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Ependymal cell lineage reprogramming as a potential therapeutic intervention for hydrocephalus. 脑外膜细胞系重编程作为治疗脑积水的一种潜在干预措施。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 Epub Date: 2024-10-28 DOI: 10.1038/s44321-024-00156-5
Konstantina Kaplani, Maria-Eleni Lalioti, Styliani Vassalou, Georgia Lokka, Evangelia Parlapani, Georgios Kritikos, Zoi Lygerou, Stavros Taraviras

Hydrocephalus is a common neurological condition, characterized by the excessive accumulation of cerebrospinal fluid in the cerebral ventricles. Primary treatments for hydrocephalus mainly involve neurosurgical cerebrospinal fluid diversion, which hold high morbidity and failure rates, highlighting the necessity for the discovery of novel therapeutic approaches. Although the pathophysiology of hydrocephalus is highly multifactorial, impaired function of the brain ependymal cells plays a fundamental role in hydrocephalus. Here we show that GemC1 and McIdas, key regulators of multiciliated ependymal cell fate determination, induce direct cellular reprogramming towards ependyma. Our study reveals that ectopic expression of GemC1 and McIdas reprograms cortical astrocytes and programs mouse embryonic stem cells into ependyma. McIdas is sufficient to establish functional activity in the reprogrammed astrocytes. Furthermore, we show that McIdas' expression promotes ependymal cell regeneration in two different postnatal hydrocephalus mouse models: an intracranial hemorrhage and a genetic form of hydrocephalus and ameliorates the cytoarchitecture of the neurogenic niche. Our study provides evidence on the restoration of ependyma in animal models mimicking hydrocephalus that could be exploited towards future therapeutic interventions.

脑积水是一种常见的神经系统疾病,其特点是脑脊液在脑室过度积聚。脑积水的主要治疗方法是通过神经外科手术进行脑脊液引流,但这种方法的发病率和失败率都很高,因此有必要探索新的治疗方法。虽然脑积水的病理生理学具有高度的多因素性,但脑外膜细胞功能受损在脑积水中起着根本性的作用。在这里,我们发现 GemC1 和 McIdas(多纤毛外膜细胞命运决定的关键调控因子)可诱导细胞直接向外膜重编程。我们的研究发现,异位表达GemC1和McIdas可以重编程大脑皮层星形胶质细胞,并将小鼠胚胎干细胞编程为外膜。McIdas足以在重编程的星形胶质细胞中建立功能活性。此外,我们还发现,McIdas的表达可促进两种不同的出生后脑积水小鼠模型(颅内出血和遗传性脑积水)中的外膜细胞再生,并改善神经源龛的细胞结构。我们的研究提供了在模拟脑积水的动物模型中恢复外膜的证据,可用于未来的治疗干预。
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引用次数: 0
Luteolin detoxifies DEHP and prevents liver injury by degrading Uroc1 protein in mice. 叶黄素通过降解小鼠体内的 Uroc1 蛋白,为 DEHP 解毒并防止肝损伤。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 Epub Date: 2024-10-29 DOI: 10.1038/s44321-024-00160-9
Huiting Wang, Ziting Zhao, Mingming Song, Wenxiang Zhang, Chang Liu, Siyu Chen

Di-(2-ethylhexyl) phthalate (DEHP), an environmental pollutant, has been widely detected in both environmental and clinical samples, representing a serious threat to the homeostasis of the endocrine system. The accumulation of DEHP is notably pronounced in the liver and can lead to liver damage. The lack of effective high-throughput screening system retards the discovery of such drugs that can specifically target and eliminate the detrimental impact of DEHP. Here, by developing a Cy5-modified single-strand DNA-aptamer-based approach targeting DEHP, we have identified luteolin as a potential drug, which showcasing robust efficacy in detoxifying the DEHP by facilitating the expulsion of DEHP in both mouse primary hepatocytes and livers. Mechanistically, luteolin enhances the protein degradation of hepatic urocanate hydratase 1 (Uroc1) by targeting its Ala270 and Val272 sites. More importantly, trans-urocanic acid (trans-UCA), as the substrate of Uroc1, possesses properties similar to luteolin by regulating the lysosomal exocytosis through the inhibition of the ERK1/2 signal cascade. In summary, luteolin serves as a potent therapeutic agent in efficiently detoxifying DEHP in the liver by regulating the UCA/Uroc1 axis.

