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    Research progress of the role of intestinal microbiota-mediated bile acids in inflammatory bowel disease
    XIA Xixi, DING Keke, ZHANG Huiheng, PENG Xufei, SUN Yimin, TANG Yajun, TANG Xiaofang
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 839-846.   DOI: 10.3969/j.issn.1674-8115.2024.07.005
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    It is estimated that approximately seven million people worldwide are affected by inflammatory bowel disease (IBD), causing a huge burden on healthcare systems and society. In the occurrence, progression, and treatment of IBD, the intestinal microbiota and its key metabolic product, bile acids, play a crucial role. The intestinal microbiota not only participates in the biotransformation of bile acids, enriching the diversity of bile acids, but also regulates their synthesis and transport through the farnesoid X receptor (FXR). Meanwhile, bile acids contribute to regulating the structure and function of the intestinal microbiota by supporting microbial diversity, exerting direct toxicity, participating in indirect antimicrobial pathways, and influencing microbial metabolic capabilities. Furthermore, under normal physiological conditions, intestinal microbiota-derived bile acids facilitate the repair process of the intestinal epithelial barrier. They also promote the balance of the immune system by modulating the functions of various immune cells including helper T (Th) cells 17, regulatory T (Treg) cells, CD8+ T cells and natural killer T(NKT) cells, thereby slowing down the development of IBD. This article focuses on exploring the role of intestinal microbiota and bile acids in the onset and progression of IBD, and investigating new effective treatment strategies by targeting intestinal microbiota and bile acids, such as bile acid receptor modulators, probiotics, prebiotics, fecal microbiota transplantation (FMT), and phage therapy.

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    Research progress in immune cells regulating drug resistance of tumor cells in tumor microenvironment
    ZHANG Yesheng, YANG Yijing, HUANG Yiwen, SHI Longyu, WANG Manyuan, CHEN Sisi
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 830-838.   DOI: 10.3969/j.issn.1674-8115.2024.07.004
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    Tumor microenvironment (TME) is a complex cellular environment where tumor cells reside, along with various types of cells and extracellular components surrounding the tumor cells. Immune cells are key components of TME, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), lymphocytes, regulatory T cells (Tregs), natural killer cells (NK cells), dendritic cells (DCs), and many others. It is worth noting that drug resistance is currently a major factor limiting the efficacy of cancer treatment methods such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy, and a leading cause of treatment failure. Research has found that the development of drug resistance in tumor cells is the result of interactions between tumor cells and TME. Consequently, overcoming drug resistance in tumors caused by TME is considered a significant challenge in cancer treatment. In recent years, with in-depth research into immune cells within TME, significant progress has been made in understanding the specific mechanisms by which immune cells regulate drug resistance in tumor cells. Furthermore, therapeutic strategies that target these immune cells, signaling pathways, or cytokines have been shown to effectively combat tumor drug resistance and enhance the therapeutic outcomes of cancer treatment. This article reviews the research advancements regarding the roles of TAMs, MDSCs, Tregs, and NK cells in tumor drug resistance within TME and discusses the development of targeting strategies to overcome this resistance. Additionally, we explore the relationship of tumor-associated neutrophils (TANs) and B regulatory cells (Bregs) with tumor drug resistance. It is hoped that this review will offer insights and serve as reference for reducing tumor drug resistance and improving the efficacy of anti-tumor therapies.

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    Progress in cumulative risk assessment of human health from combined exposure to environmental pollutants
    CHENG Xiaomeng, ZHANG Yan, GAO Yu, TIAN Ying
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (8): 1037-1043.   DOI: 10.3969/j.issn.1674-8115.2024.08.013
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    The combined exposure to environmental pollutants can result in unanticipated adverse effects on human health, and how to compare and assess these effects has always been a matter of great concern for the international community. Currently, several prevalent methods for assessing combined exposure risks in the field of human health risk assessment primarily encompass the hazard index (HI) method, the point of departure index (PODI) method, the margin of exposure (MOE) method, and the relative potency factor (RPF) method. The review summarizes the application of these methods to the cumulative risk assessment of combined exposure to the same class of chemicals with the same toxic mechanism, primarily focusing on pesticides such as organophosphorus pesticides, pyrethroids, carbamates, and neonicotinoids, as well as typical compounds intimately related to human production and life, including organophosphorus flame retardants, per- and poly-fluoroalkyl substances, and bisphenols. Furthermore, progress in the application of physiologically based pharmacokinetics models to human health risk assessment has been introduced, which might provide more options for risk assessment of combined exposure to multiple chemicals, and help to provide insights for further exploration and establishment of more systematic and scientific approaches to human health risk assessment.

