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Pivotal functions and impact of long con-coding RNAs on cellular processes and genome integrity. 长编码 RNA 对细胞过程和基因组完整性的关键功能和影响。
IF 11 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-05-14 DOI: 10.1186/s12929-024-01038-1
Siddhant Sharma, Aicha Asma Houfani, Leonard J Foster

Recent advances in uncovering the mysteries of the human genome suggest that long non-coding RNAs (lncRNAs) are important regulatory components. Although lncRNAs are known to affect gene transcription, their mechanisms and biological implications are still unclear. Experimental research has shown that lncRNA synthesis, subcellular localization, and interactions with macromolecules like DNA, other RNAs, or proteins can all have an impact on gene expression in various biological processes. In this review, we highlight and discuss the major mechanisms through which lncRNAs function as master regulators of the human genome. Specifically, the objective of our review is to examine how lncRNAs regulate different processes like cell division, cell cycle, and immune responses, and unravel their roles in maintaining genomic architecture and integrity.

揭开人类基因组奥秘的最新进展表明,长非编码 RNA(lncRNA)是重要的调控成分。尽管已知 lncRNAs 会影响基因转录,但其机制和生物学意义仍不清楚。实验研究表明,lncRNA 的合成、亚细胞定位以及与 DNA、其他 RNA 或蛋白质等大分子的相互作用都会对各种生物过程中的基因表达产生影响。在这篇综述中,我们将重点讨论 lncRNA 作为人类基因组主调控因子发挥作用的主要机制。具体来说,我们的综述旨在研究 lncRNA 如何调控细胞分裂、细胞周期和免疫反应等不同过程,并揭示它们在维持基因组结构和完整性方面的作用。
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引用次数: 0
Somatic PDGFRB activating variants promote smooth muscle cell phenotype modulation in intracranial fusiform aneurysm. 体细胞表皮生长因子受体活化变异促进颅内纺锤形动脉瘤平滑肌细胞表型的改变。
IF 9 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-05-13 DOI: 10.1186/s12929-024-01040-7
Li Hao, Xiaolong Ya, Jiaye Wu, Chuming Tao, Ruochen Ma, Zhiyao Zheng, Siqi Mou, Yiming Ling, Yingxi Yang, Jiguang Wang, Yan Zhang, Qing Lin, Jizong Zhao

Background: The fusiform aneurysm is a nonsaccular dilatation affecting the entire vessel wall over a short distance. Although PDGFRB somatic variants have been identified in fusiform intracranial aneurysms, the molecular and cellular mechanisms driving fusiform intracranial aneurysms due to PDGFRB somatic variants remain poorly understood.

Methods: In this study, single-cell sequencing and immunofluorescence were employed to investigate the phenotypic changes in smooth muscle cells within fusiform intracranial aneurysms. Whole-exome sequencing revealed the presence of PDGFRB gene mutations in fusiform intracranial aneurysms. Subsequent immunoprecipitation experiments further explored the functional alterations of these mutated PDGFRB proteins. For the common c.1684 mutation site of PDGFRβ, we established mutant smooth muscle cell lines and zebrafish models. These models allowed us to simulate the effects of PDGFRB mutations. We explored the major downstream cellular pathways affected by PDGFRBY562D mutations and evaluated the potential therapeutic effects of Ruxolitinib.

Results: Single-cell sequencing of two fusiform intracranial aneurysms sample revealed downregulated smooth muscle cell markers and overexpression of inflammation-related markers in vascular smooth muscle cells, which was validated by immunofluorescence staining, indicating smooth muscle cell phenotype modulation is involved in fusiform aneurysm. Whole-exome sequencing was performed on seven intracranial aneurysms (six fusiform and one saccular) and PDGFRB somatic mutations were detected in four fusiform aneurysms. Laser microdissection and Sanger sequencing results indicated that the PDGFRB mutations were present in smooth muscle layer. For the c.1684 (chr5: 149505131) site mutation reported many times, further cell experiments showed that PDGFRBY562D mutations promoted inflammatory-related vascular smooth muscle cell phenotype and JAK-STAT pathway played a crucial role in the process. Notably, transfection of PDGFRBY562D in zebrafish embryos resulted in cerebral vascular anomalies. Ruxolitinib, the JAK inhibitor, could reversed the smooth muscle cells phenotype modulation in vitro and inhibit the vascular anomalies in zebrafish induced by PDGFRB mutation.

Conclusion: Our findings suggested that PDGFRB somatic variants played a role in regulating smooth muscle cells phenotype modulation in fusiform aneurysms and offered a potential therapeutic option for fusiform aneurysms.

