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[Nitrosative stress promotes the malignant biological behavior of breast cancer through the glycolytic pathway]. [亚硝化应激通过糖酵解途径促进乳腺癌的恶性生物学行为]。
Q3 Medicine Pub Date : 2025-10-28 DOI: 10.11817/j.issn.1672-7347.2025.250460
Yalu Wang, Mingyan Gong, Yunhao Zhu, Yuxiang Xu, Jianming Hu, Chenghua Luo
<p><strong>Objectives: </strong>Breast cancer is one of the most common malignant tumors in women, and some patients face poor therapeutic efficacy and recurrence. Tumor cells are extremely dependent on the energy produced by the glycolytic pathway, which not only provides adenosine triphosphate (ATP) for rapid tumor cell proliferation, but also creates favorable conditions for tumor cell growth by regulating the acidity of the tumor microenvironment. Nitrosative stress refers to a pathophysiological state characterized by intracellular accumulation of reactive nitrogen species (RNS). Studies have found that nitrosative stress is closely associated with the occurrence and progression of cancer. This study aims to investigate the effects of nitrosative stress and tumor cell glycolysis, to provide new ideas for breast cancer treatment.</p><p><strong>Methods: </strong>Postoperative tumor tissues from breast cancer patients at the First Affiliated Hospital of Shihezi University were collected. Immunohistochemistry (IHC) staining was used to analyze the expression levels of inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in breast cancer tissues and adjacent normal breast tissues. Fluorescent probes were used to detect nitric oxide (NO) and reactive oxygen species (ROS) levels in normal breast cells (MCF-10A) and breast cancer cells (MDA-MB-231 and MCF-7). Western blotting was used to compare the expression levels of iNOS and 3-NT between normal and breast cancer cells. The optimal concentrations of the peroxynitrite (ONOO⁻) donor (SIN-1) and the scavenger (FeTMPyP) were determined using cell counting kit-8 (CCK-8). Glycolysis levels were measured using a glycolysis assay kit. CCK-8, Transwell, and wound-healing assays were further used to detect the proliferation, migration, and invasion abilities of MDA-MB-231 and MCF-7 cells under the effects of the two drugs. Western blotting was used to detect the expression levels of E-cadherin, N-cadherin, and vimentin, as well as glycolysis-related proteins hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and enolase 1 (ENO1).</p><p><strong>Results: </strong>The expression levels of iNOS and 3-NT in breast cancer tissues were significantly higher than those in normal breast tissues (<i>P</i><0.001), NO (<i>P</i><0.01), ROS (<i>P</i><0.001), iNOS (<i>P</i><0.05), and 3-NT (<i>P</i><0.01) levels in breast cancer cell lines (MDA-MB-231 and MCF-7) were all significantly higher than those in normal breast cells (MCF-10A). Breast cancer cells exhibited higher glycolysis levels (<i>P</i><0.001). Treatment with the nitrosative-stress down-regulating drug FeTMPyP significantly inhibited glycolysis levels (<i>P</i><0.001), and the expression of glycolytic enzymes HK2, PKM2, and ENO1 was significantly decreased (all <i>P</i><0.05). The proliferation, migration, and invasion abilities of the two breast cancer cell lines were weakened, and the expression of EMT-related protein E-cadherin was increased, whil
目的:乳腺癌是女性最常见的恶性肿瘤之一,部分患者治疗效果差,易复发。肿瘤细胞极其依赖糖酵解途径产生的能量,糖酵解途径不仅为肿瘤细胞快速增殖提供三磷酸腺苷(ATP),而且通过调节肿瘤微环境的酸度,为肿瘤细胞的生长创造有利条件。亚硝化应激是指以细胞内活性氮(RNS)积累为特征的一种病理生理状态。研究发现,亚硝化应激与癌症的发生发展密切相关。本研究旨在探讨亚硝化应激对肿瘤细胞糖酵解的影响,为乳腺癌的治疗提供新的思路。方法:收集石河子大学第一附属医院乳腺癌患者术后肿瘤组织。采用免疫组化(IHC)染色法分析诱导型一氧化氮合酶(iNOS)和3-硝基酪氨酸(3-NT)在乳腺癌组织及邻近正常乳腺组织中的表达水平。采用荧光探针检测正常乳腺细胞(MCF-10A)和乳腺癌细胞(MDA-MB-231和MCF-7)中一氧化氮(NO)和活性氧(ROS)水平。采用Western blotting比较正常和乳腺癌细胞中iNOS和3-NT的表达水平。使用细胞计数试剂盒-8 (CCK-8)确定过氧亚硝酸盐(ONOO毒血症)供体(SIN-1)和清除率(FeTMPyP)的最佳浓度。使用糖酵解测定试剂盒测定糖酵解水平。进一步采用CCK-8、Transwell和创面愈合法检测MDA-MB-231和MCF-7细胞在两种药物作用下的增殖、迁移和侵袭能力。Western blotting检测E-cadherin、N-cadherin、vimentin以及糖酵解相关蛋白己糖激酶2 (HK2)、丙酮酸激酶M2 (PKM2)、烯醇化酶1 (ENO1)的表达水平。结果:乳腺癌组织中iNOS和3-NT的表达水平明显高于正常乳腺组织(ppppppppppppppppp)。结论:亚硝化应激可通过糖酵解途径促进乳腺癌细胞的恶性生物学行为。
{"title":"[Nitrosative stress promotes the malignant biological behavior of breast cancer through the glycolytic pathway].","authors":"Yalu Wang, Mingyan Gong, Yunhao Zhu, Yuxiang Xu, Jianming Hu, Chenghua Luo","doi":"10.11817/j.issn.1672-7347.2025.250460","DOIUrl":"10.11817/j.issn.1672-7347.2025.250460","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;Breast cancer is one of the most common malignant tumors in women, and some patients face poor therapeutic efficacy and recurrence. Tumor cells are extremely dependent on the energy produced by the glycolytic pathway, which not only provides adenosine triphosphate (ATP) for rapid tumor cell proliferation, but also creates favorable conditions for tumor cell growth by regulating the acidity of the tumor microenvironment. Nitrosative stress refers to a pathophysiological state characterized by intracellular accumulation of reactive nitrogen species (RNS). Studies have found that nitrosative stress is closely associated with the occurrence and progression of cancer. This study aims to investigate the effects of nitrosative stress and tumor cell glycolysis, to provide new ideas for breast cancer treatment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Postoperative tumor tissues from breast cancer patients at the First Affiliated Hospital of Shihezi University were collected. Immunohistochemistry (IHC) staining was used to analyze the expression levels of inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in breast cancer tissues and adjacent normal breast tissues. Fluorescent probes were used to detect nitric oxide (NO) and reactive oxygen species (ROS) levels in normal breast cells (MCF-10A) and breast cancer cells (MDA-MB-231 and MCF-7). Western blotting was used to compare the expression levels of iNOS and 3-NT between normal and breast cancer cells. The optimal concentrations of the peroxynitrite (ONOO⁻) donor (SIN-1) and the scavenger (FeTMPyP) were determined using cell counting kit-8 (CCK-8). Glycolysis levels were measured using a glycolysis assay kit. CCK-8, Transwell, and wound-healing assays were further used to detect the proliferation, migration, and invasion abilities of MDA-MB-231 and MCF-7 cells under the effects of the two drugs. Western blotting was used to detect the expression levels of E-cadherin, N-cadherin, and vimentin, as well as glycolysis-related proteins hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and enolase 1 (ENO1).