邻苯二甲酸二(2-乙基己基)酯(DEHP)是一种环境污染物,在环境和临床样本中被广泛检测到,对内分泌系统的平衡构成严重威胁。DEHP 在肝脏中的蓄积尤为明显,可导致肝损伤。由于缺乏有效的高通量筛选系统,阻碍了能特异性靶向消除 DEHP 有害影响的药物的发现。在这里,通过开发一种基于Cy5修饰的单链DNA-aptamer方法来靶向DEHP,我们发现了木犀草素这种潜在的药物,它通过促进小鼠原代肝细胞和肝脏中DEHP的排出,在DEHP的解毒方面显示出强大的功效。从机理上讲,木犀草素通过靶向肝脏尿氨酸水解酶1(Uroc1)的Ala270和Val272位点,促进其蛋白质降解。更重要的是,反式尿囊酸(trans-UCA)作为 Uroc1 的底物,通过抑制 ERK1/2 信号级联调节溶酶体的外泌,具有与叶黄素类似的特性。总之,通过调节 UCA/Uroc1 轴,木犀草素可作为一种有效的治疗药物,在肝脏中有效地解毒 DEHP。
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引用次数: 0
Reciprocal inhibition of NOTCH and SOX2 shapes tumor cell plasticity and therapeutic escape in triple-negative breast cancer. NOTCH和SOX2的相互抑制塑造了肿瘤细胞的可塑性和三阴性乳腺癌的治疗逃逸。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-30 DOI: 10.1038/s44321-024-00161-8
Morgane Fournier, Joaquim Javary, Vincent Roh, Nadine Fournier, Freddy Radtke

Cancer cell plasticity contributes significantly to the failure of chemo- and targeted therapies in triple-negative breast cancer (TNBC). Molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance are largely unknown. Using a genome-wide CRISPR-Cas9 screen, we investigated escape mechanisms of NOTCH-driven TNBC treated with a gamma-secretase inhibitor (GSI) and identified SOX2 as a target of resistance to Notch inhibition. We describe a novel reciprocal inhibitory feedback mechanism between Notch signaling and SOX2. Specifically, Notch signaling inhibits SOX2 expression through its target genes of the HEY family, and SOX2 inhibits Notch signaling through direct interaction with RBPJ. This mechanism shapes divergent cell states with NOTCH positive TNBC being more epithelial-like, while SOX2 expression correlates with epithelial-mesenchymal transition, induces cancer stem cell features and GSI resistance. To counteract monotherapy-induced tumor relapse, we assessed GSI-paclitaxel and dasatinib-paclitaxel combination treatments in NOTCH inhibitor-sensitive and -resistant TNBC xenotransplants, respectively. These distinct preventive combinations and second-line treatment option dependent on NOTCH1 and SOX2 expression in TNBC are able to induce tumor growth control and reduce metastatic burden.

癌细胞可塑性是三阴性乳腺癌(TNBC)化疗和靶向治疗失败的重要原因。治疗诱导的肿瘤细胞可塑性及相关耐药性的分子机制在很大程度上尚属未知。通过全基因组 CRISPR-Cas9 筛选,我们研究了用γ-分泌酶抑制剂(GSI)治疗 NOTCH 驱动的 TNBC 的逃逸机制,并确定 SOX2 为 Notch 抑制的耐药靶点。我们描述了Notch信号传导与SOX2之间一种新型的相互抑制反馈机制。具体来说,Notch信号通过其HEY家族的靶基因抑制SOX2的表达,而SOX2则通过与RBPJ的直接相互作用抑制Notch信号。这种机制形成了不同的细胞状态,Notch 阳性的 TNBC 更像上皮细胞,而 SOX2 的表达则与上皮-间质转化相关,诱导癌症干细胞特征和 GSI 抗性。为了应对单药治疗诱导的肿瘤复发,我们分别在对NOTCH抑制剂敏感和耐药的TNBC异种移植中评估了GSI-紫杉醇和达沙替尼-紫杉醇联合疗法。这些不同的预防性组合和二线治疗方案依赖于 TNBC 中 NOTCH1 和 SOX2 的表达,能够诱导肿瘤生长控制并减少转移负荷。
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引用次数: 0
Aberrant fragmentomic features of circulating cell-free mitochondrial DNA as novel biomarkers for multi-cancer detection. 将循环细胞游离线粒体 DNA 的异常片段组特征作为检测多种癌症的新型生物标记物。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-30 DOI: 10.1038/s44321-024-00163-6
Yang Liu, Fan Peng, Siyuan Wang, Huanmin Jiao, Miao Dang, Kaixiang Zhou, Wenjie Guo, Shanshan Guo, Huanqin Zhang, Wenjie Song, Jinliang Xing