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    Prospect of naturally derived polysaccharides in intervention in neurodevelopmental disorders
    ZENG Dejie, CHEN Zenghui, DING Qiankun, SUN Xiaqing, SUN Qi, ZHAO Shibing
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (6): 779-787.   DOI: 10.3969/j.issn.1674-8115.2024.06.014
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    Neurodevelopmental disorders (NDDs) are chronic developmental brain disorders that can affect cognition, motor, social adaptation, behavior and so on due to multiple genetic or acquired causes. Natural polysaccharides are synthesized by living organisms, located in the cell wall, inside and between cells, and outside the cells, and are essential components of life activities. Previous studies have found that natural polysaccharides play an important role in neurological diseases, which mainly ameliorate the behavioral abnormalities and clinical symptoms caused by anti-oxidative stress, anti-neuronal apoptosis, anti-neuroinflammation, anti-excitatory amino acid toxicity, and regulation of the brain-gut axis. This review summarizes the intervention role of 17 bioactive polysaccharides from plants and fungi in neurological diseases, aiming to provide new ideas for the research and treatment of NDDs.

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    Research status of receptor-interacting protein kinase 1 in regulating cancer progression and immune response
    ZHANG Yong, LI Weihong, CHENG Zhipeng, WANG bin, WANG Siheng, WANG Yubin
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (6): 788-794.   DOI: 10.3969/j.issn.1674-8115.2024.06.015
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    Receptor-interacting protein kinase 1 (RIPK1) is a multi-domain serine/threonine protein kinase that causes downstream signal transduction and biological effects by phosphorylating specific proteins. In recent years, with the in-depth study of RIPK1, scholars have found that it is of great significance in autoimmune diseases, neurodegenerative diseases, and a variety of solid tumors and hematological tumors. On the one hand, RIPK1 promotes cell survival and inflammatory responses by activating specific pathways such as nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK). On the other hand, RIPK1 promotes apoptosis by interacting with cysteinyl aspartate specific proteinase-8 (caspase-8), or promotes necroptosis by interacting with RIPK3 and mixed lineage kinase domain-like protein (MLKL). As an upstream signal, RIPK1 has different expression levels in patients with different tumors. Its scaffold function and kinase activity can regulate cancer progression, initiate adaptive immunity, inhibit tumor progression, and generate an immunosuppressive tumor microenvironment to promote tumor development. Its dual role has been demonstrated in regulating the occurrence and development of tumors and the body's immune response, and can be used as a new therapeutic target to control cancer progression. This paper starts with the structure of RIPK1 to further explore its function in regulating cancer progression and immune response, and to provide new ideas for the development of cancer-targeted drugs.

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    Progress in translational research on immunotherapy for osteosarcoma
    HU Fei, CAI Xiaohan, CHENG Rui, JI Shiyu, MIAO Jiaxin, ZHU Yan, FAN Guangjian
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 814-821.   DOI: 10.3969/j.issn.1674-8115.2024.07.002
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    Osteosarcoma is a common primary malignant bone tumor in adolescents and children, characterized by a high recurrence rate and metastasis, making its treatment extremely challenging. Traditional treatment modalities, including surgery, radiation therapy, and chemotherapy, can alleviate symptoms to some extent, but improving long-term survival rates remains a pressing issue. With the continuous development of immunotherapy, breakthroughs have been made in the research of tumor immune microenvironment and the application of immunotherapy in recent years, providing new perspectives and strategies for osteosarcoma treatment. Currently, immunotherapy strategies include tumor vaccines, targeted cytokines, immune checkpoint inhibition, adoptive cell therapy, combination therapy, etc., significantly enhancing patient immune responses from the aspects of boosting immunity, overcoming immune tolerance, and preventing immune evasion, thereby effectively improving the patients′ survival rates and prognosis. This review aims to systematically introduce the immune microenvironment of osteosarcoma and discuss the latest advances in immunotherapy in clinical translational research of osteosarcoma. By deeply understanding the immune characteristics of osteosarcoma and corresponding treatment methods, it is hopeful to provide more effective strategies for personalized treatment, contributing to the improvement of the patients′ survival rates and prognosis.

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    Advances in molecular mechanisms of iodine-131 therapy resistance in thyroid carcinoma
    LIU Shiqi, WANG Hui, FENG Fang
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 915-921.   DOI: 10.3969/j.issn.1674-8115.2024.07.013
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    Thyroid cancer is the most common malignant tumor of the endocrine system, with differentiated thyroid carcinoma (DTC) accounting for over 90%. Most DTC patients have a good prognosis after systematic treatment, but a few develop dedifferentiation of primary tumor site or metastases, progressing to radioiodine-refractory DTC (RAIR-DTC), leading to significantly worse prognosis, which is a major cause of thyroid carcinoma-related mortality. Dysregulation of sodium iodide symporter (NIS) expression and function is the main reason for iodine-131 therapy resistance in thyroid carcinoma, influenced by genetic changes, epigenetic changes, tumor microenvironment, autophagy, and other factors. Genetic alterations such as the BRAFV600E mutation and RET/PTC chromosomal rearrangements activate oncogenic signaling pathways, directly or indirectly affecting NIS expression and its normal localization on the cell membrane. Epigenetic regulation modulates specific gene expression patterns, regulating NIS gene expression levels, thereby affecting the radioiodine uptake function of thyroid cells. Components in the tumor microenvironment, including immune cells, cytokines, and extracellular matrix, may also disrupt iodine uptake by reducing the expression levels of NIS and/or disrupting its normal function on the cell membrane. Additionally, autophagy, as an intracellular metabolic regulatory mechanism, can also modulate NIS expression and its intracellular distribution, thus impacting the radioiodine uptake and the sensitivity to iodine-131 therapy. Reviewing the roles of these factors in thyroid carcinoma dedifferentiation comprehensively can provide a more thorough understanding of the occurrence and progression of RAIR-DTC, aiding in the exploration of new therapeutic targets, improving prognosis, and providing more effective personalized treatment strategies for patients.

