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The role and mechanism of HMGB1-mediated Notch1/Hes-1 pathway in anxiety and depression-like behaviors in mice with chronic rhinosinusitis. hmgb1介导的Notch1/Hes-1通路在慢性鼻窦炎小鼠焦虑和抑郁样行为中的作用及机制
IF 6 2区 医学
Molecular Medicine Pub Date : 2025-01-09 DOI: 10.1186/s10020-024-01057-6
Fangwei Zhou, Yiting Jiang, Yangsong Li, Jianyao Li, Tian Zhang, Guodong Yu
{"title":"The role and mechanism of HMGB1-mediated Notch1/Hes-1 pathway in anxiety and depression-like behaviors in mice with chronic rhinosinusitis.","authors":"Fangwei Zhou, Yiting Jiang, Yangsong Li, Jianyao Li, Tian Zhang, Guodong Yu","doi":"10.1186/s10020-024-01057-6","DOIUrl":"10.1186/s10020-024-01057-6","url":null,"abstract":"<p><strong>Background: </strong>Chronic rhinosinusitis (CRS) is a global health issue, with some patients experiencing anxiety and depression-like symptoms. This study investigates the role of HMGB1 in anxiety and depression-like behaviors associated with the microglial Notch1/Hes-1 pathway in CRS mice.</p><p><strong>Methods: </strong>A CRS mouse model was developed, and behavioral assessments were conducted to evaluate anxiety and depression-like behaviors. Techniques including <sup>18</sup>F-FDG PET, Nissl staining, and immunofluorescence were used to assess hippocampal metabolic activity in CRS mice. Western Blot and RT-qPCR were employed to measure HMGB1 and Notch1/Hes-1 expression in the hippocampus, while ELISA determined inflammatory cytokine levels. The study also examined the effects of metformin on these behaviors and its mechanisms.</p><p><strong>Results: </strong>CRS mice exhibited increased anxiety and depression-like behaviors, accompanied by enhanced hippocampal metabolic activity. HMGB1-siRNA treatment reduced these behaviors. Hippocampal glucose metabolism was markedly higher in CRS mice than in controls. Nissl staining revealed hippocampal neuron damage, and immunofluorescence indicated microglial activation in CRS mice. Reducing HMGB1 expression inhibited Notch1/Hes-1 pathway activation. In microglia, HMGB1 knockdown suppressed the Notch1/Hes-1 pathway, reducing inflammatory cytokine secretion. Metformin improved neuropsychiatric symptoms in CRS mice by inhibiting the Notch1/Hes-1 pathway after HMGB1 downregulation.</p><p><strong>Conclusion: </strong>HMGB1 activates the microglial Notch1/Hes-1 pathway in CRS mice, promoting neuroinflammation and anxiety and depression-like behaviors. Metformin alleviates these effects.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"8"},"PeriodicalIF":6.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multi‑omics identification of a novel signature for serous ovarian carcinoma in the context of 3P medicine and based on twelve programmed cell death patterns: a multi-cohort machine learning study. 基于12种程序性细胞死亡模式的3P医学背景下浆液性卵巢癌新特征的多组学鉴定:一项多队列机器学习研究
IF 6 2区 医学
Molecular Medicine Pub Date : 2025-01-08 DOI: 10.1186/s10020-024-01036-x
Lele Ye, Chunhao Long, Binbing Xu, Xuyang Yao, Jiaye Yu, Yunhui Luo, Yuan Xu, Zhuofeng Jiang, Zekai Nian, Yawen Zheng, Yaoyao Cai, Xiangyang Xue, Gangqiang Guo
{"title":"Multi‑omics identification of a novel signature for serous ovarian carcinoma in the context of 3P medicine and based on twelve programmed cell death patterns: a multi-cohort machine learning study.","authors":"Lele Ye, Chunhao Long, Binbing Xu, Xuyang Yao, Jiaye Yu, Yunhui Luo, Yuan Xu, Zhuofeng Jiang, Zekai Nian, Yawen Zheng, Yaoyao Cai, Xiangyang Xue, Gangqiang Guo","doi":"10.1186/s10020-024-01036-x","DOIUrl":"https://doi.org/10.1186/s10020-024-01036-x","url":null,"abstract":"<p><strong>Background: </strong>Predictive, preventive, and personalized medicine (PPPM/3PM) is a strategy aimed at improving the prognosis of cancer, and programmed cell death (PCD) is increasingly recognized as a potential target in cancer therapy and prognosis. However, a PCD-based predictive model for serous ovarian carcinoma (SOC) is lacking. In the present study, we aimed to establish a cell death index (CDI)-based model using PCD-related genes.