背景:纺锤形动脉瘤是一种在短距离内影响整个血管壁的非圆形扩张。虽然已在纺锤形颅内动脉瘤中发现了 PDGFRB 体细胞变异,但对 PDGFRB 体细胞变异导致纺锤形颅内动脉瘤的分子和细胞机制仍知之甚少:本研究采用单细胞测序和免疫荧光技术研究了纺锤形颅内动脉瘤内平滑肌细胞的表型变化。全外显子组测序显示,纺锤形颅内动脉瘤中存在 PDGFRB 基因突变。随后的免疫沉淀实验进一步探究了这些突变的 PDGFRB 蛋白的功能变化。针对 PDGFRβ 的常见 c.1684 突变位点,我们建立了突变平滑肌细胞系和斑马鱼模型。通过这些模型,我们可以模拟 PDGFRB 突变的影响。我们探索了受PDGFRBY562D突变影响的主要下游细胞通路,并评估了Ruxolitinib的潜在治疗效果:对两例纺锤形颅内动脉瘤样本进行单细胞测序发现,血管平滑肌细胞中平滑肌细胞标志物下调,炎症相关标志物过度表达,免疫荧光染色验证了这一点,表明平滑肌细胞表型调控参与了纺锤形动脉瘤的发生。对 7 个颅内动脉瘤(6 个纺锤形动脉瘤和 1 个囊状动脉瘤)进行了全外显子组测序,在 4 个纺锤形动脉瘤中检测到了 PDGFRB 体细胞突变。激光显微切割和 Sanger 测序结果表明,PDGFRB 突变存在于平滑肌层。对于多次报道的c.1684(chr5: 149505131)位点突变,进一步的细胞实验表明,PDGFRBY562D突变促进了炎症相关的血管平滑肌细胞表型,而JAK-STAT通路在这一过程中发挥了关键作用。值得注意的是,在斑马鱼胚胎中转染 PDGFRBY562D 会导致脑血管异常。JAK抑制剂Ruxolitinib可逆转体外平滑肌细胞表型的改变,并抑制PDGFRB突变诱导的斑马鱼血管异常:我们的研究结果表明,PDGFRB体细胞变异在纺锤形动脉瘤平滑肌细胞表型调控中发挥了作用,为纺锤形动脉瘤提供了一种潜在的治疗方案。
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引用次数: 0
A G-quadruplex-binding platinum complex induces cancer mitochondrial dysfunction through dual-targeting mitochondrial and nuclear G4 enriched genome. 通过线粒体和核G4富集基因组的双重靶向作用,G-四叠体结合铂复合物可诱导癌症线粒体功能障碍。
IF 11 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-05-13 DOI: 10.1186/s12929-024-01041-6
Keli Kuang, Chunyan Li, Fatlinda Maksut, Deepanjan Ghosh, Robin Vinck, Maolin Wang, Joël Poupon, Run Xiang, Wen Li, Fei Li, Zhu Wang, Junrong Du, Marie-Paule Teulade-Fichou, Gilles Gasser, Sophie Bombard, Tao Jia

Background: G-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored.

Methods: The mechanisms of action and therapeutic effects of a G4-binding platinum(II) complex, Pt-ttpy, on mitochondria were conducted through a comprehensive approaches with in vitro and in vivo models, including ICP-MS for platinum measurement, PCR-based genetic analysis, western blotting (WB), confocal microscope for mt morphology study, extracellular flux analyzer, JC1 and Annexin V apoptosis assay, flow cytometry and high content microscope screening with single-cell quantification of both ROS and mt specific ROS, as well as click-chemistry for IF study of mt translation. Decipher Pt-ttpy effects on nuclear-encoded mt related genes expression were undertaken via RNA-seq, Chip-seq and CUT-RUN assays.

Results: Pt-ttpy, shows a highest accumulation in the mitochondria of A2780 cancer cells as compared with two other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy induces mtDNA deletion, copy reduction and transcription inhibition, hindering mt protein translation. Functional analysis reveals potent mt dysfunction without reactive oxygen species (ROS) induction. Mechanistic study provided first evidence that most of mt ribosome genes are highly enriched in G4 structures in their promoter regions, notably, Pt-ttpy impairs most nuclear-encoded mt ribosome genes' transcription through dampening the recruiting of transcription initiation and elongation factors of NELFB and TAF1 to their promoter with G4-enriched sequences. In vivo studies show Pt-ttpy's efficient anti-tumor effects, disrupting mt genome function with fewer side effects than cisplatin.

Conclusion: This study underscores Pt-ttpy as a G4-binding platinum(II) complex, effectively targeting cancer mitochondria through dual action on mt and nuclear G4-enriched genomes without inducing ROS, offering promise for safer and effective platinum-based G4-targeted cancer therapy.

背景:G-quadruplex DNA(G4)是一种在富含鸟嘌呤区域形成的非经典结构,在癌症生物学中发挥着重要作用,目前在核基因组和线粒体(mt)基因组中都得到了认可。然而,基于 G4 的靶向治疗对核基因组和线粒体基因组的影响、对线粒体功能的影响及其内在机制在很大程度上仍有待探索:方法:通过体外和体内模型的综合方法,包括ICP-MS铂测量、基于PCR的基因分析、Western印迹(WB)、共聚焦显微镜观察线粒体的形态,研究了G4结合铂(II)复合物Pt-ttpy对线粒体的作用机制和治疗效果、共聚焦显微镜(用于 mt 形态学研究)、细胞外通量分析仪、JC1 和 Annexin V 细胞凋亡检测、流式细胞术和高分辨显微镜筛选(单细胞定量 ROS 和 mt 特异性 ROS),以及点击化学(用于 mt 翻译的 IF 研究)。通过 RNA-seq、Chip-seq 和 CUT-RUN 分析,解读了 Pt-ttpy 对核编码 mt 相关基因表达的影响:结果:与其他两种不具有/弱 G4 结合特性的铂(II)复合物 Pt-tpy 和顺铂相比,Pt-ttpy 在 A2780 癌细胞线粒体中的蓄积量最高。Pt-ttpy 可诱导 mtDNA 缺失、拷贝减少和转录抑制,阻碍 mt 蛋白的翻译。功能分析显示,在不诱导活性氧(ROS)的情况下,铂锑会导致 mt 功能障碍。机理研究首次证明,大多数mt核糖体基因的启动子区域高度富含G4结构,特别是Pt-ttpy通过抑制NELFB和TAF1等转录起始因子和延伸因子招募到具有G4富集序列的启动子,从而损害了大多数核编码mt核糖体基因的转录。体内研究表明,Pt-ttpy具有高效的抗肿瘤作用,能破坏mt基因组的功能,而且副作用比顺铂小:本研究强调了 Pt-ttpy 作为一种 G4 结合型铂(II)复合物,可通过对 mt 和核 G4 富集基因组的双重作用有效靶向癌症线粒体,且不会诱发 ROS,为更安全有效的基于 G4 的铂靶向癌症疗法带来了希望。
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引用次数: 0
Excess glucose alone depress young mesenchymal stromal/stem cell osteogenesis and mitochondria activity within hours/days via NAD+/SIRT1 axis. 仅过量葡萄糖就会在数小时/数天内通过 NAD+/SIRT1 轴抑制年轻间充质基质/干细胞的成骨和线粒体活性。
IF 9 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-05-13 DOI: 10.1186/s12929-024-01039-0
B Linju Yen, Li-Tzu Wang, Hsiu-Huang Wang, Chin-Pao Hung, Pei-Ju Hsu, Chia-Chi Chang, Chien-Yu Liao, Huey-Kang Sytwu, Men-Luh Yen

