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The Foxo1-YAP-Notch1 axis reprograms STING-mediated innate immunity in NASH progression Foxo1-YAP-Notch1轴重新规划了STING介导的先天性免疫在NASH进展中的作用。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-09 DOI: 10.1038/s12276-024-01280-5
Dongwei Xu, Xiaoye Qu, Tao Yang, Mingwei Sheng, Xiyun Bian, Yongqiang Zhan, Yizhu Tian, Yuanbang Lin, Yuting Jin, Xiao Wang, Michael Ke, Longfeng Jiang, Changyong Li, Qiang Xia, Douglas G. Farmer, Bibo Ke
Innate immune activation is critical for initiating hepatic inflammation during nonalcoholic steatohepatitis (NASH) progression. However, the mechanisms by which immunoregulatory molecules recognize lipogenic, fibrotic, and inflammatory signals remain unclear. Here, we show that high-fat diet (HFD)-induced oxidative stress activates Foxo1, YAP, and Notch1 signaling in hepatic macrophages. Macrophage Foxo1 deficiency (Foxo1M-KO) ameliorated hepatic inflammation, steatosis, and fibrosis, with reduced STING, TBK1, and NF-κB activation in HFD-challenged livers. However, Foxo1 and YAP double knockout (Foxo1/YAPM-DKO) or Foxo1 and Notch1 double knockout (Foxo1/Notch1M-DKO) promoted STING function and exacerbated HFD-induced liver injury. Interestingly, Foxo1M-KO strongly reduced TGF-β1 release from palmitic acid (PA)- and oleic acid (OA)-stimulated Kupffer cells and decreased Col1α1, CCL2, and Timp1 expression but increased MMP1 expression in primary hepatic stellate cells (HSCs) after coculture with Kupffer cells. Notably, PA and OA challenge in Kupffer cells augmented LIMD1 and LATS1 colocalization and interaction, which induced YAP nuclear translocation. Foxo1M-KO activated PGC-1α and increased nuclear YAP activity, modulating mitochondrial biogenesis. Using chromatin immunoprecipitation (ChIP) coupled with massively parallel sequencing (ChIP-Seq) and in situ RNA hybridization, we found that NICD colocalizes with YAP and targets Mb21d1 (cGAS), while YAP functions as a novel coactivator of the NICD, which is crucial for reprogramming STING function in NASH progression. These findings highlight the importance of the macrophage Foxo1–YAP–Notch1 axis as a key molecular regulator that controls lipid metabolism, inflammation, and innate immunity in NASH. In the battle against nonalcoholic steatohepatitis, it’s vital to understand how our immune system contributes to liver harm. Researchers found that a protein named STING is crucial in liver inflammation and damage as it identifies damaged DNA. They investigate how certain proteins and processes in immune cells affect STING’s function and NASH’s progression. Researchers discovered that decreasing the activity of a protein named Foxo1 in macrophagesresults in less liver damage and inflammation in mice on a high-fat diet. They also examined how other signaling processes, like the Hippo–YAP and Notch1 processes, interact with STING and contribute to the disease. Their findings indicate that adjusting these processes can reduce liver damage, steatosis, and inflammation, suggesting new potential treatment targets for NASH, potentially improving the lives of those affected by this condition.This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
在非酒精性脂肪性肝炎(NASH)发展过程中,先天性免疫激活是引发肝脏炎症的关键。然而,免疫调节分子识别致脂、纤维化和炎症信号的机制仍不清楚。在这里,我们发现高脂饮食(HFD)诱导的氧化应激激活了肝巨噬细胞中的 Foxo1、YAP 和 Notch1 信号传导。巨噬细胞 Foxo1 缺乏症(Foxo1M-KO)可改善肝脏炎症、脂肪变性和纤维化,同时减少 STING、TBK1 和 NF-κB 在高脂饮食挑战肝脏中的激活。然而,Foxo1和YAP双基因敲除(Foxo1/YAPM-DKO)或Foxo1和Notch1双基因敲除(Foxo1/Notch1M-DKO)可促进STING功能,并加剧高频分解诱导的肝损伤。有趣的是,Foxo1M-KO强烈减少了棕榈酸(PA)和油酸(OA)刺激的Kupffer细胞中TGF-β1的释放,并降低了Col1α1、CCL2和Timp1的表达,但增加了与Kupffer细胞共培养后原代肝星状细胞(HSCs)中MMP1的表达。值得注意的是,Kupffer 细胞中的 PA 和 OA 挑战增强了 LIMD1 和 LATS1 的共定位和相互作用,从而诱导了 YAP 的核转位。Foxo1M-KO 激活了 PGC-1α,增加了 YAP 核活性,从而调节了线粒体的生物生成。利用染色质免疫共沉淀(ChIP)结合大规模平行测序(ChIP-Seq)和原位 RNA 杂交,我们发现 NICD 与 YAP 共定位并靶向 Mb21d1 (cGAS),而 YAP 作为 NICD 的新型辅助激活剂,在 NASH 进展过程中对 STING 功能的重编程至关重要。这些发现凸显了巨噬细胞Foxo1-YAP-Notch1轴作为控制NASH中脂质代谢、炎症和先天免疫的关键分子调控因子的重要性。
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引用次数: 0
SMC3 contributes to heart development by regulating super-enhancer associated genes SMC3 通过调节超级增强子相关基因促进心脏发育。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1038/s12276-024-01293-0
Bowen Zhang, Yongchang Zhu, Zhen Zhang, Feizhen Wu, Xiaojing Ma, Wei Sheng, Ranran Dai, Zhenglong Guo, Weili Yan, Lili Hao, Guoying Huang, Duan Ma, Bingtao Hao, Jing Ma