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    Advances in dietary interventions for the treatment of depression-related symptoms
    CHEN Shentse, CHEN Yiming, WANG Fan, ZHANG Mengke, YANG Weichieh, LÜ Dongbin, HONG Wu
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (8): 1050-1055.   DOI: 10.3969/j.issn.1674-8115.2024.08.015
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    Major depressive disorder (MDD) is a common mental illness. Currently, nearly 16% of the global population is affected by depression-related symptoms, while the diagnosis and treatment rate of MDD patients in China is only 9.5%. MDD is characterised by high morbidity and low recovery rate, and how to effectively improve its therapeutic effect has been a hot research topic in recent years. Antidepressants, as the main treatment for MDD, have the disadvantages of many adverse effects and slow onset of action, prompting people to pay attention to the non-pharmacological treatments of MDD. Dietary intervention is a kind of non-pharmacological treatment by changing dietary structures and rhythms; the current application of dietary intervention to psychiatry is very extensive, and it has been proved to be effective in the treatment of depression. Recent research suggests that dietary interventions can treat and ameliorate depressive symptoms by influencing brain-gut axis-related eating mechanisms. This article reviews the multidimensional exploration of dietary interventions in the treatment of depression: dietary structure interventions, dietary rhythm interventions, and the role of intestinal flora. It details the modalities of dietary interventions and the related mechanisms involved, and provides reference for dietary interventions in the treatment of depression-related symptoms.

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    CTCF regulates lipid metabolism and gene expression in mouse AML12 liver cell line
    CHEN Huaihuang, ZUO Wu, BIAN Qian
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (9): 1069-1082.   DOI: 10.3969/j.issn.1674-8115.2024.09.002
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    Objective ·To clarify the regulatory role of CCCTC-binding factor (CTCF) in lipid metabolism in liver cells, and explore the mechanisms by which CTCF regulates liver cell gene expression. Methods ·Immortalized AML12 liver cell line was used as a model to investigate the functions of CTCF in liver cells. To stably knock down Ctcf, DNA sequences stably expressing Ctcf shRNA were integrated into AML12 cells through lentivirus. The knockdown efficiency of Ctcf was verified by RT-qPCR and Western blotting. The effects of Ctcf knockdown on cell growth and cell cycle were assessed by performing CCK-8 assay and propidium iodide (PI) staining. Intracellular lipids, labeled with Oil Red O staining, were analyzed and quantified to detect the effect of CTCF on lipid metabolism and lipid droplet accumulation in AML12 cells. Changes in CTCF genome distribution after Ctcf knockdown were analyzed using the Cleavage Under Targets and Tagmentation (CUT&Tag) method. Transcriptome changes in AML12 cells after Ctcf knockdown were quantified by RNA sequencing (RNA-seq). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and gene set enrichment analysis (GSEA) were employed to evaluate the functions of differentially expressed genes. The correlation between gene expression changes and CTCF binding changes was further assessed by performing statistical analyses. Results ·The result of RT-qPCR showed that Ctcf is downregulated 63.4% in mRNA level and 57.7% in protein level (both P<0.05). Assay of the growth curve and cycle phase confirmed that cell proliferation was inhibited in the G1/G0 phase after Ctcf knockdown. After Ctcf knockdown, AML12 cells exhibited spontaneous accumulation of intracellular lipids, indicating dysregulation of lipid metabolism (P<0.05). Genome-wide CTCF binding analysis revealed significant changes, with most differential CTCF peaks showing decreased binding, although a subset of regions exhibited increased CTCF binding. Transcriptome analyses revealed that knocking down Ctcf resulted in significant expression changes in 1 344 genes. These differentially expressed genes were enriched in lipid metabolism pathways. Further analysis showed that genes associated with regions of increased CTCF binding were enriched in pathways related to lipid transport and localization, whereas genes associated with regions of decreased CTCF binding were mainly enriched in processes such as DNA damage repair, apoptosis, and cell cycle regulation. However, the binding changes of CTCF in the genome were not sufficient to lead to the expression changes of their neighboring genes. Conclusion ·CTCF affects the metabolic function of liver cells by regulating the expression of lipid metabolism-related genes. However, the binding changes of CTCF in the genome lack significant correlation with the expression of their neighboring genes, suggesting that CTCF mainly influences liver gene expression through long-distance regulation, possibly by modulating higher-order chromatin structure and enhancer-promoter interactions.

