Molecular Medicine最新文献

{"title":"Transcriptomic analysis of non-leukemic cell subsets in azacytidine-responsive AML highlights pathways associated with adhesion, platelet aggregation, and angiogenesis in mice and humans.","authors":"Nancy D Ebelt, Suvithanandhini Loganathan, Lara C Avsharian, Edwin R Manuel","doi":"10.1186/s10020-025-01233-2","DOIUrl":"10.1186/s10020-025-01233-2","url":null,"abstract":"<p><strong>Background: </strong>Hypomethylating agents (HMAs), such as 5-azacytidine (AZA), are valuable treatment options for patients with acute myeloid leukemia (AML). Despite providing significant extensions in survival when used alone or in combination with BCL-2 inhibitors, resistance and eventual relapse is observed. Reported mechanisms of these outcomes are inconsistent when focusing on leukemic populations within bone marrow, indicating a need for studies on the impact of HMAs on non-leukemic cells in the blood and other tissue compartments.</p><p><strong>Methods: </strong>Whole blood and spleens from vehicle- or AZA-treated mice implanted with the syngeneic AML line C1498 were transcriptionally profiled using a comprehensive panel of immune-related gene probes. Publicly available RNAseq data from blood of AZA-responsive, human AML patients were analyzed compared to matched, pre-treatment samples. Genes differentially expressed between vehicle- and AZA-treated (mouse) or pre- and post-AZA treatment (human) samples were analyzed for statistical overrepresentation in gene ontologies using Fisher's one-tailed t-test. Pathological analyses of various tissues in AML relapsed, AZA-responsive mice were compared to the corresponding tissues in vehicle-treated mice.</p><p><strong>Results: </strong>We observed hematologic recovery in the peripheral blood of AZA-treated groups, versus vehicle control, that was associated with significant extensions in survival. Transcriptional analysis of AZA-treated samples revealed decreased cell type scores for suppressive subsets and increased pathway scores for T and B cell functions. Comparisons of gene ontology annotations enriched from genes differentially regulated by AZA in human and mouse blood samples revealed overlap in numerous biological pathways including adhesion, thrombosis, and angiogenesis. Consistently, C1498 permeated the liver at end-stage disease in vehicle-treated mice, while AZA treatment limited their spread to just outside the bone after relapse.</p><p><strong>Conclusions: </strong>AZA-induced differences in C1498 spread could be a result of gene expression changes in adhesion, platelet aggregation and/or angiogenesis in non-leukemic compartments; however, further mechanistic studies must be done to confirm a direct link between modulated genes and disease manifestation. Overall, these studies provide rationale for expanding the exploration of biomarkers and therapeutic targets to include normal immune cells in blood, spleen, or other microenvironments of AML patients treated with HMA, rather than limiting studies to the bone marrow and leukemic blasts.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"185"},"PeriodicalIF":6.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144011683","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}

{"title":"Correction: 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/s10020-025-01234-1","DOIUrl":"https://doi.org/10.1186/s10020-025-01234-1","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"182"},"PeriodicalIF":6.0,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005746","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}

