kidney axis" theory. Further research has discovered that gut microbiota may be involved in IgAN development and progression, and that several interventions to regulate gut microbiota, such as probiotics, fecal microbiota transplantation, and intestinal immunity modulation, may be used in the treatment of IgAN. In patients with IgAN, targeted-release formulation-budesonide has been shown to reduce urinary protein levels and delay kidney progression. Gut microbiota has promising potential as a preventive, diagnostic and therapeutic target for IgAN, and further research is needed.

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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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    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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    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 of m 6A methylation modification in regulating tumor immunity
    ZHOU Haixia, ZHANG Jing
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (1): 137-144.   DOI: 10.3969/j.issn.1674-8115.2024.01.016
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    N6-methyladenosine (m6A) is the most prevalent modification that regulates gene expression in eukaryotes. It regulates splicing, degradation, stability, and translation of RNA. Numerous studies have demonstrated the close association between m6A methylation and tumor development, highlighting its crucial role in regulating tumor immune response. The m6A modification actively participates in governing immune cell differentiation and maturation as well as modulating anti-tumor immune responses. Within the tumor microenvironment, m6A modification can also impact the recruitment, activation, and polarization of immune cells, thereby either promoting or inhibiting tumor cell proliferation and metastasis. Consequently, it plays a pivotal role in reshaping the tumor immune microenvironment. In recent years, immunotherapy for tumors has been increasingly applied to clinical practice with notable success achieved through approaches such as immune checkpoint inhibitor therapy and adoptive cell immunotherapy. Targeting m6A modifications to interfere with the immune system, such as targeting dysregulated m6A regulators through small molecule inhibitors and inducing immune cell reprogramming, can improve anti-tumor immune response and strengthen immune cells′ ability to recognize and kill tumor cells. The m6A modification represents a novel avenue for potential clinical application within tumor immunotherapy. This review provides a comprehensive summary of the regulatory impact of m6A methylation modification on immune cells in the context of cancer, while also delving into novel targets for tumor immunotherapy.

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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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    Research progress in ceruloplasmin regulation of lipid metabolism homeostasis
    JIANG Quanxin, CHEN Suzhen, LIU Junli
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (1): 124-130.   DOI: 10.3969/j.issn.1674-8115.2024.01.014
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    Ceruloplasmin (Cp) is a crucial protein secreted by the liver and plays a vital role in regulating the distribution and transport of copper throughout the body, thereby maintaining copper homeostasis. Additionally, Cp functions as a significant enzyme known as ferroxidase, which is involved in iron metabolism within the body. Numerous studies have suggested a close relationship between Cp and metabolic disorders, such as diabetes and cardiovascular diseases. Recent research has also shed light on the involvement of Cp in the regulation of lipid metabolism. The various activities associated with lipid metabolism, including lipid synthesis, adipose hydrolysis, fatty acid oxidation, lipid transport, and absorption, collectively contribute to maintaining lipid homeostasis. Dysregulation of lipid metabolism can lead to metabolic disorders and cardiovascular complications. Cp regulates lipid metabolism through two main mechanisms. Firstly, Cp participates in the regulation of oxidative stress by modulating iron metabolism through its ferroxidase activity and involvement in redox reaction. Secondly, copper along with copper-dependent enzymes directly participates in the processes such as cholesterol metabolism, lipoprotein metabolism, and fatty acid synthesis. As a result, the role of Cp in maintaining the homeostasis of copper and iron allows it to regulate lipid metabolism by influencing copper or iron-dependent enzymes and related pathways. Although the correlation between Cp and lipid metabolism has been identified, an in-depth exploration of the precise mechanisms by which Cp governs lipid metabolism is warranted. This article provides an overview of the role of Cp in lipid metabolism and highlights the progress in related research, with the aim of providing new insights for the development and treatment of disorders related to lipid metabolism.

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    Research progress in the effect of nutritional intervention on cognitive impairment related to Alzheimer 's disease
    JIANG Xinting, HUANG Gaozhong
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (6): 788-794.   DOI: 10.3969/j.issn.1674-8115.2023.06.017
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    Alzheimer's disease (AD) is an age-related neurodegenerative disease with insidious onset and slow progression. The progression of AD from only brain pathological changes to clinically identifiable cognitive changes is affected by a variety of environmental factors inside and outside the organism and can last for decades. Cognitive impairment is an important clinical feature of AD that impairs the quality of life of the elderly in their later years, and the available drugs for the treatment of AD have failed to cure the disease, indicating the importance of early prevention of AD-related cognitive impairment. Most current research on the relationship between nutrition and AD takes nutritional intervention as a preventive method for AD-related cognitive impairment. The role of dietary supplement or restriction on AD-related cognitive impairment is related to multiple pathways. It is worth noting that the gut microbiome, as an important medium in the effect of dietary on the host, can influence cognitive function through the "microbial-gut-brain axis". The antioxidant and anti-inflammatory properties of some foods are beneficial for improving cognitive function. In this paper, relevant studies in recent years were analyzed to discuss the effects of certain single nutrients (vitamins, polyphenols, and long chain polyunsaturated fatty acids) and overall nutritional patterns (Mediterranean diet, dietary approaches to stop hypertension diet, Mediterranean-DASH intervention for neurodegenerative delay, and ketogenic diet) on cognitive function, so as to provide ideas and reference for the prevention and treatment of AD-related cognitive impairment.