Background: The impact of global overconsumption of simple sugars on bone health, which peaks in adolescence/early adulthood and correlates with osteoporosis (OP) and fracture risk decades, is unclear. Mesenchymal stromal/stem cells (MSCs) are the progenitors of osteoblasts/bone-forming cells, and known to decrease their osteogenic differentiation capacity with age. Alarmingly, while there is correlative evidence that adolescents consuming greatest amounts of simple sugars have the lowest bone mass, there is no mechanistic understanding on the causality of this correlation.

Methods: Bioinformatics analyses for energetics pathways involved during MSC differentiation using human cell information was performed. In vitro dissection of normal versus high glucose (HG) conditions on osteo-/adipo-lineage commitment and mitochondrial function was assessed using multi-sources of non-senescent human and murine MSCs; for in vivo validation, young mice was fed normal or HG-added water with subsequent analyses of bone marrow CD45- MSCs.

Results: Bioinformatics analyses revealed mitochondrial and glucose-related metabolic pathways as integral to MSC osteo-/adipo-lineage commitment. Functionally, in vitro HG alone without differentiation induction decreased both MSC mitochondrial activity and osteogenesis while enhancing adipogenesis by 8 h' time due to depletion of nicotinamide adenine dinucleotide (NAD+), a vital mitochondrial co-enzyme and co-factor to Sirtuin (SIRT) 1, a longevity gene also involved in osteogenesis. In vivo, HG intake in young mice depleted MSC NAD+, with oral NAD+ precursor supplementation rapidly reversing both mitochondrial decline and osteo-/adipo-commitment in a SIRT1-dependent fashion within 1 ~ 5 days.

Conclusions: We found a surprisingly rapid impact of excessive glucose, a single dietary factor, on MSC SIRT1 function and osteogenesis in youthful settings, and the crucial role of NAD+-a single molecule-on both MSC mitochondrial function and lineage commitment. These findings have strong implications on future global OP and disability risks in light of current worldwide overconsumption of simple sugars.