Abnormal cardiac development has been observed in individuals with Cornelia de Lange syndrome (CdLS) due to mutations in genes encoding members of the cohesin complex. However, the precise role of cohesin in heart development remains elusive. In this study, we aimed to elucidate the indispensable role of SMC3, a component of the cohesin complex, in cardiac development and its underlying mechanism. Our investigation revealed that CdLS patients with SMC3 mutations have high rates of congenital heart disease (CHD). We utilized heart-specific Smc3-knockout (SMC3-cKO) mice, which exhibit varying degrees of outflow tract (OFT) abnormalities, to further explore this relationship. Additionally, we identified 16 rare SMC3 variants with potential pathogenicity in individuals with isolated CHD. By employing single-nucleus RNA sequencing and chromosome conformation capture high-throughput genome-wide translocation sequencing, we revealed that Smc3 deletion downregulates the expression of key genes, including Ets2, in OFT cardiac muscle cells by specifically decreasing interactions between super-enhancers (SEs) and promoters. Notably, Ets2-SE-null mice also exhibit delayed OFT development in the heart. Our research revealed a novel role for SMC3 in heart development via the regulation of SE-associated genes, suggesting its potential relevance as a CHD-related gene and providing crucial insights into the molecular basis of cardiac development. Understanding heart development is vital as defects in this process are a major cause of birth abnormalities. This study focuses on a protein, SMC3, and its role in heart development. Experiments were conducted on mice genetically altered to lack SMC3 in heart cells. Researchers found that mice without SMC3 had various heart defects, like those seen in humans with congenital heart disease. They also found mutations in the SMC3 gene in patients with congenital heart disease, suggesting a link between SMC3 and heart development in humans. The findings reveal that SMC3 plays a crucial role in heart development, with its absence leading to significant heart defects in mice. These results suggest a potential genetic cause for some forms of congenital heart disease in humans. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author. Introduction
科尼莉亚-德-朗格综合征(CdLS)患者的心脏发育异常是由于编码凝聚素复合体成员的基因发生突变所致。然而,凝聚素在心脏发育过程中的确切作用仍然难以捉摸。在本研究中,我们旨在阐明凝聚素复合体的一个成分 SMC3 在心脏发育中不可或缺的作用及其内在机制。我们的调查发现,SMC3突变的CdLS患者患有先天性心脏病(CHD)的比例很高。我们利用表现出不同程度流出道(OFT)异常的心脏特异性 Smc3 基因敲除(SMC3-cKO)小鼠来进一步探讨这种关系。此外,我们还发现了 16 个罕见的 SMC3 变体,这些变体在孤立性先天性心脏病患者中具有潜在的致病性。通过采用单核 RNA 测序和染色体构象捕获高通量全基因组易位测序,我们发现 Smc3 缺失会通过特异性减少超级增强子(SE)和启动子之间的相互作用,下调包括 Ets2 在内的关键基因在 OFT 心肌细胞中的表达。值得注意的是,Ets2-SE缺失小鼠也表现出心脏OFT发育延迟。我们的研究揭示了SMC3通过调控SE相关基因在心脏发育过程中的新作用,表明其作为CHD相关基因的潜在相关性,并为了解心脏发育的分子基础提供了重要信息。
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引用次数: 0
Inhibition of BCAT1-mediated cytosolic leucine metabolism regulates Th17 responses via the mTORC1-HIF1α pathway 抑制 BCAT1 介导的细胞膜亮氨酸代谢可通过 mTORC1-HIF1α 途径调节 Th17 反应。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1038/s12276-024-01286-z
Yeon Jun Kang, Woorim Song, Su Jeong Lee, Seung Ah Choi, Sihyun Chae, Bo Ruem Yoon, Hee Young Kim, Jung Ho Lee, Chulwoo Kim, Joo-Youn Cho, Hyun Je Kim, Won-Woo Lee
Branched-chain amino acids (BCAAs), particularly leucine, are indispensable AAs for immune regulation through metabolic rewiring. However, the molecular mechanism underlying this phenomenon remains unclear. Our investigation revealed that T-cell receptor (TCR)-activated human CD4+ T cells increase the expression of BCAT1, a cytosolic enzyme responsible for BCAA catabolism, and SLC7A5, a major BCAA transporter. This upregulation facilitates increased leucine influx and catabolism, which are particularly crucial for Th17 responses. Activated CD4+ T cells induce an alternative pathway of cytosolic leucine catabolism, generating a pivotal metabolite, β-hydroxy β-methylbutyric acid (HMB), by acting on BCAT1 and 4-hydroxyphenylpyruvate dioxygenase (HPD)/HPD-like protein (HPDL). Inhibition of BCAT1-mediated cytosolic leucine metabolism, either with BCAT1 inhibitor 2 (Bi2) or through BCAT1, HPD, or HPDL silencing using shRNA, attenuates IL-17 production, whereas HMB supplementation abrogates this effect. Mechanistically, HMB contributes to the regulation of the mTORC1-HIF1α pathway, a major signaling pathway for IL-17 production, by increasing the mRNA expression of HIF1α. This finding was corroborated by the observation that treatment with L-β-homoleucine (LβhL), a leucine analog and competitive inhibitor of BCAT1, decreased IL-17 production by TCR-activated CD4+ T cells. In an in vivo experimental autoimmune encephalomyelitis (EAE) model, blockade of BCAT1-mediated leucine catabolism, either through a BCAT1 inhibitor or LβhL treatment, mitigated EAE severity by decreasing HIF1α expression and IL-17 production in spinal cord mononuclear cells. Our findings elucidate the role of BCAT1-mediated cytoplasmic leucine catabolism in modulating IL-17 production via HMB-mediated regulation of mTORC1-HIF1α, providing insights into its relevance to inflammatory conditions. T-cell, a type of infection-fighting white blood cell, alter their metabolic process, relying heavily on amino acids, the building blocks of proteins. This study investigates how T cells use the amino acid leucine to power their response. Researchers conducted experiments with human T-cell and a mouse model of autoimmune disease, a condition where the body attacks its own cells. They studied how leucine’s metabolic process affects T-cell function. The study discovered that a specific process involving leucine’s metabolic pathway in T cells is vital for their ability to produce IL-17. Blocking a crucial enzyme reduced IL-17 production and eased symptoms in a mouse model of autoimmune disease. These findings underline the importance of leucine’s metabolic process in T-cell function and suggest a potential target for treating autoimmune diseases more effectively, offering hope for new treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