</p><p><strong>Methods: </strong>We included 1254 genes from 12 PCD patterns in our analysis. Differentially expressed genes (DEGs) from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) were screened. Subsequently, 14 PCD-related genes were included in the PCD-gene-based CDI model. Genomics, single-cell transcriptomes, bulk transcriptomes, spatial transcriptomes, and clinical information from TCGA-OV, GSE26193, GSE63885, and GSE140082 were collected and analyzed to verify the prediction model.</p><p><strong>Results: </strong>The CDI was recognized as an independent prognostic risk factor for patients with SOC. Patients with SOC and a high CDI had lower survival rates and poorer prognoses than those with a low CDI. Specific clinical parameters and the CDI were combined to establish a nomogram that accurately assessed patient survival. We used the PCD-genes model to observe differences between high and low CDI groups. The results showed that patients with SOC and a high CDI showed immunosuppression and hardly benefited from immunotherapy; therefore, trametinib_1372 and BMS-754807 may be potential therapeutic agents for these patients.</p><p><strong>Conclusions: </strong>The CDI-based model, which was established using 14 PCD-related genes, accurately predicted the tumor microenvironment, immunotherapy response, and drug sensitivity of patients with SOC. Thus this model may help improve the diagnostic and therapeutic efficacy of PPPM.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"5"},"PeriodicalIF":6.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ubiquitin specific peptidase 11 knockdown slows Huntington's disease progression via regulating mitochondrial dysfunction and neuronal damage depending on PTEN-mediated AKT pathway. 泛素特异性肽酶11敲低通过调节线粒体功能障碍和依赖于pten介导的AKT通路的神经元损伤来减缓亨廷顿病的进展。
IF 6 2区 医学
Molecular Medicine Pub Date : 2025-01-08 DOI: 10.1186/s10020-024-01061-w
Bai Gao, Yuchen Jing, Xi Li, Shuyan Cong
{"title":"Ubiquitin specific peptidase 11 knockdown slows Huntington's disease progression via regulating mitochondrial dysfunction and neuronal damage depending on PTEN-mediated AKT pathway.","authors":"Bai Gao, Yuchen Jing, Xi Li, Shuyan Cong","doi":"10.1186/s10020-024-01061-w","DOIUrl":"10.1186/s10020-024-01061-w","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial dysfunction and neuronal damage are major sign of cytopathology in Huntington's disease (HD), a neurodegenerative disease. Ubiquitin specific peptidase 11 (USP11) is a deubiquitinating enzyme involved in various physiological processes through regulating protein degradation. However, its specific role in HD is unclear.</p><p><strong>Methods: </strong>To interfere with USP11 expression, adeno-associated viruses 2 containing USP11-specific shRNA were injected into the bilateral striatum of 12-week-old R6/1 and WT mice. In vitro, the inducible PC12 cell model of HD was used in which the expression of an N-terminal truncation of huntingtin, with either wild type (Q23) or expanded polyglutamine (Q74) can be induced by the doxycycline. USP11 was knocked down to study its role in HD. The protein expression patterns in Q74 cells were quantified by label-free proteomics to further explore the target protein of USP11. Detecting the association between USP11 and Phosphatase and Tensin Homolog (PTEN) through Co-IP.</p><p><strong>Results: </strong>Herein, USP11 was found to be upregulated in the striatum of R6/1 mice (an HD model with gradual development of symptoms) in an age-dependent manner. The spontaneous HD was alleviated by silencing USP11, as evidenced by improved locomotor activity and spatial memory, attenuated striatal atrophy in R6/1 mice, reduced accumulation of mutant huntingtin protein, and restored mitochondrial function in vitro and in vivo. The results of label-free proteomics revealed a significant change in the protein expression profile. Through functional enrichment, we focused on PTEN, known as a negative regulator of the AKT pathway. We demonstrated that USP11 downregulation promoted ubiquitination modification of PTEN and activated the AKT pathway, and PTEN overexpression reversed the effects of USP11 knockdown.</p><p><strong>Conclusions: </strong>Collectively, USP11 knockdown protects R6/1 mouse neurons from oxidative stress by alleviating mitochondrial dysfunction, thereby preventing the HD progression. This is achieved by inhibiting PTEN expression, which in turn activates the AKT pathway. This study suggests that USP11-PTEN-AKT signaling pathway may be a new attractive therapeutic target for HD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"7"},"PeriodicalIF":6.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11715466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Correction: CKS2 induces autophagy-mediated glutathione metabolic reprogramming to facilitate ferroptosis resistance in colon cancer. 更正:CKS2诱导自噬介导的谷胱甘肽代谢重编程,促进结肠癌对铁下沉的抵抗。