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    Targeting folate cycle enhances effects of cancer immunotherapy by modulating myeloid-derived suppressor cells
    HE Rui, YAN Kepeng, WANG Jing
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (8): 1011-1022.   DOI: 10.3969/j.issn.1674-8115.2024.08.010
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    Objective ·To explore the regulatory mechanism of folate cycle metabolism in the immunosuppressive effect of myeloid derived suppressor cells (MDSCs). Methods ·Bone marrow cells were isolated from C57BL/6 mice and cultured in RPMI 1640 medium supplemented with GM-CSF, G-CSF, and IL-6 to induce MDSCs in vitro. PD-L1 expression level and ROS production level of induced MDSCs were detected by flow cytometry. CD8+ T cells were enriched from the spleen by MACS with anti-CD8a-conjugated microbeads, labeled with Celltrace violet, and then co-cultured with MDSCs. After 72 h, proliferation was assessed by flow cytometry. Folate cycle-related metabolic enzymes in MDSCs were detected by real-time quantitative PCR. MDSCs were treated with folate cycle metabolic enzyme MTHFD2 inhibitor DS18561882 (DS18) and folic acid antagonist Pemetrexed. ROS and mitoROS production in MDSCs were assessed by flow cytometry. CD8+ T cells were enriched from the spleen by MACS with anti-CD8a-conjugated microbeads, labeled with Celltrace violet, and then co-cultured with Pemetrexed or DS18-treated MDSCs. After 72 h, proliferation was assessed by flow cytometry. Transcript levels of folate cycle-related metabolic enzymes in pemetrexed or DS18-treated MDSCs were detected by RNAseq. A subcutaneous tumor mouse model of colon cancer was established. From the tenth day post-implantation, tumor-bearing mice were intraperitoneally injected with Pemetrexed (200 mg/kg) and tumor size was recorded for tumor growth curve. On the fourteenth day, mice were sacrificed, and tumors were harvested. MC38 tumor-bearing mice were treated with isotype antibody, anti-CD8 monoclonal antibody (1 mg/kg, deplete CD8+ T cells), Pemetrexed (200 mg/kg), and combination of Pemetrexed with anti-CD8 antibody. MC38 tumor-bearing mice were treated with isotype antibody, anti-Gr1 monoclonal antibody (1.25 mg/kg, clearing MDSCs), combination of Pemetrexed with anti-Gr1 antibody. On the tenth day after implantation, tumor-bearing mice were treated with Pemetrexed (50 mg/kg), anti-PD-1 monoclonal antibody (250 μg/kg), Pemetrexed, and combination of Pemetrexed with anti-PD-1 antibody. Results ·Flow cytometry data showed that PD-L1 level and ROS production were increased in induced MDSCs, and CD8+ T cell proliferation was also suppressed significantly. qPCR data revealed the expression of folate cycle-related metabolic enzymes MTHFD2 and others was increased in MDSCs. The accumulation of MDSCs was affected by DS18 or Pemetrexed, ROS production in MDSCs was reduced, and the immunosuppression of CD8+ T cells was relieved. RNA-seq results showed that genes related to MDSCs differentiation, such as S100 calc-binding protein A8, and genes related to MDSCs inhibition, such as cytochrome b-245β chain, which is related to ROS production, were also down-regulated after treatment with two folic acid cycling inhibitors. Tumor growth was suppressed by Pemetrexed. Tumor progression was promoted by combination of Pemetrexed with anti-CD8 antibody, compared with Pemetrexed monotherapy. However, tumor growth delay was inhibited by combination of Pemetrexed and anti-CD8, compared with anti-CD8 monotherapy. Tumor growth delay was caused by MDSCs depletion. But tumor growth was promoted by combination of pemetrexed and anti-Gr1, compared with pemetrexed monotherapy. Tumor growth was restricted by combination of pemetrexed and anti-PD-1 antibody, compared with anti-PD-1 monotherapy. Conclusion ·Pemetrexed relies on CD8+ T cells for anti-tumor effects and further retards tumor growth by reprogramming MDSCs to an anti-tumor phenotype. Modulating MDSCs by targeting folate cycle could impair their immunosuppressive ability and enhance the efficacy of immune checkpoint blockade in cancer treatment.

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    Advances in drug therapy of diabetic retinopathy
    CHEN Minghao, LIU Peiyu, WANG Xuan, WU Yixiang, JIANG Yujin, ZHANG Chaoyang, ZHANG Jingfa
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 822-829.   DOI: 10.3969/j.issn.1674-8115.2024.07.003
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    Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes and has become one of the leading causes of blindness and visual impairment in diabetes patients. The pathogenesis of DR is multifaceted, involving inflammation, oxidative stress, neurovascular abnormalities, and other factors that present potential targets for disease management interventions. Currently, anti-vascular endothelial growth factor (VEGF) drugs serve as the primary treatment for advanced stages of DR when irreversible neurovascular damage and visual impairment have occurred. Additionally, some patients show poor or no response to anti-VEGF treatment. There is a lack of early intervention options for the initial phases of the disease. Therefore, there is an urgent need to develop novel local or systemic therapies based on the underlying mechanisms of DR to enable early prevention and treatment with the aim of preserving patients′ vision. Medications targeting various pathways including anti-inflammatory agents (corticosteroids and nonsteroidal anti-inflammatory drugs), neurotrophic and neuroprotective drugs, drugs modulating biochemical pathways, antioxidant phytochemicals, and gene therapy can complement each other in terms of therapeutic effects to benefit a larger number of individuals affected by DR. This article reviews previous research reports on the pathogenesis, drug treatment methods, and potential therapeutic targets associated with DR in order to provide guidance for clinical practice.