支链氨基酸(BCAAs),尤其是亮氨酸,是通过新陈代谢重新布线进行免疫调节的不可或缺的氨基酸。然而,这一现象的分子机制仍不清楚。我们的研究发现,T 细胞受体(TCR)激活的人类 CD4+ T 细胞会增加 BCAT1(一种负责 BCAA 分解代谢的细胞膜酶)和 SLC7A5(一种主要的 BCAA 转运体)的表达。这种上调促进了亮氨酸流入和分解的增加,这对 Th17 反应尤为重要。活化的 CD4+ T 细胞通过作用于 BCAT1 和 4-hydroxyphenylpyruvate dioxygenase (HPD)/HPD-like protein (HPDL),诱导细胞膜亮氨酸分解代谢的替代途径,产生一种关键的代谢产物--β-羟基 β-甲基丁酸 (HMB)。使用 BCAT1 抑制剂 2(Bi2)或使用 shRNA 抑制 BCAT1、HPD 或 HPDL 可抑制 BCAT1 介导的细胞质亮氨酸代谢,从而减少 IL-17 的产生,而补充 HMB 则可消除这种影响。从机理上讲,HMB通过增加HIF1α的mRNA表达,有助于调节mTORC1-HIF1α通路(IL-17产生的主要信号通路)。用亮氨酸类似物和 BCAT1 竞争性抑制剂 L-β-高亮氨酸(LβhL)处理 TCR 激活的 CD4+ T 细胞,可减少 IL-17 的产生,这一观察结果证实了上述发现。在活体实验性自身免疫性脑脊髓炎(EAE)模型中,通过 BCAT1 抑制剂或 LβhL 处理阻断 BCAT1 介导的亮氨酸分解,可降低脊髓单核细胞中 HIF1α 的表达和 IL-17 的产生,从而减轻 EAE 的严重程度。我们的研究结果阐明了 BCAT1 介导的细胞质亮氨酸分解代谢在通过 HMB 介导的 mTORC1-HIF1α 调节 IL-17 生成过程中的作用,为其与炎症条件的相关性提供了见解。
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引用次数: 0
Comprehensive molecular characterization of TFE3-rearranged renal cell carcinoma TFE3重排肾细胞癌的综合分子特征。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1038/s12276-024-01291-2
Cho-Rong Lee, Jungyo Suh, Dongjun Jang, Bo-Yeong Jin, Jaeso Cho, Moses Lee, Hyungtai Sim, Minyong Kang, Jueun Lee, Ju Hyun Park, Kyoung-Hwa Lee, Geum-Sook Hwang, Kyung Chul Moon, Cheryn Song, Ja Hyeon Ku, Cheol Kwak, Hyeon Hoe Kim, Sung-Yup Cho, Murim Choi, Chang Wook Jeong
TFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC. Understanding the unique traits of a rare kidney cancer type, TFE3-rearranged renal cell carcinoma, is important due to its poor response to usual treatments. This study explores the genetic and metabolic makeup of tRCC, comparing it with clear cell RCC and normal kidney cells. Using a mix of cell culture, whole exome sequencing, and various molecular analyses, the team conducted an experiment to reveal the unique genetic and metabolic profiles of tRCC. The researchers conclude that targeting the metabolic changes in tRCC, specifically through inhibiting PPARGC1A-mediated mitochondrial respiration, offers a new treatment approach. This approach marks a significant step in understanding and potentially treating tRCC. The implications of this study could lead to more effective treatments for patients with this challenging cancer type, emphasizing the importance of metabolic pathways in cancer therapy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
TFE3重排肾细胞癌(tRCC)是一种罕见的肾细胞癌,涉及Xp11.2 TFE3基因的染色体易位。尽管tRCC发病早、预后差,但其发病的分子机制仍然难以捉摸。本研究旨在为原发性和复发性 tRCC 患者确定新的治疗靶点。我们收集了19个经免疫组化确诊的TFE3阳性RCC组织,并对它们进行了基因鉴定,以检查它们的基因组和转录组特征。利用全外显子组测序(WES)和RNA测序(RNA-seq)数据提取了肿瘤特异性特征,并在TFE3易位的细胞系中分析了其功能性后果。结果发现,体细胞单核苷酸变异(SNV)的负担较低,体细胞变异的数量与发病年龄呈正相关。转录组分析表明,有四个样本(21.1%)缺乏预期的融合事件,并与透明细胞RCC(ccRCC)组织的基因组图谱聚集在一起。与ccRCC的表达图谱相比,融合事件还显示出与线粒体呼吸相关的基因富集上调。RNA 表达谱与 TFE3 ChIP-seq 模式数据的比较表明,PPARGC1A 是致癌过程的代谢调节因子。当 PPARGC1A 及其相关代谢通路被其抑制剂 SR-18292 抑制时,细胞增殖会减少。总之,我们证明 PPARGC1A 介导的线粒体呼吸可被视为 tRCC 的潜在治疗靶点。这项研究确定了一种具有独特临床特征的 RCC 亚型的未定性遗传特征,并提供了针对 tRCC 的治疗方案。
{"title":"Comprehensive molecular characterization of TFE3-rearranged renal cell carcinoma","authors":"Cho-Rong Lee, Jungyo Suh, Dongjun Jang, Bo-Yeong Jin, Jaeso Cho, Moses Lee, Hyungtai Sim, Minyong Kang, Jueun Lee, Ju Hyun Park, Kyoung-Hwa Lee, Geum-Sook Hwang, Kyung Chul Moon, Cheryn Song, Ja Hyeon Ku, Cheol Kwak, Hyeon Hoe Kim, Sung-Yup Cho, Murim Choi, Chang Wook Jeong","doi":"10.1038/s12276-024-01291-2","DOIUrl":"10.1038/s12276-024-01291-2","url":null,"abstract":"TFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC. Understanding the unique traits of a rare kidney cancer type, TFE3-rearranged renal cell carcinoma, is important due to its poor response to usual treatments. This study explores the genetic and metabolic makeup of tRCC, comparing it with clear cell RCC and normal kidney cells. Using a mix of cell culture, whole exome sequencing, and various molecular analyses, the team conducted an experiment to reveal the unique genetic and metabolic profiles of tRCC. The researchers conclude that targeting the metabolic changes in tRCC, specifically through inhibiting PPARGC1A-mediated mitochondrial respiration, offers a new treatment approach. This approach marks a significant step in understanding and potentially treating tRCC. The implications of this study could lead to more effective treatments for patients with this challenging cancer type, emphasizing the importance of metabolic pathways in cancer therapy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01291-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A dual inhibitor of PIP5K1C and PIKfyve prevents SARS-CoV-2 entry into cells PIP5K1C 和 PIKfyve 的双重抑制剂可阻止 SARS-CoV-2 进入细胞。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1038/s12276-024-01283-2