背景:全球过量摄入单糖对骨骼健康的影响尚不清楚,这种影响在青春期/成年早期达到高峰,并与骨质疏松症(OP)和骨折风险数十年相关。间充质基质/干细胞(MSCs)是成骨细胞/成骨细胞的祖细胞,已知其成骨分化能力会随着年龄的增长而降低。令人担忧的是,虽然有相关证据表明,摄入单糖最多的青少年骨量最低,但对这种相关性的因果关系还没有机制性的认识:方法:利用人体细胞信息对间叶干细胞分化过程中涉及的能量途径进行生物信息学分析。方法:利用人体细胞信息对间叶干细胞分化过程中涉及的能量通路进行生物信息学分析;利用多种来源的非衰老人和小鼠间叶干细胞,评估正常与高糖(HG)条件对骨/髓系形成和线粒体功能的影响;为了进行体内验证,给幼鼠喂食正常或添加 HG 的水,随后对骨髓 CD45- 间叶干细胞进行分析:结果:生物信息学分析表明,线粒体和葡萄糖相关代谢途径是间充质干细胞骨/髓系定向不可或缺的组成部分。在功能上,体外单用 HG 而不诱导分化会降低间充质干细胞线粒体活性和骨生成,同时在 8 小时后会增强脂肪生成,这是由于烟酰胺腺嘌呤二核苷酸(NAD+)耗竭所致,NAD+ 是一种重要的线粒体辅酶,也是 Sirtuin(SIRT)1 的辅助因子,SIRT 是一种长寿基因,也参与骨生成。在体内,年轻小鼠摄入的 HG 会耗尽间充质干细胞 NAD+,而口服 NAD+前体补充剂可在 1 ~ 5 天内以 SIRT1 依赖性方式迅速逆转线粒体衰退和骨/脂肪承诺:我们发现过量的葡萄糖(一种单一的膳食因素)对间充质干细胞 SIRT1 功能和年轻时的成骨过程有惊人的快速影响,而且 NAD+(一种单一的分子)对间充质干细胞线粒体功能和血统承诺都起着至关重要的作用。鉴于目前全球范围内对单糖的过度摄入,这些发现对未来全球OP和残疾风险具有重要意义。
{"title":"Excess glucose alone depress young mesenchymal stromal/stem cell osteogenesis and mitochondria activity within hours/days via NAD<sup>+</sup>/SIRT1 axis.","authors":"B Linju Yen, Li-Tzu Wang, Hsiu-Huang Wang, Chin-Pao Hung, Pei-Ju Hsu, Chia-Chi Chang, Chien-Yu Liao, Huey-Kang Sytwu, Men-Luh Yen","doi":"10.1186/s12929-024-01039-0","DOIUrl":"10.1186/s12929-024-01039-0","url":null,"abstract":"<p><strong>Background: </strong>The impact of global overconsumption of simple sugars on bone health, which peaks in adolescence/early adulthood and correlates with osteoporosis (OP) and fracture risk decades, is unclear. Mesenchymal stromal/stem cells (MSCs) are the progenitors of osteoblasts/bone-forming cells, and known to decrease their osteogenic differentiation capacity with age. Alarmingly, while there is correlative evidence that adolescents consuming greatest amounts of simple sugars have the lowest bone mass, there is no mechanistic understanding on the causality of this correlation.</p><p><strong>Methods: </strong>Bioinformatics analyses for energetics pathways involved during MSC differentiation using human cell information was performed. In vitro dissection of normal versus high glucose (HG) conditions on osteo-/adipo-lineage commitment and mitochondrial function was assessed using multi-sources of non-senescent human and murine MSCs; for in vivo validation, young mice was fed normal or HG-added water with subsequent analyses of bone marrow CD45<sup>-</sup> MSCs.</p><p><strong>Results: </strong>Bioinformatics analyses revealed mitochondrial and glucose-related metabolic pathways as integral to MSC osteo-/adipo-lineage commitment. Functionally, in vitro HG alone without differentiation induction decreased both MSC mitochondrial activity and osteogenesis while enhancing adipogenesis by 8 h' time due to depletion of nicotinamide adenine dinucleotide (NAD<sup>+</sup>), a vital mitochondrial co-enzyme and co-factor to Sirtuin (SIRT) 1, a longevity gene also involved in osteogenesis. In vivo, HG intake in young mice depleted MSC NAD<sup>+</sup>, with oral NAD<sup>+</sup> precursor supplementation rapidly reversing both mitochondrial decline and osteo-/adipo-commitment in a SIRT1-dependent fashion within 1 ~ 5 days.</p><p><strong>Conclusions: </strong>We found a surprisingly rapid impact of excessive glucose, a single dietary factor, on MSC SIRT1 function and osteogenesis in youthful settings, and the crucial role of NAD<sup>+</sup>-a single molecule-on both MSC mitochondrial function and lineage commitment. These findings have strong implications on future global OP and disability risks in light of current worldwide overconsumption of simple sugars.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"49"},"PeriodicalIF":9.0,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11089752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140911864","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
Contribution of extracellular vesicles for the pathogenesis of retinal diseases: shedding light on blood-retinal barrier dysfunction. 细胞外囊泡对视网膜疾病发病机制的贡献:揭示血液-视网膜屏障功能障碍。
IF 9 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-05-10 DOI: 10.1186/s12929-024-01036-3
Beatriz Martins, Maria Pires, António Francisco Ambrósio, Henrique Girão, Rosa Fernandes

Retinal degenerative diseases, including diabetic retinopathy (DR) and age-related macular degeneration (AMD), loom as threats to vision, causing detrimental effects on the structure and function of the retina. Central to understanding these diseases, is the compromised state of the blood-retinal barrier (BRB), an effective barrier that regulates the influx of immune and inflammatory components. Whether BRB breakdown initiates retinal distress, or is a consequence of disease progression, remains enigmatic. Nevertheless, it is an indication of retinal dysfunction and potential vision loss.The intricate intercellular dialogues among retinal cell populations remain unintelligible in the complex retinal milieu, under conditions of inflammation and oxidative stress. The retina, a specialized neural tissue, sustains a ceaseless demand for oxygen and nutrients from two vascular networks. The BRB orchestrates the exchange of molecules and fluids within this specialized region, comprising the inner BRB (iBRB) and the outer BRB (oBRB). Extracellular vesicles (EVs) are small membranous structures, and act as messengers facilitating intercellular communication in this milieu.EVs, both from retinal and peripheral immune cells, increase complexity to BRB dysfunction in DR and AMD. Laden with bioactive cargoes, these EVs can modulate the retinal microenvironment, influencing disease progression. Our review delves into the multifaceted role of EVs in retinal degenerative diseases, elucidating the molecular crosstalk they orchestrate, and their microRNA (miRNA) content. By shedding light on these nanoscale messengers, from their biogenesis, release, to interaction and uptake by target cells, we aim to deepen the comprehension of BRB dysfunction and explore their therapeutic potential, therefore increasing our understanding of DR and AMD pathophysiology.