IF 6 2区 医学
Molecular Medicine Pub Date : 2025-01-08 DOI: 10.1186/s10020-024-01041-0
Leilei Yang, Chengfeng Fang, Jiaju Han, Yufeng Ren, Zaiping Yang, Lingyan Shen, Dinghai Luo, Ruili Zhang, Yan Chen, Shenkang Zhou
{"title":"Correction: CKS2 induces autophagy-mediated glutathione metabolic reprogramming to facilitate ferroptosis resistance in colon cancer.","authors":"Leilei Yang, Chengfeng Fang, Jiaju Han, Yufeng Ren, Zaiping Yang, Lingyan Shen, Dinghai Luo, Ruili Zhang, Yan Chen, Shenkang Zhou","doi":"10.1186/s10020-024-01041-0","DOIUrl":"10.1186/s10020-024-01041-0","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"6"},"PeriodicalIF":6.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Differential expression of plasma proteins and pathway enrichments in pediatric diabetic ketoacidosis. 儿童糖尿病酮症酸中毒血浆蛋白的差异表达和途径富集。
IF 6 2区 医学
Molecular Medicine Pub Date : 2025-01-07 DOI: 10.1186/s10020-024-01056-7
Paolo Spagnolo, Enis Cela, Maitray A Patel, David Tweddell, Mark Daley, Cheril Clarson, Saverio Stranges, Gediminas Cepinskas, Douglas D Fraser
{"title":"Differential expression of plasma proteins and pathway enrichments in pediatric diabetic ketoacidosis.","authors":"Paolo Spagnolo, Enis Cela, Maitray A Patel, David Tweddell, Mark Daley, Cheril Clarson, Saverio Stranges, Gediminas Cepinskas, Douglas D Fraser","doi":"10.1186/s10020-024-01056-7","DOIUrl":"https://doi.org/10.1186/s10020-024-01056-7","url":null,"abstract":"<p><strong>Background: </strong>In children with type 1 diabetes (T1D), diabetic ketoacidosis (DKA) triggers a significant inflammatory response; however, the specific effector proteins and signaling pathways involved remain largely unexplored. This pediatric case-control study utilized plasma proteomics to explore protein alterations associated with severe DKA and to identify signaling pathways that associate with clinical variables.</p><p><strong>Methods: </strong>We conducted a proteome analysis of plasma samples from 17 matched pairs of pediatric patients with T1D; one cohort with severe DKA and another with insulin-controlled diabetes. Proximity extension assays were used to quantify 3072 plasma proteins. Data analysis was performed using multivariate statistics, machine learning, and bioinformatics.</p><p><strong>Results: </strong>This study identified 214 differentially expressed proteins (162 upregulated, 52 downregulated; adj P < 0.05 and a fold change > 2), reflecting cellular dysfunction and metabolic stress in severe DKA. We characterized protein expression across various organ systems and cell types, with notable alterations observed in white blood cells. Elevated inflammatory pathways suggest an enhanced inflammatory response, which may contribute to the complications of severe DKA. Additionally, upregulated pathways related to hormone signaling and nitrogen metabolism were identified, consistent with increased hormone release and associated metabolic processes, such as glycogenolysis and lipolysis. Changes in lipid and fatty acid metabolism were also observed, aligning with the lipolysis and ketosis characteristic of severe DKA. Finally, several signaling pathways were associated with clinical biochemical variables.</p><p><strong>Conclusions: </strong>Our findings highlight differentially expressed plasma proteins and enriched signaling pathways that were associated with clinical features, offering insights into the pathophysiology of severe DKA.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"4"},"PeriodicalIF":6.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
NEK8 promotes the progression of gastric cancer by reprogramming asparagine metabolism.