Yuri Seo, Yejin Jang, Seon-gyeong Lee, Joon Ho Rhlee, Sukyeong Kong, Thi Tuyet Hanh Vo, Myung hun Kim, Myoung Kyu Lee, Byungil Kim, Sung You Hong, Meehyein Kim, Joo-Yong Lee, Kyungjae Myung
The SARS-CoV-2 pandemic has had an unprecedented impact on global public health and the economy. Although vaccines and antivirals have provided effective protection and treatment, the development of new small molecule-based antiviral candidates is imperative to improve clinical outcomes against SARS-CoV-2. In this study, we identified UNI418, a dual PIKfyve and PIP5K1C inhibitor, as a new chemical agent that inhibits SARS-CoV-2 entry into host cells. UNI418 inhibited the proteolytic activation of cathepsins, which is regulated by PIKfyve, resulting in the inhibition of cathepsin L-dependent proteolytic cleavage of the SARS-CoV-2 spike protein into its mature form, a critical step for viral endosomal escape. We also demonstrated that UNI418 prevented ACE2-mediated endocytosis of the virus via PIP5K1C inhibition. Our results identified PIKfyve and PIP5K1C as potential antiviral targets and UNI418 as a putative therapeutic compound against SARS-CoV-2. The COVID-19 pandemic, triggered by the SARS-CoV-2 virus, underscores the immediate need for effective treatments, particularly for severe cases. Even with vaccines, treatments that block the virus’s entry into cells are vital. SARS-CoV-2 enters host cells by attaching to the ACE2 receptor, a process that is a prime target for intervention. This research concentrates on blocking the virus’s entry into cells as a potential treatment method. The study is an experiment using cellular models to assess the effectiveness of a new compound, UNI418, in preventing SARS-CoV-2 infection. UNI418 targets enzymes involved in cell membrane dynamics, essential for the virus’s entry. The researchers conclude that UNI418, by blocking PIP5K1C and PIKfyve, offers a promising approach to preventing SARS-CoV-2 infection and emphasizes the importance of targeting the virus’s entry process as a treatment strategy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
SARS-CoV-2 大流行对全球公共卫生和经济造成了前所未有的影响。尽管疫苗和抗病毒药物提供了有效的保护和治疗,但要改善 SARS-CoV-2 的临床治疗效果,开发新的小分子抗病毒候选药物势在必行。在这项研究中,我们发现 UNI418(一种 PIKfyve 和 PIP5K1C 双重抑制剂)是一种能抑制 SARS-CoV-2 进入宿主细胞的新型化学制剂。UNI418 可抑制由 PIKfyve 调节的蛋白酶的蛋白水解活化,从而抑制依赖于蛋白酶 L 的蛋白水解作用,将 SARS-CoV-2 穗状病毒蛋白裂解为成熟形式,这是病毒内体逃逸的关键步骤。我们还证明,UNI418 通过抑制 PIP5K1C 阻止了 ACE2 介导的病毒内吞。我们的研究结果将 PIKfyve 和 PIP5K1C 确定为潜在的抗病毒靶点,并将 UNI418 确定为一种可治疗 SARS-CoV-2 的化合物。
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引用次数: 0
Cholesterol imbalance and neurotransmission defects in neurodegeneration 胆固醇失衡与神经变性中的神经传递缺陷
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1038/s12276-024-01273-4
Kyung Chul Shin, Houda Yasmine Ali Moussa, Yongsoo Park
The brain contains the highest concentration of cholesterol in the human body, which emphasizes the importance of cholesterol in brain physiology. Cholesterol is involved in neurogenesis and synaptogenesis, and age-related reductions in cholesterol levels can lead to synaptic loss and impaired synaptic plasticity, which potentially contribute to neurodegeneration. The maintenance of cholesterol homeostasis in the neuronal plasma membrane is essential for normal brain function, and imbalances in cholesterol distribution are associated with various neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. This review aims to explore the molecular and pathological mechanisms by which cholesterol imbalance can lead to neurotransmission defects and neurodegeneration, focusing on four key mechanisms: (1) synaptic dysfunction, (2) alterations in membrane structure and protein clustering, (3) oligomers of amyloid beta (Aβ) protein, and (4) α-synuclein aggregation. Cholesterol, a substance crucial for the brain, can lead to diseases like Alzheimer’s and Parkinson’s when imbalanced. This review investigates how this imbalance causes brain cell degeneration, focusing on issues like communication breakdown and harmful protein build-up. The study combines findings from different experiments to understand cholesterol’s role in the brain. The review emphasizes the need for cholesterol balance for brain health and identifies potential treatment targets for neurodegenerative diseases. The main findings suggest that cholesterol imbalance disrupts brain cell communication and leads to harmful protein build-up, causing brain cell degeneration. The researchers conclude that focusing on cholesterol metabolism and distribution could lead to new treatments for these conditions. Future research may lead to treatments that correct cholesterol imbalances, possibly slowing or preventing neurodegenerative diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
