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The Frank-Starling mechanism is not enough: blood volume expansion prominently decreases pulmonary O2 uptake. 仅靠弗兰克-斯塔林机制是不够的:血容量扩张会显著减少肺部对氧气的吸收。
IF 16.7 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-07-02 DOI: 10.1186/s40779-024-00546-3
Mei-Han Guo, Candela Diaz-Canestro, David Montero
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引用次数: 0
Gut microbiota helps identify clinical subtypes of Parkinson's disease. 肠道微生物群有助于确定帕金森病的临床亚型。
IF 16.7 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-07-01 DOI: 10.1186/s40779-024-00545-4
Jing-Yi Wang, Rui Xie, Yun Feng, Min-Na Zhang, Le He, Bo Yang, Hong-Gang Wang, Xiao-Zhong Yang
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引用次数: 0
PANX1-mediated ATP release confers FAM3A's suppression effects on hepatic gluconeogenesis and lipogenesis. PANX1 介导的 ATP 释放赋予了 FAM3A 对肝脏葡萄糖生成和脂肪生成的抑制作用。
IF 16.7 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-06-27 DOI: 10.1186/s40779-024-00543-6
Cheng-Qing Hu, Tao Hou, Rui Xiang, Xin Li, Jing Li, Tian-Tian Wang, Wen-Jun Liu, Song Hou, Di Wang, Qing-He Zhao, Xiao-Xing Yu, Ming Xu, Xing-Kai Liu, Yu-Jing Chi, Ji-Chun Yang

Background: Extracellular adenosine triphosphate (ATP) is an important signal molecule. In previous studies, intensive research had revealed the crucial roles of family with sequence similarity 3 member A (FAM3A) in controlling hepatic glucolipid metabolism, islet β cell function, adipocyte differentiation, blood pressure, and other biological and pathophysiological processes. Although mitochondrial protein FAM3A plays crucial roles in the regulation of glucolipid metabolism via stimulating ATP release to activate P2 receptor pathways, its mechanism in promoting ATP release in hepatocytes remains unrevealed.

Methods: db/db, high-fat diet (HFD)-fed, and global pannexin 1 (PANX1) knockout mice, as well as liver sections of individuals, were used in this study. Adenoviruses and adeno-associated viruses were utilized for in vivo gene overexpression or inhibition. To evaluate the metabolic status in mice, oral glucose tolerance test (OGTT), pyruvate tolerance test (PTT), insulin tolerance test (ITT), and magnetic resonance imaging (MRI) were conducted. Protein-protein interactions were determined by coimmunoprecipitation with mass spectrometry (MS) assays.

Results: In livers of individuals and mice with steatosis, the expression of ATP-permeable channel PANX1 was increased (P < 0.01). Hepatic PANX1 overexpression ameliorated the dysregulated glucolipid metabolism in obese mice. Mice with hepatic PANX1 knockdown or global PANX1 knockout exhibited disturbed glucolipid metabolism. Restoration of hepatic PANX1 rescued the metabolic disorders of PANX1-deficient mice (P < 0.05). Mechanistically, ATP release is mediated by the PANX1-activated protein kinase B-forkhead box protein O1 (Akt-FOXO1) pathway to inhibit gluconeogenesis via P2Y receptors in hepatocytes. PANX1-mediated ATP release also activated calmodulin (CaM) (P < 0.01), which interacted with c-Jun N-terminal kinase (JNK) to inhibit its activity, thereby deactivating the transcription factor activator protein-1 (AP1) and repressing fatty acid synthase (FAS) expression and lipid synthesis (P < 0.05). FAM3A stimulated the expression of PANX1 via heat shock factor 1 (HSF1) in hepatocytes (P < 0.05). Notably, FAM3A overexpression failed to promote ATP release, inhibit the expression of gluconeogenic and lipogenic genes, and suppress gluconeogenesis and lipid deposition in PANX1-deficient hepatocytes and livers.

Conclusions: PANX1-mediated release of ATP plays a crucial role in maintaining hepatic glucolipid homeostasis, and it confers FAM3A's suppressive effects on hepatic gluconeogenesis and lipogenesis.

