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Low-level brain somatic mutations in exonic regions are collectively implicated in autism with germline mutations in autism risk genes 外显子区域的低水平脑体细胞突变与自闭症风险基因的种系突变共同牵涉到自闭症。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1038/s12276-024-01284-1
Il Bin Kim, Myeong-Heui Kim, Saehoon Jung, Woo Kyeong Kim, Junehawk Lee, Young Seok Ju, Maree J. Webster, Sanghyeon Kim, Ja Hye Kim, Hyun Jung Kim, Junho Kim, Sangwoo Kim, Jeong Ho Lee
Low-level somatic mutations in the human brain are implicated in various neurological disorders. The contribution of low-level brain somatic mutations to autism spectrum disorder (ASD), however, remains poorly understood. Here, we performed high-depth exome sequencing with an average read depth of 559.3x in 181 cortical, cerebellar, and peripheral tissue samples to identify brain somatic single nucleotide variants (SNVs) in 24 ASD subjects and 31 controls. We detected ~2.4 brain somatic SNVs per exome per single brain region, with a variant allele frequency (VAF) as low as 0.3%. The mutational profiles, including the number, signature, and type, were not significantly different between the ASD patients and controls. Intriguingly, when considering genes with low-level brain somatic SNVs and ASD risk genes with damaging germline SNVs together, the merged set of genes carrying either somatic or germline SNVs in ASD patients was significantly involved in ASD-associated pathophysiology, including dendrite spine morphogenesis (p = 0.025), mental retardation (p = 0.012), and intrauterine growth retardation (p = 0.012). Additionally, the merged gene set showed ASD-associated spatiotemporal expression in the early and mid-fetal cortex, striatum, and thalamus (all p < 0.05). Patients with damaging mutations in the merged gene set had a greater ASD risk than did controls (odds ratio = 3.92, p = 0.025, 95% confidence interval = 1.12–14.79). The findings of this study suggest that brain somatic SNVs and germline SNVs may collectively contribute to ASD-associated pathophysiology. Autism Spectrum Disorder is a complex condition influenced by various genetic factors, including inherited traits and new changes in genes. This study investigates the role of low-level brain somatic mutations in ASD. The researchers analyzed brain tissues from deceased individuals, both with and without ASD, using high-depth whole-exome sequencing. The results showed that low-level brain somatic mutations, along with inherited genetic variations, contribute to ASD’s genetic makeup. These mutations were found in genes linked to brain development and function. The study emphasizes the need to consider both inherited and somatic mutations to understand ASD’s genetic complexity. Researchers conclude that the interaction between somatic and inherited mutations is crucial in ASD, providing new insights into its genetic basis. This study enhances our understanding of ASD’s genetic diversity and suggests a multifaceted genetic contribution to the disorder. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
人脑中的低水平体细胞突变与各种神经系统疾病有关。然而,人们对低水平大脑体细胞突变对自闭症谱系障碍(ASD)的影响仍然知之甚少。在这里,我们对 181 份皮层、小脑和外周组织样本进行了平均读取深度为 559.3 倍的高深度外显子测序,以鉴定 24 名 ASD 受试者和 31 名对照者的脑体细胞单核苷酸变异(SNVs)。我们在每个脑区的每个外显子组检测到约 2.4 个脑部体细胞 SNV,变异等位基因频率 (VAF) 低至 0.3%。ASD患者和对照组的突变特征,包括数量、特征和类型,均无显著差异。耐人寻味的是,当把低水平脑部体细胞SNV基因和具有破坏性种系SNV基因的ASD风险基因放在一起考虑时,ASD患者中携带体细胞或种系SNV基因的合并基因集明显参与了ASD相关的病理生理学,包括树突棘形态发生(p = 0.025)、智力迟钝(p = 0.012)和宫内生长迟缓(p = 0.012)。此外,合并后的基因组在胎儿早期和中期皮层、纹状体和丘脑中显示出与 ASD 相关的时空表达(均 p = 0.025)。
