EMBO Molecular Medicine最新文献

Improving the odds of survival: transgenerational effects of infections.

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-22 DOI: 10.1038/s44321-025-00192-9

Victoria M Spanou, Theano P Andriopoulou, Evangelos J Giamarellos-Bourboulis, Mihai G Netea

{"title":"Improving the odds of survival: transgenerational effects of infections.","authors":"Victoria M Spanou, Theano P Andriopoulou, Evangelos J Giamarellos-Bourboulis, Mihai G Netea","doi":"10.1038/s44321-025-00192-9","DOIUrl":"https://doi.org/10.1038/s44321-025-00192-9","url":null,"abstract":"Recent studies argue for a novel concept of the role of chromatin as a carrier of epigenetic memory through cellular and organismal generations, defining and coordinating gene activity states and physiological functions. Environmental insults, such as exposures to unhealthy diets, smoking, toxic compounds, and infections, can epigenetically reprogram germ-line cells and influence offspring phenotypes. This review focuses on intergenerational and transgenerational epigenetic inheritance in different plants, animal species and humans, presenting the up-to-date evidence and arguments for such effects in light of Darwinian and Lamarckian evolutionary theories. An overview of the epigenetic changes induced by infection or other immune challenges is presented, and how these changes, known as epimutations, contribute to shaping offspring phenotypes. The mechanisms that mediate the transmission of epigenetic alterations via the germline are also discussed. Understanding the relationship between environmental fluctuations, epigenetic changes, resistance, and susceptibility to diseases is critical for unraveling disease etiology and adaptive evolution.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

FABP4 as a therapeutic host target controlling SARS-CoV-2 infection.

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-22 DOI: 10.1038/s44321-024-00188-x

Hatoon Baazim, Emre Koyuncu, Gürol Tuncman, M Furkan Burak, Lea Merkel, Nadine Bahour, Ezgi Simay Karabulut, Grace Yankun Lee, Alireza Hanifehnezhad, Zehra Firat Karagoz, Katalin Földes, Ilayda Engin, Ayse Gokce Erman, Sidika Oztop, Nazlican Filazi, Buket Gul, Ahmet Ceylan, Ozge Ozgenc Cinar, Fusun Can, Hahn Kim, Ali Al-Hakeem, Hui Li, Fatih Semerci, Xihong Lin, Erkan Yilmaz, Onder Ergonul, Aykut Ozkul, Gökhan S Hotamisligil

{"title":"FABP4 as a therapeutic host target controlling SARS-CoV-2 infection.","authors":"Hatoon Baazim, Emre Koyuncu, Gürol Tuncman, M Furkan Burak, Lea Merkel, Nadine Bahour, Ezgi Simay Karabulut, Grace Yankun Lee, Alireza Hanifehnezhad, Zehra Firat Karagoz, Katalin Földes, Ilayda Engin, Ayse Gokce Erman, Sidika Oztop, Nazlican Filazi, Buket Gul, Ahmet Ceylan, Ozge Ozgenc Cinar, Fusun Can, Hahn Kim, Ali Al-Hakeem, Hui Li, Fatih Semerci, Xihong Lin, Erkan Yilmaz, Onder Ergonul, Aykut Ozkul, Gökhan S Hotamisligil","doi":"10.1038/s44321-024-00188-x","DOIUrl":"https://doi.org/10.1038/s44321-024-00188-x","url":null,"abstract":"Host metabolic fitness is a critical determinant of infectious disease outcomes. Obesity, aging, and other related metabolic disorders are recognized as high-risk disease modifiers for respiratory infections, including coronavirus infections, though the underlying mechanisms remain unknown. Our study highlights fatty acid-binding protein 4 (FABP4), a key regulator of metabolic dysfunction and inflammation, as a modulator of SARS-CoV-2 pathogenesis, correlating strongly with disease severity in COVID-19 patients. We demonstrate that loss of FABP4 function, by genetic or pharmacological means, reduces SARS-CoV-2 replication and disrupts the formation of viral replication organelles in adipocytes and airway epithelial cells. Importantly, FABP4 inhibitor treatment of infected hamsters diminished lung viral titers, alleviated lung damage and reduced collagen deposition. These findings highlight the therapeutic potential of targeting host metabolism in limiting coronavirus replication and mitigating the pathogenesis of infection.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gut microbiota interact with breast cancer therapeutics to modulate efficacy. 肠道微生物群与乳腺癌治疗药物相互作用以调节疗效。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-16 DOI: 10.1038/s44321-024-00185-0