背景:细胞外三磷酸腺苷(ATP)是一种重要的信号分子。以往的深入研究揭示了序列相似性 3 家族成员 A(FAM3A)在控制肝脏糖脂代谢、胰岛β细胞功能、脂肪细胞分化、血压等生物和病理生理过程中的关键作用。尽管线粒体蛋白 FAM3A 通过刺激 ATP 释放激活 P2 受体通路在调节糖脂代谢中发挥着关键作用,但其促进肝细胞中 ATP 释放的机制仍未被揭示。方法:本研究使用了 db/db、高脂饮食(HFD)喂养和全基因 pannexin 1(PANX1)敲除小鼠以及个体肝脏切片。腺病毒和腺相关病毒被用于体内基因过表达或抑制。为了评估小鼠的代谢状况,进行了口服葡萄糖耐量试验(OGTT)、丙酮酸耐量试验(PTT)、胰岛素耐量试验(ITT)和磁共振成像(MRI)。蛋白质与蛋白质之间的相互作用是通过免疫共沉淀和质谱分析测定的:结果:在患有脂肪变性的个体和小鼠肝脏中,ATP 通透性通道 PANX1 的表达量增加(P 结论:PANX1 介导了脂肪变性的释放:PANX1 介导的 ATP 释放在维持肝糖脂平衡中起着至关重要的作用,它赋予了 FAM3A 对肝糖脂生成和脂肪生成的抑制作用。
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引用次数: 0
Role of signaling pathways in age-related orthopedic diseases: focus on the fibroblast growth factor family. 信号通路在老年骨科疾病中的作用:关注成纤维细胞生长因子家族。
IF 16.7 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-06-21 DOI: 10.1186/s40779-024-00544-5
Heng-Zhen Li, Jing-Lve Zhang, Dong-Liang Yuan, Wen-Qing Xie, Christoph H Ladel, Ali Mobasheri, Yu-Sheng Li

Fibroblast growth factor (FGF) signaling encompasses a multitude of functions, including regulation of cell proliferation, differentiation, morphogenesis, and patterning. FGFs and their receptors (FGFR) are crucial for adult tissue repair processes. Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage, bone loss, muscle reduction, and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and sarcopenia. In OA and IVDD pathologies specifically, FGF1, FGF2, FGF8, FGF9, FGF18, FGF21, and FGF23 regulate the synthesis, catabolism, and ossification of cartilage tissue. Additionally, the dysregulation of FGFR expression (FGFR1 and FGFR3) promotes the pathological process of cartilage degradation. In OP and sarcopenia, endocrine-derived FGFs (FGF19, FGF21, and FGF23) modulate bone mineral synthesis and decomposition as well as muscle tissues. FGF2 and other FGFs also exert regulatory roles. A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration. Moreover, an increasing number of potential targets within the FGF signaling have been identified, such as FGF9, FGF18, and FGF23. However, it should be noted that most of these discoveries are still in the experimental stage, and further studies are needed before clinical application can be considered. Presently, this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases. Besides, current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.