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The expression levels of iNOS and 3-NT in breast cancer tissues were significantly higher than those in normal breast tissues (&lt;i&gt;P&lt;/i&gt;&lt;0.001), NO (&lt;i&gt;P&lt;/i&gt;&lt;0.01), ROS (&lt;i&gt;P&lt;/i&gt;&lt;0.001), iNOS (&lt;i&gt;P&lt;/i&gt;&lt;0.05), and 3-NT (&lt;i&gt;P&lt;/i&gt;&lt;0.01) levels in breast cancer cell lines (MDA-MB-231 and MCF-7) were all significantly higher than those in normal breast cells (MCF-10A). Breast cancer cells exhibited higher glycolysis levels (&lt;i&gt;P&lt;/i&gt;&lt;0.001). Treatment with the nitrosative-stress down-regulating drug FeTMPyP significantly inhibited glycolysis levels (&lt;i&gt;P&lt;/i&gt;&lt;0.001), and the expression of glycolytic enzymes HK2, PKM2, and ENO1 was significantly decreased (all &lt;i&gt;P&lt;/i&gt;&lt;0.05). The proliferation, migration, and invasion abilities of the two breast cancer cell lines were weakened, and the expression of EMT-related protein E-cadherin was increased, whil","PeriodicalId":39801,"journal":{"name":"中南大学学报(医学版)","volume":"50 10","pages":"1800-1810"},"PeriodicalIF":0.0,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12949866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146144138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
[A multi-molecular predictive model for lymph node metastasis in papillary thyroid carcinoma based on machine learning algorithms]. [基于机器学习算法的甲状腺乳头状癌淋巴结转移多分子预测模型]。
Q3 Medicine Pub Date : 2025-10-28 DOI: 10.11817/j.issn.1672-7347.2025.250216
Zhijun Zhan, Lu Chen, Yan Sun, Jiaxing Zeng, Ning Li, Junda Yin, Hailong Tan, Shi Chang
<p><strong>Objectives: </strong>Accurate preoperative evaluation of lymph node metastasis (LNM) status in patients with papillary thyroid carcinoma (PTC) is essential for the development of individualized diagnosis and treatment strategies; however, the predictive performance of current clinical approaches remains limited. This study aims to identify key molecular biomarkers associated with LNM in PTC, construct LNM-risk prediction models using machine learning (ML) algorithms, and assess their potential value in supporting clinical decision-making.</p><p><strong>Methods: </strong>Transcriptomic data from 507 PTC patients were obtained from The Cancer Genome Atlas (TCGA). After rigorous quality control, 50 patients with unknown lymph node status (N-stage) were excluded, leaving 457 eligible patients [229 with no LNM (N0) and 228 with LNM (N1)]. Patients were randomly stratified into a training set (<i>n</i>=321) and a validation set (<i>n</i>=136) at a 7꞉3 ratio. Four independent analytical methods-Differential Expression analysis based on the Negative Binomial distribution (DESeq2), Empirical analysis of Digital Gene Expression in R (edgeR), Linear Models for Microarray Analysis (Limma), and Weighted Gene Co-expression Network Analysis (WGCNA)-were applied to identify LNM-associated candidate gene sets. Core genes were further selected from each set using least absolute shrinkage and selection operator (LASSO) regression, and multivariate logistic regression models were built on the training cohort. Model performance and generalizability were evaluated using receiver operating characteristic (ROC) curves, confusion matrices, calibration curves (CC), decision curve analysis (DCA), and ML cross-validation across six algorithms: Generalized linear model (GLM), random forest (RF), extreme gradient boosting (XGBoost), artificial neural network (ANN), support vector machine (SVM), and naive Bayes model (NBM).</p><p><strong>Results: </strong>EdgeR combined with LASSO regression identified 11 signature genes associated with LNM in PTC: <i>PI15, IL11, PLA2G5, LY6G6C, FAM178B, MUC21, FN1, PDZK1IP1, STAC2, TMPRSS4,</i> and <i>WARS1P1</i>. The multivariate logistic model constructed from these genes (Model 2) showed the best predictive performance. In the training set, the area under the ROC curve (AUC) was 0.802, with a sensitivity of 0.771 and specificity of 0.797. In the validation set, the AUC was 0.793, with a sensitivity of 0.773 and specificity of 0.634. Sex-stratified analyses confirmed stable performance in the overall cohort (AUC=0.780), females (AUC=0.775), and males (AUC=0.807). ML cross-validation demonstrated that Model 2 achieved superior and well-balanced predictive performance across all 6 ML algorithms. CC analysis demonstrated strong agreement between predicted and observed LNM probabilities (Hosmer-Lemeshow goodness-of-fit test: <i>P</i><sub>training</sub>=0.851, <i>P</i><sub>validation</sub>=0.842). DCA revealed significant net clinical
