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Elucidating the dual roles of apoptosis and necroptosis in diabetic wound healing: implications for therapeutic intervention 阐明凋亡和坏死下垂在糖尿病伤口愈合中的双重作用:治疗干预的意义
IF 5.3 1区 医学 Q1 DERMATOLOGY Pub Date : 2025-01-22 DOI: 10.1093/burnst/tkae061
Xingqian Wu, Rifang Gu, Ming Tang, Xingrui Mu, Wenjie He, Xuqiang Nie
Wound healing is a complex and multistep biological process that involves the cooperation of various cell types. Programmed cell death, including apoptosis and necrotizing apoptosis, plays a crucial role in this process. Apoptosis, a controlled and orderly programmed cell death regulated by genes, helps eliminate unnecessary or abnormal cells and maintain internal environmental stability. It also regulates various cell functions and contributes to the development of many diseases. In wound healing, programmed cell death is essential for removing inflammatory cells and forming scars. On the other hand, necroptosis, another form of programmed cell death, has not been thoroughly investigated regarding its role in wound healing. This review explores the changes and apoptosis of specific cell groups during wound healing after an injury and delves into the potential underlying mechanisms. Furthermore, it briefly discusses the possible mechanisms linking wound inflammation and fibrosis to apoptosis in wound healing. By understanding the relationship between apoptosis and wound healing and investigating the molecular mechanisms involved in apoptosis regulation, new strategies for the clinical treatment of wound healing may be discovered.
伤口愈合是一个复杂的多步骤的生物学过程,涉及各种细胞类型的合作。程序性细胞死亡,包括凋亡和坏死性凋亡,在这一过程中起着至关重要的作用。细胞凋亡是一种受基因控制的有序程序性细胞死亡,有助于消除不必要的或异常的细胞,维持内部环境的稳定。它还调节各种细胞功能,并有助于许多疾病的发展。在伤口愈合过程中,程序性细胞死亡对于清除炎症细胞和形成疤痕至关重要。另一方面,坏死下垂,另一种形式的程序性细胞死亡,在伤口愈合中的作用尚未得到彻底的研究。本文综述了创伤愈合过程中特定细胞群的变化和凋亡,并探讨了可能的潜在机制。此外,它简要地讨论了可能的机制连接伤口炎症和纤维化与细胞凋亡在伤口愈合。通过了解细胞凋亡与创面愈合的关系,探讨细胞凋亡调控的分子机制,为创面愈合的临床治疗提供新的策略。
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引用次数: 0
Multi-omics perspective: mechanisms of gastrointestinal injury repair 多组学视角:胃肠道损伤修复机制
IF 5.3 1区 医学 Q1 DERMATOLOGY Pub Date : 2025-01-22 DOI: 10.1093/burnst/tkae057
Haibin Zhao, Zhigang Zhang, Hongyu Liu, Mingxiu Ma, Peng Sun, Yang Zhao, Xun Liu
In this review, we examine the significance of multi-omics technologies in understanding the plethora of intricate processes that activate gastrointestinal (GI) injury repair. Multi-omics, which includes genomics, transcriptomics, proteomics, and metabolomics, allows intricate mapping of cellular responses and molecular pathways involved in GI repair. We highlight the potential of multi-omics to discover previously unknown therapeutic targets or elucidate the molecular basis of the pathogenesis of GI. Furthermore, we explore the possibilities of integrating omics data to improve prediction models, and summarize the state-of-the-art technological developments and persisting obstacles that hinder the translation of multi-omics into clinical practice. Finally, innovative multi-omics approaches that can improve patient outcomes and advance therapeutic strategies in GI medicine are discussed.