成纤维细胞生长因子(FGF)信号传导具有多种功能,包括调节细胞增殖、分化、形态发生和模式化。成纤维细胞生长因子及其受体(FGFR)对成人组织的修复过程至关重要。异常的 FGF 信号转导与各种病理状况有关,如软骨损伤、骨质流失、肌肉减少以及骨科退行性疾病(如骨关节炎(OA)、椎间盘变性(IVDD)、骨质疏松症(OP)和肌肉疏松症)中观察到的其他核心病理变化。特别是在 OA 和 IVDD 病变中,FGF1、FGF2、FGF8、FGF9、FGF18、FGF21 和 FGF23 调节软骨组织的合成、分解和骨化。此外,表皮生长因子受体表达失调(表皮生长因子受体 1 和表皮生长因子受体 3)会促进软骨降解的病理过程。在 OP 和肌肉疏松症中,内分泌源性 FGF(FGF19、FGF21 和 FGF23)可调节骨矿物质的合成和分解以及肌肉组织。FGF2 和其他 FGFs 也发挥着调节作用。越来越多的研究集中于了解 FGF 信号在骨科退化中的影响。此外,人们还发现了越来越多的 FGF 信号转导潜在靶点,如 FGF9、FGF18 和 FGF23。但需要注意的是,这些发现大多仍处于实验阶段,在考虑临床应用之前还需要进一步的研究。目前,本综述旨在记录 FGF 信号通路与骨科疾病的发生和发展之间的关联。此外,还将对目前针对 FGF 信号通路预防和治疗骨科退化的治疗策略进行评估。
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引用次数: 0
Novel radiopaque ethanol injection: physicochemical properties, animal experiments, and clinical application in vascular malformations. 新型不透射线乙醇注射液:理化特性、动物实验以及在血管畸形中的临床应用。
IF 16.7 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-06-20 DOI: 10.1186/s40779-024-00542-7
Yu-Chen Shen, De-Ming Wang, Xi-Tao Yang, Zhen-Feng Wang, Ming-Zhe Wen, Yi-Feng Han, Lian-Zhou Zheng, Ruo-Yu Di, Chun-Yu Jiang, Jing-Bing Wang, Jian-Xiong You, Li-Ming Zhang, Li-Xin Su, Xin-Dong Fan
<p><strong>Background: </strong>Despite the efficacy of absolute ethanol (EtOH), its radiolucency introduces several risks in interventional therapy for treating vascular malformations. This study aims to develop a novel radiopaque ethanol injection (REI) to address this issue.</p><p><strong>Methods: </strong>Iopromide is mixed with ethanol to achieve radiopacity and improve the physicochemical properties of the solution. Overall, 82 male New Zealand white rabbits are selected for in vivo radiopacity testing, peripheral vein sclerosis [animals were divided into the following 5 groups (n = 6): negative control (NC, saline, 0.250 ml/kg), positive control (EtOH, 0.250 ml/kg), low-dose REI (L-D REI, 0.125 ml/kg), moderate-dose REI (M-D REI, 0.250 ml/kg), and high-dose REI (H-D REI 0.375 ml/kg)], pharmacokinetic analyses (the blood sample was harvested before injection, 5 min, 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, and 8 h after injection in peripheral vein sclerosis experiment), peripheral artery embolization [animals were divided into the following 5 groups (n = 3): NC (saline, 0.250 ml/kg), positive control (EtOH, 0.250 ml/kg), L-D REI (0.125 ml/kg), M-D REI (0.250 ml/kg), and H-D REI (0.375 ml/kg)], kidney transcatheter arterial embolization [animals were divided into the following 4 groups (n = 3): positive control (EtOH, 0.250 ml/kg), L-D REI (0.125 ml/kg), M-D REI (0.250 ml/kg), and H-D REI (0.375 ml/kg); each healthy kidney was injected with saline as negative control], and biosafety evaluations [animals were divided into the following 5 groups (n = 3): NC (0.250 ml/kg), high-dose EtOH (0.375 ml/kg), L-D REI (0.125 ml/kg), M-D REI (0.250 ml/kg), and H-D REI (0.375 ml/kg)]. Then, a prospective cohort study involving 6 patients with peripheral venous malformations (VMs) is performed to explore the clinical safety and effectiveness of REI. From Jun 1, 2023 to August 31, 2023, 6 patients [age: (33.3 ± 17.2) years] with lingual VMs received sclerotherapy of REI and 2-month follow-up. Adverse events and serious adverse events were evaluated, whereas the efficacy of REI was determined by both the traceability of the REI under DSA throughout the entire injection and the therapeutic effect 2 months after a single injection.</p><p><strong>Results: </strong>The REI contains 81.4% ethanol (v/v) and 111.3 mg/ml iodine, which can be traced throughout the injection in the animals and patients. The REI also exerts a similar effect as EtOH on peripheral venous sclerosis, peripheral arterial embolization, and renal embolization. Furthermore, the REI can be metabolized at a similar rate compared to EtOH and Ultravist® and did not cause injury to the animals' heart, liver, spleen, lungs, kidneys and brain. No REI-related adverse effects have occurred during sclerotherapy of VMs, and 4/6 patients (66.7%) have achieved complete response at follow-up.</p><p><strong>Conclusion: </strong>In conclusion, REI is safe, exerts therapeutic effects, and compensates for the r