{"title":"Unraveling the complex genetic landscape of OTOF-related hearing loss: a deep dive into cryptic variants and haplotype phasing.","authors":"Pei-Hsuan Lin, Cheng-Yu Tsai, Yu-Ting Chiang, Chang-Han Ho, Yue-Sheng Lu, Jacob Shu-Jui Hsu, Yen-Fu Cheng, Shih-Feng Tsai, Chuan-Jen Hsu, Pei-Lung Chen, Chen-Chi Wu","doi":"10.1186/s10020-025-01225-2","DOIUrl":"https://doi.org/10.1186/s10020-025-01225-2","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in OTOF are a major cause of auditory synaptopathy. However, challenges remain in interpreting OTOF variants, including difficulties in confirming haplotype phasing using traditional short-read sequencing (SRS) due to the large gene size, the potential incomplete penetrance of certain variants, and difficulties in assessing variants at non-canonical splice sites. This study aims to revisit the genetic landscape of OTOF variants in a Taiwanese non-syndromic auditory neuropathy spectrum disorder (ANSD) cohort using a combination of sequencing technologies, predictive tools, and experimental validations.</p><p><strong>Methods: </strong>We performed SRS to analyze OTOF variants in 65 unrelated Taiwanese patients diagnosed with non-syndromic ANSD, complemented by long-read sequencing (LRS) for haplotype phasing. A prediction-to-validation pipeline was implemented to assess the pathogenicity of cryptic variants using SpliceAI software and minigene assays.</p><p><strong>Results: </strong>Biallelic pathogenic OTOF variants were identified in 33 patients (50.8%), while monoallelic variants were found in five patients. Three novel variants, c.3864G > A (p.Ala1288 =), c.4501G > A (p.Ala1501Thr), and c.5813 + 2T > C, were detected. The pathogenicity of two non-canonical mis-splicing variants, c.3894 + 5G > C and c.3864G > A (p.Ala1288 =), was confirmed by minigene assays. LRS-based haplotype phasing revealed that the common missense variant c.5098G > C (p.Glu1700Gln) and the novel variant c.5975A > G (p.Lys1992Arg) are in cis and form a founder pathogenic allele in the Taiwanese population.</p><p><strong>Conclusions: </strong>Our study highlights the genetic heterogeneity of DFNB9 and emphasizes the importance of population-specific variant interpretation. The integration of advanced sequencing technologies, predictive algorithms, and functional validation assays will improve the accuracy of molecular diagnosis and inform personalized treatment strategies for individuals with DFNB9.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"181"},"PeriodicalIF":6.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019358","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}

{"title":"The MYC/TXNIP axis mediates NCL-Suppressed CD8⁺T cell immune response in lung adenocarcinoma.","authors":"Dan Xiao, Tanxiu Chen, Xinlin Yu, Ying Song, Yigang Liu, Wei Yan","doi":"10.1186/s10020-025-01224-3","DOIUrl":"https://doi.org/10.1186/s10020-025-01224-3","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma is a deadly malignancy with immune evasion playing a key role in tumor progression. Glucose metabolism is crucial for T cell function, and the nucleolar protein NCL may influence T cell glucose metabolism. This study aims to investigate NCL's role in T cell glucose metabolism and immune evasion by lung adenocarcinoma cells.</p><p><strong>Methods: </strong>Utilizing single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), we analyzed cell clustering, annotation, and prognosis. In vitro experiments involved manipulating NCL expression in CD8⁺ T cells to study immune function and glucose metabolism. In vivo studies using an orthotopic transplant mouse model monitored NCL's impact on CD8⁺ T cell glucose metabolism and anti-tumor immune function.</p><p><strong>Results: </strong>NCL was associated with T cell dysfunction and glucose metabolism. NCL silencing enhanced CD8⁺ T cell glucose metabolism, cytotoxicity, and infiltration, while NCL overexpression had the opposite effect. NCL overexpression relieved MYC-mediated transcriptional repression of TXNIP, reducing CD8⁺ T cell glucose metabolism. In vivo, NCL inhibited CD8⁺ T cell glucose metabolism through the MYC/TXNIP axis, hindering anti-tumor immune function.</p><p><strong>Conclusions: </strong>NCL overexpression suppresses CD8⁺ T cell glucose metabolism and anti-tumor immune function, promoting lung adenocarcinoma progression via the MYC/TXNIP axis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"180"},"PeriodicalIF":6.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008790","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}