Alana A Arnone,Katherine Ansley,Arielle L Heeke,Marissa Howard-McNatt,Katherine L Cook

引用次数: 0

Female sex is linked to a stronger association between sTREM2 and CSF p-tau in Alzheimer's disease. 女性在阿尔茨海默病中与strem - 2和CSF p-tau之间有更强的联系。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-10 DOI: 10.1038/s44321-024-00190-3

Davina Biel, Marc Suárez-Calvet, Anna Dewenter, Anna Steward, Sebastian N Roemer, Amir Dehsarvi, Zeyu Zhu, Julia Pescoller, Lukas Frontzkowski, Annika Kreuzer, Christian Haass, Michael Schöll, Matthias Brendel, Nicolai Franzmeier

{"title":"Female sex is linked to a stronger association between sTREM2 and CSF p-tau in Alzheimer's disease.","authors":"Davina Biel, Marc Suárez-Calvet, Anna Dewenter, Anna Steward, Sebastian N Roemer, Amir Dehsarvi, Zeyu Zhu, Julia Pescoller, Lukas Frontzkowski, Annika Kreuzer, Christian Haass, Michael Schöll, Matthias Brendel, Nicolai Franzmeier","doi":"10.1038/s44321-024-00190-3","DOIUrl":"https://doi.org/10.1038/s44321-024-00190-3","url":null,"abstract":"In Alzheimer's disease (AD), Aβ triggers p-tau secretion, which drives tau aggregation. Therefore, it is critical to characterize modulators of Aβ-related p-tau increases which may alter AD trajectories. Here, we assessed whether factors known to alter tau levels in AD modulate the association between fibrillar Aβ and secreted p-tau181 determined in the cerebrospinal fluid (CSF). To assess potentially modulating effects of female sex, younger age, and ApoE4, we included 322 ADNI participants with cross-sectional/longitudinal p-tau181. To determine effects of microglial activation on p-tau181, we included 454 subjects with cross-sectional CSF sTREM2. Running ANCOVAs for nominal and linear regressions for metric variables, we found that women had higher Aβ-related p-tau181 levels. Higher sTREM2 was associated with elevated p-tau181, with stronger associations in women. Similarly, ApoE4 was related to higher p-tau181 levels and faster p-tau181 increases, with stronger effects in female ApoE4 carriers. Our results show that sex alone modulates the Aβ to p-tau axis, where women show higher Aβ-dependent p-tau secretion, potentially driven by elevated sTREM2-related microglial activation and stronger effects of ApoE4 carriership in women.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oncolytic viruses expressing MATEs facilitate target-independent T-cell activation in tumors. 表达MATEs的溶瘤病毒促进肿瘤中不依赖靶标的t细胞活化。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-09 DOI: 10.1038/s44321-024-00187-y

Malin Peter, Bettina Mundt, Arne Menze, Norman Woller, Valery Volk, Amanda M Ernst, Leon A Öhler, Steven R Talbot, Heiner Wedemeyer, Christine Falk, Friedrich Feuerhake, Thomas C Wirth, Florian Kühnel