背景:尽管绝对乙醇(EtOH)疗效显著,但在治疗血管畸形的介入疗法中,其放射性不透光性会带来一些风险。本研究旨在开发一种新型不透射线乙醇注射液(REI)来解决这一问题:方法:将碘普罗米特与乙醇混合,以达到不透射线的效果,并改善溶液的理化性质。总体而言,选择 82 只雄性新西兰白兔进行体内放射能力测试,外周静脉硬化[动物分为以下 5 组(n = 6):阴性对照组(NC,生理盐水,0.250 毫升/千克)、阳性对照组(EtOH,0.250 毫升/千克)、低剂量 REI 组(L-D REI,0.125 毫升/千克)、中等剂量 REI 组(M-D REI,0.250 ml/kg)和高剂量 REI(H-D REI,0.375 ml/kg)]、药代动力学分析(注射前、注射后 5 分钟、10 分钟、20 分钟、40 分钟、1 小时、2 小时、4 小时和 8 小时采血)、外周静脉硬化实验、外周动脉栓塞[动物分为以下 5 组(n = 3):NC(生理盐水,0.250 ml/kg)、阳性对照(EtOH,0.250 ml/kg)、L-D REI(0.125 ml/kg)、M-D REI(0.250 ml/kg)和 H-D REI(0.375 ml/kg)]、肾经导管动脉栓塞[动物分为以下 4 组(n = 3):阳性对照(EtOH,0.250毫升/千克)、L-D REI(0.125毫升/千克)、M-D REI(0.250毫升/千克)和H-D REI(0.375毫升/千克);每个健康肾脏注射生理盐水作为阴性对照],以及生物安全评估[动物分为以下5组(n = 3):NC(0.250 毫升/千克)、高剂量 EtOH(0.375 毫升/千克)、L-D REI(0.125 毫升/千克)、M-D REI(0.250 毫升/千克)和 H-D REI(0.375 毫升/千克)]。然后,进行一项涉及 6 名外周静脉畸形(VMs)患者的前瞻性队列研究,以探讨 REI 的临床安全性和有效性。从2023年6月1日至2023年8月31日,6名舌侧静脉畸形患者[年龄:(33.3 ± 17.2)岁]接受了REI硬化疗法,并进行了2个月的随访。对不良事件和严重不良事件进行了评估,而 REI 的疗效则通过 REI 在整个注射过程中在 DSA 下的可追踪性以及单次注射 2 个月后的治疗效果来确定:结果:REI 含有 81.4% 的乙醇(v/v)和 111.3 毫克/毫升的碘,在动物和患者的整个注射过程中均可追踪到。REI 对外周静脉硬化、外周动脉栓塞和肾脏栓塞的作用与乙醇相似。此外,与乙醇和 Ultravist® 相比,REI 的代谢速度相似,不会对动物的心、肝、脾、肺、肾和大脑造成伤害。在对血管瘤进行硬化治疗期间,没有发生与 REI 相关的不良反应,4/6 的患者(66.7%)在随访时获得了完全应答:总之,REI 在治疗血管瘤方面是安全的,具有治疗效果,并能弥补 EtOH 的放射性:该临床试验于 2023 年 5 月 24 日注册,注册号为 ChiCTR2300071751。
{"title":"Novel radiopaque ethanol injection: physicochemical properties, animal experiments, and clinical application in vascular malformations.","authors":"Yu-Chen Shen, De-Ming Wang, Xi-Tao Yang, Zhen-Feng Wang, Ming-Zhe Wen, Yi-Feng Han, Lian-Zhou Zheng, Ruo-Yu Di, Chun-Yu Jiang, Jing-Bing Wang, Jian-Xiong You, Li-Ming Zhang, Li-Xin Su, Xin-Dong Fan","doi":"10.1186/s40779-024-00542-7","DOIUrl":"10.1186/s40779-024-00542-7","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Despite the efficacy of absolute ethanol (EtOH), its radiolucency introduces several risks in interventional therapy for treating vascular malformations. This study aims to develop a novel radiopaque ethanol injection (REI) to address this issue.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Iopromide is mixed with ethanol to achieve radiopacity and improve the physicochemical properties of the solution. Overall, 82 male New Zealand white rabbits are selected for in vivo radiopacity testing, peripheral vein sclerosis [animals were divided into the following 5 groups (n = 6): negative control (NC, saline, 0.250 ml/kg), positive control (EtOH, 0.250 ml/kg), low-dose REI (L-D REI, 0.125 ml/kg), moderate-dose REI (M-D REI, 0.250 ml/kg), and high-dose REI (H-D REI 0.375 ml/kg)], pharmacokinetic analyses (the blood sample was harvested before injection, 5 min, 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, and 8 h after injection in peripheral vein sclerosis experiment), peripheral artery embolization [animals were divided into the following 5 groups (n = 3): NC (saline, 0.250 ml/kg), positive control (EtOH, 0.250 ml/kg), L-D REI (0.125 ml/kg), M-D REI (0.250 ml/kg), and H-D REI (0.375 ml/kg)], kidney transcatheter arterial embolization [animals were divided into the following 4 groups (n = 3): positive control (EtOH, 0.250 ml/kg), L-D REI (0.125 ml/kg), M-D REI (0.250 ml/kg), and H-D REI (0.375 ml/kg); each healthy kidney was injected with saline as negative control], and biosafety evaluations [animals were divided into the following 5 groups (n = 3): NC (0.250 ml/kg), high-dose EtOH (0.375 ml/kg), L-D REI (0.125 ml/kg), M-D REI (0.250 ml/kg), and H-D REI (0.375 ml/kg)]. Then, a prospective cohort study involving 6 patients with peripheral venous malformations (VMs) is performed to explore the clinical safety and effectiveness of REI. From Jun 1, 2023 to August 31, 2023, 6 patients [age: (33.3 ± 17.2) years] with lingual VMs received sclerotherapy of REI and 2-month follow-up. Adverse events and serious adverse events were evaluated, whereas the efficacy of REI was determined by both the traceability of the REI under DSA throughout the entire injection and the therapeutic effect 2 months after a single injection.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The REI contains 81.4% ethanol (v/v) and 111.3 mg/ml iodine, which can be traced throughout the injection in the animals and patients. The REI also exerts a similar effect as EtOH on peripheral venous sclerosis, peripheral arterial embolization, and renal embolization. Furthermore, the REI can be metabolized at a similar rate compared to EtOH and Ultravist® and did not cause injury to the animals' heart, liver, spleen, lungs, kidneys and brain. No REI-related adverse effects have occurred during sclerotherapy of VMs, and 4/6 patients (66.7%) have achieved complete response at follow-up.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;In conclusion, REI is safe, exerts therapeutic effects, and compensates for the r","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"39"},"PeriodicalIF":16.7,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11188249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432193","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
Digital in-line holographic microscopy for label-free identification and tracking of biological cells. 用于生物细胞无标签识别和跟踪的数字在线全息显微镜。
IF 21.1 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-06-13 DOI: 10.1186/s40779-024-00541-8
Jihwan Kim, Sang Joon Lee