目的:术前准确评估甲状腺乳头状癌(PTC)患者的淋巴结转移(LNM)状态,对制定个体化诊断和治疗策略至关重要;然而,目前临床方法的预测性能仍然有限。本研究旨在识别PTC中与LNM相关的关键分子生物标志物,利用机器学习(ML)算法构建LNM风险预测模型,并评估其在支持临床决策中的潜在价值。方法:从癌症基因组图谱(TCGA)中获取507例PTC患者的转录组学数据。经过严格的质量控制,排除了50例淋巴结状态未知(n期)的患者,剩下457例符合条件的患者[229例无淋巴结转移(N0), 228例有淋巴结转移(N1)]。患者按7 3的比例随机分为训练组(n=321)和验证组(n=136)。四种独立的分析方法——基于负二项分布的差异表达分析(DESeq2)、R中数字基因表达的实证分析(edgeR)、微阵列分析的线性模型(Limma)和加权基因共表达网络分析(WGCNA)——被用于识别lnm相关的候选基因集。使用最小绝对收缩和选择算子(LASSO)回归从每个集合中进一步选择核心基因,并在训练队列中建立多元逻辑回归模型。使用受试者工作特征(ROC)曲线、混淆矩阵、校准曲线(CC)、决策曲线分析(DCA)和ML交叉验证六种算法(广义线性模型(GLM)、随机森林(RF)、极端梯度增强(XGBoost)、人工神经网络(ANN)、支持向量机(SVM)和朴素贝叶斯模型(NBM))来评估模型的性能和泛化性。结果:EdgeR联合LASSO回归鉴定出PTC中与LNM相关的11个特征基因:PI15、IL11、PLA2G5、LY6G6C、FAM178B、MUC21、FN1、PDZK1IP1、STAC2、TMPRSS4、WARS1P1。由这些基因构建的多元逻辑模型(模型2)显示出最好的预测性能。在训练集中,ROC曲线下面积(AUC)为0.802,敏感性为0.771,特异性为0.797。在验证集中,AUC为0.793,敏感性为0.773,特异性为0.634。性别分层分析证实了整个队列(AUC=0.780)、女性(AUC=0.775)和男性(AUC=0.807)的稳定表现。ML交叉验证表明,模型2在所有6种ML算法中都取得了卓越且平衡的预测性能。CC分析显示预测和观察到的LNM概率之间有很强的一致性(Hosmer-Lemeshow拟合优度检验:Ptraining=0.851, Pvalidation=0.842)。DCA显示,培训队列在0.1 - 0.75的风险阈值范围内有显著的净临床获益,而验证队列仅在低阈值范围内有获益。基于11个特征基因构建的优化多分子logistic回归模型(model 2)能够有效预测PTC患者的淋巴结转移风险,具有较强的跨性别稳定性和跨多种ML算法的强兼容性,作为淋巴结状态评估和个性化治疗计划的术前决策支持工具具有潜在的临床实用性。
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引用次数: 0
[Progress in the application of artificial intelligence in assisted reproduction]. 人工智能在辅助生殖中的应用进展。
Q3 Medicine Pub Date : 2025-10-28 DOI: 10.11817/j.issn.1672-7347.2025.240638
Qiuyao Li, Ting Wang, Yidan Liu, Xinghan Wang, Xiaoling Ma, Lin Liu

As a disease that seriously affects the health of men and women of childbearing age, the incidence of infertility is increasing worldwide, and the popularization of assisted reproductive technology (ART) is expected to improve the situation. However, invitro fertilization and embryo transfer (IVF) success rates are only about 50%, and IVF success rates are affected by a number of factors. For example, semen quality, endometrial thickness, fallopian tube patency, embryo selection and transplantation, uterine microenvironment, etc., and the treatment process of IVF is highly dependent on the clinical experience of embryologists, and there is a lack of objective and unified evaluation criteria. Artificial intelligence (AI) is ideally suited to processing and analyzing large, dynamic temporal data sets to assist physicians in making more objective and precise decisions, thereby improving IVF success. At present, artificial intelligence technology using different types of algorithms has been used for sperm classification, oocyte and embryo selection, and prediction of embryo development after implantation, etc. The application of AI in the field of assisted reproduction is expected to improve infertility diagnosis results and increase the pregnancy rate and live birth rate of ART, but there are still certain controversies in privacy, safety and other aspects.In the future, with the accumulation of high-quality datasets, algorithm optimization and the advancement of imaging technology, AI is expected to increase the success rate of ART by selecting higher-quality sperm and oocytes, as well as embryos with greater developmental potential. This will bring significant innovation to the field of reproductive medicine and the entire healthcare sector, while also reducing treatment costs.

不孕症作为严重影响育龄男女健康的疾病,在世界范围内发病率呈上升趋势,辅助生殖技术的普及有望改善这一状况。然而,体外受精和胚胎移植(IVF)的成功率只有50%左右,试管婴儿成功率受到许多因素的影响。如精液质量、子宫内膜厚度、输卵管通畅、胚胎选择与移植、子宫微环境等,体外受精的治疗过程高度依赖于胚胎学家的临床经验,缺乏客观统一的评价标准。人工智能(AI)非常适合处理和分析大型动态时间数据集,以帮助医生做出更客观和精确的决策,从而提高试管婴儿成功率。目前,采用不同类型算法的人工智能技术已被用于精子分类、卵母细胞和胚胎选择、胚胎着床后发育预测等方面。人工智能在辅助生殖领域的应用有望改善不孕症诊断结果,提高ART的妊娠率和活产率,但在隐私、安全等方面仍存在一定争议。未来,随着高质量数据集的积累、算法的优化和成像技术的进步,人工智能有望通过选择更高质量的精子和卵母细胞,以及更大发育潜力的胚胎,提高ART的成功率。这将为生殖医学领域和整个医疗保健部门带来重大创新,同时也降低了治疗成本。
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引用次数: 0
[Mechanistic research progress on radiotherapy resistance of cancer stem cells]. 肿瘤干细胞放疗耐药机制研究进展
Q3 Medicine Pub Date : 2025-10-28 DOI: 10.11817/j.issn.1672-7347.2025.240599
Zhiwei Luo, Mingkai Yu, Jingyi Li, Shurong Zhang, Ting Shen

Radiotherapy is an important treatment modality for tumors and is involved in the treatment course of more than 50% of cancer patients. However, resistance to ionizing radiation results in suboptimal radiotherapy efficacy and contributes to tumor recurrence and metastasis at later stages. With the increasing understanding of tumor pathogenesis, cancer stem cell (CSC), characterized by self-renewal capacity and differentiation potential, have attracted growing attention and play key roles in radiotherapy resistance, tumor progression, metastasis, immune evasion, and other processes. Mechanisms including the tumor microenvironment, DNA damage repair, and epithelial-mesenchymal transition (EMT) are critical drivers of CSC-mediated radiotherapy resistance. Reviewing the key pathways involved and identifying CSC-specific therapeutic targets may provide new insights for developing more efficient and less toxic radiotherapy strategies.

放疗是肿瘤的一种重要治疗方式,超过50%的癌症患者的治疗过程中都涉及到放疗。然而,对电离辐射的抵抗导致放疗效果不佳,并导致肿瘤后期复发和转移。随着人们对肿瘤发病机制认识的不断深入,肿瘤干细胞(cancer stem cell, CSC)因其具有自我更新能力和分化潜力,在放疗抵抗、肿瘤进展、转移、免疫逃避等过程中发挥着关键作用,越来越受到人们的关注。包括肿瘤微环境、DNA损伤修复和上皮-间质转化(EMT)在内的机制是csc介导的放疗耐药的关键驱动因素。回顾所涉及的关键途径并确定csc特异性治疗靶点可能为开发更有效和毒性更低的放射治疗策略提供新的见解。
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引用次数: 0
[Application of flavonoid in disease treatment based on multi-omics technologies]. [基于多组学技术的类黄酮在疾病治疗中的应用]。
Q3 Medicine Pub Date : 2025-10-28 DOI: 10.11817/j.issn.1672-7347.2025.250227
Weihua Zhang, Kezhen Han, Kexin Zhao, Chao Yang, Manfei Jin, Ying Wang, Zhao Jiang

Flavonoids are naturally occurring polyphenolic compounds widely distributed in nature, exhibiting pharmacological activities including anti-inflammatory effects and inhibition of cell proliferation. Their broader application has been constrained by unclear therapeutic targets. Recent advances in high-throughput sequencing and high-resolution mass spectrometry have elevated the importance of multi-omics analysis for elucidating flavonoid pharmacological effects, therapeutic targets, and regulatory networks. Integration of genomics, transcriptomics, proteomics, metabolomics, and metagenomics enables systematic characterization of flavonoid targets and modulation networks. Clarifying the application of multi-omics technologies in this field may support the clinical translation of flavonoids and provide new strategies for precision research in traditional Chinese medicine.