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引用次数: 0
Neutrophil extracellular traps mediate the crosstalk between plaque microenvironment and unstable carotid plaque formation 中性粒细胞胞外捕获器介导斑块微环境与不稳定颈动脉斑块形成之间的相互影响。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1038/s12276-024-01281-4
Yu Cao, Minghui Chen, Xinyu Jiao, Shuijie Li, Dong Wang, Yongxuan Zhan, Jiaju Li, Zhongfei Hao, Qingbin Li, Yang Liu, Yan Feng, Ruiyan Li, Hongjun Wang, Mingli Liu, Qiang Fu, Yongli Li
The development of unstable carotid atherosclerotic plaques is associated with the induction of neutrophil extracellular traps (NETs) via the activation of diverse inflammatory mediators in the circulating bloodstream. However, the underlying mechanisms through which NETs influence the microenvironment of atherosclerotic plaques and contribute to the development of unstable carotid plaques remain largely elusive. The objective of this study was to elucidate the role of myeloid differentiation protein 1 (MD-1, LY86)-induced NETs underlying the crosstalk between unstable plaque formation and the plaque microenvironment. We employed bioinformatics analysis to identify key genes associated with carotid-unstable plaque, followed by comprehensive validation using various experimental approaches on tissue specimens and plasma samples classified based on pathological characteristics. Patients with carotid-unstable plaques exhibited elevated plasma concentrations of MD-1 (LY86), while patients with stable plaques demonstrated comparatively lower levels. Furthermore, soluble MD-1 was found to induce the formation of NETs through activation of Toll-like receptor signaling pathway. The proliferative and immature vascularization effects of NETs on endothelial cells, as well as their inhibitory impact on cell migration, are directly correlated with the concentration of NETs. Additionally, NETs were found to activate the NF-κB signaling pathway, thereby upregulating ICAM1, VCAM1, MMP14, VEGFA, and IL6 expression in both Human umbilical vein endothelial cells (HUVECs) and HAECs. Subsequently, a significant increase in intraplaque neovascularization by NETs results in poor carotid plaque stability, and NETs in turn stimulate macrophages to produce more MD-1, generating a harmful positive feedback loop. Our findings suggest that soluble MD-1 in the bloodstream triggers the production of NETs through activation of the Toll-like receptor signaling pathway and further indicate NETs mediate a crosstalk between the microenvironment of the carotid plaque and the neovascularization of the intraplaque region. Inhibiting NETs formation or MD-1 secretion may represent a promising strategy to effectively suppress the development of unstable carotid plaques. Atherosclerosis, a disease where arteries get blocked with fat, is a main cause of heart disease and stroke. Predicting which atherosclerotic plaques will cause heart attacks is hard. Researchers analyzed gene data from unstable and stable carotid plaques, focusing on neutrophils and a protein called MD-1. The study involved 30 patients and 10 healthy volunteers to understand how MD-1 and neutrophils contribute to plaque instability. The main finding is that MD-1 could be a biomarker for unstable plaques, offering a new target for therapies to prevent major heart events. This progress in understanding the molecular mechanisms behind plaque instability could lead to better prevention strategies for heart disease. Future re