Digital in-line holographic microscopy (DIHM) is a non-invasive, real-time, label-free technique that captures three-dimensional (3D) positional, orientational, and morphological information from digital holographic images of living biological cells. Unlike conventional microscopies, the DIHM technique enables precise measurements of dynamic behaviors exhibited by living cells within a 3D volume. This review outlines the fundamental principles and comprehensive digital image processing procedures employed in DIHM-based cell tracking methods. In addition, recent applications of DIHM technique for label-free identification and digital tracking of various motile biological cells, including human blood cells, spermatozoa, diseased cells, and unicellular microorganisms, are thoroughly examined. Leveraging artificial intelligence has significantly enhanced both the speed and accuracy of digital image processing for cell tracking and identification. The quantitative data on cell morphology and dynamics captured by DIHM can effectively elucidate the underlying mechanisms governing various microbial behaviors and contribute to the accumulation of diagnostic databases and the development of clinical treatments.

数字在线全息显微镜(DIHM)是一种非侵入式、实时、无标记技术,可从活体生物细胞的数字全息图像中捕捉三维(3D)位置、方向和形态信息。与传统显微镜不同,DIHM 技术能精确测量活细胞在三维空间内的动态行为。本综述概述了基于 DIHM 的细胞追踪方法的基本原理和综合数字图像处理程序。此外,还深入探讨了 DIHM 技术在各种运动生物细胞(包括人类血细胞、精子、病变细胞和单细胞微生物)的无标记识别和数字跟踪方面的最新应用。利用人工智能大大提高了用于细胞跟踪和识别的数字图像处理的速度和准确性。DIHM 所获取的细胞形态和动态定量数据可有效阐明各种微生物行为的内在机制,有助于诊断数据库的积累和临床治疗方法的开发。
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引用次数: 0
Bone-organ axes: bidirectional crosstalk. 骨-器官轴:双向串扰。
IF 21.1 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-06-12 DOI: 10.1186/s40779-024-00540-9
An-Fu Deng, Fu-Xiao Wang, Si-Cheng Wang, Ying-Ze Zhang, Long Bai, Jia-Can Su

In addition to its recognized role in providing structural support, bone plays a crucial role in maintaining the functionality and balance of various organs by secreting specific cytokines (also known as osteokines). This reciprocal influence extends to these organs modulating bone homeostasis and development, although this aspect has yet to be systematically reviewed. This review aims to elucidate this bidirectional crosstalk, with a particular focus on the role of osteokines. Additionally, it presents a unique compilation of evidence highlighting the critical function of extracellular vesicles (EVs) within bone-organ axes for the first time. Moreover, it explores the implications of this crosstalk for designing and implementing bone-on-chips and assembloids, underscoring the importance of comprehending these interactions for advancing physiologically relevant in vitro models. Consequently, this review establishes a robust theoretical foundation for preventing, diagnosing, and treating diseases related to the bone-organ axis from the perspective of cytokines, EVs, hormones, and metabolites.

除了在提供结构支撑方面的公认作用外,骨骼还通过分泌特定的细胞因子(也称为骨激酶),在维持各种器官的功能和平衡方面发挥着至关重要的作用。这种相互影响延伸到这些调节骨平衡和发育的器官,但这方面的研究还没有系统的综述。本综述旨在阐明这种双向的相互影响,尤其关注骨生成素的作用。此外,这篇综述还提供了一份独特的证据汇编,首次强调了细胞外小泡(EVs)在骨-器官轴中的关键功能。此外,它还探讨了这种串扰对设计和实施片上骨和装配体的影响,强调了理解这些相互作用对推进生理相关体外模型的重要性。因此,这篇综述从细胞因子、EVs、激素和代谢物的角度为预防、诊断和治疗与骨-器官轴相关的疾病奠定了坚实的理论基础。
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引用次数: 0
Genome-wide enhancer RNA profiling adds molecular links between genetic variation and human cancers. 全基因组增强子 RNA 分析增加了基因变异与人类癌症之间的分子联系。
IF 21.1 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-06-11 DOI: 10.1186/s40779-024-00539-2
Yi-Min Cai, Ze-Qun Lu, Bin Li, Jin-Yu Huang, Ming Zhang, Can Chen, Lin-Yun Fan, Qian-Ying Ma, Chun-Yi He, Shuo-Ni Chen, Yuan Jiang, Yan-Min Li, Cai-Bo Ning, Fu-Wei Zhang, Wen-Zhuo Wang, Yi-Zhuo Liu, Heng Zhang, Meng Jin, Xiao-Yang Wang, Jin-Xin Han, Zhen Xiong, Ming Cai, Chao-Qun Huang, Xiao-Jun Yang, Xu Zhu, Ying Zhu, Xiao-Ping Miao, Shao-Kai Zhang, Yong-Chang Wei, Jian-Bo Tian

Background: Dysregulation of enhancer transcription occurs in multiple cancers. Enhancer RNAs (eRNAs) are transcribed products from enhancers that play critical roles in transcriptional control. Characterizing the genetic basis of eRNA expression may elucidate the molecular mechanisms underlying cancers.

Methods: Initially, a comprehensive analysis of eRNA quantitative trait loci (eRNAQTLs) was performed in The Cancer Genome Atlas (TCGA), and functional features were characterized using multi-omics data. To establish the first eRNAQTL profiles for colorectal cancer (CRC) in China, epigenomic data were used to define active enhancers, which were subsequently integrated with transcription and genotyping data from 154 paired CRC samples. Finally, large-scale case-control studies (34,585 cases and 69,544 controls) were conducted along with multipronged experiments to investigate the potential mechanisms by which candidate eRNAQTLs affect CRC risk.