黄酮类化合物是广泛存在于自然界的天然多酚类化合物,具有抗炎、抑制细胞增殖等药理作用。它们的广泛应用受到治疗靶点不明确的限制。高通量测序和高分辨率质谱的最新进展提高了多组学分析在阐明类黄酮药理作用、治疗靶点和调控网络方面的重要性。基因组学、转录组学、蛋白质组学、代谢组学和宏基因组学的整合使黄酮类化合物靶点和调节网络的系统表征成为可能。阐明多组学技术在该领域的应用,可为黄酮类化合物的临床翻译提供支持,并为中药精准研究提供新策略。
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引用次数: 0
Tear fluid participates in systemic immunity. 泪液参与全身免疫。
Q3 Medicine Pub Date : 2025-10-28 DOI: 10.11817/j.issn.1672-7347.2025.250186
Tong Wu, Xiya Wen, Jiaxin Zhang, Yiren Zhang, Min Fu, Guoguo Yi

Tear fluid, also referred to as tears or tear film, is an important biological fluid that plays a key role in maintaining ocular surface health and immune homeostasis. Recent studies have found that tear fluid not only participates in the occurrence and development of ocular diseases, but also exerts profound effects in the immune pathological mechanisms of systemic diseases, breaking through the inherent understanding previously held by the scientific community. Immune cells in tear fluid (such as T cells, neutrophils, natural killer cells, macrophages), cytokines, and immunoglobulins can specifically participate in autoimmune diseases (such as Sjögren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Graves' ophthalmopathy) and systemic diseases (such as Alzheimer's disease, diabetes mellitus, graft-versus-host disease). The dynamic changes in tear fluid components can reflect systemic immune homeostasis imbalance. Tear fluid biomarkers, such as exosomal microRNA (miR)-204, miR-200b-5p, and the protein marker β2-microglobulin, have shown great potential in early disease screening, diagnostic stratification, and therapeutic target discovery. Tear fluid immune component analysis may provide innovative diagnostic tools and therapeutic targets for systemic diseases. Future research should focus on promoting the standardization and clinical transformation of tear fluid testing technologies and their clinical application.

泪液,也称为泪液或泪膜,是一种重要的生物液体,在维持眼表健康和免疫稳态方面起着关键作用。近年来的研究发现,泪液不仅参与眼部疾病的发生发展,而且在全身性疾病的免疫病理机制中发挥着深远的作用,突破了科学界以往固有的认识。泪液中的免疫细胞(如T细胞、中性粒细胞、自然杀伤细胞、巨噬细胞)、细胞因子和免疫球蛋白可特异性参与自身免疫性疾病(如Sjögren综合征、类风湿关节炎、系统性红斑狼疮、多发性硬化症、Graves眼病)和全身性疾病(如阿尔茨海默病、糖尿病、移植物抗宿主病)。泪液成分的动态变化可以反映全身免疫稳态失衡。泪液生物标志物,如外泌体microRNA (miR)-204、miR-200b-5p和蛋白质标志物β2-微球蛋白,在早期疾病筛查、诊断分层和治疗靶点发现方面显示出巨大的潜力。泪液免疫成分分析可为全身性疾病提供创新的诊断工具和治疗靶点。今后的研究应着眼于促进泪液检测技术的规范化和临床转化及其临床应用。
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引用次数: 0
Exploration of safety indicators for radiotherapy in hepatocellular carcinoma: A real-world study. 肝癌放疗安全指标的探索:一项现实世界的研究。
Q3 Medicine Pub Date : 2025-10-28 DOI: 10.11817/j.issn.1672-7347.2025.250218
Xueyi Xie, Xi Zhang, Honghua Peng, Jun Zhang, Yuliang Pan, Zhen Zhang, Qiao Jin, Peiguo Cao
<p><strong>Objectives: </strong>Hepatocellular carcinoma (HCC) is the most common pathological subtype of primary liver cancer and is associated with high incidence and mortality. External beam radiation therapy (EBRT) is a widely used local treatment modality for HCC across different disease stages. In the era of precision radiotherapy, standardized safety evaluation indicators for HCC radiotherapy remain lacking. Normal liver tissue surrounding the tumor may lose hepatic function after high-dose irradiation. In this study, remnant functional liver volume (RFLV) was defined as the volume of liver tissue that retains normal function after irradiation, and the residual remnant functional liver volume after x Gy irradiation (rRFLV<sub>x</sub>) was defined as the absolute liver volume receiving less than a given dose threshold (x Gy), and plans to explore the performance of rRFLV<sub>x</sub> as a radiotherapy safety dose indicator based on real-world data, as well as to explore the safety and efficacy of EBRT in HCC.</p><p><strong>Methods: </strong>A total of 113 HCC patients who received stereotactic body radiotherapy (a SBRT group, <i>n</i>=35) or intensity-modulated radiation therapy (a IMRT group, <i>n</i>=78) for liver lesions at the Third Xiangya Hospital of Central South University between 2015 and 2023 were prospectively collected and selected. The occurrence of radiation-induced liver diseases (RILDs) was recorded. Dosimetric parameters potentially associated with RILDs were analyzed using binary logistic regression with Hosmer-Lemeshow test, mainly including mean liver dose (MLD), remnant liver volume (RLV), standard liver volume (SLV), and rRFLV<sub>x</sub>. Radiotherapy-related hepatitis virus reactivation and other radiotherapy-related toxicities were also observed. Progression-free survival (PFS) and overall survival (OS) were used to evaluate the efficacy of EBRT in HCC.</p><p><strong>Results: </strong>Among the 113 HCC patients, 12 were diagnosed with RILDs, including 11 in the IMRT group and only 1 in the SBRT group. Binary logistic regression with Hosmer-Lemeshow test results suggested that rRFLV<sub>25</sub>, rRFLV<sub>20</sub>, rRFLV<sub>15</sub>, rRFLV<sub>25</sub>/SLV, rRFLV<sub>20</sub>/SLV, and rRFLV<sub>15</sub>/SLV were significantly associated with the occurrence of RILDs in HCC patients in the IMRT group (all <i>P</i><0.05), while MLD and RLV were not associated with the occurrence of RILDs (<i>P</i>=0.88). One patient without regular anti-hepatitis viral treatment was diagnosed with radiotherapy-related HBV clinical reactivation, and one patient was diagnosed with immunotherapy-related HBV clinical reactivation. The median PFS was 5.6 months in the IMRT group and 16.4 months in the SBRT group, and the best local control rates were 98.6% and 100.0%, respectively. The median OS was 12.2 months in the IMRT group and 33.5 months in the SBRT group. The 6-month, 1-year, and 2-year OS rates in the IMRT group were 77.1%, 52.6%,