Fragmentomic features of circulating cell free mitochondrial DNA (ccf-mtDNA) including fragmentation profile, 5' end base preference and motif diversity are poorly understood. Here, we generated ccf-mtDNA sequencing data of 1607 plasma samples using capture-based next generation sequencing. We firstly found that fragmentomic features of ccf-mtDNA were remarkably different from those of circulating cell free nuclear DNA. Furthermore, region-specific fragmentomic features of ccf-mtDNA were observed, which was associated with protein binding, base composition and special structure of mitochondrial DNA. When comparing to non-cancer controls, six types of cancer patients exhibited aberrant fragmentomic features. Then, cancer detection models were built based on the fragmentomic features. Both internal and external validation cohorts demonstrated the excellent capacity of our model in distinguishing cancer patients from non-cancer control, with all area under curve higher than 0.9322. The overall accuracy of tissue-of-origin was 89.24% and 87.92% for six cancer types in two validation cohort, respectively. Altogether, our study comprehensively describes cancer-specific fragmentomic features of ccf-mtDNA and provides a proof-of-principle for the ccf-mtDNA fragmentomics-based multi-cancer detection and tissue-of-origin classification.

人们对循环游离细胞线粒体 DNA(ccf-mtDNA)的片段组学特征,包括片段轮廓、5'端碱基偏好和基序多样性知之甚少。在此,我们利用基于捕获的新一代测序技术,对1607份血浆样本进行了ccf-mtDNA测序。我们首先发现,ccf-mtDNA的片段组特征与循环细胞游离核DNA的片段组特征明显不同。此外,我们还观察到ccf-mtDNA的区域特异性片段组特征,这与线粒体DNA的蛋白质结合、碱基组成和特殊结构有关。与非癌症对照组相比,六种癌症患者表现出异常片段组特征。然后,根据片段组特征建立了癌症检测模型。内部和外部验证组群都证明了我们的模型在区分癌症患者和非癌症对照组方面的卓越能力,所有模型的曲线下面积都高于 0.9322。在两个验证队列中,六种癌症类型的原发组织总体准确率分别为 89.24% 和 87.92%。总之,我们的研究全面描述了ccf-mtDNA的癌症特异性片段组学特征,为基于ccf-mtDNA片段组学的多癌症检测和原发组织分类提供了原理性证明。
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引用次数: 0
Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas. 针对 ADAM12 的纤维化疫苗接种可减少临床前胰腺腺癌中的脱落细胞。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-30 DOI: 10.1038/s44321-024-00157-4
Jing Chen, Michal Sobecki, Ewelina Krzywinska, Kevin Thierry, Mélissa Masmoudi, Shunmugam Nagarajan, Zheng Fan, Jingyi He, Irina Ferapontova, Eric Nelius, Frauke Seehusen, Dagmar Gotthardt, Norihiko Takeda, Lukas Sommer, Veronika Sexl, Christian Münz, David DeNardo, Ana Hennino, Christian Stockmann

A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is massive intratumoral fibrosis, designated as desmoplasia. Desmoplasia is characterized by the expansion of cancer-associated fibroblasts (CAFs) and a massive increase in extracellular matrix (ECM). During fibrogenesis, distinct genes become reactivated specifically in fibroblasts, e.g., the disintegrin metalloprotease, ADAM12. Previous studies have shown that immunotherapeutic ablation of ADAM12+ cells reduces fibrosis in various organs. In preclinical mouse models of PDAC, we observe ADAM12 expression in CAFs as well as in tumor cells but not in healthy mouse pancreas. Therefore, we tested prophylactic and therapeutic vaccination against ADAM12 in murine PDAC and observed delayed tumor growth along with a reduction in CAFs and tumor desmoplasia. This is furthermore associated with vascular normalization and alleviated tumor hypoxia. The ADAM12 vaccine induces a redistribution of CD8+ T cells within the tumor and cytotoxic responses against ADAM12+ cells. In summary, vaccination against the endogenous fibroblast target ADAM12 effectively depletes CAFs, reduces desmoplasia and delays the growth of murine PDACs. These results provide proof-of-principle for the development of vaccination-based immunotherapies to treat tumor desmoplasia.