Results: A total of 300,112 eRNAQTLs were identified across 30 different cancer types, which exert their influence on eRNA transcription by modulating chromatin status, binding affinity to transcription factors and RNA-binding proteins. These eRNAQTLs were found to be significantly enriched in cancer risk loci, explaining a substantial proportion of cancer heritability. Additionally, tumor-specific eRNAQTLs exhibited high responsiveness to the development of cancer. Moreover, the target genes of these eRNAs were associated with dysregulated signaling pathways and immune cell infiltration in cancer, highlighting their potential as therapeutic targets. Furthermore, multiple ethnic population studies have confirmed that an eRNAQTL rs3094296-T variant decreases the risk of CRC in populations from China (OR = 0.91, 95%CI 0.88-0.95, P = 2.92 × 10-7) and Europe (OR = 0.92, 95%CI 0.88-0.95, P = 4.61 × 10-6). Mechanistically, rs3094296 had an allele-specific effect on the transcription of the eRNA ENSR00000155786, which functioned as a transcriptional activator promoting the expression of its target gene SENP7. These two genes synergistically suppressed tumor cell proliferation. Our curated list of variants, genes, and drugs has been made available in CancereRNAQTL ( http://canernaqtl.whu.edu.cn/#/ ) to serve as an informative resource for advancing this field.

Conclusion: Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.

背景:增强子转录失调发生在多种癌症中。增强子 RNA(eRNA)是增强子的转录产物,在转录控制中发挥着关键作用。表征 eRNA 表达的遗传基础可阐明癌症的分子机制:最初,在癌症基因组图谱(TCGA)中对eRNA定量性状位点(eRNAQTLs)进行了全面分析,并利用多组学数据对其功能特征进行了表征。为了建立中国首个结直肠癌(CRC)eRNAQTL图谱,研究人员利用表观基因组学数据定义了活跃的增强子,随后将这些增强子与来自154个配对CRC样本的转录和基因分型数据进行了整合。最后,进行了大规模的病例对照研究(34585例病例和69544例对照),并通过多管齐下的实验研究候选eRNAQTLs影响CRC风险的潜在机制:结果:在30种不同的癌症类型中,共鉴定出300 112个eRNAQTL,它们通过调节染色质状态、与转录因子和RNA结合蛋白的结合亲和力,对eRNA转录产生影响。研究发现,这些 eRNAQTLs 显著富集于癌症风险位点,可解释癌症遗传性的很大一部分。此外,肿瘤特异性 eRNAQTL 对癌症的发生表现出高度的反应性。此外,这些 eRNA 的靶基因与癌症中失调的信号通路和免疫细胞浸润有关,突出了它们作为治疗靶点的潜力。此外,多项种族人群研究证实,在中国(OR = 0.91,95%CI 0.88-0.95,P = 2.92 × 10-7)和欧洲(OR = 0.92,95%CI 0.88-0.95,P = 4.61 × 10-6)人群中,eRNAQTL rs3094296-T 变体可降低患 CRC 的风险。从机制上看,rs3094296 对 eRNA ENSR00000155786 的转录具有等位基因特异性影响,而 eRNA ENSR00000155786 是一种转录激活剂,可促进其靶基因 SENP7 的表达。这两个基因协同抑制了肿瘤细胞的增殖。我们策划的变体、基因和药物列表已在 CancereRNAQTL ( http://canernaqtl.whu.edu.cn/#/ ) 中公布,成为推动这一领域发展的信息资源:我们的研究结果强调了 eRNAQTL 在转录调控和疾病遗传性方面的重要性,并指出了基于 eRNA 的癌症治疗策略的潜力。
{"title":"Genome-wide enhancer RNA profiling adds molecular links between genetic variation and human cancers.","authors":"Yi-Min Cai, Ze-Qun Lu, Bin Li, Jin-Yu Huang, Ming Zhang, Can Chen, Lin-Yun Fan, Qian-Ying Ma, Chun-Yi He, Shuo-Ni Chen, Yuan Jiang, Yan-Min Li, Cai-Bo Ning, Fu-Wei Zhang, Wen-Zhuo Wang, Yi-Zhuo Liu, Heng Zhang, Meng Jin, Xiao-Yang Wang, Jin-Xin Han, Zhen Xiong, Ming Cai, Chao-Qun Huang, Xiao-Jun Yang, Xu Zhu, Ying Zhu, Xiao-Ping Miao, Shao-Kai Zhang, Yong-Chang Wei, Jian-Bo Tian","doi":"10.1186/s40779-024-00539-2","DOIUrl":"10.1186/s40779-024-00539-2","url":null,"abstract":"<p><strong>Background: </strong>Dysregulation of enhancer transcription occurs in multiple cancers. Enhancer RNAs (eRNAs) are transcribed products from enhancers that play critical roles in transcriptional control. Characterizing the genetic basis of eRNA expression may elucidate the molecular mechanisms underlying cancers.