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    Transcriptional regulatory network analysis of microglia in multiple sclerosis
    CAI Qiangwei, SUN Feng, WU Wenyu, SHAO Fuming, GAO Zhengliang, JIN Shengkai
    Journal of Shanghai Jiao Tong University (Medical Science)    2025, 45 (1): 29-41.   DOI: 10.3969/j.issn.1674-8115.2025.01.004
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    Objective ·To investigate the differential gene expression of microglia in the gray and white matter of multiple sclerosis (MS) using single-nucleus transcriptomic analysis, aiming to explore their roles in disease progression, and identify key transcriptional regulatory networks associated with the disease. Methods ·snRNA-seq data of frozen human brain tissue samples from MS patients and control individuals were obtained from the Gene Expression Omnibus (GEO) database. R language, along with R packages such as Seurat, was employed to identify cell types based on specific cell markers. Microglia were extracted from the identified cell populations and classified based on their anatomical origin, either gray matter or white matter. Dimensionality reduction and clustering techniques were utilized to identify distinct microglial subpopulations with differential characteristics. Differentially expressed genes (DEGs) between the MS and control groups at the subpopulation level were analyzed by using the Seurat package. Gene set enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was conducted on the DEGs to further explore the biological significance of these differences. Monocle3 was used for pseudotime analysis to study dynamic changes in microglia subpopulations during disease progression. Single cell regulatory network inference and clustering (SCENIC) method was applied to analyze transcription factor (TF) regulatory networks, aiming to identify key transcription factors potentially involved in MS regulation. Results ·After quality control, a total of 149 062 nuclei were retained for analysis. Following dimensional reduction and clustering, 12 238 microglia were identified by using key markers, including DOCK8, CSF1R, P2RY12, and CD74. The results of GO and KEGG pathway analysis showed that in gray matter microglia, functions such as endocytosis, ion homeostasis, and lipid localization were downregulated during disease progression, while in white matter microglia, functions such as protein folding, cytoplasmic translation, and response to thermal stimuli were upregulated. SCENIC analysis revealed that the expression of transcription factors such as FLI1, MITF, and FOXP1 was upregulated in MS. Conclusion ·Microglia play a critical role in MS, with white matter microglia being more significantly impacted by MS than their gray matter counterparts. Transcription factors such as FLI1, MITF, and FOXP1 are identified as key regulators involved in disease modulation, with their associated transcriptional regulatory networks playing a central role in disease modulation.

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    Research progress in food preferences mechanisms and their impact on obesity
    KANG Piao, ZHANG Ying, LI Huating
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (9): 1190-1196.   DOI: 10.3969/j.issn.1674-8115.2024.09.014
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    In recent years, the global prevalence of obesity has continued to rise, with a preference for high-sugar and high-fat foods being one of the primary contributors to this condition. Food preference refers to the degree of individual liking for specific foods, and its formation is closely related to the physiological effects such as satiety, satisfaction and reward that occur after food digestion in the gastrointestinal tract. With the continuous advancement of technologies such as neuroimaging and chemogenetics, the underlying neural and physiological mechanisms of food preference behavior are gradually being elucidated. Studies have shown that the digestion and absorption of food in the gastrointestinal tract can release chemical or electrical signals, which are transmitted to the central nervous system via neural pathways, humoral pathways and the gut-brain axis mediated by gut microbiota. Subsequently, these signals regulate feeding behavior by activating or inhibiting neurons in the nucleus of the solitary tract, the dopaminergic reward pathways and relevant neural circuits in the hypothalamus. Based on this, the article introduces the definition, evaluation methods and mechanisms of food preference, and reviews the pathways of food information transmission within the gut-brain axis, the reward circuits that modulate food preference and the application of food preference behavior to the treatment of obesity, in order to provide reference for research in the field of food preference and obesity treatment.

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    Study on the effect and mechanism of sorting nexin 1 on inhibiting the proliferation and migration of colorectal cancer cells
    QIAN Liheng, WEN Kailing, LIAO Yingna, LI Shuxin, NIE Huizhen
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (9): 1124-1135.   DOI: 10.3969/j.issn.1674-8115.2024.09.007
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    Objective ·To explore the expression of sorting nexin 1 (SNX1) in colorectal cancer (CRC) and its impact on the proliferation and migration of CRC cells. Methods ·Transcriptomic data and clinical pathological information of CRC were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases for enrichment analysis with Gene Set Enrichment Analysis (GSEA) software. The expression of SNX1 in CRC tissues and cells was detected by quantitative real-time polymerase chain reaction (qPCR), Western blotting, and immunohistochemistry staining (IHC). Small interfering RNA (siRNA) was used to knock down the expression of SNX1 to observe its effect on tumor cell proliferation and migration. Correlation analysis was conducted to explore the potential molecular mechanisms underlying SNX1-mediated CRC cell migration, and mRNA level validation was performed in SNX1 knockdown cell lines. Results ·Analysis of CRC patients data in TCGA and tissue microarrays revealed that SNX1 expression was downregulated in CRC tissues and correlated with tumor diameter and distant metastasis. Knockdown of SNX1 enhanced tumor cell proliferation and migration. The expression of SNX1 was negatively correlated with metastasis associated in colon cancer 1 (MACC1), mesenchymal to epithelial transition factor (MET), and Notch; knockdown of SNX1 led to upregulation of these genes. Silencing SNX1 resulted in the downregulation of the epithelial marker cadherin 1 (CDH1) and the upregulation of vimentin (VIM) and Snail family transcriptional repressor 1 (SNAI1). Conclusion ·SNX1 expression was significantly downregulated in CRC tissues and correlated with patient prognosis. Low expression of SNX1 enhanced the proliferation and migration of CRC cells and was associated with the MACC1-MET pathway and EMT. SNX1 may serve as a potential biomarker for poor prognosis and a novel therapeutic target in CRC.

