Molecular Medicine最新文献

{"title":"Exosomes derived from human amniotic mesenchymal stem cells promotes angiogenesis in hUVECs by delivering novel miRNA N-194.","authors":"Yang Song, Tao Zhang, Ping Shi, Yingzhuo Gao, Xining Pang","doi":"10.1186/s10020-025-01192-8","DOIUrl":"https://doi.org/10.1186/s10020-025-01192-8","url":null,"abstract":"<p><strong>Background: </strong>To investigate the effect and mechanism of exosomes derived from human amniotic mesenchymal stem cells (hAMSC-Exos) promoting angiogenesis.</p><p><strong>Methods: </strong>HAMSC-Exos were isolated using ultracentrifugation and characterized by transmission electron microscopy, NTA, and Western blot. The uptake of hAMSC-Exos by hUVECs was analyzed using PKH-26 labeling, and the effect of hAMSC-Exos on angiogenesis was analyzed in human umbilical vein endothelial cells hUVECs by cell viability assay, Transwell migration assay, Matrigel tube formation assay, and Matrigel plug assays in nude mice. Bioinformatics methods were used to analyze miRNA high-throughput sequencing data of hAMSC-Exos, and RT-qPCR was used to validate the novel miRNAs. HAMSC-Exos with high and low N-194 expression were obtained by transfection, respectively. Target genes were predicted using TargetScan, and the mRNA and protein levels of potential target genes were analyzed by RT-qPCR and Western blot after N-194 mimics transfection. Interaction between miRNAs and target genes was detected using the dual-luciferase reporter assay. Target genes were overexpressed in hUVECs by transfection. The roles of target genes in the influence of N-194 on cell function were determined by analyzing angiogenesis.</p><p><strong>Results: </strong>The extracted hAMSC-Exos showed saucer-shaped under transmission electron microscopy, and the NTA results showed the particle size of 115.6 ± 38.6 nm. The positive expression of CD9, CD63, and CD81 were verified using Western blot. The treatment of hUVECs with hAMSC-Exos significantly increased cell proliferation, migration, and angiogenesis. HAMSC-Exos contained the novel miRNAs N-194, N-314, N-19, N-393, and N-481, and the expression of N-194 was higher. The Exos derived from hAMSCs which were transfected with FAM-N-194 mimics were able to deliver FAM-N-194 mimics to hUVECs. The hAMSC-Exos with high N-194 significantly promoted angiogenesis in hUVECs. N-194 mimics transfection significantly reduced mRNA and protein levels of potential target gene ING5, and N-194 mimics significantly reduced the luciferase activities expressed by wild-type reporter gene vectors for ING5. The ING5 overexpression significantly reduced the angiogenic capacity of hUVECs. ING5 overexpression suppressed the expression of HSP27 and PLCG2.</p><p><strong>Conclusions: </strong>HAMSC-Exos promotes angiogenesis in hUVECs by delivering novel miRNA N-194 which targets ING5.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"173"},"PeriodicalIF":6.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024917","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":"Paclitaxel alleviates spinal cord injury via activation of the Wnt/β-catenin signaling pathway.","authors":"Zhifeng Chen, Da Wo, Celiang Wu, En Ma, Jinhui Peng, Weidong Zhu, Dan-Ni Ren","doi":"10.1186/s10020-025-01240-3","DOIUrl":"https://doi.org/10.1186/s10020-025-01240-3","url":null,"abstract":"<p><strong>Background: </strong>Spinal cord injury (SCI) is a disability that causes severe traumatic damage to the central nervous system, with increasing prevalence worldwide. Paclitaxel (PTX) is a naturally occurring plant metabolite that has been shown to exhibit various neuroprotective effects in the central nervous system, however, the specific mechanisms underlying its protective effects in SCI remain unclear. In this study, we aimed to explore the therapeutic effects of PTX in SCI, as well as elucidate the underlying molecular mechanisms associated with its neuroprotective potential.</p><p><strong>Methods: </strong>Murine models of spinal cord compression were performed followed by intrathecal administration of corresponding agents for 21 days. Mice were randomly divided into the following four groups: Sham, SCI + Saline, SCI + PTX, and SCI + PTX + XAV939. Recovery of lower limb function and strength, as well as muscular atrophy were examined via multiple scored tests. Degree of neuronal and axonal damage, as well as fibrosis were examined via immunohistochemical staining.</p><p><strong>Results: </strong>PTX administration significantly improved the recovery of lower limb function and strength, prevented muscular atrophy, as well as decreased the extent of neuronal and axonal death following SCI surgery. PTX also robustly activated the Wnt/β-catenin protein signaling pathway that played a key role in its therapeutic effects. Co-administration with a Wnt/β-catenin pathway inhibitor - XAV939, significantly abolished the beneficial effects of PTX after SCI.