目的:肝细胞癌(HCC)是原发性肝癌最常见的病理亚型,具有较高的发病率和死亡率。体外放射治疗(EBRT)是一种广泛应用于不同疾病阶段的肝癌局部治疗方式。在精准放疗时代,HCC放疗缺乏标准化的安全性评价指标。肿瘤周围的正常肝组织在高剂量照射后可能丧失肝功能。在这项研究中,残余功能性肝体积(RFLV)被定义为体积辐照后保留正常功能的肝组织,和剩余残余功能x Gy辐照后肝脏体积(rRFLVx)被定义为绝对的肝脏体积接收不到一个给定的剂量阈值(x Gy),并计划探索rRFLVx作为放射治疗安全剂量的性能指标基于真实数据,以及探索EBRT在肝癌的安全性和有效性。方法:前瞻性收集2015 - 2023年在中南大学湘雅第三医院接受立体定向体放疗(SBRT组,n=35)或调强放疗(IMRT组,n=78)的肝癌肝病变患者113例。记录放射性肝脏疾病(RILDs)发生情况。采用Hosmer-Lemeshow检验对可能与RILDs相关的剂量学参数进行二元logistic回归分析,主要包括平均肝剂量(MLD)、残肝体积(RLV)、标准肝体积(SLV)和rRFLVx。还观察到放射治疗相关的肝炎病毒再活化和其他放射治疗相关的毒性。采用无进展生存期(PFS)和总生存期(OS)来评估EBRT治疗HCC的疗效。结果:113例HCC患者中,12例被诊断为RILDs,其中IMRT组11例,SBRT组仅1例。结合Hosmer-Lemeshow检验的二元logistic回归结果显示,在IMRT组中,rRFLV25、rRFLV20、rRFLV15、rRFLV25/SLV、rRFLV20/SLV、rRFLV15/SLV与HCC患者中RILDs的发生存在显著相关性(均PP=0.88)。1例未接受常规抗肝炎病毒治疗的患者被诊断为放疗相关HBV临床再激活,1例被诊断为免疫治疗相关HBV临床再激活。IMRT组中位PFS为5.6个月,SBRT组中位PFS为16.4个月,最佳局部控制率分别为98.6%和100.0%。IMRT组的中位OS为12.2个月,SBRT组的中位OS为33.5个月。IMRT组6个月、1年和2年的OS率分别为77.1%、52.6%和18.6%。SBRT组1年、2年、3年、4年、5年的总生存率分别为86.1%、61.7%、39.2%、25.7%、18.3%。结论:EBRT治疗不同阶段HCC患者安全有效。与MLD和RLV相比,rRFLVx和rRFLVx/SLV可能更可靠地评估IMRT治疗后RILDs的发生。对于有肝炎背景的患者,放疗期间同时进行抗病毒治疗是相对安全的,但应密切监测血清病毒载量。放疗联合靶向和免疫治疗的有效性和安全性有待进一步研究。
{"title":"Exploration of safety indicators for radiotherapy in hepatocellular carcinoma: A real-world study.","authors":"Xueyi Xie, Xi Zhang, Honghua Peng, Jun Zhang, Yuliang Pan, Zhen Zhang, Qiao Jin, Peiguo Cao","doi":"10.11817/j.issn.1672-7347.2025.250218","DOIUrl":"10.11817/j.issn.1672-7347.2025.250218","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;Hepatocellular carcinoma (HCC) is the most common pathological subtype of primary liver cancer and is associated with high incidence and mortality. External beam radiation therapy (EBRT) is a widely used local treatment modality for HCC across different disease stages. In the era of precision radiotherapy, standardized safety evaluation indicators for HCC radiotherapy remain lacking. Normal liver tissue surrounding the tumor may lose hepatic function after high-dose irradiation. In this study, remnant functional liver volume (RFLV) was defined as the volume of liver tissue that retains normal function after irradiation, and the residual remnant functional liver volume after x Gy irradiation (rRFLV&lt;sub&gt;x&lt;/sub&gt;) was defined as the absolute liver volume receiving less than a given dose threshold (x Gy), and plans to explore the performance of rRFLV&lt;sub&gt;x&lt;/sub&gt; as a radiotherapy safety dose indicator based on real-world data, as well as to explore the safety and efficacy of EBRT in HCC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A total of 113 HCC patients who received stereotactic body radiotherapy (a SBRT group, &lt;i&gt;n&lt;/i&gt;=35) or intensity-modulated radiation therapy (a IMRT group, &lt;i&gt;n&lt;/i&gt;=78) for liver lesions at the Third Xiangya Hospital of Central South University between 2015 and 2023 were prospectively collected and selected. The occurrence of radiation-induced liver diseases (RILDs) was recorded. Dosimetric parameters potentially associated with RILDs were analyzed using binary logistic regression with Hosmer-Lemeshow test, mainly including mean liver dose (MLD), remnant liver volume (RLV), standard liver volume (SLV), and rRFLV&lt;sub&gt;x&lt;/sub&gt;. Radiotherapy-related hepatitis virus reactivation and other radiotherapy-related toxicities were also observed. Progression-free survival (PFS) and overall survival (OS) were used to evaluate the efficacy of EBRT in HCC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Among the 113 HCC patients, 12 were diagnosed with RILDs, including 11 in the IMRT group and only 1 in the SBRT group. Binary logistic regression with Hosmer-Lemeshow test results suggested that rRFLV&lt;sub&gt;25&lt;/sub&gt;, rRFLV&lt;sub&gt;20&lt;/sub&gt;, rRFLV&lt;sub&gt;15&lt;/sub&gt;, rRFLV&lt;sub&gt;25&lt;/sub&gt;/SLV, rRFLV&lt;sub&gt;20&lt;/sub&gt;/SLV, and rRFLV&lt;sub&gt;15&lt;/sub&gt;/SLV were significantly associated with the occurrence of RILDs in HCC patients in the IMRT group (all &lt;i&gt;P&lt;/i&gt;&lt;0.05), while MLD and RLV were not associated with the occurrence of RILDs (&lt;i&gt;P&lt;/i&gt;=0.88). One patient without regular anti-hepatitis viral treatment was diagnosed with radiotherapy-related HBV clinical reactivation, and one patient was diagnosed with immunotherapy-related HBV clinical reactivation. The median PFS was 5.6 months in the IMRT group and 16.4 months in the SBRT group, and the best local control rates were 98.6% and 100.0%, respectively. The median OS was 12.2 months in the IMRT group and 33.5 months in the SBRT group. The 6-month, 1-year, and 2-year OS rates in the IMRT group were 77.1%, 52.6%, ","PeriodicalId":39801,"journal":{"name":"中南大学学报(医学版)","volume":"50 10","pages":"1811-1827"},"PeriodicalIF":0.0,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12949857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146144132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
[Application of large language models in health education for patients with pediatric cataract]. [大型语言模型在儿童白内障患者健康教育中的应用]
Q3 Medicine Pub Date : 2025-10-28 DOI: 10.11817/j.issn.1672-7347.2025.250181
Yuyu Guo, Yue Zhang, Yanhui Xu, Wei Wei, Keqing Meng, Yumeng Chen, Zhimin Chen