</p><p><strong>Methods: </strong>Initially, a comprehensive analysis of eRNA quantitative trait loci (eRNAQTLs) was performed in The Cancer Genome Atlas (TCGA), and functional features were characterized using multi-omics data. To establish the first eRNAQTL profiles for colorectal cancer (CRC) in China, epigenomic data were used to define active enhancers, which were subsequently integrated with transcription and genotyping data from 154 paired CRC samples. Finally, large-scale case-control studies (34,585 cases and 69,544 controls) were conducted along with multipronged experiments to investigate the potential mechanisms by which candidate eRNAQTLs affect CRC risk.</p><p><strong>Results: </strong>A total of 300,112 eRNAQTLs were identified across 30 different cancer types, which exert their influence on eRNA transcription by modulating chromatin status, binding affinity to transcription factors and RNA-binding proteins. These eRNAQTLs were found to be significantly enriched in cancer risk loci, explaining a substantial proportion of cancer heritability. Additionally, tumor-specific eRNAQTLs exhibited high responsiveness to the development of cancer. Moreover, the target genes of these eRNAs were associated with dysregulated signaling pathways and immune cell infiltration in cancer, highlighting their potential as therapeutic targets. Furthermore, multiple ethnic population studies have confirmed that an eRNAQTL rs3094296-T variant decreases the risk of CRC in populations from China (OR = 0.91, 95%CI 0.88-0.95, P = 2.92 × 10<sup>-7</sup>) and Europe (OR = 0.92, 95%CI 0.88-0.95, P = 4.61 × 10<sup>-6</sup>). Mechanistically, rs3094296 had an allele-specific effect on the transcription of the eRNA ENSR00000155786, which functioned as a transcriptional activator promoting the expression of its target gene SENP7. These two genes synergistically suppressed tumor cell proliferation. Our curated list of variants, genes, and drugs has been made available in CancereRNAQTL ( http://canernaqtl.whu.edu.cn/#/ ) to serve as an informative resource for advancing this field.</p><p><strong>Conclusion: </strong>Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"36"},"PeriodicalIF":21.1,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11165858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306281","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
Gastroenteropancreatic neuroendocrine neoplasms: current development, challenges, and clinical perspectives. 胃肠胰神经内分泌肿瘤:当前发展、挑战和临床前景。
IF 21.1 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-06-04 DOI: 10.1186/s40779-024-00535-6
Xian-Bin Zhang, Yi-Bao Fan, Rui Jing, Mikiyas Amare Getu, Wan-Ying Chen, Wei Zhang, Hong-Xia Dong, Tikam Chand Dakal, Akhtar Hayat, Hua-Jun Cai, Milad Ashrafizadeh, A M Abd El-Aty, Ahmet Hacimuftuoglu, Peng Liu, Tian-Feng Li, Gautam Sethi, Kwang Seok Ahn, Yavuz Nuri Ertas, Min-Jiang Chen, Jian-Song Ji, Li Ma, Peng Gong