</p><p><strong>Conclusion: </strong>This study provides important new mechanistic insight on the beneficial effects of PTX in protecting against spinal cord injury, as well as the experimental basis for its potential therapeutic use.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"172"},"PeriodicalIF":6.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028430","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":"Recent advances in the roles of extracellular vesicles in cardiovascular diseases: pathophysiological mechanisms, biomarkers, and cell-free therapeutic strategy.","authors":"Mengyang Wang, Yuwu Chen, Biyi Xu, Xinxin Zhu, Junke Mou, Jiani Xie, Ziao Che, Liyang Zuo, Ji Li, Haibo Jia, Bo Yu","doi":"10.1186/s10020-025-01200-x","DOIUrl":"https://doi.org/10.1186/s10020-025-01200-x","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) represent a profound challenge with inflammation playing a significant role in their pathophysiology. Extracellular vesicles (EVs), which are membranous structures encapsulated by a lipid bilayer, are essential for intercellular communication by facilitating the transport of specific bioactive molecules, including microRNAs, proteins, and lipids. Emerging evidence suggests that the regulatory mechanisms governing cardiac resident cells are influenced by EVs, which function as messengers in intercellular communication and thereby contribute to the advancement of CVDs. In this review, we discuss the multifaceted biological functions of EVs and their involvement in the pathogenesis of various CVDs, encompassing myocardial infarction, ischemia-reperfusion injury, heart failure, atherosclerosis, myocarditis, cardiomyopathy, and aneurysm. Furthermore, we summarize the recent advancements in utilizing EVs as non-invasive biomarkers and in cell-free therapy based on EVs for the diagnosis and treatment of CVDs. Future research should investigate effective techniques for the isolation and purification of EVs from body fluids, while also exploring the pathways for the clinical translation of therapy based on EVs. Additionally, it is imperative to identify appropriate EV-miRNA profiles or combinations present in the circulation of patients, which could serve as biomarkers to improve the diagnostic accuracy of CVDs. By synthesizing and integrating recent research findings, this review aims to provide innovative perspectives for the pathogenesis of CVDs and potential therapeutic strategies.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"169"},"PeriodicalIF":6.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032130","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":"Bacteriophage-derived endolysins restore antibiotic susceptibility in β-lactam- and macrolide-resistant Streptococcus pneumoniae infections.","authors":"Niels Vander Elst, Kristine Farmen, Lisa Knörr, Lotte Merlijn, Federico Iovino","doi":"10.1186/s10020-025-01226-1","DOIUrl":"https://doi.org/10.1186/s10020-025-01226-1","url":null,"abstract":"<p><p>Streptococcus pneumoniae, the pneumococcus, is a cause of major illness globally. Invasive pneumococcal disease (IPD) is characterized by pneumococci invading blood (bacteremia), lungs (pneumonia), or brain and cerebrospinal fluid (meningitis). Meningitis remains an important global health concern because half of the survivors experience long-term neurological damage. The antibiotics commonly used to treat pneumococcal infections are β-lactams and macrolides, however, S. pneumoniae is nowadays often resistant to one or several antibiotics, therefore novel antimicrobials are needed. Here, we found that the bacteriophage-derived cpl-1 endolysin showed consistent antibacterial activity against β-lactam- and macrolide-resistant pneumococcal clinical strains grown in human blood and human cerebrospinal fluid. Exploiting synergistic and additive mechanisms, supplementation of cpl-1 to either penicillin or erythromycin, as representatives for β-lactam and macrolide antibiotics, rescued human neuronal cells from the cytotoxicity of antibiotic-resistant pneumococcal infections. Finally, systemic administration of cpl-1 supplemented to penicillin in mice infected with penicillin-resistant pneumococci successfully reduced bacteremia, and, thanks to the efficient penetration across the blood-brain barrier, abolished bacterial load in the brain, resulting in increased (89%) survival accompanied by an asymptomatic course of infection. These findings strongly suggest that cpl-1 can enhance antibiotic susceptibility in β-lactam- and macrolide-resistant S. pneumoniae, serving as a valuable adjunct therapy to standard-of-care antibiotics for multidrug-resistant IPD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"170"},"PeriodicalIF":6.