<p><strong>Objectives: </strong>Pediatric cataract occurs during the critical period of visual development, and early intervention is essential to avoid irreversible visual impairment. The health literacy and self-management ability of children and their parents directly affect treatment adherence and prognosis. With the rapid development of artificial intelligence, this study aims to evaluate the accuracy, completeness, and repeatability of domestic open-source large language model (LLM) in answering common clinical questions from pediatric cataract patients, and to explore their application potential as an online health information resource tool for pediatric cataract patients.</p><p><strong>Methods: </strong>The research team collected real patient questions from mainstream online medical platforms since 2016, and categorized them into 5 major domains: Risk factors, disease diagnosis, symptoms and staging, screening and examinations, treatment and prognosis. After expert review, 40 high-attention questions were finalized and manual reference answers were provided by experts. Four domestic open-source LLM (Kimi chat, Doubao, ERNIE Bot 3.5, DeepSeek) were selected. Each question was asked repeatedly 4 times, including 2 times with a "patient-physician" role prompt. Three cataract specialists with the title of associate chief physician or above scored the answers blindly using a 4-level accuracy scale, 3-level completeness scale, and 3-level reproducibility scale. The evaluation followed a two-stage assessment scheme: Stage 1 preliminarily tested the 4 LLM using 6 questions of recognized lower difficulty; Stage 2 performed a full evaluation of all 40 questions on the highest-scoring LLM from Stage 1.</p><p><strong>Results: </strong>In the first stage of evaluation, regardless of whether role prompts were included, among the 4 LLM, Kimi chat performed the best, followed by Doubao and ERNIE Bot 3.5, and finally DeepSeek. In Stage 1, regardless of role prompting, Kimi chat performed best, followed by Doubao and ERNIE Bot 3.5, with DeepSeek ranking last. The proportion of answers from Kimi chat scoring accuracy=4, completeness=3, and reproducibility=3 was higher than Doubao, ERNIE Bot 3.5, and DeepSeek. In Stage 2, Kimi chat completed all 40 questions. Its median answer length was 531 (277, 1 059) words, significantly higher than the manual reference 369 (162, 707) words (<i>Z</i>=-4.096, <i>P</i><0.001). However, answer length showed no significant correlation with accuracy or completeness (both <i>P</i>>0.05). Across 240 model responses, the proportions were: accuracy ≥ 3: 83.8%, completeness=3: 77.9%, and repeatability≥70%: 66.7%. 62.1% (149/240) of evaluators selected Kimi chat answers as their top preference. Reasons for not selecting included off-topic responses, controversial suggestions, and redundant information.</p><p><strong>Conclusions: </strong>Domestic open-source LLM, especially Kimi chat, demonstrated relatively good performance in pe
目的:儿童白内障发生在视力发育的关键时期,早期干预是避免不可逆视力损害的必要措施。儿童及其家长的健康素养和自我管理能力直接影响治疗依从性和预后。随着人工智能的快速发展,本研究旨在评估国内开源大语言模型(LLM)在回答儿童白内障临床常见问题时的准确性、完整性和可重复性,并探索其作为儿童白内障患者在线健康信息资源工具的应用潜力。方法:研究团队收集2016年以来主流在线医疗平台的患者真实问题,并将其分为危险因素、疾病诊断、症状与分期、筛查与检查、治疗与预后5大领域。经过专家评审,最终确定了40个高度关注的问题,并由专家提供人工参考答案。选取了国内4个开源LLM (Kimi chat、豆包、ERNIE Bot 3.5、DeepSeek)。每个问题被重复问了4次,其中包括2次“病人-医生”角色提示。3名副主任医师以上白内障专科医师采用4级准确性量表、3级完整性量表、3级再现性量表对答案进行盲目评分。评估采用两阶段评估方案:第一阶段用6道公认的低难度题对4门LLM进行初步测试;第二阶段对第一阶段得分最高的法学硕士的所有40个问题进行全面评估。结果:在第一阶段的评价中,无论是否包含角色提示,在4个LLM中,Kimi chat表现最好,豆宝和ERNIE Bot 3.5次之,DeepSeek最后。在第一阶段,无论角色提示如何,Kimi chat表现最好,豆宝和ERNIE Bot 3.5紧随其后,DeepSeek排名最后。Kimi聊天评分的答案比例准确率=4,完整性=3,可重复性=3,高于豆宝、ERNIE Bot 3.5和DeepSeek。在第二阶段,Kimi chat完成了全部40道题。其答案长度中位数为531(277,1 059)个单词,显著高于人工参考的369(162,707)个单词(Z=-4.096, PP>0.05)。在240个模型回答中,准确率≥3:83.8%,完整性= 3:77.9%,重复性≥70%:66.7%。62.1%(149/240)的评价者选择了Kimi聊天答案作为他们的首选。不选择的原因包括离题的回答、有争议的建议和冗余的信息。结论:国内开源LLM,尤其是Kimi chat在儿童白内障健康教育场景中表现较好,为家长提供的医疗信息具有较好的准确性、完整性和可重复性。LLM在医疗保健领域有很大的潜力,但信息安全、幻觉和偏见仍然是主要挑战,他们仍然不能取代临床医生。在未来,LLM有望与医生合作,提供更高效和个性化的医疗服务,推动医疗保健的发展。
{"title":"[Application of large language models in health education for patients with pediatric cataract].","authors":"Yuyu Guo, Yue Zhang, Yanhui Xu, Wei Wei, Keqing Meng, Yumeng Chen, Zhimin Chen","doi":"10.11817/j.issn.1672-7347.2025.250181","DOIUrl":"10.11817/j.issn.1672-7347.2025.250181","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;Pediatric cataract occurs during the critical period of visual development, and early intervention is essential to avoid irreversible visual impairment. The health literacy and self-management ability of children and their parents directly affect treatment adherence and prognosis. With the rapid development of artificial intelligence, this study aims to evaluate the accuracy, completeness, and repeatability of domestic open-source large language model (LLM) in answering common clinical questions from pediatric cataract patients, and to explore their application potential as an online health information resource tool for pediatric cataract patients.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The research team collected real patient questions from mainstream online medical platforms since 2016, and categorized them into 5 major domains: Risk factors, disease diagnosis, symptoms and staging, screening and examinations, treatment and prognosis. After expert review, 40 high-attention questions were finalized and manual reference answers were provided by experts. Four domestic open-source LLM (Kimi chat, Doubao, ERNIE Bot 3.5, DeepSeek) were selected. Each question was asked repeatedly 4 times, including 2 times with a \"patient-physician\" role prompt. Three cataract specialists with the title of associate chief physician or above scored the answers blindly using a 4-level accuracy scale, 3-level completeness scale, and 3-level reproducibility scale. The evaluation followed a two-stage assessment scheme: Stage 1 preliminarily tested the 4 LLM using 6 questions of recognized lower difficulty; Stage 2 performed a full evaluation of all 40 questions on the highest-scoring LLM from Stage 1.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In the first stage of evaluation, regardless of whether role prompts were included, among the 4 LLM, Kimi chat performed the best, followed by Doubao and ERNIE Bot 3.5, and finally DeepSeek. In Stage 1, regardless of role prompting, Kimi chat performed best, followed by Doubao and ERNIE Bot 3.5, with DeepSeek ranking last. The proportion of answers from Kimi chat scoring accuracy=4, completeness=3, and reproducibility=3 was higher than Doubao, ERNIE Bot 3.5, and DeepSeek. In Stage 2, Kimi chat completed all 40 questions. Its median answer length was 531 (277, 1 059) words, significantly higher than the manual reference 369 (162, 707) words (&lt;i&gt;Z&lt;/i&gt;=-4.096, &lt;i&gt;P&lt;/i&gt;&lt;0.001). However, answer length showed no significant correlation with accuracy or completeness (both &lt;i&gt;P&lt;/i&gt;&gt;0.05). Across 240 model responses, the proportions were: accuracy ≥ 3: 83.8%, completeness=3: 77.9%, and repeatability≥70%: 66.7%. 