人体内胆固醇含量最高的部位是大脑,这凸显了胆固醇在大脑生理学中的重要性。胆固醇参与神经发生和突触生成,与年龄相关的胆固醇水平降低会导致突触丢失和突触可塑性受损,从而可能导致神经退化。维持神经元质膜中胆固醇的平衡对大脑的正常功能至关重要,而胆固醇分布的失衡与阿尔茨海默病、帕金森病和亨廷顿病等多种神经退行性疾病有关。本综述旨在探讨胆固醇失衡导致神经传导缺陷和神经退行性病变的分子和病理机制,重点关注以下四种关键机制:(1) 突触功能障碍;(2) 膜结构和蛋白质聚类的改变;(3) 淀粉样 beta(Aβ)蛋白的寡聚体;(4) α-突触核蛋白的聚集。
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引用次数: 0
A neutrophil elastase-generated mature form of IL-33 is a potent regulator of endothelial cell activation and proliferative retinopathy 中性粒细胞弹性蛋白酶生成的成熟形式 IL-33 是内皮细胞活化和增殖性视网膜病变的有效调节剂。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1038/s12276-024-01279-y
Shivantika Bisen, Shailendra Kumar Verma, Chandra Sekhar Mukhopadhyay, Nikhlesh K. Singh
Human interleukin-33 (IL-33) is a 270 amino acid protein that belongs to the IL-1 cytokine family and plays an important role in various inflammatory disorders. Neutrophil proteases (Cathepsin G and Elastase) and mast cell proteases (tryptase and chymase) regulate the activity of IL-33 by processing full-length IL-33 into its mature form. There is little evidence on the role of these mature forms of IL-33 in retinal endothelial cell signaling and pathological retinal angiogenesis. Here, we cloned, expressed, and purified the various mature forms of human IL-33 and then evaluated the effects of IL-3395-270, IL-3399-270, IL-33109-270, and IL-33112-270 on angiogenesis in human retinal microvascular endothelial cells (HRMVECs). We observed that IL-3395-270, IL-3399-270, IL-33109-270, and IL-33112-270 significantly induced HRMVEC migration, tube formation and sprouting angiogenesis. However, only IL-3399-270 could induce HRMVEC proliferation. We used a murine model of oxygen-induced retinopathy (OIR) to assess the role of these mature forms of IL-33 in pathological retinal neovascularization. Our 3′-mRNA sequencing and signaling studies indicated that IL-3399-270 and IL-33109-270 were more potent at inducing endothelial cell activation and angiogenesis than the other mature forms. We found that genetic deletion of IL-33 significantly reduced OIR-induced retinal neovascularization in the mouse retina and that intraperitoneal administration of mature forms of IL-33, mainly IL-3399–270 and IL-33109–270, significantly restored ischemia-induced angiogenic sprouting and tuft formation in the hypoxic retinas of IL-33–/– mice. Thus, our study results suggest that blockade or inhibition of IL-33 cleavage by neutrophil proteases could help mitigate pathological angiogenesis in proliferative retinopathies. Interleukin-33 plays a role in many diseases and biological processes. This study investigates how various IL-33 mature forms affects blood vessel creation in the eye, especially in eye diseases. The researchers used genetic and drug-related methods to study the effects of IL-33 on blood vessel formation in the eye, focusing on how it regulates cellular signaling. The research used both in vitro and in vivo methods to understand IL-33’s role in abnormal blood vessel growth, specifically in oxygen-induced eye disease, a model for diseases like premature retinopathy and some aspects of diabetic retinopathy. The research concludes that IL-33, especially its enzyme-processed forms, plays a key role in the development of proliferative retinopathies by promoting abnormal blood vessel growth in the eye. This new understanding of IL-33’s function could lead to new treatments for proliferative retinopathies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
人白细胞介素-33(IL-33)是一种 270 个氨基酸的蛋白质,属于 IL-1 细胞因子家族,在各种炎症性疾病中发挥着重要作用。中性粒细胞蛋白酶(凝血酶 G 和弹性蛋白酶)和肥大细胞蛋白酶(胰蛋白酶和糜蛋白酶)通过将全长 IL-33 加工成成熟形式来调节 IL-33 的活性。关于这些成熟形式的 IL-33 在视网膜内皮细胞信号传导和病理性视网膜血管生成中的作用,目前还没有什么证据。在这里,我们克隆、表达和纯化了人IL-33的各种成熟形式,然后评估了IL-3395-270、IL-3399-270、IL-33109-270和IL-33112-270对人视网膜微血管内皮细胞(HRMVECs)血管生成的影响。我们观察到,IL-3395-270、IL-3399-270、IL-33109-270 和 IL-33112-270 能显著诱导 HRMVEC 迁移、管形成和芽状血管生成。然而,只有 IL-3399-270 能诱导 HRMVEC 增殖。我们利用小鼠氧诱导视网膜病变(OIR)模型来评估这些成熟形式的 IL-33 在病理性视网膜新生血管中的作用。我们的 3'-mRNA 测序和信号研究表明,IL-3399-270 和 IL-33109-270 在诱导内皮细胞活化和血管生成方面比其他成熟形式的 IL-33 更有效。我们发现,基因缺失 IL-33 能显著减少 OIR 诱导的小鼠视网膜新生血管,而腹腔注射成熟形式的 IL-33,主要是 IL-3399-270 和 IL-33109-270,能显著恢复缺血诱导的血管新生萌芽和 IL-33-/- 小鼠缺氧视网膜中的血管丛形成。因此,我们的研究结果表明,阻断或抑制中性粒细胞蛋白酶对IL-33的裂解有助于缓解增殖性视网膜病变中的病理性血管生成。
{"title":"A neutrophil elastase-generated mature form of IL-33 is a potent regulator of endothelial cell activation and proliferative retinopathy","authors":"Shivantika Bisen, Shailendra Kumar Verma, Chandra Sekhar Mukhopadhyay, Nikhlesh K. Singh","doi":"10.1038/s12276-024-01279-y","DOIUrl":"10.1038/s12276-024-01279-y","url":null,"abstract":"Human interleukin-33 (IL-33) is a 270 amino acid protein that belongs to the IL-1 cytokine family and plays an important role in various inflammatory disorders. Neutrophil proteases (Cathepsin G and Elastase) and mast cell proteases (tryptase and chymase) regulate the activity of IL-33 by processing full-length IL-33 into its mature form. There is little evidence on the role of these mature forms of IL-33 in retinal endothelial cell signaling and pathological