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028079","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":"Inhibition of TLR4 mitigates sensorineural hearing loss resulting from cochlear inflammation.","authors":"Jintao Lou, Fan Wu, Wei Liu, Rui Hu, Wuhui He, Yisi Feng, Yan Huang, Jia Guo, Jingman Deng, Zhen Zhao, Zhigang Zhang, Yu Si","doi":"10.1186/s10020-025-01219-0","DOIUrl":"https://doi.org/10.1186/s10020-025-01219-0","url":null,"abstract":"<p><strong>Background: </strong>Inflammation is a principal cause of sensorineural hearing loss resulting from cochlear injury. However, current research investigating the mechanisms of sensorineural inflammatory injury remains inadequate.</p><p><strong>Methods: </strong>Cochlear inflammation was induced by administering lipopolysaccharide (LPS) into the otic bulla (OB) and posterior semicircular canal (PSCC). Auditory brainstem responses (ABR) were recorded, and cochlear tissue alterations were analyzed using hematoxylin and eosin (HE) staining and immunofluorescence. Levels of cochlear inflammation were quantified using a cytokine array. Additionally, Toll-like receptor 4 (TLR4) knockout mice were employed to evaluate sensorineural neuroprotection.</p><p><strong>Results: </strong>LPS injection into the PSCC caused more pronounced and stable cochlear inflammatory damage compared to injection into the OB. LPS exposure led to significant loss of cochlear hair cells, atrophy of the stria vascularis, and spiral ganglion damage. Furthermore, LPS treatment upregulated TLR4 receptor expression, increased the number of Ionized calcium-binding adapter molecule 1 (IBA1) positive cells, and elevated levels of inflammatory cytokines in the cochlea. TLR4 knockout (TLR4-KO) mice demonstrated reduced LPS-induced cochlear sensorineural damage.</p><p><strong>Conclusion: </strong>LPS injection into the PSCC induces sensorineural tissue damage in the cochlea and results in sensorineural hearing loss. These findings suggest that TLR4 inhibition can alleviate cochlear inflammation-induced sensorineural hearing loss. TLR4 represents a potential therapeutic target for sensorineural hearing loss.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"168"},"PeriodicalIF":6.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031936","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":"Drug screening targeting TREM2-TYROBP transmembrane binding.","authors":"M Cobas-Carreño, A Esteban-Martos, L Tomas-Gallardo, I Iribarren, L Gonzalez-Palma, A Rivera-Ramos, J Elena-Guerra, E Alarcon-Martin, R Ruiz, M J Bravo, J L Venero, X Morató, A Ruiz, J L Royo","doi":"10.1186/s10020-025-01229-y","DOIUrl":"https://doi.org/10.1186/s10020-025-01229-y","url":null,"abstract":"<p><p>TREM2 encodes a microglial membrane receptor involved in the disease-associated microglia (DAM) phenotype whose activation requires the transmembrane interaction with TYROBP. Mutations in TREM2 represent a high-impact risk factor for Alzheimer's disease (AD) which turned TREM2 into a significant drug target. We present a bacterial two-hybrid (B2H) system designed for high-throughput screening of modulators for the TREM2-TYROBP transmembrane interaction. In a pilot study, 315 FDA-approved drugs were analyzed to identify potential binding modifiers. Our pipeline includes multiple filtering steps to ensure candidate specificity. The screening suggested two potential candidates that were finally assayed in the human microglial cell line HMC3. Upon stimulation with anti-TREM2 mAb, pSYK/SYK ratios were calculated in the presence of the candidates. As a result, we found that varenicline, a smoking cessation medication, can be considered as a transmembrane agonist of the TREM2-TYROBP interaction.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"171"},"PeriodicalIF":6.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027530","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":"STMN1-IGFBP5 axis induces senescence and extracellular matrix degradation in nucleus pulposus cells: In vivo and in vitro insights.","authors":"Lei Li, Guangzhi Zhang, Zhili Yang, Zhenyu Cao, Dongxin Wang, Xuewen Kang","doi":"10.1186/s10020-025-01220-7","DOIUrl":"https://doi.org/10.1186/s10020-025-01220-7","url":null,"abstract":"<p><p>Cellular dysfunction induced by senescent nucleus pulposus (NP) cells is a key factor in the pathogenesis of intervertebral disc degeneration (IDD). Stathmin 1 (STMN1) has been proposed as a telomere-associated senescence marker implicated in senescence in many age-related diseases. Nevertheless, its role in NP cell senescence remains unclear. This study revealed that STMN1 was significantly upregulated in human degenerative and naturally aged rat