胰腺导管腺癌(PDAC)的一个标志性特征是大量瘤内纤维化,即脱落细胞增多症(desmoplasia)。脱模增生的特点是癌相关成纤维细胞(CAFs)的扩张和细胞外基质(ECM)的大量增加。在纤维形成过程中,不同的基因会在成纤维细胞中重新激活,例如崩解金属蛋白酶 ADAM12。先前的研究表明,通过免疫治疗消减 ADAM12+ 细胞可减少各种器官的纤维化。在 PDAC 临床前小鼠模型中,我们观察到 ADAM12 在 CAFs 和肿瘤细胞中的表达,但在健康小鼠胰腺中却没有发现。因此,我们在小鼠 PDAC 中测试了针对 ADAM12 的预防性和治疗性疫苗接种,观察到肿瘤生长延迟、CAFs 减少和肿瘤脱钙化。这还与血管正常化和肿瘤缺氧缓解有关。ADAM12 疫苗能诱导肿瘤内 CD8+ T 细胞重新分布,并诱导针对 ADAM12+ 细胞的细胞毒性反应。总之,针对内源性成纤维细胞靶标 ADAM12 的疫苗接种能有效地消耗 CAFs、减少脱钙并延缓小鼠 PDAC 的生长。这些结果为开发基于疫苗的免疫疗法治疗肿瘤脱钙提供了原理性证明。
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引用次数: 0
Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations. 多聚酶抑制复合体 1 的表观遗传调控促进了脑海绵畸形。
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-14 DOI: 10.1038/s44321-024-00152-9
Van-Cuong Pham,Claudia Jasmin Rödel,Mariaelena Valentino,Matteo Malinverno,Alessio Paolini,Juliane Münch,Candice Pasquier,Favour C Onyeogaziri,Bojana Lazovic,Romuald Girard,Janne Koskimäki,Melina Hußmann,Benjamin Keith,Daniel Jachimowicz,Franziska Kohl,Astrid Hagelkruys,Josef M Penninger,Stefan Schulte-Merker,Issam A Awad,Ryan Hicks,Peetra U Magnusson,Eva Faurobert,Massimiliano Pagani,Salim Abdelilah-Seyfried
Cerebral cavernous malformations (CCMs) are anomalies of the cerebral vasculature. Loss of the CCM proteins CCM1/KRIT1, CCM2, or CCM3/PDCD10 trigger a MAPK-Krüppel-like factor 2 (KLF2) signaling cascade, which induces a pathophysiological pattern of gene expression. The downstream target genes that are activated by KLF2 are mostly unknown. Here we show that Chromobox Protein Homolog 7 (CBX7), component of the Polycomb Repressive Complex 1, contributes to pathophysiological KLF2 signaling during zebrafish cardiovascular development. CBX7/cbx7a mRNA is strongly upregulated in lesions of CCM patients, and in human, mouse, and zebrafish CCM-deficient endothelial cells. The silencing or pharmacological inhibition of CBX7/Cbx7a suppresses pathological CCM phenotypes in ccm2 zebrafish, CCM2-deficient HUVECs, and in a pre-clinical murine CCM3 disease model. Whole-transcriptome datasets from zebrafish cardiovascular tissues and human endothelial cells reveal a role of CBX7/Cbx7a in the activation of KLF2 target genes including TEK, ANGPT1, WNT9, and endoMT-associated genes. Our findings uncover an intricate interplay in the regulation of Klf2-dependent biomechanical signaling by CBX7 in CCM. This work also provides insights for therapeutic strategies in the pathogenesis of CCM.
脑海绵畸形(CCMs)是一种脑血管畸形。CCM蛋白CCM1/KRIT1、CCM2或CCM3/PDCD10的缺失会触发MAPK-Krüppel样因子2(KLF2)信号级联,从而诱导病理生理模式的基因表达。KLF2激活的下游靶基因大多不为人知。在这里,我们发现多聚核抑制复合体 1 的成分 Chromobox Protein Homolog 7(CBX7)在斑马鱼心血管发育过程中有助于病理生理 KLF2 信号转导。CBX7/cbx7a mRNA在CCM患者的病变部位以及人、小鼠和斑马鱼CCM缺陷内皮细胞中强烈上调。沉默或药物抑制 CBX7/Cbx7a 可抑制 ccm2 斑马鱼、CCM2 缺失的 HUVEC 以及临床前小鼠 CCM3 疾病模型中的病理 CCM 表型。来自斑马鱼心血管组织和人类内皮细胞的全转录组数据集揭示了 CBX7/Cbx7a 在激活 KLF2 靶基因(包括 TEK、ANGPT1、WNT9 和 endoMT 相关基因)中的作用。我们的研究结果揭示了 CBX7 在 CCM 中调控 Klf2 依赖性生物力学信号转导过程中错综复杂的相互作用。这项研究还为 CCM 发病机制的治疗策略提供了启示。
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引用次数: 0
Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models. 揭示 Mecp2 缺陷模型的自噬失衡和治疗启示
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-14 DOI: 10.1038/s44321-024-00151-w
Alessandro Esposito,Tommaso Seri,Martina Breccia,Marzia Indrigo,Giuseppina De Rocco,Francesca Nuzzolillo,Vanna Denti,Francesca Pappacena,Gaia Tartaglione,Simone Serrao,Giuseppe Paglia,Luca Murru,Stefano de Pretis,Jean-Michel Cioni,Nicoletta Landsberger,Fabrizia Claudia Guarnieri,Michela Palmieri