不稳定颈动脉粥样硬化斑块的形成与中性粒细胞胞外捕获物(NET)通过激活循环血液中的多种炎症介质诱导有关。然而,NETs 影响动脉粥样硬化斑块的微环境并导致不稳定颈动脉斑块发展的潜在机制在很大程度上仍然难以捉摸。本研究的目的是阐明髓系分化蛋白1(MD-1,LY86)诱导的NET在不稳定斑块形成和斑块微环境之间的相互作用。我们采用生物信息学分析方法确定了与颈动脉不稳定斑块相关的关键基因,然后利用各种实验方法对根据病理特征分类的组织标本和血浆样本进行了全面验证。颈动脉不稳定斑块患者的血浆中MD-1(LY86)浓度升高,而稳定斑块患者的浓度相对较低。此外,研究还发现可溶性 MD-1 可通过激活 Toll 样受体信号通路诱导 NET 的形成。NETs对内皮细胞的增殖和未成熟血管形成作用以及对细胞迁移的抑制作用与NETs的浓度直接相关。此外,研究还发现 NETs 能激活 NF-κB 信号通路,从而上调 ICAM1、VCAM1、MMP14、VEGFA 和 IL6 在人脐静脉内皮细胞(HUVECs)和 HAECs 中的表达。随后,NET 导致斑块内新生血管显著增加,导致颈动脉斑块稳定性变差,NET 反过来又刺激巨噬细胞产生更多的 MD-1,从而产生有害的正反馈循环。我们的研究结果表明,血液中的可溶性MD-1通过激活Toll样受体信号通路触发NET的产生,并进一步表明NET介导了颈动脉斑块微环境与斑块内新生血管之间的串联。抑制NETs的形成或MD-1的分泌可能是有效抑制不稳定颈动脉斑块发展的一种有前途的策略。
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引用次数: 0
The potential role of gut microbiota-derived metabolites as regulators of metabolic syndrome-associated mitochondrial and endolysosomal dysfunction in Alzheimer’s disease 肠道微生物群衍生代谢物作为阿尔茨海默病代谢综合征相关线粒体和内溶酶体功能障碍调节剂的潜在作用。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1038/s12276-024-01282-3
Young Hyun Jung, Chang Woo Chae, Ho Jae Han
Although the role of gut microbiota (GMB)-derived metabolites in mitochondrial and endolysosomal dysfunction in Alzheimer’s disease (AD) under metabolic syndrome remains unclear, deciphering these host–metabolite interactions represents a major public health challenge. Dysfunction of mitochondria and endolysosomal networks (ELNs) plays a crucial role in metabolic syndrome and can exacerbate AD progression, highlighting the need to study their reciprocal regulation for a better understanding of how AD is linked to metabolic syndrome. Concurrently, metabolic disorders are associated with alterations in the composition of the GMB. Recent evidence suggests that changes in the composition of the GMB and its metabolites may be involved in AD pathology. This review highlights the mechanisms of metabolic syndrome-mediated AD development, focusing on the interconnected roles of mitochondrial dysfunction, ELN abnormalities, and changes in the GMB and its metabolites. We also discuss the pathophysiological role of GMB-derived metabolites, including amino acids, fatty acids, other metabolites, and extracellular vesicles, in mediating their effects on mitochondrial and ELN dysfunction. Finally, this review proposes therapeutic strategies for AD by directly modulating mitochondrial and ELN functions through targeting GMB metabolites under metabolic syndrome. Although mitochondrial and endolysosomal network (ELN) impairment in metabolic syndrome is considered a risk factor for neurodegenerative diseases, the regulatory role of gut microbiota (GMB)-derived metabolites in this dysfunction remains unclear. This research explores the roles and molecular mechanisms of mitochondrial dysfunction, ELN abnormalities, dysregulation of mitochondria-ELN crosstalk, and changes in GMB and its metabolites in metabolic syndrome, especially in relation to Alzheimer’s disease (AD). The researchers conclude by highlighting the potential of targeting GMB and its metabolites to develop new AD treatments, especially for those with metabolic syndrome. They suggest that understanding and modulating the links between gut health, mitochondrial function, and ELN activity could lead to new management strategies for AD in the context of gut microbiota and its metabolites. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