NP tissue specimens. In vitro models demonstrated that STMN1 expression levels were elevated in replicative and TNF-α-induced NP senescence models. Lentiviral knockdown of STMN1 inhibited NP cell senescence, while overexpression promoted NP cell senescence, along with extracellular matrix (ECM) degradation. An in-depth mechanism indicated that insulin-like growth factor-binding protein 5 (IGFBP5), a downstream pro-senescence gene of STMN1, can induce NP cellular senescence and ECM degradation following its upregulation by STMN1. Furthermore, STMN1 knockdown reduced IGFBP5 expression and mitigated IDD development in a rat model of caudal discs puncture-induced IDD. Combined with the abovementioned results, we demonstrated for the first time that the STMN1-IGFBP5 axis can induce NP cell senescence and ECM degradation, thereby accelerating IDD development. This provides a robust foundation for the development of molecular-targeted therapies for IDD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"167"},"PeriodicalIF":6.0,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032131","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":"Calpain1 inhibition enhances autophagy-lysosomal pathway and ameliorates tubulointerstitial fibrosis in Nephronophthisis.","authors":"Dantong Li, Jinglan Zhang, Xinyu Su, Yichen Yang, Jiayong Lai, Xiaoya Wei, Huamu Chen, Yaqing Liu, Haiyan Wang, Liangzhong Sun","doi":"10.1186/s10020-025-01231-4","DOIUrl":"https://doi.org/10.1186/s10020-025-01231-4","url":null,"abstract":"<p><strong>Background: </strong>Nephronophthisis (NPH) is classified under the category of renal ciliopathies and is the most common genetic disease leading to renal failure in children. Early-onset and progressive renal tubulointerstitial fibrosis represents one of the most significant features, culminating in renal insufficiency. However, the molecular mechanism of tubulointerstitial fibrosis remains unclear. Previously, we constructed an NPH mouse model via CRISPR-Cas9. This mouse model demonstrated typical features of tubulointerstitial fibrosis. In this study, we aimed to explore the pathogenesis of tubulointerstitial fibrosis in NPH and identify early intervention targets in both the NPH models and patients.</p><p><strong>Methods: </strong>In this study, transcriptome changes in mouse kidneys were analyzed through RNA sequencing to explore the molecular mechanisms of renal tubulointerstitial fibrosis in NPH. We found an increased abundance of calpain1 in both the NPH models and patients. Pathway enrichment analysis indicated autophagy-lysosomal pathway was altered in the NPH models. Western blot, immunofluorescence or immunohistochemical staining were used to verify the expression of calpain1. We also detected autophagy activities in NPH models by lysotracker staining and transmission electron microscopy (TEM). Epithelial or mesenchymal-specific markers and Masson's trichrome staining were used to detect the status of tubulointerstitial fibrosis. Furthermore, NPH models were treated with a calpain1 inhibitor to explore the role of calpain1 in autophagy-lysosomal pathway and tubulointerstitial fibrosis.</p><p><strong>Results: </strong>The increased abundance of calpain1 impaired the autophagy-lysosomal pathway and induced tubulointerstitial fibrosis by promoting epithelial-to-mesenchymal transition. On the other hand, calpain1 inhibition could enhance the autophagy-lysosomal pathway and ameliorate the phenotypes of tubulointerstitial fibrosis in NPH models.</p><p><strong>Conclusions: </strong>Calpain1-mediated autophagy-lysosomal pathway disorder may be an important cause of tubulointerstitial fibrosis in NPH. Calpain1 may have therapeutic implications for renal tubulointerstitial fibrosis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"166"},"PeriodicalIF":6.0,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990572","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":"Peripheral tissue BDNF expression is affected by promoter IV defect and enriched environments in mice: negative hippocampus-intestine and positive thymus-serum-muscle correlations.","authors":"Janet Wang, William Schupp, Kazuko Sakata","doi":"10.1186/s10020-025-01196-4","DOIUrl":"https://doi.org/10.1186/s10020-025-01196-4","url":null,"abstract":"<p><strong>Background: </strong>Brain-derived neurotrophic factor (BDNF) expression is reduced in the brain of various central nervous system (CNS) disorders, but its relation to peripheral expression remains unclear. This study aimed to determine peripheral BDNF expression affected by BDNF promoter IV defect and enriched environment treatment (EET). Promoter IV defect is associated with CNS disorders and chronic stress, whereas EET increases hippocampal BDNF expression and ameliorates CNS dysfunctions.