{"title":"Oncolytic viruses expressing MATEs facilitate target-independent T-cell activation in tumors.","authors":"Malin Peter, Bettina Mundt, Arne Menze, Norman Woller, Valery Volk, Amanda M Ernst, Leon A Öhler, Steven R Talbot, Heiner Wedemeyer, Christine Falk, Friedrich Feuerhake, Thomas C Wirth, Florian Kühnel","doi":"10.1038/s44321-024-00187-y","DOIUrl":"https://doi.org/10.1038/s44321-024-00187-y","url":null,"abstract":"Oncolytic viruses (OV) expressing bispecific T-cell engagers (BiTEs) are promising tools for tumor immunotherapy but the range of target tumors is limited. To facilitate effective T-cell stimulation with broad-range applicability, we established membrane-associated T-cell engagers (MATEs) harboring the protein transduction domain of the HIV-Tat protein to achieve non-selective binding to target cells. In vitro, MATEs effectively activated murine T cells and improved killing of MC38 colon carcinoma cells. Similarly, humanized MATEs activated T cells in PBMCs from human donors. In MC38-tumors in mice, MATE-expression by the oncolytic adenovirus Ad5/11 facilitated intratumoral T-cell activation, reduced tumor growth and prolonged survival accompanied by infiltration of tumor-directed CD8+ T cells and improved CD8/CD4 T-cell ratio. Absence of early T-cell activation in tumor draining lymph nodes suggests the safe applicability of this strategy. Furthermore, MATE-expression by Ad5/11 was capable of breaking resistance to αPD-1 checkpoint therapy thereby promoting T-cell/tumor cell proximity and clustering of CD8+ and CD4+ T cells. In summary, we demonstrated that MATE expressing OVs are powerful T-cell activating tools suitable for local immunotherapy of a broad range of tumors.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PlexinD1 is a driver and a therapeutic target in advanced prostate cancer. PlexinD1是晚期前列腺癌的驱动因子和治疗靶点。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-02 DOI: 10.1038/s44321-024-00186-z

Jing Wei, Jing Wang, Wen Guan, Jingjing Li, Tianjie Pu, Eva Corey, Tzu-Ping Lin, Allen C Gao, Boyang Jason Wu

{"title":"PlexinD1 is a driver and a therapeutic target in advanced prostate cancer.","authors":"Jing Wei, Jing Wang, Wen Guan, Jingjing Li, Tianjie Pu, Eva Corey, Tzu-Ping Lin, Allen C Gao, Boyang Jason Wu","doi":"10.1038/s44321-024-00186-z","DOIUrl":"10.1038/s44321-024-00186-z","url":null,"abstract":"Aggressive prostate cancer (PCa) variants associated with androgen receptor signaling inhibitor (ARSI) resistance and metastasis remain poorly understood. Here, we identify the axon guidance semaphorin receptor PlexinD1 as a crucial driver of cancer aggressiveness in metastatic castration-resistant prostate cancer (CRPC). High PlexinD1 expression in human PCa is correlated with adverse clinical outcomes. PlexinD1 critically maintains CRPC aggressive behaviors in vitro and in vivo, and confers stemness and cellular plasticity to promote multilineage differentiation including a neuroendocrine-like phenotype for ARSI resistance. Mechanistically, PlexinD1 is upregulated upon relief of AR-mediated transcriptional repression of PlexinD1 under ARSI treatment, and subsdquently transactivates ErbB3 and cMet via direct interaction, which triggers the ERK/AKT pathways to induce noncanonical Gli1-dictated Hedgehog signaling, facilitating the growth and plasticity of PCa cells. Blockade of PlexinD1 by the protein inhibitor D1SP restricted CRPC growth in multiple preclinical models. Collectively, these findings characterize PlexinD1's contribution to PCa progression and offer a potential PlexinD1-targeted therapy for advanced PCa.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A therapeutic regimen using neoantigen-specific TCR-T cells for HLA-A*2402-positive solid tumors. 新抗原特异性TCR-T细胞治疗HLA-A*2402阳性实体瘤的治疗方案

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-02 DOI: 10.1038/s44321-024-00184-1