62.1% (149/240) of evaluators selected Kimi chat answers as their top preference. Reasons for not selecting included off-topic responses, controversial suggestions, and redundant information.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Domestic open-source LLM, especially Kimi chat, demonstrated relatively good performance in pe","PeriodicalId":39801,"journal":{"name":"中南大学学报(医学版)","volume":"50 10","pages":"1716-1726"},"PeriodicalIF":0.0,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12949873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146144119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mechanisms of gypenosides in type 2 diabetes mellitus via regulation of m6A methylase METTL3/14 and demethylase FTO. 绞股蓝皂苷通过调节m6A甲基化酶METTL3/14和去甲基化酶FTO在2型糖尿病中的作用机制。
Q3 Medicine Pub Date : 2025-10-28 DOI: 10.11817/j.issn.1672-7347.2025.250091
Jiayi Li, Shaoqian Zhang, Renwei Tian, Hebei Tai, Yating Zhang, Mingyi Hu, Guangbin Gong, Jianfei Sun, Ning Wu
<p><strong>Objectives: </strong>Type 2 diabetes mellitus (T2DM) is characterized by insufficient insulin secretion and insulin resistance. Gypenosides (GPs) are the major bioactive saponins extracted from Gynostemma pentaphyllum. Previous studies suggest that GPs have beneficial effects on T2DM, but the underlying mechanisms remain unclear. This study aims to investigate whether GPs exert therapeutic effects by influencing RNA N<sup>6</sup>-methyladenosine (m6A) methylation modification, thereby regulating the downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway.</p><p><strong>Methods: </strong>Expression levels and methylation changes of <i>METTL3, METTL14</i>, and <i>FTO</i> in T2DM were analyzed using public databases, and related pathways were explored via gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The main active components of GPs were screened from pharmacological databases, followed by compound-target network construction, enrichment analyses, and prediction of potential targets and pathways. A T2DM model was induced in Sprague-Dawley rats using a high-fat/high-sugar diet combined with low-dose streptozotocin. Rats were randomly divided into 4 groups: GPs-treated group (GPG, 400 mg/kg), positive control group (PCG, metformin 100 mg/kg), normal saline control group (CONTROL), and T2DM model group (MODEL). Fasting blood glucose (FBG), oral glucose tolerance test (OGTT)-area under the glucose curve from 0 to 120 min (<i>AUC<sub>0-120</sub></i>), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), serum inflammatory factors, and tissue pathology of pancreas and liver hematoxylin and eosin (HE) staining were assessed. Real-time fluorescence quantitative PCR and Western blotting were used to detect RNA and protein expression levels of <i>METTL3, METTL14, FTO</i>, <i>PI3K</i>, and <i>AKT</i> in pancreatic tissues. Molecular docking was applied to evaluate interactions between GPs' main components and <i>METTL3</i>, <i>METTL14</i>, and <i>FTO</i> to infer potential binding modes.</p><p><strong>Results: </strong>Bioinformatic analyses showed downregulation of <i>METTL3</i>/<i>14</i> and upregulation of FTO in T2DM samples (all <i>P</i><0.05), with enrichment in pathways related to insulin signaling, PI3K/AKT activation, oxidative stress response, and hormone secretion. Network pharmacology indicated that GPs components may act on targets involved in RNA modification and insulin-related pathways. In diabetic rats, GPs significantly reduced FBG, improved glucose tolerance, decreased HOMA-IR, and decreased the serum tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 levels compared with MODEL (all <i>P</i><0.05). Pancreatic pathology showed alleviated islet injury and improved cell morphology. GPs treatment up-regulated <i>METTL3/14</i> mRNA and protein levels, and down-regulated <i>FTO</i> mRNA/protein levels in pancreatic tissue
目的:2型糖尿病(T2DM)以胰岛素分泌不足和胰岛素抵抗为特征。绞股蓝皂苷(Gynostemma pentaphyllum, gp)是从绞股蓝中提取的主要活性皂苷。先前的研究表明,全科医生对2型糖尿病有有益的影响,但潜在的机制尚不清楚。本研究旨在探讨GPs是否通过影响RNA n6 -甲基腺苷(m6A)甲基化修饰,从而调控下游磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B (AKT)信号通路发挥治疗作用。方法:利用公共数据库分析T2DM患者METTL3、METTL14和FTO的表达水平和甲基化变化,并通过基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析探索相关途径。从药理学数据库中筛选GPs的主要活性成分,构建化合物靶点网络,富集分析,预测潜在靶点和通路。采用高脂/高糖饮食联合低剂量链脲佐菌素诱导Sprague-Dawley大鼠T2DM模型。将大鼠随机分为4组:gps治疗组(GPG, 400 mg/kg)、阳性对照组(PCG,二甲双胍100 mg/kg)、生理盐水对照组(control)和T2DM模型组(model)。评估空腹血糖(FBG)、口服葡萄糖耐量试验(OGTT)- 0-120 min葡萄糖曲线下面积(AUC0-120)、空腹胰岛素(FINS)、胰岛素抵抗稳态模型评估(HOMA-IR)、血清炎症因子、胰腺和肝脏组织病理苏木精和伊红(HE)染色。采用实时荧光定量PCR和Western blotting检测胰腺组织中METTL3、METTL14、FTO、PI3K、AKT的RNA和蛋白表达水平。利用分子对接方法评估GPs主要成分与METTL3、METTL14和FTO之间的相互作用,推断潜在的结合模式。结果:生物信息学分析显示T2DM样本中METTL3/14表达下调,FTO表达上调(均为PPMETTL3/14 mRNA和蛋白水平),胰腺组织中FTO mRNA/蛋白水平下调(均为ppp)。结论:全科医生可有效改善T2DM大鼠糖代谢紊乱,减轻炎症,保护胰腺组织。其机制可能与METTL3/14上调和FTO下调有关,导致m6A甲基化增强,随后激活PI3K/AKT信号通路。这些发现为GPs调控表观遗传m6A RNA修饰和胰岛素相关的下游通路提供了强有力的证据,并提示未来可能会探索靶向m6A调控的天然化合物用于代谢性疾病的干预。