IF 6 2区 医学
Molecular Medicine Pub Date : 2025-01-06 DOI: 10.1186/s10020-024-01062-9
Mingliang Wang, Kexun Yu, Futao Meng, Huizhen Wang, Yongxiang Li
{"title":"NEK8 promotes the progression of gastric cancer by reprogramming asparagine metabolism.","authors":"Mingliang Wang, Kexun Yu, Futao Meng, Huizhen Wang, Yongxiang Li","doi":"10.1186/s10020-024-01062-9","DOIUrl":"https://doi.org/10.1186/s10020-024-01062-9","url":null,"abstract":"<p><p>Several members of the NIMA-related kinase (NEK) family have been implicated in tumor progression; however, the role and underlying mechanisms of NEK8 in gastric cancer (GC) remain unclear. This study revealed a significant upregulation of NEK8 in GC, identifying it as an independent prognostic marker in patients with GC. Consistent with these findings, NEK8 silencing substantially impeded GC aggressiveness both in vitro and in vivo, while its overexpression produced the opposite effect. Gene Ontology enrichment analysis and metabolic profiling indicated that the impact of NEK8 on GC is primarily associated with reprogramming asparagine metabolism and modulating the mTORC1 pathway. Specifically, NEK8 knockdown suppressed asparagine synthesis by downregulating asparagine synthetase (ASNS) expression in GC cells. A strong correlation was observed between NEK8 levels and ASNS expression in human GC cells and tissue samples. Mechanistically, NEK8 directly interacts with ASNS, phosphorylating it at the S349 site, which inhibits its ubiquitination and subsequent degradation. Moreover, substituting the ASNS-S349 site with alanine abrogated the pro-tumorigenic effects of ASNS-WT overexpression. Additionally, asparagine was identified as an activator of the mTORC1 pathway, with reintroducing asparagine after NEK8 silencing restoring mTORC1 activity. Collectively, these findings demonstrate that NEK8-mediated asparagine synthesis and activation of the mTORC1 pathway play a critical role in promoting GC progression.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"3"},"PeriodicalIF":6.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11702068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Advancing therapeutic strategies for graft-versus-host disease by targeting gut microbiome dynamics in allogeneic hematopoietic stem cell transplantation: current evidence and future directions. 通过靶向同种异体造血干细胞移植中的肠道微生物组动力学来推进移植物抗宿主病的治疗策略:目前的证据和未来的方向。
IF 6 2区 医学
Molecular Medicine Pub Date : 2025-01-03 DOI: 10.1186/s10020-024-01060-x
Muhammad Azhar Ud Din, Yan Lin, Changkun Lyu, Chengxue Yi, Anning Fang, Fei Mao
{"title":"Advancing therapeutic strategies for graft-versus-host disease by targeting gut microbiome dynamics in allogeneic hematopoietic stem cell transplantation: current evidence and future directions.","authors":"Muhammad Azhar Ud Din, Yan Lin, Changkun Lyu, Chengxue Yi, Anning Fang, Fei Mao","doi":"10.1186/s10020-024-01060-x","DOIUrl":"10.1186/s10020-024-01060-x","url":null,"abstract":"<p><p>Hematopoietic stem cell transplantation (HSCT) is a highly effective therapy for malignant blood illnesses that pose a high risk, as well as diseases that are at risk due to other variables, such as genetics. However, the prevalence of graft-versus-host disease (GVHD) has impeded its widespread use. Ensuring the stability of microbial varieties and associated metabolites is crucial for supporting metabolic processes, preventing pathogen intrusion, and modulating the immune system. Consequently, it significantly affects the overall well-being and susceptibility of the host to disease. Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) may experience a disruption in the balance between the immune system and gut bacteria when treated with medicines and foreign cells. This can lead to secondary intestinal inflammation and GVHD. Thus, GM is both a reliable indicator of post-transplant mortality and a means of enhancing GVHD prevention and treatment after allo-HSCT. This can be achieved through various strategies, including nutritional support, probiotics, selective use of antibiotics, and fecal microbiota transplantation (FMT) to target gut microbes. This review examines research advancements and the practical use of intestinal bacteria in GVHD following allo-HSCT. These findings may offer novel insights into the prevention and treatment of GVHD after allo-HSCT.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"2"},"PeriodicalIF":6.0,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Hyperoxia-activated Nrf2 regulates ferroptosis in intestinal epithelial cells and intervenes in inflammatory reaction through COX-2/PGE2/EP2 pathway. 高氧激活的Nrf2通过COX-2/PGE2/EP2通路调控肠上皮细胞铁下沉,干预炎症反应。
IF 6 2区 医学
Molecular Medicine Pub Date : 2025-01-03 DOI: 10.1186/s10020-024-00993-7
Yanping Liu, Tianming Li, Changping Niu, Zhengwei Yuan, Siyu Sun, Dongyan Liu