虽然肠道微生物群(GMB)产生的代谢物在代谢综合征下阿尔茨海默病(AD)的线粒体和内溶酶体功能障碍中的作用仍不清楚,但破译这些宿主-代谢物之间的相互作用是一项重大的公共卫生挑战。线粒体和内溶酶体网络(ELNs)的功能障碍在代谢综合征中起着至关重要的作用,并可加剧阿尔茨海默病的进展,这突出表明有必要研究它们之间的相互调控,以更好地了解阿尔茨海默病如何与代谢综合征联系在一起。同时,代谢紊乱与 GMB 组成的改变有关。最近的证据表明,GMB及其代谢物的组成变化可能与AD病理有关。本综述强调了代谢综合征介导的 AD 发病机制,重点是线粒体功能障碍、ELN 异常和 GMB 及其代谢物变化的相互关联作用。我们还讨论了 GMB 衍生代谢物(包括氨基酸、脂肪酸、其他代谢物和细胞外囊泡)在介导线粒体和 ELN 功能障碍方面的病理生理作用。最后,本综述提出了针对代谢综合征的 GMB 代谢物直接调节线粒体和 ELN 功能的 AD 治疗策略。
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引用次数: 0
Author Correction: Insulin signaling is critical for sinoatrial node maintenance and function 作者更正:胰岛素信号对中房节点的维持和功能至关重要
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-24 DOI: 10.1038/s12276-024-01278-z
Sangmi Ock, Seong Woo Choi, Seung Hee Choi, Hyun Kang, Sung Joon Kim, Wang-Soo Lee, Jaetaek Kim
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引用次数: 0
Publisher Correction: Alleviation of preeclampsia-like symptoms through PlGF and eNOS regulation by hypoxia- and NF-κB-responsive miR-214-3p deletion 出版商更正:缺氧和 NF-κB 响应型 miR-214-3p 基因缺失可通过 PlGF 和 eNOS 调节缓解先兆子痫样症状。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-18 DOI: 10.1038/s12276-024-01275-2
Suji Kim, Sungbo Shim, Jisoo Kwon, Sungwoo Ryoo, Junyoung Byeon, Jungwoo Hong, Jeong-Hyung Lee, Young-Guen Kwon, Ji-Yoon Kim, Young-Myeong Kim
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引用次数: 0
Accelerated aging of skeletal muscle and the immune system in patients with chronic liver disease 加速慢性肝病患者骨骼肌和免疫系统的衰老。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-18 DOI: 10.1038/s12276-024-01287-y
Thomas Nicholson, Amritpal Dhaliwal, Jonathan I. Quinlan, Sophie L. Allen, Felicity R. Williams, Jon Hazeldine, Kirsty C. McGee, Jack Sullivan, Leigh Breen, Ahmed M. Elsharkawy, Matthew J. Armstrong, Simon W. Jones, Carolyn A. Greig, Janet M. Lord
Patients with chronic liver disease (CLD) often present with significant frailty, sarcopenia, and impaired immune function. However, the mechanisms driving the development of these age-related phenotypes are not fully understood. To determine whether accelerated biological aging may play a role in CLD, epigenetic, transcriptomic, and phenotypic assessments were performed on the skeletal muscle tissue and immune cells of CLD patients and age-matched healthy controls. Accelerated biological aging of the skeletal muscle tissue of CLD patients was detected, as evidenced by an increase in epigenetic age compared with chronological age (mean +2.2 ± 4.8 years compared with healthy controls at −3.0 ± 3.2 years, p = 0.0001). Considering disease etiology, age acceleration was significantly greater in both the alcohol-related (ArLD) (p = 0.01) and nonalcoholic fatty liver disease (NAFLD) (p = 0.0026) subgroups than in the healthy control subgroup, with no age acceleration observed in the immune-mediated subgroup or healthy control subgroup (p = 0.3). The skeletal muscle transcriptome was also enriched for genes associated with cellular senescence. Similarly, blood cell epigenetic age was significantly greater than that in control individuals, as calculated using the PhenoAge (p < 0.0001), DunedinPACE (p < 0.0001), or Hannum (p = 0.01) epigenetic clocks, with no difference using the Horvath clock. Analysis of the IMM-Age score indicated a prematurely aged immune phenotype in CLD patients that was 2-fold greater than that observed in age-matched healthy controls (p < 0.0001). These findings suggested that accelerated cellular aging may contribute to a phenotype associated with advanced age in CLD patients. Therefore, therapeutic interventions to reduce biological aging in CLD patients may improve health outcomes. Chronic liver disease, a long-term condition damaging