{"title":"Transcriptome-wide analysis reveals potential roles of CFD and ANGPTL4 in fibroblasts regulating B cell lineage for extracellular matrix-driven clustering and novel avenues for immunotherapy in breast cancer.","authors":"Hongwei Wang, Yu-Nan Zhu, Sifan Zhang, Kexin Liu, Rong Huang, Zhigao Li, Lan Mei, Yingpu Li","doi":"10.1186/s10020-025-01237-y","DOIUrl":"https://doi.org/10.1186/s10020-025-01237-y","url":null,"abstract":"<p><strong>Background: </strong>The remodeling of the extracellular matrix (ECM) plays a pivotal role in tumor progression and drug resistance. However, the compositional patterns of ECM in breast cancer and their underlying biological functions remain elusive.</p><p><strong>Methods: </strong>Transcriptome and genome data of breast cancer patients from TCGA database was downloaded. Patients were classified into different clusters by using non-negative matrix factorization (NMF) based on signatures of ECM components and regulators. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify core genes related to ECM clusters. Additional 10 independent public cohorts including Metabric, SCAN_B, GSE12276, GSE16446, GSE19615, GSE20685, GSE21653, GSE58644, GSE58812, and GSE88770 were collected to construct Training or Testing cohort, following machine learning calculating ECM correlated index (ECI) for survival analysis. Pathway enrichment and correlation analysis were used to explore the relationship among ECM clusters, ECI and TME. Single-cell transcriptome data from GSE161529 was processed for uncovering the differences among ECM clusters.</p><p><strong>Results: </strong>Using NMF, we identified three ECM clusters in the TCGA database: C1 (Neuron), C2 (ECM), and C3 (Immune). Subsequently, WGCNA was employed to pinpoint cluster-specific genes and develop a prognostic model. This model demonstrated robust predictive power for breast cancer patient survival in both the Training cohort (n = 5,392, AUC = 0.861) and the Testing cohort (n = 1,344, AUC = 0.711). Upon analyzing the tumor microenvironment (TME), we discovered that fibroblasts and B cell lineage were the core cell types associated with the ECM cluster phenotypes. Single-cell RNA sequencing data further revealed that angiopoietin like 4 (ANGPTL4)⁺ fibroblasts were specifically linked to the C2 phenotype, while complement factor D (CFD)⁺ fibroblasts characterized the other ECM clusters. CellChat analysis indicated that ANGPTL4⁺ and CFD⁺ fibroblasts regulate B cell lineage via distinct signaling pathways. Additionally, analysis using the Kaplan-Meier Plotter website showed that CFD was favorable for immunotherapy response, whereas ANGPTL4 negatively impacted the outcomes of cancer patients receiving immunotherapy.</p><p><strong>Conclusion: </strong>We identified distinct ECM clusters in breast cancer patients, irrespective of molecular subtypes. Additionally, we constructed an effective prognostic model based on these ECM clusters and recognized ANGPTL4⁺ and CFD⁺ fibroblasts as potential biomarkers for immunotherapy in breast cancer.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"179"},"PeriodicalIF":6.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027534","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}

{"title":"Surgery/anesthesia may cause monocytes to promote tumor development.","authors":"Yang-Yang Wang, Rui-Lou Zhu, En-Qiang Chang, Xiao-Zhuan Liu, Guang-Zhi Wang, Ning-Tao Li, Wei Zhang, Jun Zhou, Ming-Yang Sun, Xin Zou, Jie Hao, Jia-Qiang Zhang","doi":"10.1186/s10020-025-01213-6","DOIUrl":"https://doi.org/10.1186/s10020-025-01213-6","url":null,"abstract":"<p><strong>Background: </strong>The immune system of patients undergoing major surgery usually has obvious immune responses during the perioperative period, and the patient's immune status would affect the patient's prognosis. In this study single-cell sequencing technology was used to investigate the effect of surgery/anesthesia on peripheral blood mononuclear cells (PBMCs) in depth during the perioperative period.</p><p><strong>Methods: </strong>We performed an in-depth analysis of our previously published data, which included a total of 4 patients were recruited in this study. Their peripheral blood samples were collected pre operation, 0, 24, and 48 h post operation, and then PBMCs were extracted, followed by single cell sequencing. The results of sequencing were analyzed with R packages seurat and scSTAR. Finally, RT-PCR technology was used to verify the expression of key genes in monocyte.</p><p><strong>Results: </strong>The ratio of CD4⁺ and CD8⁺ T cells and Tregs showed little change, and the function of CD4⁺ and CD8⁺ T cells recovered soon. The function of Treg had not been restored 48 h post operation. Non-classical monocyte was impressed after surgery and showed no recovery trend within 48 h. Similar to scRNA-seq, the expression levels of MDM2 and SESN1 in patients with tumor increased significantly after surgery.</p><p><strong>Conclusions: </strong>Surgery/anesthesia had little effect on CD4⁺ and CD8⁺ T cells, and continued to affect the functional changes of Treg. It had more impact on monocytes, which may cause them to promote tumor development to a certain extent.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"178"},"PeriodicalIF":6.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028437","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}