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    Mechanism of DUX-induced differentiation of mESC into extraembryonic endoderm
    HONG Lei, GUO Chuanliang, CAI Qin, LI Wanrui, ZENG Yitao, XUE Yan, ZENG Fanyi
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (11): 1359-1369.   DOI: 10.3969/j.issn.1674-8115.2024.11.003
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    Objective ·To explore the effect of double homeobox (DUX) protein on the differentiation potential of mouse embryonic stem cells (mESCs) into extraembryonic endoderm (XEN) and the possible mechanism of its action. Methods ·Overexpression of DUX cell lines in mESCs was achieved by using a lentiviral system. The proportion of 2-cell-like cells (2CLCs) before and after DUX overexpression was detected by flow cytometry, and the expression of 2-cell stage-specific genes, Dux, zinc finger and SCAN domain containing 4c (Zscan4c), zinc finger protein 352 (Zfp352) and murine endogenous retrovirus-L polymerase (MERVL-pol), were detected by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). RT-qPCR assay was used to detect the expression of pluripotency factors, nanog homeobox (Nanog), kruppel-like transcription factor 4 (Klf4), sex determining region Y-box 2 (Sox2), and octamer-binding transcription factor 4 (Oct4), in pluripotent state, as well as the expression of signature genes for different germ layers in the differentiated state [endodermal: GATA binding protein 4 (Gata4), GATA binding protein 6 (Gata6), and sex determining region Y-box 17 (Sox17); ectodermal: Nestin and tubulin beta 3 class Ⅲ (Tubb3); mesodermal: heart and neural crest derivatives expressed 1 (Hand1), myogenic differentiation 1 (Myod1), and kinase insert domain protein receptor (Flk1)]. Public RNA sequencing (RNA-seq) data were mined to further clarify the effect of DUX on the differentiation of mESCs into extraembryonic endoderm. Functional and pathway enrichment analyses of differentially expressed genes were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) to identify the signaling pathways regulated by DUX. Additionally, an in-depth analysis of existing chromatin immunoprecipitation sequencing (ChIP-seq) data was conducted to explore the potential target genes of DUX. Results ·Molecular biology experiments showed that overexpression of DUX could effectively maintain the pluripotency of mESCs, which was consistent with the analysis of public RNA-seq data. Differential gene analysis revealed that endodermal genes were specifically upregulated. After differentiation assay of mESCs, RT-qPCR assay experiments showed that mRNA expression of the XEN marker genes (Gata4, Gata6, Sox17) was significantly upregulated (P<0.001). In contrast, there was no specific change in mesodermal and ectodermal genes. GSEA enrichment analysis indicated that DUX might activate the retinoid metabolism signaling pathway, and the analysis of the ChIP-seq data further revealed the presence of a large number of known retinoic acid receptor motif in DUX-bound peaks, which could activate downstream target genes related to the development of the XEN. Conclusion ·DUX has a strong correlation with the retinoic acid signaling pathway and it is predicted to activate the retinoic acid signaling pathway, which could promote the tendency of mESCs toward XEN differentiation.