视网膜退行性疾病,包括糖尿病视网膜病变(DR)和老年性黄斑变性(AMD),对视力构成威胁,对视网膜的结构和功能造成有害影响。血液视网膜屏障(BRB)是调节免疫和炎症成分流入的有效屏障,其受损状态是了解这些疾病的关键。究竟是血-视网膜屏障的破坏引发了视网膜损伤,还是疾病进展的结果,目前仍是一个谜。在炎症和氧化应激条件下,视网膜细胞群之间错综复杂的细胞间对话在复杂的视网膜环境中仍然难以理解。视网膜是一种特殊的神经组织,它不断需要两个血管网络提供氧气和营养物质。视网膜血管网由内视网膜血管网(iBRB)和外视网膜血管网(oBRB)组成,负责协调这一特殊区域内的分子和液体交换。细胞外囊泡(EVs)是一种小型膜结构,在这种环境中充当着促进细胞间交流的信使。来自视网膜和外周免疫细胞的EVs增加了DR和AMD中BRB功能障碍的复杂性。来自视网膜和外周免疫细胞的EV增加了DR和AMD中BRB功能障碍的复杂性。这些EV含有生物活性载体,可调节视网膜微环境,影响疾病的进展。我们的综述深入探讨了EVs在视网膜退行性疾病中的多方面作用,阐明了它们所协调的分子串联及其microRNA(miRNA)含量。通过揭示这些纳米级信使从生物生成、释放、相互作用到被靶细胞吸收的全过程,我们旨在加深对BRB功能障碍的理解,探索其治疗潜力,从而加深我们对DR和AMD病理生理学的理解。
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引用次数: 0
Targeting cathepsin S promotes activation of OLF1-BDNF/TrkB axis to enhance cognitive function. 靶向 cathepsin S 可促进 OLF1-BDNF/TrkB 轴的激活,从而增强认知功能。
IF 11 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-05-09 DOI: 10.1186/s12929-024-01037-2
Hao-Wei Lee, Szu-Jung Chen, Kuen-Jer Tsai, Kuei-Sen Hsu, Yi-Fan Chen, Chih-Hua Chang, Hsiao-Han Lin, Wen-Yun Hsueh, Hsing-Pang Hsieh, Yueh-Feng Lee, Huai-Chueh Chiang, Jang-Yang Chang

Background: Cathepsin S (CTSS) is a cysteine protease that played diverse roles in immunity, tumor metastasis, aging and other pathological alterations. At the cellular level, increased CTSS levels have been associated with the secretion of pro-inflammatory cytokines and disrupted the homeostasis of Ca2+ flux. Once CTSS was suppressed, elevated levels of anti-inflammatory cytokines and changes of Ca2+ influx were observed. These findings have inspired us to explore the potential role of CTSS on cognitive functions.

Methods: We conducted classic Y-maze and Barnes Maze tests to assess the spatial and working memory of Ctss-/- mice, Ctss+/+ mice and Ctss+/+ mice injected with the CTSS inhibitor (RJW-58). Ex vivo analyses including long-term potentiation (LTP), Golgi staining, immunofluorescence staining of sectioned whole brain tissues obtained from experimental animals were conducted. Furthermore, molecular studies were carried out using cultured HT-22 cell line and primary cortical neurons that treated with RJW-58 to comprehensively assess the gene and protein expressions.

Results: Our findings reported that targeting cathepsin S (CTSS) yields improvements in cognitive function, enhancing both working and spatial memory in behavior models. Ex vivo studies showed elevated levels of long-term potentiation levels and increased synaptic complexity. Microarray analysis demonstrated that brain-derived neurotrophic factor (BDNF) was upregulated when CTSS was knocked down by using siRNA. Moreover, the pharmacological blockade of the CTSS enzymatic activity promoted BDNF expression in a dose- and time-dependent manner. Notably, the inhibition of CTSS was associated with increased neurogenesis in the murine dentate gyrus. These results suggested a promising role of CTSS modulation in cognitive enhancement and neurogenesis.

Conclusion: Our findings suggest a critical role of CTSS in the regulation of cognitive function by modulating the Ca2+ influx, leading to enhanced activation of the BDNF/TrkB axis. Our study may provide a novel strategy for improving cognitive function by targeting CTSS.

背景:Cathepsin S(CTSS)是一种半胱氨酸蛋白酶,在免疫、肿瘤转移、衰老和其他病理改变中发挥着多种作用。在细胞水平上,CTSS 水平的升高与促炎细胞因子的分泌和 Ca2+ 通量平衡的破坏有关。一旦 CTSS 被抑制,就会观察到抗炎细胞因子水平的升高和 Ca2+ 流入的变化。这些发现启发我们探索 CTSS 对认知功能的潜在作用:我们进行了经典的Y迷宫和巴恩斯迷宫测试,以评估Ctss-/-小鼠、Ctss+/+小鼠和注射了CTSS抑制剂(RJW-58)的Ctss+/+小鼠的空间记忆和工作记忆。对实验动物的全脑组织切片进行了体内外分析,包括长期延时(LTP)、高尔基体染色和免疫荧光染色。此外,还使用培养的 HT-22 细胞系和经 RJW-58 处理的原代皮层神经元进行了分子研究,以全面评估基因和蛋白质的表达:我们的研究结果表明,靶向 cathepsin S(CTSS)可改善认知功能,增强行为模型中的工作记忆和空间记忆。体内外研究显示,长期延时水平升高,突触复杂性增加。微阵列分析表明,使用 siRNA 敲除 CTSS 后,脑源性神经营养因子(BDNF)上调。此外,药物阻断 CTSS 酶活性能以剂量和时间依赖的方式促进 BDNF 的表达。值得注意的是,抑制 CTSS 与小鼠齿状回神经发生的增加有关。这些结果表明,CTSS调节在认知增强和神经发生中具有重要作用:我们的研究结果表明,通过调节 Ca2+ 流入,CTSS 在认知功能调控中发挥了关键作用,从而增强了 BDNF/TrkB 轴的激活。我们的研究可能为通过靶向 CTSS 改善认知功能提供了一种新策略。
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引用次数: 0
Exploiting urine-derived induced pluripotent stem cells for advancing precision medicine in cell therapy, disease modeling, and drug testing. 利用尿源诱导多能干细胞推进细胞疗法、疾病建模和药物测试方面的精准医疗。
IF 11 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-05-09 DOI: 10.1186/s12929-024-01035-4
Xiya Yin, Qingfeng Li, Yan Shu, Hongbing Wang, Biju Thomas, Joshua T Maxwell, Yuanyuan Zhang