</p><p><strong>Methods: </strong>Enzyme-linked immunosorbent assay measured BDNF protein levels in eleven regions (hippocampus, frontal cortex, heart, lung, liver, spleen, intestine, kidney, intestine, thymus, muscle, serum) in wild-type and knock-in promoter IV (KIV) mice with or without 3 weeks of EET provided after weaning.</p><p><strong>Results: </strong>Knock-in promoter IV resulted in BDNF levels significantly decreased in muscle, but significantly increased in intestine, liver, thymus, and serum, which suggests compensatory upregulation of other promoters in those tissues. EET increased BDNF levels in muscle and serum of KIV mice and thymus of wild-type mice, suggesting EET's beneficial effects in muscle motor and adaptive immune regulation. EET increased hippocampal BDNF levels in both genotypes, which significantly negatively correlated with intestine BDNF levels, suggesting its role in the brain-gut axis. EET reduced wild-type heart BDNF levels, possibly through parasympathetic regulation. Significant positive BDNF correlations were observed among serum-muscle, serum-thymus, lung-spleen, and intestine-liver, suggesting inter-organ interaction and regulation of BDNF. Partial Least Squares discriminant analyses (PLS-DA) identified that variations in BDNF levels in intestine, liver, frontal cortex, and serum contribute most to classify promoter IV defect, and those in hippocampus, serum, heart, thymus, and liver contribute most to classify EET effects.</p><p><strong>Conclusion: </strong>This is the first study to demonstrate how genetic and environmental factors affect BDNF expression in peripheral tissues, highlighting the complex BDNF correlations across organ systems and suggesting usefulness of multivariate BDNF analyses for detecting promoter IV defect and enriched environment effects. Elucidation of BDNF's role and regulatory mechanisms in peripheral organ systems may help better our understanding of its connection to CNS disorders and their treatments.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"164"},"PeriodicalIF":6.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033700","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":"Electron-beam FLASH whole brain irradiation induced a unique changes of intestinal flora.","authors":"Feifei Gao, Wei Cheng, Yanxi Ma, Boyi Yu, Xinle Lang, Xiaodong Jin, Jianxin Wang, Xianhong Liu, Cuixia Di, Hui Wang, Fei Ye, Ting Zhao, Weiqiang Chen, Qiang Li","doi":"10.1186/s10020-024-01053-w","DOIUrl":"https://doi.org/10.1186/s10020-024-01053-w","url":null,"abstract":"<p><strong>Background: </strong>Whole-brain radiotherapy (WBRT) is an important way to treat multiple metastases. Ultra-high dose rate (FLASH) can avoid neurotoxicity caused by conventional irradiation, it has attracted much attention. This study aims to study the difference of irradiation-induced intestinal flora between conventional dose rate and FLASH WBRT.</p><p><strong>Methods: </strong>WBRT with 10 Gy was performed with electron-beam conventional irradiation (2 Gy/s) and electron-beam FLASH (eFLASH) irradiation (230 Gy/s). The intestinal feces and whole brain of mice were isolated after behavioral evaluation at 1st, 3rd and 10th weeks post-irradiation. HE staining and immunofluorescence were used to access the level of brain damage. The differences in intestinal microbes and transcription levels were detected by 16S rRNA gene sequencing and transcriptome sequencing, respectively.</p><p><strong>Results: </strong>eFLASH irradiation significantly reduced radiation neurotoxicity and had a long-term protective effect on cognitive function and learning and memory ability. Compared with conventional irradiation, eFLASH irradiation not only up-regulated the expression of genes related to neuronal regeneration and digestive system, but also induced more abundant intestinal microflora, especially the \"probiotics\" such as Lachnospiraceae and others, which were proved to play a role in radiation protection, increased significantly after eFLASH irradiation. The up-regulated microbiota after eFLASH irradiation was significantly positively correlated with genes related to neuronal development and regeneration, while significantly negatively correlated with genes related to inhibitory synapses. Additionally, conventional irradiation down-regulated microbial metabolism-related pathways, while FLASH did not.</p><p><strong>Conclusions: </strong>In summary, we explored the unique gut microbiota changes induced by eFLASH WBRT for the first time, providing a theoretical basis for exploring the mechanism of action of FLASH.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"165"},"PeriodicalIF":6.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028317","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}