在这篇综述中,我们研究了多组学技术在理解激活胃肠道(GI)损伤修复的众多复杂过程中的意义。多组学,包括基因组学、转录组学、蛋白质组学和代谢组学,可以绘制复杂的细胞反应和参与胃肠道修复的分子途径。我们强调多组学在发现以前未知的治疗靶点或阐明GI发病机制的分子基础方面的潜力。此外,我们探讨了整合组学数据以改进预测模型的可能性,并总结了最新的技术发展和阻碍多组学转化为临床实践的持续障碍。最后,讨论了创新的多组学方法可以改善患者的治疗效果和推进胃肠道医学的治疗策略。
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引用次数: 0
Receptor activity-modifying protein 1 regulates the differentiation of mouse skin fibroblasts by downregulating α-SMA expression via suppression of high mobility group AT-hook 1 to promote skin wound repair 受体活性修饰蛋白1通过抑制高迁移率组AT-hook 1下调α-SMA表达,调节小鼠皮肤成纤维细胞分化,促进皮肤创面修复
IF 5.3 1区 医学 Q1 DERMATOLOGY Pub Date : 2025-01-22 DOI: 10.1093/burnst/tkae068
Ru Song, Jiaxu Ma, Siyuan Yin, Zhenjie Wu, Chunyan Liu, Rui Sun, Guoqi Cao, Yongpan Lu, Jian Liu, Linqi Su, Yibing Wang
Background Skin innervation is very important for normal wound healing, and receptor activity-modifying protein 1 (RAMP1) has been reported to modulate calcitonin gene-related peptide (CGRP) receptor function and thus be a potential treatment target. This study aimed to elucidate the intricate regulatory effect of RAMP1 on skin fibroblast function, thereby addressing the existing knowledge gap in this area. Methods Immunohistochemical staining and immunofluorescence (IF) staining were used to measure the dynamic changes in the expression of RAMP1 and α-smooth muscle actin (α-SMA) in skin wound tissue in mice. Mouse skin fibroblasts (MSFs) stably transfected with Tet-on-Flag-RAMP1 overexpression (OE) and Tet-on-Flag control (Ctrl) lentiviruses were constructed for in vitro experiments. High mobility group AT-hook 1 (HMGA1) plasmids and α-SMA plasmids were used to overexpress HMGA1 and α-SMA, respectively. An α-SMA siRNA was used to silence α-SMA. Quantitative real-time polymerase chain reaction (qPCR), western blot and IF staining analyses were used to determine the mRNA and protein levels in the cells in different groups. A scratch wound healing assay was used to evaluate the cell migration ability of different groups. Cleavage under targets and release using nuclease (CUT & RUN) assays and dual-luciferase reporter assays were used to predict and verify the interaction between HMGA1 and the α-SMA promoter. Results RAMP1 and α-SMA protein expression levels in the dermis changed dynamically and were negatively correlated during dorsal skin wound healing in mice. RAMP1 OE in vitro inhibited the differentiation and promoted the migration of MSFs by decreasing α-SMA expression via the suppression of HMGA1, which was shown for the first time to bind to the α-SMA promoter and increase α-SMA transcription. RAMP1 OE also modulated extracellular matrix (ECM) synthesis and remodeling by promoting collagen III and MMP9 expression and decreasing collagen I, MMP2, and tissue inhibitor of metalloproteinases 1 expression. Conclusions Our findings suggest that RAMP1 OE decreases differentiation and promotes migration in MSFs by downregulating α-SMA expression via the suppression of HMGA1 and modulates ECM synthesis and remodeling, revealing a novel mechanism regulating α-SMA transcription, providing new insights into the RAMP1-mediated regulation of fibroblast function, and identifying effective nerve-related targets for skin wound repair.
皮肤神经支配对伤口的正常愈合非常重要,而受体活性修饰蛋白1 (RAMP1)已被报道可以调节降钙素基因相关肽(CGRP)受体的功能,从而成为潜在的治疗靶点。本研究旨在阐明RAMP1对皮肤成纤维细胞功能的复杂调控作用,从而解决该领域现有的知识空白。方法采用免疫组织化学染色和免疫荧光(IF)染色法检测RAMP1和α-平滑肌肌动蛋白(α-SMA)在小鼠皮肤创面组织中的表达动态变化。构建稳定转染Tet-on-Flag- ramp1过表达(OE)和Tet-on-Flag控制(Ctrl)慢病毒的小鼠皮肤成纤维细胞(MSFs)进行体外实验。高迁移率组AT-hook 1 (HMGA1)质粒和α-SMA质粒分别过表达HMGA1和α-SMA。用α-SMA siRNA沉默α-SMA。采用实时荧光定量聚合酶链反应(qPCR)、western blot和IF染色法检测各组细胞mRNA和蛋白表达水平。采用抓伤愈合实验评价不同组的细胞迁移能力。利用核酸酶(CUT &;采用RUN法和双荧光素酶报告基因法预测并验证HMGA1与α-SMA启动子之间的相互作用。结果RAMP1与α-SMA蛋白表达水平在小鼠背侧皮肤创面愈合过程中呈动态变化,呈负相关。RAMP1 OE在体外通过抑制HMGA1降低α-SMA的表达,从而抑制MSFs的分化和促进迁移,首次发现HMGA1与α-SMA启动子结合,增加α-SMA转录。RAMP1 OE还通过促进胶原III和MMP9的表达,降低胶原I、MMP2和组织金属蛋白酶抑制剂1的表达,调节细胞外基质(ECM)的合成和重塑。结论RAMP1 OE通过抑制HMGA1下调α-SMA的表达,从而抑制MSFs的分化和促进迁移,调控ECM的合成和重塑,揭示了一种调节α-SMA转录的新机制,为RAMP1介导的成纤维细胞功能调控提供了新的思路,并为皮肤创面修复找到了有效的神经相关靶点。