Neuroendocrine neoplasms (NENs) are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are the most common subtype of NENs. Historically, GEP-NENs have been regarded as infrequent and slow-growing malignancies; however, recent data have demonstrated that the worldwide prevalence and incidence of GEP-NENs have increased exponentially over the last three decades. In addition, an increasing number of studies have proven that GEP-NENs result in a limited life expectancy. These findings suggested that the natural biology of GEP-NENs is more aggressive than commonly assumed. Therefore, there is an urgent need for advanced researches focusing on the diagnosis and management of patients with GEP-NENs. In this review, we have summarized the limitations and recent advancements in our comprehension of the epidemiology, clinical presentations, pathology, molecular biology, diagnosis, and treatment of GEP-NETs to identify factors contributing to delays in diagnosis and timely treatment of these patients.

神经内分泌肿瘤(NENs)是神经内分泌系统分泌细胞产生的高度异质性和潜在恶性肿瘤。胃肠胰神经内分泌肿瘤(GEP-NENs)是神经内分泌肿瘤中最常见的亚型。一直以来,GEP-NENs 被认为是不常见且生长缓慢的恶性肿瘤;然而,最近的数据表明,在过去的三十年中,GEP-NENs 的全球流行率和发病率呈指数增长。此外,越来越多的研究证明,GEP-NENs 会导致患者寿命缩短。这些研究结果表明,GEP-NENs 的自然生物学特性比通常认为的更具侵袭性。因此,亟需对 GEP-NENs 患者的诊断和治疗进行深入研究。在这篇综述中,我们总结了我们在了解 GEP-NET 的流行病学、临床表现、病理学、分子生物学、诊断和治疗方面的局限性和最新进展,以找出导致这些患者延误诊断和及时治疗的因素。
{"title":"Gastroenteropancreatic neuroendocrine neoplasms: current development, challenges, and clinical perspectives.","authors":"Xian-Bin Zhang, Yi-Bao Fan, Rui Jing, Mikiyas Amare Getu, Wan-Ying Chen, Wei Zhang, Hong-Xia Dong, Tikam Chand Dakal, Akhtar Hayat, Hua-Jun Cai, Milad Ashrafizadeh, A M Abd El-Aty, Ahmet Hacimuftuoglu, Peng Liu, Tian-Feng Li, Gautam Sethi, Kwang Seok Ahn, Yavuz Nuri Ertas, Min-Jiang Chen, Jian-Song Ji, Li Ma, Peng Gong","doi":"10.1186/s40779-024-00535-6","DOIUrl":"10.1186/s40779-024-00535-6","url":null,"abstract":"<p><p>Neuroendocrine neoplasms (NENs) are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are the most common subtype of NENs. Historically, GEP-NENs have been regarded as infrequent and slow-growing malignancies; however, recent data have demonstrated that the worldwide prevalence and incidence of GEP-NENs have increased exponentially over the last three decades. In addition, an increasing number of studies have proven that GEP-NENs result in a limited life expectancy. These findings suggested that the natural biology of GEP-NENs is more aggressive than commonly assumed. Therefore, there is an urgent need for advanced researches focusing on the diagnosis and management of patients with GEP-NENs. In this review, we have summarized the limitations and recent advancements in our comprehension of the epidemiology, clinical presentations, pathology, molecular biology, diagnosis, and treatment of GEP-NETs to identify factors contributing to delays in diagnosis and timely treatment of these patients.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"35"},"PeriodicalIF":21.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11149301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141248357","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
Advances in the isolation, cultivation, and identification of gut microbes. 肠道微生物的分离、培养和鉴定方面的进展。
IF 21.1 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-06-03 DOI: 10.1186/s40779-024-00534-7
Meng-Qi Xu, Fei Pan, Li-Hua Peng, Yun-Sheng Yang

The gut microbiome is closely associated with human health and the development of diseases. Isolating, characterizing, and identifying gut microbes are crucial for research on the gut microbiome and essential for advancing our understanding and utilization of it. Although culture-independent approaches have been developed, a pure culture is required for in-depth analysis of disease mechanisms and the development of biotherapy strategies. Currently, microbiome research faces the challenge of expanding the existing database of culturable gut microbiota and rapidly isolating target microorganisms. This review examines the advancements in gut microbe isolation and cultivation techniques, such as culturomics, droplet microfluidics, phenotypic and genomics selection, and membrane diffusion. Furthermore, we evaluate the progress made in technology for identifying gut microbes considering both non-targeted and targeted strategies. The focus of future research in gut microbial culturomics is expected to be on high-throughput, automation, and integration. Advancements in this field may facilitate strain-level investigation into the mechanisms underlying diseases related to gut microbiota.

肠道微生物组与人类健康和疾病的发生密切相关。分离、描述和鉴定肠道微生物是研究肠道微生物组的关键,也是促进我们了解和利用肠道微生物组的必要条件。虽然已经开发出了不依赖培养物的方法,但要深入分析疾病机制和开发生物疗法策略,还需要纯培养物。目前,微生物组研究面临着扩大现有可培养肠道微生物群数据库和快速分离目标微生物的挑战。本综述探讨了肠道微生物分离和培养技术的进展,如培养组学、液滴微流控、表型和基因组学选择以及膜扩散。此外,我们还评估了非靶向和靶向策略在鉴定肠道微生物技术方面取得的进展。未来肠道微生物培养组学的研究重点将是高通量、自动化和集成化。这一领域的进步可能会促进对与肠道微生物群相关的疾病机制进行菌株级研究。
{"title":"Advances in the isolation, cultivation, and identification of gut microbes.","authors":"Meng-Qi Xu, Fei Pan, Li-Hua Peng, Yun-Sheng Yang","doi":"10.1186/s40779-024-00534-7","DOIUrl":"10.1186/s40779-024-00534-7","url":null,"abstract":"<p><p>The gut microbiome is closely associated with human health and the development of diseases. Isolating, characterizing, and identifying gut microbes are crucial for research on the gut microbiome and essential for advancing our understanding and utilization of it. Although culture-independent approaches have been developed, a pure culture is required for in-depth analysis of disease mechanisms and the development of biotherapy strategies. Currently, microbiome research faces the challenge of expanding the existing database of culturable gut microbiota and rapidly isolating target microorganisms. This review examines the advancements in gut microbe isolation and cultivation techniques, such as culturomics, droplet microfluidics, phenotypic and genomics selection, and membrane diffusion. Furthermore, we evaluate the progress made in technology for identifying gut microbes considering both non-targeted and targeted strategies. The focus of future research in gut microbial culturomics is expected to be on high-throughput, automation, and integration. Advancements in this field may facilitate strain-level investigation into the mechanisms underlying diseases related to gut microbiota.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"34"},"PeriodicalIF":21.1,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11145792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141237759","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
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Military Medical Research
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