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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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    Analysis of m 6A methylation expression profiles in liver tissue of high -fat diet -induced mouse models of NAFLD
    LIU Junjun, LU Sumei, ZHANG Bingyang, LI Yongqing, MA Wanshan
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1227-1235.   DOI: 10.3969/j.issn.1674-8115.2023.10.002
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    Objective ·To detect the differences in m6A methylation modification and gene expression of liver tissue mRNA in high-fat diet-induced mouse models of non-alcoholic fatty liver disease (NAFLD) using microarray technology. Methods ·The NAFLD models were established in 6-8 weeks old male C57BL/6J mice fed with high-fat chow for 16 weeks (high-fat group, n=10). The basal group (n=10) was given 10% fat diet. Hematoxylin-eosin (H-E) staining was used to assess the histopathological changes in liver tissue and to determine the success of the NAFLD models. The changes of mRNA m6A methylation and expression levels in the liver tissues of the two groups were detected by using methylated RNA immunoprecipitation (MeRIP) and microarray expression profiling. Results ·The livers of the mice in the basal group were bright red with few fat deposits, while the livers of the mice in the high-fat group were yellowish with diffuse infiltration and fusion of lipid droplets in the hepatocytes by H-E staining, suggesting that the high-fat diet-induced NAFLD models were successfully constructed. The results of the MeRIP-microarray showed that the m6A methylation levels of 320 genes in the livers of mice in the high-fat group were significantly altered compared with those in the basal group (P<0.05 and fold change>1.5), of which 108 genes were up-regulated and 212 genes were down-regulated. Genes with significant differences in m6A methylation levels between the two groups were intersected with those with differentially expressed mRNAs, and 163 genes were found to have significant differences in both m6A methylation level and mRNA expression level. Conclusion ·The change in m6A modification of liver tissue mRNA in the high-fat diet-induced mouse models of NAFLD is significant and the change is associated with the gene expression of mRNA.

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    Research progress of integrated stress response in pathogenesis of Alzheimer 's disease
    SUN Hui, JIN Hongfu, GUO Shenrui, FENG Yiyuan, YIN Yafu, WANG Hui, CHENG Weiwei
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (6): 755-760.   DOI: 10.3969/j.issn.1674-8115.2023.06.012
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    Integrated stress response (ISR) is a cellular adaptive response induced by stress, which is strictly regulated by multiple phosphokinases, phosphatases and other proteins to maintain protein homeostasis. Studies have shown that ISR is abnormally activated in Alzheimer's disease, and targeted regulation of different proteins in ISR pathway inhibits the abnormal activation of ISR, leading to restoration of protein homeostasis and alleviation of the neuropathological changes and memory impairment in Alzheimer's disease models. These lines of evidence suggest that ISR has the potential to be a therapeutic target in Alzheimer's disease treatment. This paper reviews the abnormal activation and regulation mechanism of ISR in Alzheimer's disease and discusses the application of ISR as therapeutic targets to Alzheimer's disease models.

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    Identification of pathogenic mutations for a Wolfram syndrome pedigree by whole exome sequencing and analysis of its clinical characteristics
    MENG Xiangyu, YAN Dandan, CHEN Xianghui, LAI Siyu, XU Yun, GENG Ruina, ZHANG Hong, ZHANG Rong, HU Cheng, YAN Jing
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (7): 898-905.   DOI: 10.3969/j.issn.1674-8115.2023.07.012
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    Objective ·To identify the causative gene and mutations and describe the clinical traits in a Chinese diabetes pedigree suspected of Wolfram syndrome. Methods ·A total of 12 subjects from one family were included. The proband was admitted to the Department of Endocrinology, The First Affiliated Hospital of Xinxiang Medical University, for the first time in May 2013. Then he visited the hospital for follow-up in July 2022 and in April 2023, respectively. The other members of this family included the proband′s sister, father, mother, paternal grandfather, paternal grandmother, uncle, aunt, as well as maternal grandfather, maternal grandmother, and two brothers of the proband′s mother. Clinical data of all subjects were collected. The whole exome sequencing was used to screen the pathogenic genes and mutation sites of six members of the family, and Sanger sequencing was used to verify the above results. Effects of the mutation of the pathogenic gene WFS1 in Wolfram syndrome on the function of the wolframin protein were evaluated by bioinformatics softwares, including CADD, DANN, MetaSVM, Polyphen-2, SIFT and M-CAP. The three-dimensional structures of wild-type and mutant wolframin proteins were constructed with Swiss-Model software, and visualized with PyMOL software. Cluster Omega software was used for evaluating species conservation of WFS1 gene mutation sites. JNetPRED software was used for online prediction of wolframin protein secondary structure. Results ·The proband and his sister both carried R558H and S411Cfs*131 mutations, two compound heterozygous mutations of the Wolfram syndrome pathogenic gene WFS1. The proband′s father and parental grandfather both carried the R558H mutation, while the proband′s mother and maternal grandfather both carried the S411Cfs*131 mutation. The R558H mutation was a rare missense mutation, and the S411Cfs*131 mutation was a novel frameshift mutation. Bioinformatics analysis softwares predicted that the R558H mutation located in the α-helical structure of the wolframin protein. This mutation was a damage mutation and the amino acid sequence of the mutation region was highly conservative among 12 species with varying degrees of evolution, including humans. Conclusion ·Two causative mutations of WFS1 gene are identified in a Chinese diabetes pedigree by whole exome sequencing. The study supplements the existing genotype and phenotype profiles of Wolfram syndrome, which can realize early diagnosis of diabetes pedigrees and help in performing timely follow-up of patients, so as to achieve early intervention and treatment of this disease.

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