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引用次数: 0
Masterful macrophages: understanding and targeting activation dysfunction in diabetic wounds 精通巨噬细胞:了解和靶向糖尿病伤口的激活功能障碍
IF 5.3 1区 医学 Q1 DERMATOLOGY Pub Date : 2025-01-21 DOI: 10.1093/burnst/tkaf003
Linian Peng, Gaoxing Luo, Weifeng He, Guangping Liang
Diabetes mellitus is a group of chronic metabolic diseases worldwide seriously threatens human health and increases social and economic burden; underlying drivers of impaired healing include uncontrolled inflammation, repeated ischemia–reperfusion injury, and neuropathy alongside infection risks. Macrophages orchestrate standard repair, exhibit sustained classical pro-inflammatory activation in diabetes, disrupting growth factor secretion, angiogenesis, and matrix regulation. Hyperglycemia- mediated advanced glycation end products and reactive oxygen species heighten pattern recognition receptor stimulation, causing reduced alternative macrophage differentiation. Promising immunomodulation approaches redirecting their phenotypes to resolve inflammation and stimulate regeneration provides optimism. We discuss macrophage origination, polarization dynamics, diabetic wound phenotypic imbalance, and critical microenvironmental disruptions perpetuating pathological function. Elucidating specific regulatory nodes upholding their activation states will inform intelligent targeting opportunities. Overall, infiltrating macrophages constitute indispensable yet amenable diabetic wound healing coordinators.
糖尿病是一种世界性的慢性代谢性疾病,严重威胁人类健康,增加社会经济负担;愈合受损的潜在驱动因素包括不受控制的炎症、反复的缺血-再灌注损伤和伴有感染风险的神经病变。巨噬细胞协调标准修复,在糖尿病中表现出持续的经典促炎激活,破坏生长因子分泌,血管生成和基质调节。高血糖介导的晚期糖基化终产物和活性氧会增强模式识别受体的刺激,导致替代性巨噬细胞分化减少。有希望的免疫调节方法重定向他们的表型来解决炎症和刺激再生提供了乐观。我们讨论巨噬细胞的起源,极化动力学,糖尿病伤口表型失衡,和关键的微环境破坏延续病理功能。阐明维持其激活状态的特定调控节点将为智能靶向机会提供信息。总之,浸润性巨噬细胞是糖尿病伤口愈合不可缺少的协调者。
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引用次数: 0
A bioactive Hydrogel Patch Accelerates Revascularization in Ischemic Lesions for Tissue Repair 生物活性水凝胶贴片加速缺血损伤组织修复的血运重建
IF 5.3 1区 医学 Q1 DERMATOLOGY Pub Date : 2025-01-21 DOI: 10.1093/burnst/tkaf005
Zhuo Liu, Kang Wu, Hong Zeng, Wenxin Huang, Xuemeng Wang, Ying Qu, Chuntao Chen, Lei Zhang, Dongpin Sun, Sifeng Chen, Xiao Lin, Ning Sun, Lei Yang, Chen Xu
Background Magnesium ions play crucial roles in maintaining cellular functions. Research has shown that Mg2+ can promote angiogenesis, indicating its potential for treating cardiovascular ischemic diseases. However, conventional intravenous or oral administration of Mg2+ presents several challenges, including the risk of systemic side effects, diminished bioavailability, and a lack of targeted delivery mechanisms. In this study, we designed a Mg2+-releasing adhesive tissue patch (MgAP) that enables the dural release of Mg2+ ions. Methods A novel Mg2+-releasing adhesive patch (MgAP) was developed on the basis of ionic crosslinking. Fourier transform infrared spectroscopy confirmed the chemical structure, whereas rheological analysis demonstrated stable mechanical properties and adaptability to dynamic loads. Sustained Mg2+ release was quantified over 7 days by inductively coupled plasma–mass spectrometry. In a rat acute myocardial infarction model, we performed echocardiography and strain analysis to assess cardiac function and histological staining to evaluate adverse remodeling. We also verified the proangiogenic effect through in vitro