The field of regenerative medicine has witnessed remarkable advancements with the emergence of induced pluripotent stem cells (iPSCs) derived from a variety of sources. Among these, urine-derived induced pluripotent stem cells (u-iPSCs) have garnered substantial attention due to their non-invasive and patient-friendly acquisition method. This review manuscript delves into the potential and application of u-iPSCs in advancing precision medicine, particularly in the realms of drug testing, disease modeling, and cell therapy. U-iPSCs are generated through the reprogramming of somatic cells found in urine samples, offering a unique and renewable source of patient-specific pluripotent cells. Their utility in drug testing has revolutionized the pharmaceutical industry by providing personalized platforms for drug screening, toxicity assessment, and efficacy evaluation. The availability of u-iPSCs with diverse genetic backgrounds facilitates the development of tailored therapeutic approaches, minimizing adverse effects and optimizing treatment outcomes. Furthermore, u-iPSCs have demonstrated remarkable efficacy in disease modeling, allowing researchers to recapitulate patient-specific pathologies in vitro. This not only enhances our understanding of disease mechanisms but also serves as a valuable tool for drug discovery and development. In addition, u-iPSC-based disease models offer a platform for studying rare and genetically complex diseases, often underserved by traditional research methods. The versatility of u-iPSCs extends to cell therapy applications, where they hold immense promise for regenerative medicine. Their potential to differentiate into various cell types, including neurons, cardiomyocytes, and hepatocytes, enables the development of patient-specific cell replacement therapies. This personalized approach can revolutionize the treatment of degenerative diseases, organ failure, and tissue damage by minimizing immune rejection and optimizing therapeutic outcomes. However, several challenges and considerations, such as standardization of reprogramming protocols, genomic stability, and scalability, must be addressed to fully exploit u-iPSCs' potential in precision medicine. In conclusion, this review underscores the transformative impact of u-iPSCs on advancing precision medicine and highlights the future prospects and challenges in harnessing this innovative technology for improved healthcare outcomes.