{"title":"Mechanisms of gypenosides in type 2 diabetes mellitus via regulation of m6A methylase METTL3/14 and demethylase FTO.","authors":"Jiayi Li, Shaoqian Zhang, Renwei Tian, Hebei Tai, Yating Zhang, Mingyi Hu, Guangbin Gong, Jianfei Sun, Ning Wu","doi":"10.11817/j.issn.1672-7347.2025.250091","DOIUrl":"10.11817/j.issn.1672-7347.2025.250091","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;Type 2 diabetes mellitus (T2DM) is characterized by insufficient insulin secretion and insulin resistance. Gypenosides (GPs) are the major bioactive saponins extracted from Gynostemma pentaphyllum. Previous studies suggest that GPs have beneficial effects on T2DM, but the underlying mechanisms remain unclear. This study aims to investigate whether GPs exert therapeutic effects by influencing RNA N&lt;sup&gt;6&lt;/sup&gt;-methyladenosine (m6A) methylation modification, thereby regulating the downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Expression levels and methylation changes of &lt;i&gt;METTL3, METTL14&lt;/i&gt;, and &lt;i&gt;FTO&lt;/i&gt; in T2DM were analyzed using public databases, and related pathways were explored via gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The main active components of GPs were screened from pharmacological databases, followed by compound-target network construction, enrichment analyses, and prediction of potential targets and pathways. A T2DM model was induced in Sprague-Dawley rats using a high-fat/high-sugar diet combined with low-dose streptozotocin. Rats were randomly divided into 4 groups: GPs-treated group (GPG, 400 mg/kg), positive control group (PCG, metformin 100 mg/kg), normal saline control group (CONTROL), and T2DM model group (MODEL). Fasting blood glucose (FBG), oral glucose tolerance test (OGTT)-area under the glucose curve from 0 to 120 min (&lt;i&gt;AUC&lt;sub&gt;0-120&lt;/sub&gt;&lt;/i&gt;), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), serum inflammatory factors, and tissue pathology of pancreas and liver hematoxylin and eosin (HE) staining were assessed. Real-time fluorescence quantitative PCR and Western blotting were used to detect RNA and protein expression levels of &lt;i&gt;METTL3, METTL14, FTO&lt;/i&gt;, &lt;i&gt;PI3K&lt;/i&gt;, and &lt;i&gt;AKT&lt;/i&gt; in pancreatic tissues. Molecular docking was applied to evaluate interactions between GPs' main components and &lt;i&gt;METTL3&lt;/i&gt;, &lt;i&gt;METTL14&lt;/i&gt;, and &lt;i&gt;FTO&lt;/i&gt; to infer potential binding modes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Bioinformatic analyses showed downregulation of &lt;i&gt;METTL3&lt;/i&gt;/&lt;i&gt;14&lt;/i&gt; and upregulation of FTO in T2DM samples (all &lt;i&gt;P&lt;/i&gt;&lt;0.05), with enrichment in pathways related to insulin signaling, PI3K/AKT activation, oxidative stress response, and hormone secretion. Network pharmacology indicated that GPs components may act on targets involved in RNA modification and insulin-related pathways. In diabetic rats, GPs significantly reduced FBG, improved glucose tolerance, decreased HOMA-IR, and decreased the serum tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 levels compared with MODEL (all &lt;i&gt;P&lt;/i&gt;&lt;0.05). Pancreatic pathology showed alleviated islet injury and improved cell morphology. GPs treatment up-regulated &lt;i&gt;METTL3/14&lt;/i&gt; mRNA and protein levels, and down-regulated &lt;i&gt;FTO&lt;/i&gt; mRNA/protein levels in pancreatic tissue ","PeriodicalId":39801,"journal":{"name":"中南大学学报(医学版)","volume":"50 10","pages":"1735-1754"},"PeriodicalIF":0.0,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12949872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146144175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
[Role and mechanisms of FoxO3a-related signaling pathways in breast cancer cell apoptosis]. foxo3a相关信号通路在乳腺癌细胞凋亡中的作用及机制
Q3 Medicine Pub Date : 2025-10-28 DOI: 10.11817/j.issn.1672-7347.2025.250230
Zhongxu Wang, Haoming Tang, Xiaotong Shao, Zhenping Zhu, Wenyao Li, Shuang Chen

Breast cancer is one of the most common malignant tumors in women worldwide, and its high incidence and mortality rate seriously threaten women's health. Studies show that the forkhead box O3a (FoxO3a) plays a key role in the occurrence and progression of breast cancer, particularly in the regulation of apoptosis. As a major member of the FoxO family, FoxO3a exerts tumor-suppressive functions by participating in apoptosis regulation and cell-cycle control. In breast cancer cells, FoxO3a acts as a downstream signaling hub of multiple upstream pathways including phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinase (MAPK), and serum- and glucocorticoid-regulated kinase 1 (SGK1). Through nucleocytoplasmic shuttling and alterations in transcriptional activity, FoxO3a precisely modulates the expression of apoptosis-related target genes such as Bcl-2-interacting mediator of cell death (Bim) and p53-upregulated modulator of apoptosis (PUMA), thereby influencing cell survival or death. In addition, multiple natural compounds and combination therapies can induce apoptosis in breast cancer cells by restoring or enhancing FoxO3a activity, and may partially overcome treatment resistance. Systematic elucidation of the complexity of the FoxO3a signaling network and its dual roles in breast cancer therapy may provide theoretical support for understanding tumor-drug resistance mechanisms and for developing precision therapeutic strategies targeting FoxO3a nodes. Future research should further clarify the functional differences among FoxO3a splice variants and FoxO family members, reveal the molecular basis of FoxO3a functional switching in the tumor microenvironment, and promote the clinical translation of biomarkers and targeted drugs.

乳腺癌是世界范围内妇女最常见的恶性肿瘤之一,其高发病率和高死亡率严重威胁着妇女的健康。研究表明,叉头盒O3a (FoxO3a)在乳腺癌的发生发展中起着关键作用,尤其是在细胞凋亡的调控中。FoxO3a作为FoxO家族的主要成员,通过参与细胞凋亡调控和细胞周期调控发挥肿瘤抑制功能。在乳腺癌细胞中,FoxO3a作为多种上游通路的下游信号枢纽,包括磷脂酰肌醇3-激酶/蛋白激酶B (PI3K/AKT)、丝裂原活化蛋白激酶(MAPK)、血清和糖皮质激素调节激酶1 (SGK1)。FoxO3a通过核细胞质穿梭和转录活性的改变,精确调控凋亡相关靶基因如bcl -2相互作用的细胞死亡调节剂(Bim)和p53上调的细胞凋亡调节剂(PUMA)的表达,从而影响细胞的存活或死亡。此外,多种天然化合物和联合疗法可通过恢复或增强FoxO3a活性诱导乳腺癌细胞凋亡,并可能部分克服治疗耐药。系统阐明FoxO3a信号网络的复杂性及其在乳腺癌治疗中的双重作用,可能为理解肿瘤耐药机制和开发针对FoxO3a节点的精确治疗策略提供理论支持。未来的研究应进一步明确FoxO3a剪接变异体与FoxO家族成员之间的功能差异,揭示FoxO3a在肿瘤微环境中功能转换的分子基础,促进生物标志物和靶向药物的临床翻译。
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中南大学学报(医学版)
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