Loss-of-function mutations in MECP2 are associated to Rett syndrome (RTT), a severe neurodevelopmental disease. Mainly working as a transcriptional regulator, MeCP2 absence leads to gene expression perturbations resulting in deficits of synaptic function and neuronal activity. In addition, RTT patients and mouse models suffer from a complex metabolic syndrome, suggesting that related cellular pathways might contribute to neuropathogenesis. Along this line, autophagy is critical in sustaining developing neuron homeostasis by breaking down dysfunctional proteins, lipids, and organelles.Here, we investigated the autophagic pathway in RTT and found reduced content of autophagic vacuoles in Mecp2 knock-out neurons. This correlates with defective lipidation of LC3B, probably caused by a deficiency of the autophagic membrane lipid phosphatidylethanolamine. The administration of the autophagy inducer trehalose recovers LC3B lipidation, autophagosomes content in knock-out neurons, and ameliorates their morphology, neuronal activity and synaptic ultrastructure. Moreover, we provide evidence for attenuation of motor and exploratory impairment in Mecp2 knock-out mice upon trehalose administration. Overall, our findings open new perspectives for neurodevelopmental disorders therapies based on the concept of autophagy modulation.
MECP2功能缺失突变与严重神经发育疾病雷特综合征(RTT)有关。MeCP2 主要起转录调节作用,其缺失会导致基因表达紊乱,造成突触功能和神经元活动的缺陷。此外,RTT 患者和小鼠模型还患有复杂的代谢综合征,这表明相关的细胞通路可能会导致神经发病。沿着这一思路,自噬在通过分解功能失调的蛋白质、脂质和细胞器来维持发育中神经元的稳态方面起着至关重要的作用。这与LC3B的脂化缺陷有关,可能是自噬膜脂质磷脂酰乙醇胺缺乏所致。给予自噬诱导剂曲哈洛糖可恢复基因敲除神经元的 LC3B 脂化和自噬体含量,并改善其形态、神经元活动和突触超微结构。此外,我们还提供了证据,证明给予曲哈洛糖可减轻 Mecp2 基因敲除小鼠的运动和探索障碍。总之,我们的发现为基于自噬调节概念的神经发育障碍疗法开辟了新的前景。
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引用次数: 0
Troubling bonds: lipid unsaturation promotes selenium dependency and sensitivity to ferroptosis. 麻烦的纽带:脂质不饱和促进了对硒的依赖性和对铁中毒的敏感性。
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-07 DOI: 10.1038/s44321-024-00150-x
Ancély Ferreira Dos Santos,José Pedro Friedmann-Angeli
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引用次数: 0
Author Correction: Cell-mediated exon skipping normalizes dystrophin expression and muscle function in a new mouse model of Duchenne Muscular Dystrophy. 作者更正:细胞介导的外显子跳越可使杜氏肌营养不良症新小鼠模型中的肌营养不良蛋白表达和肌肉功能正常化。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1038/s44321-024-00134-x
Francesco Galli, Laricia Bragg, Maira Rossi, Daisy Proietti, Laura Perani, Marco Bacigaluppi, Rossana Tonlorenzi, Tendai Sibanda, Miriam Caffarini, Avraneel Talapatra, Sabrina Santoleri, Mirella Meregalli, Beatriz Bano-Otalora, Anne Bigot, Irene Bozzoni, Chiara Bonini, Vincent Mouly, Yvan Torrente, Giulio Cossu
{"title":"Author Correction: Cell-mediated exon skipping normalizes dystrophin expression and muscle function in a new mouse model of Duchenne Muscular Dystrophy.","authors":"Francesco Galli, Laricia Bragg, Maira Rossi, Daisy Proietti, Laura Perani, Marco Bacigaluppi, Rossana Tonlorenzi, Tendai Sibanda, Miriam Caffarini, Avraneel Talapatra, Sabrina Santoleri, Mirella Meregalli, Beatriz Bano-Otalora, Anne Bigot, Irene Bozzoni, Chiara Bonini, Vincent Mouly, Yvan Torrente, Giulio Cossu","doi":"10.1038/s44321-024-00134-x","DOIUrl":"10.1038/s44321-024-00134-x","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145321","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
Fertility protection during chemotherapy treatment by boosting the NAD(P)+ metabolome. 通过提高 NAD(P)+ 代谢组保护化疗期间的生育能力。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-08-21 DOI: 10.1038/s44321-024-00119-w
Wing-Hong Jonathan Ho, Maria B Marinova, Dave R Listijono, Michael J Bertoldo, Dulama Richani, Lynn-Jee Kim, Amelia Brown, Angelique H Riepsamen, Safaa Cabot, Emily R Frost, Sonia Bustamante, Ling Zhong, Kaisa Selesniemi, Derek Wong, Romanthi Madawala, Maria Marchante, Dale M Goss, Catherine Li, Toshiyuki Araki, David J Livingston, Nigel Turner, David A Sinclair, Kirsty A Walters, Hayden A Homer, Robert B Gilchrist, Lindsay E Wu

Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P)+ metabolome could protect ovarian function. We show that pharmacological or transgenic strategies to replenish the NAD+ metabolome ameliorates chemotherapy induced female infertility in mice, as measured by oocyte yield, follicle health, and functional breeding trials. Importantly, treatment of a triple-negative breast cancer mouse model with the NAD+ precursor nicotinamide mononucleotide (NMN) reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Overall, these findings raise the possibility that NAD+ precursors could be a non-invasive strategy for maintaining ovarian function in cancer patients, with potential benefits in cancer therapy.

化疗诱发的卵巢功能衰竭和不孕症是育龄或更年轻的女性癌症患者的一个重要问题,因此迫切需要非侵入性的药理方法来维持卵巢功能。鉴于还原型烟酰胺腺嘌呤二核苷酸磷酸酯(NADPH)是药物解毒的重要辅助因子,我们试图测试提高 NAD(P)+ 代谢组是否能保护卵巢功能。我们的研究表明,补充 NAD+ 代谢组的药理或转基因策略可改善化疗诱导的小鼠雌性不孕症,具体可通过卵母细胞产量、卵泡健康和功能性繁殖试验来衡量。重要的是,用 NAD+ 前体烟酰胺单核苷酸(NMN)治疗三阴性乳腺癌小鼠模型可减少肿瘤生长,而且不会损害化疗药物在体内或不同癌细胞系中的疗效。总之,这些研究结果表明,NAD+前体有可能成为维持癌症患者卵巢功能的一种非侵入性策略,在癌症治疗中具有潜在的益处。
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引用次数: 0
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