随着多种来源的诱导多能干细胞(iPSCs)的出现,再生医学领域取得了显著进步。其中,尿源诱导多能干细胞(u-iPSCs)因其非侵入性和对患者友好的获取方法而备受关注。本综述手稿深入探讨了尿源诱导多能干细胞在推进精准医疗方面的潜力和应用,尤其是在药物测试、疾病建模和细胞治疗领域。U-iPSCs 是通过对尿液样本中的体细胞进行重编程而产生的,为患者特异性多能细胞提供了独特且可再生的来源。它们在药物测试中的应用为药物筛选、毒性评估和疗效评价提供了个性化平台,从而彻底改变了制药行业。具有不同遗传背景的 u-iPSCs 有助于开发定制的治疗方法,最大限度地减少不良反应,优化治疗效果。此外,u-iPSCs 还在疾病建模方面表现出显著的功效,使研究人员能够在体外重现患者的特异性病理。这不仅加深了我们对疾病机理的了解,也是药物发现和开发的重要工具。此外,基于 u-iPSC 的疾病模型还为研究罕见和基因复杂的疾病提供了一个平台,而传统的研究方法往往对这些疾病的研究不足。u-iPSC 的多功能性还延伸到细胞治疗应用领域,在再生医学方面大有可为。u-iPSCs具有分化成神经元、心肌细胞和肝细胞等各种细胞类型的潜能,因此能够开发出针对患者的细胞替代疗法。这种个性化方法可以最大限度地减少免疫排斥反应,优化治疗效果,从而彻底改变退行性疾病、器官衰竭和组织损伤的治疗方法。然而,要充分发挥 u-iPSCs 在精准医疗中的潜力,还必须应对一些挑战和考虑因素,例如重编程协议的标准化、基因组稳定性和可扩展性。总之,这篇综述强调了u-iPSCs对推进精准医疗的变革性影响,并强调了利用这一创新技术改善医疗效果的未来前景和挑战。
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引用次数: 0
Campylobacter jejuni virulence factors: update on emerging issues and trends 空肠弯曲菌毒力因子:新出现的问题和趋势的最新情况
IF 11 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-05-01 DOI: 10.1186/s12929-024-01033-6
Alexandra Tikhomirova, Emmylee R. McNabb, Luca Petterlin, Georgia L. Bellamy, Kyaw H. Lin, Christopher A. Santoso, Ella S. Daye, Fatimah M. Alhaddad, Kah Peng Lee, Anna Roujeinikova
Campylobacter jejuni is a very common cause of gastroenteritis, and is frequently transmitted to humans through contaminated food products or water. Importantly, C. jejuni infections have a range of short- and long-term sequelae such as irritable bowel syndrome and Guillain Barre syndrome. C. jejuni triggers disease by employing a range of molecular strategies which enable it to colonise the gut, invade the epithelium, persist intracellularly and avoid detection by the host immune response. The objective of this review is to explore and summarise recent advances in the understanding of the C. jejuni molecular factors involved in colonisation, invasion of cells, collective quorum sensing-mediated behaviours and persistence. Understanding the mechanisms that underpin the pathogenicity of C. jejuni will enable future development of effective preventative approaches and vaccines against this pathogen.
空肠弯曲菌是肠胃炎的常见病因,经常通过受污染的食品或水传播给人类。重要的是,空肠弯曲菌感染会产生一系列短期和长期后遗症,如肠易激综合征和格林巴利综合征。空肠大肠杆菌通过采用一系列分子策略引发疾病,这些策略使空肠大肠杆菌能够在肠道中定植、侵入上皮细胞、在细胞内存活并避免被宿主免疫反应检测到。本综述旨在探讨和总结在了解空肠大肠杆菌定植、入侵细胞、集体法定量感应介导的行为和持续存在等分子因素方面的最新进展。了解空肠大肠杆菌致病性的基本机制将有助于未来针对这种病原体开发有效的预防方法和疫苗。
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引用次数: 0
Membrane lipid remodeling eradicates Helicobacter pylori by manipulating the cholesteryl 6'-acylglucoside biosynthesis 膜脂重塑通过操纵胆固醇-6'-酰基葡萄糖苷的生物合成根除幽门螺旋杆菌
IF 11 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-04-29 DOI: 10.1186/s12929-024-01031-8
Lih-Lih Ong, Hau-Ming Jan, Hong-Hanh Thi Le, Tsai-Chen Yang, Chou-Yu Kuo, Ai-Feng Feng, Kwok-Kong Tony Mong, Chun-Hung Lin
Helicobacter pylori, the main cause of various gastric diseases, infects approximately half of the human population. This pathogen is auxotrophic for cholesterol which it converts to various cholesteryl α-glucoside derivatives, including cholesteryl 6’-acyl α-glucoside (CAG). Since the related biosynthetic enzymes can be translocated to the host cells, the acyl chain of CAG likely comes from its precursor phosphatidylethanolamine (PE) in the host membranes. This work aims at examining how the acyl chain of CAG and PE inhibits the membrane functions, especially bacterial adhesion. Eleven CAGs that differ in acyl chains were used to study the membrane properties of human gastric adenocarcinoma cells (AGS cells), including lipid rafts clustering (monitored by immunofluorescence with confocal microscopy) and lateral membrane fluidity (by the fluorescence recovery after photobleaching). Cell-based and mouse models were employed to study the degree of bacterial adhesion, the analyses of which were conducted by using flow cytometry and immunofluorescence staining, respectively. The lipidomes of H. pylori, AGS cells and H. pylori–AGS co-cultures were analyzed by Ultraperformance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS) to examine the effect of PE(10:0)2, PE(18:0)2, PE(18:3)2, or PE(22:6)2 treatments. CAG10:0, CAG18:3 and CAG22:6 were found to cause the most adverse effect on the bacterial adhesion. Further LC–MS analysis indicated that the treatment of PE(10:0)2 resulted in dual effects to inhibit the bacterial adhesion, including the generation of CAG10:0 and significant changes in the membrane compositions. The initial (1 h) lipidome changes involved in the incorporation of 10:0 acyl chains into dihydro- and phytosphingosine derivatives and ceramides. In contrast, after 16 h, glycerophospholipids displayed obvious increase in their very long chain fatty acids, monounsaturated and polyunsaturated fatty acids that are considered to enhance membrane fluidity. The PE(10:0)2 treatment significantly reduced bacterial adhesion in both AGS cells and mouse models. Our approach of membrane remodeling has thus shown great promise as a new anti-H. pylori therapy.