{"title":"COX-2 inhibition as a therapeutic strategy for bone loss in Staphylococcus aureus osteomyelitis.","authors":"Yuhui Chen, Chao Li, Jishan Jia, Yuhui Jiang, Ping Zhang, Caiyu Cheng, Guangyan Zhang, Lang Gao, Xiang Yang, Jiawei Zhao, Kaiqun Li, Bin Yu","doi":"10.1186/s10020-025-01202-9","DOIUrl":"https://doi.org/10.1186/s10020-025-01202-9","url":null,"abstract":"<p><p>Bone loss in Staphylococcus aureus (S. aureus) osteomyelitis poses a serious challenge to orthopedic treatment, but the underlying mechanism of systemic osteoporosis caused by chronic infection is not completely clear. In this study, γ-irradiation-killed S. aureus (IKSA) was applied to simulate the inflammation and explore the mechanism of systemic bone loss caused by it. In this study, we found that the systemic application of IKSA caused bone loss in mice through increasing osteoclasts and decreasing osteoblasts. An immune response profile with up-regulated COX-2 is identified based on our transcriptional data from IKSA mice bone marrow cells. COX-2 expression is widely up-regulated in bone marrow immune cells, such as myeloid-derived suppressor cells (MDSCs), neutrophils and macrophages in the IKSA-treated mice. Mechanistically, COX-2 stimulated the increasing proportion of MDSCs and neutrophils and the inflammatory response of the bone marrow immune cells, that may regulate bone metabolism. Importantly, COX-2 inhibitor, celecoxib could rescue the bone loss induced by IKSA, which may reason from decrease of inflammatory gene expression in MDSCs, neutrophils and macrophages. Excitingly, COX-2 expression is also increased in bone marrow from mice and patients with S. aureus osteomyelitis. These findings suggested a therapeutic potential for inhibiting COX-2 in combating bone loss in S. aureus osteomyelitis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"177"},"PeriodicalIF":6.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028083","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}

{"title":"Enhanced potency of immune checkpoint inhibitors against poorly immunological solid tumors by immune stimulatory oncolytic adenoviruses-mediated remodeling of the tumor microenvironment.","authors":"Hyo Min Ahn, Bo-Kyeong Jung, JinWoo Hong, Dayoung Hong, A-Rum Yoon, Chae-Ok Yun","doi":"10.1186/s10020-025-01223-4","DOIUrl":"https://doi.org/10.1186/s10020-025-01223-4","url":null,"abstract":"<p><p>Immune checkpoint inhibitor (ICI) have shown promising results against a variety of solid tumors across clinical trials. However, ICI monotherapy is often ineffective in patients with non-immunogenic tumors that exhibit high level of immunosuppression and low level of tumor infiltrating lymphocytes. To address these limitations, we have investigated a combination of ICIs [anti-PD-1 antibody (αPD-1), anti-PD-L1 antibody (αPD-L1), or anti-CTLA-4 antibody (αCTLA-4)] with several different immune stimulatory oncolytic adenoviruses (Ads) expressing different combinations of antitumor cytokines or immune modulatory factors [e.g., (1) interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF; RdB/IL12/GMCSF), (2) IL-12 and short hairpin ribonucleic acid (shRNA) targeting vascular endothelial growth factor (RdB/IL12/shVEGF), (3) IL-12 and decorin (RdB/IL12/DCN), (4) GM-CSF, and thymidine kinase (RdB/IL12/GMCSF-TK), or (5) IL-12, GM-CSF, and relaxin (RdB/IL12/GMCSF-RLX)] to overcome tumor-induced immunosuppression. Through comparative evaluation of combination therapy regimens, our findings have identified αPD-1 as the optimal ICI candidate to synergize with different oncolytic Ads to induce potent antitumor immune response against poorly immunological solid tumors.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"175"},"PeriodicalIF":6.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982404","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}