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    Comparative study on methods for colon polyp endoscopic image segmentation and classification based on deep learning
    CHEN Jian, WANG Zhenni, XIA Kaijian, WANG Ganhong, LIU Luojie, XU Xiaodan
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (6): 762-772.   DOI: 10.3969/j.issn.1674-8115.2024.06.012
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    Objective ·To compare the performance of various deep learning methods in the segmentation and classification of colorectal polyp endoscopic images, and identify the most effective approach. Methods ·Four colorectal polyp datasets were collected from three hospitals, encompassing 1 534 static images and 15 videos. All samples were pathologically validated and categorized into two types: serrated lesions and adenomatous polyps. Polygonal annotations were performed by using the LabelMe tool, and the annotated results were converted into integer mask formats. These data were utilized to train various architectures of deep neural networks, including convolutional neural network (CNN), Transformers, and their fusion, aiming to develop an effective semantic segmentation model. Multiple performance indicators for automatic diagnosis of colon polyps by different architecture models were compared, including mIoU, aAcc, mAcc, mDice, mFscore, mPrecision and mRecall. Results ·Four different architectures of semantic segmentation models were developed, including two deep CNN architectures (Fast-SCNN and DeepLabV3plus), one Transformer architecture (Segformer), and one hybrid architecture (KNet). In a comprehensive performance evaluation of 291 test images, KNet achieved the highest mIoU of 84.59%, significantly surpassing Fast-SCNN (75.32%), DeepLabV3plus (78.63%), and Segformer (80.17%). Across the categories of “background”, “serrated lesions” and “adenomatous polyps” , KNet's intersection over union (IoU) were 98.91%, 74.12%, and 80.73%, respectively, all exceeding other models. Additionally, KNet performed excellently in key performance metrics, with aAcc, mAcc, mDice, mFscore, and mRecall reaching 98.59%, 91.24%, 91.31%, 91.31%, and 91.24%, respectively, all superior to other models. Although its mPrecision of 91.46% was not the most outstanding, KNet's overall performance remained leading. In inference testing on 80 external test images, KNet maintained an mIoU of 81.53%, demonstrating strong generalization capabilities. Conclusion ·The semantic segmentation model of colorectal polyp endoscopic images constructed by deep neural network based on KNet hybrid architecture, exhibits superior predictive performance, demonstrating its potential as an efficient tool for detecting colorectal polyps.

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    Research progress in systemic complications induced by autonomic dysfunction after acute ischemic stroke
    ZHONG Jiaqi, CAO Wenfei, ZHOU Huizhong, YANG Jiajun
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 928-934.   DOI: 10.3969/j.issn.1674-8115.2024.07.015
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    Cerebrovascular diseases pose a serious threat to human health. According to the latest epidemiological data, stroke is one of the leading causes of death and disability among adults worldwide. Acute ischemic stroke (AIS), which is caused by local circulatory disorders in the brain, accounts for over 80% of all strokes and is the most common type of stroke. Due to extensive damage to the cerebral cortex or direct involvement of the autonomic nerve centers and pathways caused by AIS, the balance between the sympathetic and parasympathetic nervous systems is disturbed (with a predominance of sympathetic activation). Therefore, the organs targeted by the downstream pathways of the sympathetic and parasympathetic nervous systems are affected by the neurotransmitters they secrete, resulting in a range of systemic complications (such as cardiac complications, stroke-related infections, gastrointestinal complications, acute kidney injury, metabolic changes, and sexual dysfunction). These systemic pathological changes, in turn, affect the progression of AIS, thereby exacerbating brain damage or directly leading to patient death. Treatments targeting imbalances in the autonomic nervous system may play a role in reducing complications and improving the prognosis of AIS. This article reviews the systemic effects of autonomic dysfunction following AIS and its mechanisms, providing insights for the treatment of AIS and intervention of systemic complications.

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    Comparison of human-induced pluripotent stem cell-derived macrophages with peripheral blood-derived macrophages using single-cell genomics
    ZHANG Yutong, HOU Guojun, SHEN Nan
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (12): 1477-1489.   DOI: 10.3969/j.issn.1674-8115.2024.12.001
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    Objective ·To explore the heterogeneity in single-cell genomics between human-induced pluripotent stem cell (iPSC)-derived macrophages (IPSDM) and human peripheral blood-derived macrophages (PBDM). Methods ·iPSCs were differentiated into IPSDMs in vitro using a feeder-free and serum-free protocol. The expression of cluster of differentiation antigen 14 (CD14) and monocyte-macrophage marker genes in IPSDMs was analyzed using flow cytometry and real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR), respectively. Single-cell sequencing was then performed on IPSDMs. Simultaneously, the single-cell sequencing dataset GSE126085 was downloaded from the Gene Expression Omnibus database as a reference dataset for PBDMs. Sequencing data for both IPSDMs and PBDMs were processed and analyzed using the seurat package in R software, with PBDMs annotated using the singleR package. A reference dataset was constructed with highly variable genes from PBDMs, and the highly variable genes of IPSDMs were projected onto the PBDM dataset using the scmap package to infer IPSDMs cell identities based on variable gene similarity. IPSDMs were annotated using cell-type annotation tools and referenced against relevant studies. The expression distribution of macrophage marker genes was compared between IPSDMs and PBDMs. Differentially expressed genes (DEGs) between IPSDMs and PBDMs were identified using the seurat package, and their potential biological functions were explored through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Results ·Suspended IPSDMs were obtained after 29 d of in vitro differentiation. Flow cytometry and RT-qPCR confirmed that approximately 23.1% of IPSDMs expressed CD14, and IPSDMs exhibited higher expression of monocyte-macrophage marker genes compared to the U-937 cell line. All cells in the PBDM dataset were annotated as macrophages. After constructing a scmap reference dataset using PBDMs, 59.8% of IPSDMs were annotated as macrophages through mapping their highly variable genes to the PBDM dataset. The remaining 40.2% of IPSDM cells could not be matched to the variable genes of PBDMs. Further manual annotation of IPSDMs revealed a composition of 97.15% macrophages, 2.71% hematopoietic precursor cell-like cells, and 0.14% dendritic cells. When comparing the expression of macrophage markers, both IPSDMs and PBDMs highly expressed the classical macrophage marker CD68 gene, while IPSDMs exhibited higher expression of markers associated with tissue-resident macrophages. GO analysis of DEGs showed enrichment in the molecular functions such as ubiquitin-like protein ligase binding, cellular components such as the nuclear speck and nuclear envelope, and biological processes such as the regulation of translation. KEGG pathway enrichment indicated that the DEGs between IPSDMs and PBDMs might be related to various intracellular pathogen infections. Conclusion ·Human IPSDMs and PBDMs exhibit certain similarities and heterogeneity at the single-cell transcriptional level. Transcriptomic analysis indicates that IPSDMs display more characteristics of tissue-resident macrophages. The DEGs between IPSDMs and PBDMs are potentially associated with intracellular infection immunity.