the liver, is causing more deaths worldwide. Patients often develop immune dysfunction and sarcopenia. This study aimed to see if CLD patients show signs of fast biological ageing, particularly in muscles and the immune system. The research compared CLD patients to healthy people, looking at muscle samples, blood samples, and immune cells to check for ageing signs. Results showed that CLD patients have faster biological ageing in muscles and immune cells, with increased epigenetic age and more senescence-associated genes. This suggests that CLD speeds up the ageing process, which could explain the common occurrence of sarcopenia and immune dysfunction in these patients. Future implications include the possibility of developing treatments targeting the ageing process in CLD patients, offering hope for better health and quality of life This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
慢性肝病(CLD)患者通常表现出明显的虚弱、肌肉疏松和免疫功能受损。然而,这些与年龄有关的表型的形成机制尚未完全明了。为了确定加速生物衰老是否可能在 CLD 中起作用,研究人员对 CLD 患者和年龄匹配的健康对照组的骨骼肌组织和免疫细胞进行了表观遗传学、转录组学和表型评估。结果发现,CLD 患者骨骼肌组织的生物衰老速度加快,表现为表观遗传年龄比实际年龄增加(平均+2.2 ± 4.8岁,而健康对照组为-3.0 ± 3.2岁,P = 0.0001)。考虑到疾病病因,与酒精相关(ArLD)(p = 0.01)和非酒精性脂肪肝(NAFLD)(p = 0.0026)亚组的年龄加速明显大于健康对照亚组,免疫介导亚组或健康对照亚组未观察到年龄加速(p = 0.3)。骨骼肌转录组也富集了与细胞衰老相关的基因。同样,使用 PhenoAge 计算得出的血细胞表观遗传年龄也明显大于对照组(p = 0.3)。
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引用次数: 0
The role of BCAA metabolism in metabolic health and disease BCAA 代谢在代谢健康和疾病中的作用。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-02 DOI: 10.1038/s12276-024-01263-6
Byeong Hun Choi, Seunghoon Hyun, Seung-Hoi Koo
It has long been postulated that dietary restriction is beneficial for ensuring longevity and extending the health span of mammals, including humans. In particular, a reduction in protein consumption has been shown to be specifically linked to the beneficial effect of dietary restriction on metabolic disorders, presumably by reducing the activity of the mechanistic target of rapamycin complex (mTORC) 1 and the reciprocal activation of AMP-activated protein kinase (AMPK) and sirtuin pathways. Although it is widely used as a dietary supplement to delay the aging process in humans, recent evidence suggests that branched-chain amino acids (BCAAs) might be a major cause of the deteriorating effect of a protein diet on aging and related disorders. In this review, we delineate the regulation of metabolic pathways for BCAAs at the tissue-specific level and summarize recent findings regarding the role of BCAAs in the control of metabolic health and disease in mammals. This review article illustrates the function of branched-chain amino acids (BCAAs - essential nutrients we get from food) and how they’re processed in our bodies, in relation to health and illness. BCAAs are connected to aging processes and metabolic health - the body’s way of converting food into energy. Recent studies found that reducing BCAA intake can improve the health and lifespan of rodents. Similar studies were also conducted by using different animal models, like yeast, flies, rodents, and primates. It also emphasized the potential influence of BCAAs on human disease and aging metabolic processes. The review article concluded that BCAAs and their processing are vital for metabolic health and lifespan, and more research is needed to understand their effect on human health. Further studies on BCAAs could be important for creating diet plans and treatments for metabolic issues and aging-related diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