{"title":"Melatonin alleviates sepsis-induced acute lung injury by inhibiting necroptosis via reducing circulating mtDNA release.","authors":"Yuce Peng, Jia Xu, Lingyu Wei, Minghao Luo, Shenglong Chen, Xuebiao Wei, Suxin Luo, Zedazhong Su, Zhonghua Wang","doi":"10.1186/s10020-025-01228-z","DOIUrl":"https://doi.org/10.1186/s10020-025-01228-z","url":null,"abstract":"<p><strong>Background: </strong>Sepsis is a life-threatening condition that often leads to severe complications, including acute lung injury (ALI), which carries high morbidity and mortality in critically ill patients. Melatonin (Mel) has shown significant protective effects against sepsis-induced ALI, but its precise mechanism remains unclear.</p><p><strong>Methods: </strong>A cecal ligation and puncture (CLP) model was used to induce sepsis in male C57BL/6 mice, which were divided into four groups: Control, Sham, CLP, and CLP + Mel. ALI severity was evaluated via hematoxylin and eosin (H&E) staining, lung wet/dry ratio, and serum biomarkers (SP-D, sRAGE). Inflammatory cytokines (IL-1β, IL-6, TNF-α) were measured in serum and bronchoalveolar lavage fluid using ELISA. Circulating mitochondrial DNA (mtDNA) subtypes (D-loop, mt-CO1, mMito) were quantified by real-time PCR. TUNEL staining was performed to assess lung cell apoptosis. Necroptosis and STING pathway activation were analyzed via Western blot and immunofluorescence.</p><p><strong>Results: </strong>Sepsis led to increased circulating mtDNA levels and activation of necroptosis signaling pathways. Melatonin treatment alleviated sepsis-induced ALI, improving survival, reducing inflammatory cytokines and mtDNA release, and suppressing necroptosis. Intraperitoneal injection of mtDNA in mice activated necroptosis, while RIP1 inhibitor Nec-1 counteracted mtDNA-induced lung damage and necroptosis in sepsis-induced ALI. Additionally, melatonin significantly inhibited STING pathway activation. Further experiments revealed that STING modulation influenced necroptosis protein expression and mediated melatonin's protective effects in sepsis-induced ALI.</p><p><strong>Conclusion: </strong>Melatonin mitigates sepsis-induced ALI by suppressing necroptosis through inhibition of STING activation and reduction of mtDNA release. These findings suggest melatonin as a potential therapeutic strategy for sepsis-induced ALI.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"176"},"PeriodicalIF":6.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030012","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}

{"title":"A pilot study on the effect of SARS-CoV-2 spike protein on IL-1β-mediated inflammation in peripheral blood immune cells from AIED patients.","authors":"Shresh Pathak, Natalie Tan, Andrea Vambutas","doi":"10.1186/s10020-025-01227-0","DOIUrl":"https://doi.org/10.1186/s10020-025-01227-0","url":null,"abstract":"<p><strong>Background: </strong>Immune-mediated hearing loss (IMHL) patients (comprised of autoimmune inner ear disease (AIED) and sudden sensorineural hearing loss (SSNHL)) may be at higher risk for hearing loss following Coronavirus disease (COVID-19) infection and/or vaccination.</p><p><strong>Methods: </strong>We compared inflammatory cytokine expression in response to SARS-CoV2 spike protein between two groups of patients with IMHL: IMHL patients that temporally demonstrated worsening SNHL following COVID vaccination or infection as compared to IMHL patients with worsening SNHL unrelated to COVID exposure: (IMHL-COVID ( +)) (n = 11) (IMHL-COVID (-)) (n = 10). In these two groups, we treated isolated PBMCs with increasing amounts of SARS-CoV-2 spike protein and compared responses to stimulation with positive and negative controls.</p><p><strong>Results: </strong>Peripheral Blood Mononuclear Cells (PBMC) from IMHL-COVID ( +) patients had increased expression and release of both IL-1β and IL-6 in response to spike protein as compared to IMHL-COVID (-) patients. However, when the IMHL-COVID ( +) group was broken down into AIED patients compared to SSNHL, it became apparent that the greatest responses were from the AIED patients (p < 0.005 for IL-6 mRNA expression and p < 0.003 for IL-6 release when compared between any two similar groups using Wilcoxon Rank-Sum Test). When we broke down the COVID ( +) group to infection versus vaccination, the immune responses in the infection group (N = 3 AIED, 1 SSNHL) were stronger.</p><p><strong>Conclusions: </strong>COVID-19 exposure with reported changes in hearing sensitivity in IMHL patients resulted in pro-inflammatory responses in response to spike protein. The inflammatory responses were greatest in AIED patients, and greater following infection rather than vaccination. Therefore, based on these studies, we would recommend AIED patients take additional precautions to avoid COVID exposure. Furthermore, we do recommend COVID vaccination during periods of hearing stability, as the immune responses are even more robust in response to infection in this vulnerable group.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"174"},"PeriodicalIF":6.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972290","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}