Yuncheng Bei, Ying Huang, Nandie Wu, Yishan Li, Ruihan Xu, Baorui Liu, Rutian Li

{"title":"A therapeutic regimen using neoantigen-specific TCR-T cells for HLA-A*2402-positive solid tumors.","authors":"Yuncheng Bei, Ying Huang, Nandie Wu, Yishan Li, Ruihan Xu, Baorui Liu, Rutian Li","doi":"10.1038/s44321-024-00184-1","DOIUrl":"https://doi.org/10.1038/s44321-024-00184-1","url":null,"abstract":"The adoptive transfer of TCR-T cells specific to neoantigens preferentially exhibits potent cytotoxicity to tumor cells and has shown promising efficacy in various preclinical human cancers. In this study, we first identified a functional TCR, Tcr-1, which selectively recognized the SYT-SSX fusion neoantigen shared by most synovial sarcomas. Engineered T-cell expressing Tcr-1 (Tcr-T1) demonstrated HLA-A*2402-restricted, antigen-specific anti-tumoral efficacy against synovial sarcoma cells, both in vitro and in vivo. Furthermore, to extend its application, we developed a cooperative therapeutic modality, in which exogenous SYT-SSX fusion neoantigen was loaded into stimuli-responsive nanoparticles (NPs) formed by mPEG-PVGLIG-PCL copolymers (Neo-AgNPs) for tumor targeting delivery. As expected, Neo-AgNPs were proven to have great tumor penetration and local release. In situ, the modification was able to direct engineered Tcr-T1 against other HLA-A*2402-positive malignant cancer cell lines with significant antigen-specific cytotoxicity despite their inherent mutation profiles. With these favorable data, our established cooperative therapeutic modality has great potential for further clinical investigation and provides new insight for future TCR-T cell therapy development.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling. BMP-9通过TGF-β信号介导进行性骨化纤维发育不良的纤维增殖。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-01 Epub Date: 2024-12-03 DOI: 10.1038/s44321-024-00174-3

Chengzhu Zhao, Yoshiko Inada, Souta Motoike, Daisuke Kamiya, Kyosuke Hino, Makoto Ikeya

{"title":"BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling.","authors":"Chengzhu Zhao, Yoshiko Inada, Souta Motoike, Daisuke Kamiya, Kyosuke Hino, Makoto Ikeya","doi":"10.1038/s44321-024-00174-3","DOIUrl":"10.1038/s44321-024-00174-3","url":null,"abstract":"Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder presenting with progressive heterotopic ossification (HO) in soft tissues. Early-stage FOP is characterized by recurrent episodes of painful tissue swelling (flare-ups), with numerous proliferation-activated mesenchymal stromal cells (MSCs) subsequently causing HO. However, the mechanisms underlying flare-up progression remain unclear. In this study, we evaluated the proliferation of MSCs obtained from FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to elucidate the mechanisms underlying flare-ups and found that bone morphogenetic protein (BMP)-9 mediated enhanced proliferation by abnormal activation of transforming growth factor (TGF)-β signaling pathway in MSCs from FOP-iPSCs. In FOP model mice, elevated BMP-9 levels correlated with elevated phosphorylation of SMAD2/3 and increased cellular proliferation in the affected tissues, while systemic BMP-9 neutralization and knockout mitigated flare-ups and HO. Thus, BMP-9 aberrantly transduces TGF-β signaling and induces fibroproliferation, initiating flare-ups. This study provides novel insights into the development of future FOP therapies.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"112-128"},"PeriodicalIF":9.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Bi-allelic variants in WDR47 cause a complex neurodevelopmental syndrome. WDR47的双等位基因变异导致复杂的神经发育综合征。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-01 Epub Date: 2024-11-28 DOI: 10.1038/s44321-024-00178-z

Efil Bayam, Peggy Tilly, Stephan C Collins, José Rivera Alvarez, Meghna Kannan, Lucile Tonneau, Elena Brivio, Bruno Rinaldi, Romain Lecat, Noémie Schwaller, Ludovica Cotellessa, Sateesh Maddirevula, Fabiola Monteiro, Carlos M Guardia, João Paulo Kitajima, Fernando Kok, Mitsuhiro Kato, Ahlam A A Hamed, Mustafa A Salih, Saeed Al Tala, Mais O Hashem, Hiroko Tada, Hirotomo Saitsu, Mariano Stabile, Paolo Giacobini, Sylvie Friant, Zafer Yüksel, Mitsuko Nakashima, Fowzan S Alkuraya, Binnaz Yalcin, Juliette D Godin