长期以来,人们一直认为限制饮食有利于确保哺乳动物(包括人类)长寿并延长其健康寿命。特别是,蛋白质摄入量的减少已被证明与饮食限制对代谢紊乱的有益影响有特别联系,这可能是通过降低雷帕霉素机理靶点复合体(mTORC)1的活性以及AMP激活蛋白激酶(AMPK)和sirtuin通路的相互激活来实现的。尽管支链氨基酸被广泛用作延缓人类衰老的膳食补充剂,但最近的证据表明,支链氨基酸可能是导致蛋白质膳食对衰老和相关疾病产生不良影响的主要原因。在这篇综述中,我们将从组织特异性水平上描述支链氨基酸代谢途径的调控,并总结有关支链氨基酸在控制哺乳动物代谢健康和疾病方面作用的最新发现。
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引用次数: 0
Circadian disruption reduces MUC4 expression via the clock molecule BMAL1 during dry eye development 在干眼发育过程中,昼夜节律紊乱会通过时钟分子 BMAL1 减少 MUC4 的表达。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-02 DOI: 10.1038/s12276-024-01269-0
Hao Zeng, Xue Yang, Kai Liao, Xin Zuo, Lihong Liang, Dalian He, Rong Ju, Bowen Wang, Jin Yuan
Circadian disruption, as a result of shiftwork, jet lag, and other lifestyle factors, is a common public health problem associated with a wide range of diseases, such as metabolic disorders, neurodegenerative diseases, and cancer. In the present study, we established a chronic jet lag model using a time shift method every 3 days and assessed the effects of circadian disruption on ocular surface homeostasis. Our results indicated that jet lag increased corneal epithelial defects, cell apoptosis, and proinflammatory cytokine expression. However, the volume of tear secretion and the number of conjunctival goblet cells did not significantly change after 30 days of jet lag. Moreover, further analysis of the pathogenic mechanism using RNA sequencing revealed that jet lag caused corneal transmembrane mucin deficiency, specifically MUC4 deficiency. The crucial role of MUC4 in pathogenic progression was demonstrated by the protection of corneal epithelial cells and the inhibition of inflammatory activation following MUC4 replenishment. Unexpectedly, genetic ablation of BMAL1 in mice caused MUC4 deficiency and dry eye disease. The underlying mechanism was revealed in cultured human corneal epithelial cells in vitro, where BMAL1 silencing reduced MUC4 expression, and BMAL1 overexpression increased MUC4 expression. Furthermore, melatonin, a circadian rhythm restorer, had a therapeutic effect on jet lag-induced dry eye by restoring the expression of BMAL1, which upregulated MUC4. Thus, we generated a novel dry eye mouse model induced by circadian disruption, elucidated the underlying mechanism, and identified a potential clinical treatment. Dry eye disease, a long-term issue causing discomfort and vision problems, impacts millions globally. In this research, scientists studied how disturbances in our internal clock contribute to DED. Researchers made the mice experience an 8-hour shift in their day-night cycle every 3 days, imitating chronic jet lag. The findings showed that chronic jet lag resulted in a significant decrease in MUC4 expression in the cornea, leading to DED symptoms. Supplementing with MUC4 or treating the mice with melatonin, eased these symptoms. This indicates that disruptions to our internal clock can directly affect eye health by impacting key protective proteins in the eye. Researchers conclude that maintaining a healthy internal clock is vital for eye health and that treatments targeting internal clock disruptions could help DED patients. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
由于轮班工作、时差和其他生活方式因素造成的昼夜节律紊乱是一个常见的公共健康问题,与代谢紊乱、神经退行性疾病和癌症等多种疾病相关。在本研究中,我们使用每 3 天一次的时间转换方法建立了一个慢性时差模型,并评估了昼夜节律紊乱对眼表平衡的影响。结果表明,时差增加了角膜上皮缺陷、细胞凋亡和促炎细胞因子的表达。然而,时差 30 天后,泪液分泌量和结膜上皮细胞的数量并无明显变化。此外,利用 RNA 测序对致病机制的进一步分析表明,时差导致角膜跨膜粘蛋白缺乏,特别是 MUC4 缺乏。补充 MUC4 后,角膜上皮细胞得到保护,炎症激活也受到抑制,这证明了 MUC4 在致病过程中的关键作用。意想不到的是,小鼠BMAL1基因消减会导致MUC4缺乏和干眼症。在体外培养的人类角膜上皮细胞中,BMAL1沉默会减少MUC4的表达,而BMAL1过表达则会增加MUC4的表达。此外,褪黑激素是一种昼夜节律恢复剂,它能恢复 BMAL1 的表达,从而上调 MUC4,对时差引起的干眼症有治疗作用。因此,我们建立了一种由昼夜节律紊乱诱发的新型干眼症小鼠模型,阐明了其潜在机制,并确定了一种潜在的临床治疗方法。