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    Progress in the regulatory mechanisms of mandibular condylar development and deformity
    LIU Jingyi, XU Hongyuan, DAI Qinggang, JIANG Lingyong
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (8): 951-958.   DOI: 10.3969/j.issn.1674-8115.2024.08.003
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    The temporomandibular joint is the only joint structure within the craniofacial skeletal system, responsible for performing functions related to opening and closing mouth movements, such as chewing, speaking, and facial expression in daily life. The condyle of the mandible, as a vital component of the temporomandibular joint, originates from the mandibular process formed by the first gill arch and is the key growth center at the end of the mandibular ramus. Condyle is composed of a layer of cartilage as its surface and subchondral bone below, exhibiting unique biological processes during its growth and development. In the articular fossa, the functional movement of the condyle depends on its normal physiological and anatomical structure, which plays a crucial role in establishing occlusion and shaping facial features. Abnormal growth and development can lead to the occurrence of condylar deformities, which affect the vertical height of the patient's maxillofacial region and ultimately lead to secondary skeletal class Ⅱ or Ⅲ craniofacial deformities. During the process of growth and development, the condyle is subject to complex signal regulation. In recent years, with in-depth research on the temporomandibular joint, researchers have begun to discuss the regulatory mechanisms of condyle growth and development from the perspectives of gene expression and molecular level, in order to explain the causes of temporomandibular joint diseases and condylar deformities. This article provides a review on the growth process and structure of condyle, classification and pathological manifestations of condylar deformities, and related regulatory mechanisms of the growth and development of condyle, as well as pathogenesis of condylar deformities. The aim of this article is to provide research ideas for temporomandibular joint diseases and craniofacial malformations caused by abnormal development of the mandibular condyle in clinical practice.

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    Trend analysis of differentially expressed genes in retinoic acid-induced neural tube defects in mouse model
    CAO Rui, WEI Kaixin, ZHANG Xiaona, LIU Yurong, ZHANG Li
    Journal of Shanghai Jiao Tong University (Medical Science)    2024, 44 (7): 859-870.   DOI: 10.3969/j.issn.1674-8115.2024.07.007
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    Objective ·To explore the molecular regulatory mechanism of neural tube defect (NTD) induced by retinoic acid (RA) in mouse embryos, and reveal the gene expression regularity of neural tube closure in mice. Methods ·Based on the high-quality brain vesicle transcriptome data of mouse embryo during the critical period of neural tube closure [embryonic day 8.5 (E8.5), E9.5 and E10.5], the gene expression trend data of the NTD group and the control group were obtained by using Short Time-series Expression Miner (STEM) software. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed for genes with different expression trends between the NTD group and the control group. Some candidate genes were screened for validation. Pregnant mice were divided into the NTD group and control group, with 9 mice in each group. Pregnant mice in the NTD group were treated with RA and those in the control group were treated with sesame oil by gavage at E7.5. Foetal rat brain vesicle tissues were collected at E8.5, E9.5 and E10.5 for experiments. Based on the above animal tissues, the screened candidate genes were validated by quantitative real-time PCR (RT-PCR). Results ·A total of 18 255 genes were detected in the transcriptome data of the control group, and the expression patterns of these genes could be summarized into 7 significant profiles. A total of 19 037 gene expression data were detected in the transcriptome data of the NTD group, and gene expression patterns could be summarized into 6 profiles with significant significance. A total of 46 genes in the control group showed an upward trend but a downward trend in the NTD group. They were enriched in the positive and negative regulation of organ development, neuronal apoptosis, oligodendrocyte proliferation, and fibroblast growth factor signaling pathway at the biological process level. At the cellular component level, they were mainly involved in the basic structure of cells and neurons; At the molecular functional level, they were mainly related to the binding of fibroblast growth factor receptor. A total of 61 genes showed a downward trend in the control group but an upward trend in the NTD group. These genes were enriched in functions such as cell lysis and amino acid/ion transport at the biological process level. At the cellular component level, they were enriched in intracellular molecules, particles, extracellular region, intercellular space, etc. At the molecular function level, they were related to the activity of a series of enzymes and transporters. The results of RT-qPCR showed that the transcriptome sequencing data were authentic and reliable. Conclusion ·RA intervention causes abnormal cellular activities and stress responses during mouse embryo development, leading to abnormal embryo development, activation of signalling pathways related to organismal self-protection, and suppression of genes that maintain normal embryo development.

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