tube formation and in vivo immunofluorescence assays. Furthermore, transcriptomics and Western blotting were performed to explore the underlying mechanism. Additional assessments were also carried out in a rat model of lower limb ischemia. Results Compared with intravenous administration of magnesium chloride, MgAP application effectively improved cardiac function and reduced adverse remodeling in the myocardial infarction rat model. The left ventricular ejection fraction increased by 20.3 ± 6.6%, and the cardiac radial strain improved by 27.4 ± 4.1%. The cardiac fibrosis area and cell apoptosis rate decreased by 10.9 ± 1.2% and 32.1 ± 5.5%, respectively. RNA sequencing analysis also highlighted the upregulation of genes related to cardiac electrophysiological properties, structural and functional intercellular connections, and revascularization. The increased gap junction protein expression and restored local blood supply could contribute to the cardiac repair process posttreatment. The proangiogenic effect of MgAP was also observed in the rat limb ischemia model. Conclusions The above results revealed the convincing vascular regeneration effect of an ion therapy-based hydrogel, which enabled the local delivery of Mg2+ to the targeted ischemic tissue, aiding in cardiac and lower limb repair. This study presents a novel strategy and highlights its potential for use across various ischemic conditions.
镁离子在维持细胞功能中起着至关重要的作用。研究表明Mg2+可以促进血管生成,表明其治疗心血管缺血性疾病的潜力。然而,传统的静脉或口服给药Mg2+存在一些挑战,包括系统性副作用的风险、生物利用度降低和缺乏靶向给药机制。在这项研究中,我们设计了一种Mg2+释放粘连组织贴片(MgAP),使Mg2+离子在硬脑膜上释放。方法采用离子交联技术制备一种新型的Mg2+释放贴片。傅里叶变换红外光谱证实了其化学结构,而流变学分析则证明了其稳定的力学性能和对动态载荷的适应性。用电感耦合等离子体质谱法测定7天内Mg2+的持续释放量。在大鼠急性心肌梗死模型中,我们通过超声心动图和应变分析来评估心功能和组织学染色来评估不良重构。我们还通过体外成管和体内免疫荧光实验验证了其促进血管生成的作用。此外,转录组学和Western blotting研究了潜在的机制。在大鼠下肢缺血模型中也进行了额外的评估。结果与氯化镁静脉给药相比,MgAP能有效改善心肌梗死模型大鼠心功能,减少不良重构。左室射血分数提高20.3±6.6%,心脏径向应变提高27.4±4.1%。心肌纤维化面积和细胞凋亡率分别减少10.9±1.2%和32.1±5.5%。RNA测序分析也强调了与心脏电生理特性、结构和功能细胞间连接以及血运重建相关的基因的上调。间隙连接蛋白表达的增加和局部血供的恢复可能有助于心脏修复过程的后处理。在大鼠肢体缺血模型中也观察到MgAP的促血管生成作用。结论基于离子治疗的水凝胶具有令人信服的血管再生作用,可以将Mg2+局部递送到缺血组织,有助于心脏和下肢的修复。本研究提出了一种新的策略,并强调了其在各种缺血条件下使用的潜力。
{"title":"A bioactive Hydrogel Patch Accelerates Revascularization in Ischemic Lesions for Tissue Repair","authors":"Zhuo Liu, Kang Wu, Hong Zeng, Wenxin Huang, Xuemeng Wang, Ying Qu, Chuntao Chen, Lei Zhang, Dongpin Sun, Sifeng Chen, Xiao Lin, Ning Sun, Lei Yang, Chen Xu","doi":"10.1093/burnst/tkaf005","DOIUrl":"https://doi.org/10.1093/burnst/tkaf005","url":null,"abstract":"Background Magnesium ions play crucial roles in maintaining cellular functions. Research has shown that Mg2+ can promote angiogenesis, indicating its potential for treating cardiovascular ischemic diseases. However, conventional intravenous or oral administration of Mg2+ presents several challenges, including the risk of systemic side effects, diminished bioavailability, and a lack of targeted delivery mechanisms. In this study, we designed a Mg2+-releasing adhesive tissue patch (MgAP) that enables the dural release of Mg2+ ions. Methods A novel Mg2+-releasing adhesive patch (MgAP) was developed on the basis of ionic crosslinking. Fourier transform infrared spectroscopy confirmed the chemical structure, whereas rheological analysis demonstrated stable mechanical properties and adaptability to dynamic loads. Sustained Mg2+ release was quantified over 7 days by inductively coupled plasma–mass spectrometry. In a rat acute myocardial infarction model, we performed echocardiography and strain analysis to assess cardiac function and histological staining to evaluate adverse remodeling. We also verified the proangiogenic effect through in vitro tube formation and in vivo immunofluorescence