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引用次数: 0
Patient-derived tumor organoids: a new avenue for preclinical research and precision medicine in oncology 源自患者的肿瘤器官组织:肿瘤学临床前研究和精准医疗的新途径。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1038/s12276-024-01272-5
Lucie Thorel, Marion Perréard, Romane Florent, Jordane Divoux, Sophia Coffy, Audrey Vincent, Cédric Gaggioli, Géraldine Guasch, Xavier Gidrol, Louis-Bastien Weiswald, Laurent Poulain
Over the past decade, the emergence of patient-derived tumor organoids (PDTOs) has broadened the repertoire of preclinical models and progressively revolutionized three-dimensional cell culture in oncology. PDTO can be grown from patient tumor samples with high efficiency and faithfully recapitulates the histological and molecular characteristics of the original tumor. Therefore, PDTOs can serve as invaluable tools in oncology research, and their translation to clinical practice is exciting for the future of precision medicine in oncology. In this review, we provide an overview of methods for establishing PDTOs and their various applications in cancer research, starting with basic research and ending with the identification of new targets and preclinical validation of new anticancer compounds and precision medicine. Finally, we highlight the challenges associated with the clinical implementation of PDTO, such as its representativeness, success rate, assay speed, and lack of a tumor microenvironment. Technological developments and autologous cocultures of PDTOs and stromal cells are currently ongoing to meet these challenges and optimally exploit the full potential of these models. The use of PDTOs as standard tools in clinical oncology could lead to a new era of precision oncology in the coming decade. The shift from 2D to 3D cell cultures has greatly improved cancer research, providing a more realistic model of tumors. Patient-Derived Tumor Organoids (PDTOs) have become a key tool in cancer research, allowing scientists to grow efficiently tumor cells from patient samples in a 3D environment that closely mirrors the original tumor. PDTOs are a major step forward in cancer research, bridging the gap between traditional cell cultures and clinical realities, with the potential for successful clinical applications despite some challenges that could be overcome by technological developments. Thus, they offer a promising platform for understanding cancer, testing drug responses, and developing personalized treatments, with the potential to greatly impact future patient care. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
在过去十年中,患者来源肿瘤器官组织(PDTO)的出现拓宽了临床前模型的范围,并逐步革新了肿瘤学中的三维细胞培养。PDTO 可以从患者肿瘤样本中高效培养出来,并忠实再现原始肿瘤的组织学和分子特征。因此,PDTO 可作为肿瘤学研究的宝贵工具,将其应用于临床实践对肿瘤学精准医学的未来发展具有重要意义。在这篇综述中,我们概述了建立 PDTO 的方法及其在癌症研究中的各种应用,从基础研究开始,到新靶点的鉴定、新抗癌化合物的临床前验证和精准医疗。最后,我们强调了与 PDTO 临床应用相关的挑战,如其代表性、成功率、检测速度和缺乏肿瘤微环境等。为应对这些挑战并以最佳方式充分挖掘这些模型的潜力,目前正在进行技术开发以及 PDTO 和基质细胞的自体共培养。将 PDTOs 作为临床肿瘤学的标准工具可在未来十年开创精准肿瘤学的新纪元。
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引用次数: 0
Phospholipase C-β3 is dispensable for vascular constriction but indispensable for vascular hyperplasia 磷脂酶 C-β3 对于血管收缩是不可或缺的,但对于血管增生却是不可或缺的。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1038/s12276-024-01271-6
Seo Yeon Jin, Jung Min Ha, Hye Jin Kum, Ji Soo Ma, Hong Koo Ha, Sang Heon Song, Yong Ryoul Yang, Ho Lee, Yoon Soo Bae, Masahiro Yamamoto, Pann-Ghill Suh, Sun Sik Bae