{"title":"Bi-allelic variants in WDR47 cause a complex neurodevelopmental syndrome.","authors":"Efil Bayam, Peggy Tilly, Stephan C Collins, José Rivera Alvarez, Meghna Kannan, Lucile Tonneau, Elena Brivio, Bruno Rinaldi, Romain Lecat, Noémie Schwaller, Ludovica Cotellessa, Sateesh Maddirevula, Fabiola Monteiro, Carlos M Guardia, João Paulo Kitajima, Fernando Kok, Mitsuhiro Kato, Ahlam A A Hamed, Mustafa A Salih, Saeed Al Tala, Mais O Hashem, Hiroko Tada, Hirotomo Saitsu, Mariano Stabile, Paolo Giacobini, Sylvie Friant, Zafer Yüksel, Mitsuko Nakashima, Fowzan S Alkuraya, Binnaz Yalcin, Juliette D Godin","doi":"10.1038/s44321-024-00178-z","DOIUrl":"10.1038/s44321-024-00178-z","url":null,"abstract":"Brain development requires the coordinated growth of structures and cues that are essential for forming neural circuits and cognitive functions. The corpus callosum, the largest interhemispheric connection, is formed by the axons of callosal projection neurons through a series of tightly regulated cellular events, including neuronal specification, migration, axon extension and branching. Defects in any of those steps can lead to a range of disorders known as syndromic corpus callosum dysgenesis (CCD). We report five unrelated families carrying bi-allelic variants in WDR47 presenting with CCD together with other neuroanatomical phenotypes such as microcephaly and enlarged ventricles. Using in vitro and in vivo mouse models and complementation assays, we show that WDR47 is required for survival of callosal neurons by contributing to the maintenance of mitochondrial and microtubule homeostasis. We further propose that severity of the CCD phenotype is determined by the degree of the loss of function caused by the human variants. Taken together, we identify WDR47 as a causative gene of a new neurodevelopmental syndrome characterized by corpus callosum abnormalities and other neuroanatomical malformations.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"129-168"},"PeriodicalIF":9.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor. 一种新的基于一氧化氮供体的颞叶癫痫抗癫痫策略。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-01 Epub Date: 2024-12-09 DOI: 10.1038/s44321-024-00168-1

Xian-Hui Zhu, Ya-Ping Zhou, Qiao Zhang, Ming-Yi Zhu, Xiao-Wei Song, Jun Li, Jiang Chen, Yun Shi, Kang-Jian Sun, Yong-Jie Zhang, Jing Zhang, Tian Xia, Bao-Sheng Huang, Fan Meng, Qi-Gang Zhou

{"title":"A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor.","authors":"Xian-Hui Zhu, Ya-Ping Zhou, Qiao Zhang, Ming-Yi Zhu, Xiao-Wei Song, Jun Li, Jiang Chen, Yun Shi, Kang-Jian Sun, Yong-Jie Zhang, Jing Zhang, Tian Xia, Bao-Sheng Huang, Fan Meng, Qi-Gang Zhou","doi":"10.1038/s44321-024-00168-1","DOIUrl":"10.1038/s44321-024-00168-1","url":null,"abstract":"The molecular mechanism underlying the role of hippocampal hilar interneuron degeneration in temporal lobe epilepsy (TLE) remains unclear. Especially, very few studies have focused on the role of neuronal nitric oxide synthase (nNOS, encoded by Nos1) containing hilar interneurons in TLE. In the present study, Nos1 conditional knockout mice were constructed, and we found that selective deletion of Nos1 in hilar interneurons rather than dentate granular cells (DGCs) triggered epileptogenesis. The level of nNOS was downregulated in patients and mice with TLE. Nos1 deletion led to excessive epilepsy-like excitatory input circuit formation and hyperexcitation of DGCs. Replenishment of hilar nNOS protein blocked epileptogenic development and memory impairment in pilocarpine-induced TLE mice. Moreover, chronic treatment with DETA/NONOate, a slowly released exogenous nitric oxide (NO) donor, prevented aberrant neural circuits of DGCs and the consequent epileptogenesis without acute antiseizure effects. Therefore, we concluded that NO donor therapy may be a novel anti-epileptogenesis strategy, different from existing antiseizure medications (ASMs), for curing TLE.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"85-111"},"PeriodicalIF":9.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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