retinal angiogenesis. Here, we cloned, expressed, and purified the various mature forms of human IL-33 and then evaluated the effects of IL-3395-270, IL-3399-270, IL-33109-270, and IL-33112-270 on angiogenesis in human retinal microvascular endothelial cells (HRMVECs). We observed that IL-3395-270, IL-3399-270, IL-33109-270, and IL-33112-270 significantly induced HRMVEC migration, tube formation and sprouting angiogenesis. However, only IL-3399-270 could induce HRMVEC proliferation. We used a murine model of oxygen-induced retinopathy (OIR) to assess the role of these mature forms of IL-33 in pathological retinal neovascularization. Our 3′-mRNA sequencing and signaling studies indicated that IL-3399-270 and IL-33109-270 were more potent at inducing endothelial cell activation and angiogenesis than the other mature forms. We found that genetic deletion of IL-33 significantly reduced OIR-induced retinal neovascularization in the mouse retina and that intraperitoneal administration of mature forms of IL-33, mainly IL-3399–270 and IL-33109–270, significantly restored ischemia-induced angiogenic sprouting and tuft formation in the hypoxic retinas of IL-33–/– mice. Thus, our study results suggest that blockade or inhibition of IL-33 cleavage by neutrophil proteases could help mitigate pathological angiogenesis in proliferative retinopathies. Interleukin-33 plays a role in many diseases and biological processes. This study investigates how various IL-33 mature forms affects blood vessel creation in the eye, especially in eye diseases. The researchers used genetic and drug-related methods to study the effects of IL-33 on blood vessel formation in the eye, focusing on how it regulates cellular signaling. The research used both in vitro and in vivo methods to understand IL-33’s role in abnormal blood vessel growth, specifically in oxygen-induced eye disease, a model for diseases like premature retinopathy and some aspects of diabetic retinopathy. The research concludes that IL-33, especially its enzyme-processed forms, plays a key role in the development of proliferative retinopathies by promoting abnormal blood vessel growth in the eye. This new understanding of IL-33’s function could lead to new treatments for proliferative retinopathies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01279-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unique expression and critical role of metallothionein 3 in the control of osteoclastogenesis and osteoporosis 金属硫蛋白 3 在控制破骨细胞生成和骨质疏松症中的独特表达和关键作用。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1038/s12276-024-01290-3
Shenzheng Mo, Min Kyung Kim, Ji Sun Jang, Seung Hye Lee, Seo Jin Hong, Suhan Jung, Hong-Hee Kim
Bone homeostasis is maintained by an intricate balance between osteoclasts and osteoblasts, which becomes disturbed in osteoporosis. Metallothioneins (MTs) are major contributors in cellular zinc regulation. However, the role of MTs in bone cell regulation has remained unexplored. Single-cell RNA sequencing analysis discovered that, unlike the expression of other MT members, the expression of MT3 was unique to osteoclasts among various macrophage populations and was highly upregulated during osteoclast differentiation. This unique MT3 upregulation was validated experimentally and supported by ATAC sequencing data analyses. Downregulation of MT3 by gene knockdown or knockout resulted in excessive osteoclastogenesis and exacerbated bone loss in ovariectomy-induced osteoporosis. Transcriptome sequencing of MT3 knockdown osteoclasts and gene set enrichment analysis indicated that the oxidative stress and redox pathways were enriched, which was verified by MT3-dependent regulation of reactive oxygen species (ROS). In addition, MT3 deficiency increased the transcriptional activity of SP1 in a manner dependent on intracellular zinc levels. This MT3-zinc-SP1 axis was crucial for the control of osteoclasts, as zinc chelation and SP1 knockdown abrogated the promotion of SP1 activity and osteoclastogenesis by MT3 deletion. Moreover, SP1 bound to the NFATc1 promoter, and overexpression of an inactive SP1 mutant negated the effects of MT3 deletion on NFATc1 and osteoclastogenesis. In conclusion, MT3 plays a pivotal role in controlling osteoclastogenesis and bone metabolism via dual axes involving ROS and SP1. The present study demonstrated that MT3 elevation is a potential therapeutic strategy for osteolytic bone disorders, and it established for the first time that MT3 is a crucial bone mass regulator. Bone diseases such as osteoporosis often result from imbalances in bone remodeling, a process involving bone breakdown by cells called osteoclasts and formation by cells called osteoblasts. This study examines the role of Metallothionein 3, a protein that binds to zinc, in osteoclasts. Using a mix of single-cell RNA sequencing database and knockout mouse models, the study investigates how MT3 affects osteoclast development and activity. The researchers used various methods, including gene knockdown and overexpression techniques, to alter MT3 levels in cells and observed the effects on osteoclast formation and bone breakdown. The results indicate that MT3 inhibits osteoclast development and decreases bone loss, suggesting its potential as a treatment target for bone diseases. The study concludes that MT3 plays a crucial role in bone remodeling by controlling osteoclast activity. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