Angiotensin II (AngII) induces the contraction and proliferation of vascular smooth muscle cells (VSMCs). AngII activates phospholipase C-β (PLC-β), thereby inducing Ca2+ mobilization as well as the production of reactive oxygen species (ROS). Since contraction is a unique property of contractile VSMCs, signaling cascades related to the proliferation of VSMCs may differ. However, the specific molecular mechanism that controls the contraction or proliferation of VSMCs remains unclear. AngII-induced ROS production, migration, and proliferation were suppressed by inhibiting PLC-β3, inositol trisphosphate (IP3) receptor, and NOX or by silencing PLC-β3 or NOX1 but not by NOX4. However, pharmacological inhibition or silencing of PLC-β3 or NOX did not affect AngII-induced VSMC contraction. Furthermore, the AngII-dependent constriction of mesenteric arteries isolated from PLC-β3∆SMC, NOX1−/−, NOX4−/− and normal control mice was similar. AngII-induced VSMC contraction and mesenteric artery constriction were blocked by inhibiting the L-type calcium channel Rho-associated kinase 2 (ROCK2) or myosin light chain kinase (MLCK). The activation of ROCK2 and MLCK was significantly induced in PLC-β3∆SMC mice, whereas the depletion of Ca2+ in the extracellular medium suppressed the AngII-induced activation of ROCK2, MLCK, and vasoconstriction. AngII-induced hypertension was significantly induced in NOX1−/− and PLC-β3∆SMC mice, whereas LCCA ligation-induced neointima formation was significantly suppressed in NOX1−/− and PLC-β3∆SMC mice. These results suggest that PLC-β3 is essential for vascular hyperplasia through NOX1-mediated ROS production but is nonessential for vascular constriction or blood pressure regulation. Angiotensin II is important in heart health. It makes blood vessels tighten and grow. This study looked at how AngII affects the creation of reactive oxygen species (ROS, molecules that change cell function) in vascular smooth muscle cells (VSMCs, cells in blood vessel walls). The researchers tested how stopping certain cell signals changes ROS creation and cell behaviors like growth and movement. They found that a specific protein, PLC-β3, and an enzyme, NOX1, are key in this process. Stopping these molecules could lower ROS levels and change cell growth and movement, important for blood vessel health. Interestingly, these molecules didn’t affect blood vessel tightening, also controlled by AngII. This study could help develop new treatments for blood vessel diseases, potentially helping manage conditions like high blood pressure and heart disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
血管紧张素 II(AngII)可诱导血管平滑肌细胞(VSMC)收缩和增殖。血管紧张素 II 会激活磷脂酶 C-β(PLC-β),从而诱导 Ca2+ 迁移并产生活性氧(ROS)。由于收缩是收缩性血管内皮细胞的独特特性,与血管内皮细胞增殖相关的信号级联可能有所不同。然而,控制 VSMC 收缩或增殖的具体分子机制仍不清楚。抑制 PLC-β3、三磷酸肌醇(IP3)受体和 NOX 或沉默 PLC-β3 或 NOX1 均可抑制 AngII 诱导的 ROS 生成、迁移和增殖,但 NOX4 却不能抑制。然而,药物抑制或沉默 PLC-β3 或 NOX 并不影响 AngII 诱导的 VSMC 收缩。此外,从 PLC-β3∆SMC、NOX1-/-、NOX4-/- 和正常对照小鼠分离的肠系膜动脉受 AngII 依赖性收缩的情况相似。抑制 L 型钙通道罗-相关激酶 2(ROCK2)或肌球蛋白轻链激酶(MLCK)可阻断 AngII 诱导的 VSMC 收缩和肠系膜动脉收缩。在 PLC-β3∆SMC 小鼠中,ROCK2 和 MLCK 的活化被显著诱导,而细胞外培养基中 Ca2+ 的耗竭抑制了 AngII 诱导的 ROCK2、MLCK 活化和血管收缩。NOX1-/-和 PLC-β3∆SMC 小鼠明显诱发了 AngII 诱导的高血压,而 NOX1-/- 和 PLC-β3∆SMC 小鼠则明显抑制了 LCCA 结扎诱导的新内膜形成。这些结果表明,PLC-β3 通过 NOX1 介导的 ROS 生成对血管增生是必不可少的,但对血管收缩或血压调节则是非必需的。
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Experimental and Molecular Medicine
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