{"title":"Hyperoxia-activated Nrf2 regulates ferroptosis in intestinal epithelial cells and intervenes in inflammatory reaction through COX-2/PGE2/EP2 pathway.","authors":"Yanping Liu, Tianming Li, Changping Niu, Zhengwei Yuan, Siyu Sun, Dongyan Liu","doi":"10.1186/s10020-024-00993-7","DOIUrl":"10.1186/s10020-024-00993-7","url":null,"abstract":"<p><p>The lack of knowledge about the mechanism of hyperoxia-induced intestinal injury has attracted considerable attention, due to the potential for this condition to cause neonatal complications. This study aimed to explore the relationship between hyperoxia-induced oxidative damage and ferroptosis in intestinal tissue and investigate the mechanism by which hyperoxia regulates inflammation through ferroptosis. The study systematically evaluated the effects of hyperoxia on oxidative stress, mitochondrial damage, ferroptosis, and inflammation of intestinal epithelial cells both in vitro and in vivo. The results showed that ferroptosis was involved in intestinal oxidative damage caused by hyperoxia and was regulated by Nrf2. Moreover, hyperoxia-induced oxidative damage regulated inflammation through ferroptosis by upregulating the COX-2/PGE2/EP2 signaling pathway. These findings have important implications for future clinical prevention and therapeutic approaches to neonatal organ injury caused by hyperoxia treatment.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"1"},"PeriodicalIF":6.0,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Reduced irradiation exposure areas enhanced anti-tumor effect by inducing DNA damage and preserving lymphocytes. 减少辐照暴露面积可通过诱导DNA损伤和保护淋巴细胞增强抗肿瘤作用。
IF 6 2区 医学
Molecular Medicine Pub Date : 2024-12-31 DOI: 10.1186/s10020-024-01037-w
Huiqin Chen, Yuan Li, Qiaofeng Shen, Guanqun Guo, Zhigang Wang, Hanyu Pan, Min Wu, Xueqing Yan, Gen Yang
{"title":"Reduced irradiation exposure areas enhanced anti-tumor effect by inducing DNA damage and preserving lymphocytes.","authors":"Huiqin Chen, Yuan Li, Qiaofeng Shen, Guanqun Guo, Zhigang Wang, Hanyu Pan, Min Wu, Xueqing Yan, Gen Yang","doi":"10.1186/s10020-024-01037-w","DOIUrl":"10.1186/s10020-024-01037-w","url":null,"abstract":"<p><strong>Background: </strong>Partial stereotactic body radiation therapy (SBRT) targeting hypoxic regions of large tumors (SBRT-PATHY) has been shown to enhance the efficacy of tumor radiotherapy by harnessing the radiation-induced immune response. This approach suggests that reducing the irradiation target volume not only achieves effective anti-tumor effects but also minimizes damage to surrounding normal tissues. In this study, we evaluated the antitumor efficacy of reduced-tumour-area radiotherapy (RTRT) , and explored the relationship between tumor control and immune preservation and the molecular mechanisms underlying of them.</p><p><strong>Methods: </strong>In mouse breast cancer models, we compared the anti-tumor effects of RTRT and conventional radiotherapy (CNRT) by assessing tumor growth, metastasis, and survival rates. Additionally, we evaluated the peritumoral tissue damage and the immune microenvironment. The maturation of dendritic cells (DCs) and DNA damage induced by irradiated tumor cells were also assessed in vitro.</p><p><strong>Results: </strong>In pre-clinical models, both RTRT and CNRT significantly inhibited primary tumor growth when compared to non-irradiated controls, with no significant difference between RTRT and CNRT. However, RTRT significantly extended survival times in mice, and increased the likelihood of inducing abscopal effects, thereby providing potential for better control of distant metastases. Further investigations revealed that the enhanced efficacy of RTRT may be attributed to the preservation of lymphocytes within the peritumoral tissue, as well as reduced damage to the surrounding skin and circulating lymphocytes. In vitro assays demonstrated that RTRT induced DNA damage and dsDNA in tumor cells, activating the cGAS-STING pathway. RTRT also triggered the release of damage-associated molecular patterns (DAMPs), which synergistically amplified the anti-tumor immune response.</p><p><strong>Conclusions: </strong>Our findings suggested that appropriately narrowing the irradiation target volume effectively killed tumor cells while reducing damage to surrounding tissues, and preserving peritumoral lymphocytes. This approach improved the safety of radiotherapy while maintaining its efficacy in tumor control and provided an opportunity for combining high-dose radiotherapy with immunotherapy.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"30 1","pages":"284"},"PeriodicalIF":6.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
SPDEF ameliorates UUO-induced renal fibrosis by transcriptional activation of NR4A1. SPDEF通过NR4A1的转录激活改善uuo诱导的肾纤维化。
IF 6 2区 医学
Molecular Medicine Pub Date : 2024-12-30 DOI: 10.1186/s10020-024-01030-3
Hongshuang Wang, Ziheng Wei, Chang Xu, Fang Fang, Zheng Wang, Yan Zhong, Xiangting Wang
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