骨平衡由破骨细胞和成骨细胞之间错综复杂的平衡来维持,而骨质疏松症会破坏这种平衡。金属硫蛋白(MTs)是细胞锌调节的主要成分。然而,MTs 在骨细胞调控中的作用仍未得到探索。单细胞 RNA 测序分析发现,与其他 MT 成员的表达不同,在各种巨噬细胞群中,破骨细胞独有 MT3 的表达,并且在破骨细胞分化过程中高度上调。这种独特的 MT3 上调得到了实验验证和 ATAC 测序数据分析的支持。在卵巢切除术诱导的骨质疏松症中,通过基因敲除或基因敲除下调 MT3 会导致过度的破骨细胞生成并加剧骨质流失。MT3基因敲除破骨细胞的转录组测序和基因组富集分析表明,氧化应激和氧化还原通路被富集,这一点通过MT3对活性氧(ROS)的依赖性调控得到了验证。此外,MT3 的缺乏增加了 SP1 的转录活性,其方式依赖于细胞内的锌水平。MT3-锌-SP1轴对破骨细胞的控制至关重要,因为锌螯合和SP1敲除会减弱MT3缺失对SP1活性和破骨细胞生成的促进作用。此外,SP1与NFATc1启动子结合,过表达无活性的SP1突变体可抵消MT3缺失对NFATc1和破骨细胞生成的影响。总之,MT3通过涉及ROS和SP1的双轴在控制破骨细胞生成和骨代谢中起着关键作用。本研究表明,MT3的升高是溶骨性骨病的一种潜在治疗策略,并首次证实了MT3是一种关键的骨量调节因子。
{"title":"Unique expression and critical role of metallothionein 3 in the control of osteoclastogenesis and osteoporosis","authors":"Shenzheng Mo, Min Kyung Kim, Ji Sun Jang, Seung Hye Lee, Seo Jin Hong, Suhan Jung, Hong-Hee Kim","doi":"10.1038/s12276-024-01290-3","DOIUrl":"10.1038/s12276-024-01290-3","url":null,"abstract":"Bone homeostasis is maintained by an intricate balance between osteoclasts and osteoblasts, which becomes disturbed in osteoporosis. Metallothioneins (MTs) are major contributors in cellular zinc regulation. However, the role of MTs in bone cell regulation has remained unexplored. Single-cell RNA sequencing analysis discovered that, unlike the expression of other MT members, the expression of MT3 was unique to osteoclasts among various macrophage populations and was highly upregulated during osteoclast differentiation. This unique MT3 upregulation was validated experimentally and supported by ATAC sequencing data analyses. Downregulation of MT3 by gene knockdown or knockout resulted in excessive osteoclastogenesis and exacerbated bone loss in ovariectomy-induced osteoporosis. Transcriptome sequencing of MT3 knockdown osteoclasts and gene set enrichment analysis indicated that the oxidative stress and redox pathways were enriched, which was verified by MT3-dependent regulation of reactive oxygen species (ROS). In addition, MT3 deficiency increased the transcriptional activity of SP1 in a manner dependent on intracellular zinc levels. This MT3-zinc-SP1 axis was crucial for the control of osteoclasts, as zinc chelation and SP1 knockdown abrogated the promotion of SP1 activity and osteoclastogenesis by MT3 deletion. Moreover, SP1 bound to the NFATc1 promoter, and overexpression of an inactive SP1 mutant negated the effects of MT3 deletion on NFATc1 and osteoclastogenesis. In conclusion, MT3 plays a pivotal role in controlling osteoclastogenesis and bone metabolism via dual axes involving ROS and SP1. The present study demonstrated that MT3 elevation is a potential therapeutic strategy for osteolytic bone disorders, and it established for the first time that MT3 is a crucial bone mass regulator. Bone diseases such as osteoporosis often result from imbalances in bone remodeling, a process involving bone breakdown by cells called osteoclasts and formation by cells called osteoblasts. This study examines the role of Metallothionein 3, a protein that binds to zinc, in osteoclasts. Using a mix of single-cell RNA sequencing database and knockout mouse models, the study investigates how MT3 affects osteoclast development and activity. The researchers used various methods, including gene knockdown and overexpression techniques, to alter MT3 levels in cells and observed the effects on osteoclast formation and bone breakdown. The results indicate that MT3 inhibits osteoclast development and decreases bone loss, suggesting its potential as a treatment target for bone diseases. The study concludes that MT3 plays a crucial role in bone remodeling by controlling osteoclast activity. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01290-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Astrocytic 5-HT1A receptor mediates age-dependent hippocampal LTD and fear memory extinction in male mice 星形胶质细胞 5-HT1A 受体介导雄性小鼠年龄依赖性海马 LTD 和恐惧记忆的消退
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1038/s12276-024-01285-0
Qian-Yun Wu, Lian-Hong Lin, Kun Lu, Si-Fu Deng, Wei-Min Li, Yuan Xu, Bin Zhang, Ji-Hong Liu
NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. Although the underlying mechanisms remain unclear, this form of LTD cannot be induced by low-frequency stimulation (LFS) in adult mice. In this study, we found that LFS-induced LTD was not easily induced in adult animals and was age dependent. Interestingly, the level of the 5-HT1A receptor was correspondingly increased and exhibited an inverse correlation with the magnitude of LFS-LTD during development. Knockout or pharmacological inhibition of the 5-HT1A receptor reversed impaired LFS-LTD in adult mice (P60), while activation or inhibition of this receptor disturbed or enhanced LFS-LTD in adolescent mice (P21), respectively. Furthermore, the astrocytic 5-HT1A receptor in the hippocampus predominantly mediated age-dependent LFS-LTD through enhancing GABAergic neurotransmission. Finally, fear memory extinction differed among the above conditions. These observations enrich our knowledge of LTD at the cellular level and suggest a therapeutic approach for LTD-related psychiatric disorders. Understanding how our brains learn and remember is intriguing. As we age, our learning and memory abilities can alter, and scientists are trying to understand why. A recent study investigates this by studying a specific brain receptor, the 5-HT1A receptor, and its effect on learning and memory in mice. The team focused on a process called long-term depression. They found that the ability to induce LTD changes with age and that the 5-HT1A receptor plays a key role in this. They discovered that the activity of 5-HT1A receptors in certain brain cells, astrocytes, is necessary for LTD and influences fear memory extinction. The researchers conclude that the 5-HT1A receptor in astrocytes plays a crucial role in regulating learning and memory processes related to LTD. This discovery could lead to new treatments for memory-related disorders. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
海马中的 NMDA 受体依赖性长期抑制(LTD)是一种众所周知的突触可塑性形式,与不同的认知功能有关。虽然其潜在机制尚不清楚,但这种形式的LTD在成年小鼠中无法通过低频刺激(LFS)诱导。在这项研究中,我们发现低频刺激诱导的LTD在成年动物中不易诱导,而且与年龄有关。有趣的是,在发育过程中,5-HT1A 受体的水平相应升高,并与 LFS-LTD 的程度呈反相关。敲除或药物抑制 5-HT1A 受体可逆转成年小鼠(P60)受损的 LFS-LTD,而激活或抑制该受体可分别干扰或增强青少年小鼠(P21)的 LFS-LTD。此外,海马中星形胶质细胞的5-HT1A受体主要通过增强GABA能神经递质介导年龄依赖性LFS-LTD。最后,恐惧记忆的消退在上述条件下有所不同。这些观察结果丰富了我们对细胞水平LTD的认识,并为LTD相关精神疾病的治疗提供了思路。
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引用次数: 0
Tailored antisense oligonucleotides designed to correct aberrant splicing reveal actionable groups of mutations for rare genetic disorders 为纠正异常剪接而设计的定制反义寡核苷酸揭示了罕见遗传疾病的可操作突变群。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1038/s12276-024-01292-1
Htoo A. Wai, Eliska Svobodova, Natalia Romero Herrera, Andrew G. L. Douglas, John W. Holloway, Francisco E. Baralle, Marco Baralle, Diana Baralle
Effective translation of rare disease diagnosis knowledge into therapeutic applications is achievable within a reasonable timeframe; where mutations are amenable to current antisense oligonucleotide technology. In our study, we identified five distinct types of abnormal splice-causing mutations in patients with rare genetic disorders and developed a tailored antisense oligonucleotide for each mutation type using phosphorodiamidate morpholino oligomers with or without octa-guanidine dendrimers and 2′-O-methoxyethyl phosphorothioate. We observed variations in treatment effects and efficiencies, influenced by both the chosen chemistry and the specific nature of the aberrant splicing patterns targeted for correction. Our study demonstrated the successful correction of all five different types of aberrant splicing. Our findings reveal that effective correction of aberrant splicing can depend on altering the chemical composition of oligonucleotides and suggest a fast, efficient, and feasible approach for developing personalized therapeutic interventions for genetic disorders within short time frames. Millions globally suffer from rare diseases, often genetic and affecting children. This study explores using antisense oligonucleotides to fix incorrect RNA splicing, a common result of disease-causing genetic mutations. The results showed that tailored ASOs could correct incorrect splicing for various mutation types, showing this technology′s potential in treating rare genetic diseases. The team chose five mutation types disrupting normal splicing and created specific ASOs to correct these errors in cell models. They created minigenes to simulate the mutations and tested different ASOs′ effectiveness. This method was key to understanding ASOs′ ability to restore normal gene function, crucial for developing targeted treatments for rare genetic disorders. This research could lead to new, targeted treatments for rare genetic disorders, offering hope to millions of patients and their families facing limited treatment options. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
将罕见疾病诊断知识有效地转化为治疗应用可以在合理的时间范围内实现;如果突变适合当前的反义寡核苷酸技术。在我们的研究中,我们在罕见遗传疾病患者中发现了五种不同类型的异常剪接致突变,并针对每种突变类型,使用含或不含八胍树枝状聚合物和 2'-O-methoxyethyl phosphorothioate 的磷酸二铵吗啉寡核苷酸,开发了一种量身定制的反义寡核苷酸。我们观察到处理效果和效率的变化,这既受所选化学成分的影响,也受要校正的异常剪接模式的具体性质的影响。我们的研究表明,所有五种不同类型的异常剪接都能成功纠正。我们的研究结果表明,对异常剪接的有效校正可以依赖于改变寡核苷酸的化学成分,并提出了一种快速、高效、可行的方法,用于在短时间内开发针对遗传疾病的个性化治疗干预措施。
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引用次数: 0
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Experimental and Molecular Medicine
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