幽门螺杆菌是导致各种胃病的主要原因,感染了大约一半的人口。这种病原体对胆固醇具有辅助营养作用,可将胆固醇转化为各种胆固醇α-葡萄糖苷衍生物,包括胆固醇6'-酰基α-葡萄糖苷(CAG)。由于相关的生物合成酶可以转移到宿主细胞中,CAG 的酰基链很可能来自宿主膜中的前体磷脂酰乙醇胺(PE)。这项工作旨在研究 CAG 和 PE 的酰基链如何抑制膜功能,尤其是细菌粘附。研究人员利用 11 种不同酰基链的 CAG 研究了人胃腺癌细胞(AGS 细胞)的膜特性,包括脂质筏聚集(通过共聚焦显微镜的免疫荧光监测)和侧膜流动性(通过光漂白后的荧光恢复)。在研究细菌粘附程度时,采用了细胞模型和小鼠模型,分别使用流式细胞仪和免疫荧光染色法进行分析。利用超高效液相色谱-串联质谱(UPLC-MS/MS)分析了幽门螺杆菌、AGS细胞和幽门螺杆菌-AGS共培养物的脂质体,研究了PE(10:0)2、PE(18:0)2、PE(18:3)2或PE(22:6)2处理的效果。结果发现,CAG10:0、CAG18:3 和 CAG22:6 对细菌粘附的影响最大。进一步的 LC-MS 分析表明,PE(10:0)2 的处理会产生抑制细菌粘附的双重效果,包括生成 CAG10:0 和膜成分的显著变化。最初(1 小时)的脂质组变化涉及将 10:0 的酰基链纳入二氢和植物鞘氨醇衍生物以及神经酰胺。相反,16 小时后,甘油磷脂中的长链脂肪酸、单不饱和脂肪酸和多不饱和脂肪酸明显增加,这些脂肪酸被认为能增强膜的流动性。在 AGS 细胞和小鼠模型中,PE(10:0)2 处理都能显著降低细菌的粘附性。因此,我们的膜重塑方法有望成为一种新型的抗幽门螺杆菌疗法。
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引用次数: 0
T cell expressions of aberrant gene signatures and Co-inhibitory receptors (Co-IRs) as predictors of renal damage and lupus disease activity T细胞表达异常基因特征和共抑制受体(Co-IRs)作为肾损伤和狼疮疾病活动的预测因子
IF 11 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-04-22 DOI: 10.1186/s12929-024-01024-7
Chin-Man Wang, Yeong-Jian Jan Wu, Jian-Wen Zheng, Li Yu Huang, Keng Poo Tan, Ji-Yih Chen
Systemic lupus erythematosus (SLE) is distinguished by an extensive range of clinical heterogeneity with unpredictable disease flares and organ damage. This research investigates the potential of aberrant signatures on T cell genes, soluble Co-IRs/ligands, and Co-IRs expression on T cells as biomarkers for lupus disease parameters. Comparative transcriptome profiling analysis of non-renal and end-stage renal disease (ESRD) phenotypes of SLE was performed using CD4 + and CD8 + cDNA microarrays of sorted T cells. Comparing the expression of Co-IRs on T cells and serum soluble mediators among healthy and SLE phenotypes. SLE patients with ESRD were downregulated CD38, PLEK, interferon-γ, CX3CR1, FGFBP2, and SLCO4C1 transcripts on CD4 + and CD8 + T cells simultaneously and NKG7, FCRL6, GZMB/H, FcγRIII, ITGAM, Fas ligand, TBX21, LYN, granulysin, CCL4L1, CMKLR1, HLA-DRβ, KIR2DL3, and KLRD1 in CD8 T cells. Pathway enrichment and PPI network analyses revealed that the overwhelming majority of Differentially Expressed Genes (DEGs) have been affiliated with novel cytotoxic, antigen presentation, and chemokine-cell migration signature pathways. CD8 + GZMK + T cells that are varied in nature, including CD161 + Mucosal-associated invariant T (MAIT) cells and CD161- aged-associated T (Taa) cells and CD161-GZMK + GZMB + T cells might account for a higher level of GZMK in CD8 + T cells associated with ESRD. SLE patients have higher TIGIT + , PD1 + , and lower CD127 + cell percentages on CD4 + T cells, higher TIM3 + , TIGIT + , HLA-DR + cell frequency, and lower MFI expression of CD127, CD160 in CD8 T cells. Co-IRs expression in T cells was correlated with soluble PD-1, PDL-2, and TIM3 levels, as well as SLE disease activity, clinical phenotypes, and immune-therapy responses. The signature of dysfunctional pathways defines a distinct immunity pattern in LN ESRD patients. Expression levels of Co-IRs in peripheral blood T cells and serum levels of soluble PD1/PDL-2/TIM3 can serve as biomarkers for evaluating clinical parameters and therapeutic responses.
系统性红斑狼疮(SLE)具有广泛的临床异质性,疾病发作和器官损伤难以预测。这项研究探讨了T细胞基因、可溶性Co-IRs/配体和T细胞上的Co-IRs表达异常特征作为狼疮疾病参数生物标志物的潜力。使用CD4 +和CD8 + cDNA芯片对分选的T细胞进行了系统性红斑狼疮非肾病和终末期肾病(ESRD)表型的比较转录组图谱分析。比较了健康表型和系统性红斑狼疮表型的 T 细胞和血清可溶性介质中 Co-IRs 的表达。患有 ESRD 的系统性红斑狼疮患者在 CD4 + 和 CD8 + T 细胞上的 CD38、PLEK、干扰素-γ、CX3CR1、FGFBP2 和 SLCO4C1 转录物同时下调,而在 CD8 T 细胞上的 NKG7、FCRL6、GZMB/H、FcγRIII、ITGAM、Fas 配体、TBX21、LYN、granulysin、CCL4L1、CMKLR1、HLA-DRβ、KIR2DL3 和 KLRD1 则同时下调。通路富集和PPI网络分析显示,绝大多数差异表达基因(DEG)都与新型细胞毒性、抗原递呈和趋化因子-细胞迁移特征通路有关。CD8 + GZMK + T细胞的性质多种多样,包括CD161 +粘膜相关不变T细胞(MAIT)和CD161-老化相关T细胞(Taa)以及CD161-GZMK + GZMB + T细胞,这可能是与ESRD相关的CD8 + T细胞中GZMK水平较高的原因。系统性红斑狼疮患者的 CD4 + T 细胞中 TIGIT + 、PD1 + 细胞比例较高,CD127 + 细胞比例较低;CD8 T 细胞中 TIM3 + 、TIGIT + 、HLA-DR + 细胞频率较高,CD127、CD160 的 MFI 表达较低。T细胞中Co-IRs的表达与可溶性PD-1、PDL-2和TIM3水平以及系统性红斑狼疮的疾病活动、临床表型和免疫疗法反应相关。功能障碍通路的特征定义了 LN ESRD 患者独特的免疫模式。外周血 T 细胞中 Co-IRs 的表达水平和血清中可溶性 PD1/PDL-2/TIM3 的水平可作为评估临床参数和治疗反应的生物标记物。
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