assays. Furthermore, transcriptomics and Western blotting were performed to explore the underlying mechanism. Additional assessments were also carried out in a rat model of lower limb ischemia. Results Compared with intravenous administration of magnesium chloride, MgAP application effectively improved cardiac function and reduced adverse remodeling in the myocardial infarction rat model. The left ventricular ejection fraction increased by 20.3 ± 6.6%, and the cardiac radial strain improved by 27.4 ± 4.1%. The cardiac fibrosis area and cell apoptosis rate decreased by 10.9 ± 1.2% and 32.1 ± 5.5%, respectively. RNA sequencing analysis also highlighted the upregulation of genes related to cardiac electrophysiological properties, structural and functional intercellular connections, and revascularization. The increased gap junction protein expression and restored local blood supply could contribute to the cardiac repair process posttreatment. The proangiogenic effect of MgAP was also observed in the rat limb ischemia model. Conclusions The above results revealed the convincing vascular regeneration effect of an ion therapy-based hydrogel, which enabled the local delivery of Mg2+ to the targeted ischemic tissue, aiding in cardiac and lower limb repair. This study presents a novel strategy and highlights its potential for use across various ischemic conditions.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"45 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Basic helix–loop–helix ARNT like 1 regulates the function of immune cells and participates in the development of immune-related diseases 基本螺旋-环-螺旋ARNT样1调节免疫细胞的功能,参与免疫相关疾病的发生
IF 5.3 1区 医学 Q1 DERMATOLOGY Pub Date : 2025-01-17 DOI: 10.1093/burnst/tkae075
Fanglin Shao, Zhipeng Wang, Luxia Ye, Ruicheng Wu, Jie Wang, Qing-Xin Yu, Dilinaer Wusiman, Zhouting Tuo, Koo Han Yoo, Ziyu Shu, Wuran Wei, Dengxiong Li, William C Cho, Zhihong Liu, Dechao Feng
The circadian clock is an internal timekeeper system that regulates biological processes through a central circadian clock and peripheral clocks controlling various genes. Basic helix–loop–helix ARNT-like 1 (BMAL1), also known as aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL1), is a key component of the circadian clock. The deletion of BMAL1 alone can abolish the circadian rhythms of the human body. BMAL1 plays a critical role in immune cell function. Dysregulation of BMAL1 is linked to immune-related diseases such as autoimmune diseases, infectious diseases, and cancer, and vice versa. This review highlights the significant role of BMAL1 in governing immune cells, including their development, differentiation, migration, homing, metabolism, and effector functions. This study also explores how dysregulation of BMAL1 can have far-reaching implications and potentially contribute to the onset of immune-related diseases such as autoimmune diseases, infectious diseases, cancer, sepsis, and trauma. Furthermore, this review discusses treatments for immune-related diseases that target BMAL1 disorders. Understanding the impact of BMAL1 on immune function can provide insights into the pathogenesis of immune-related diseases and help in the development of more effective treatment strategies. Targeting BMAL1 has been demonstrated to achieve good efficacy in immune-related diseases, indicating its promising potential as a targetable therapeutic target in these diseases.
生物钟是一种内部计时系统,通过中央生物钟和控制各种基因的外围时钟来调节生物过程。碱性螺旋-环-螺旋ARNT-like 1 (BMAL1),也被称为芳烃受体核易位蛋白1 (ARNTL1),是生物钟的关键组成部分。仅BMAL1的缺失就能破坏人体的昼夜节律。BMAL1在免疫细胞功能中起关键作用。BMAL1的失调与免疫相关疾病,如自身免疫性疾病、传染病和癌症有关,反之亦然。本文综述了BMAL1在免疫细胞调控中的重要作用,包括其发育、分化、迁移、归巢、代谢和效应功能。本研究还探讨了BMAL1的失调如何具有深远的影响,并可能导致免疫相关疾病的发病,如自身免疫性疾病、传染病、癌症、败血症和创伤。此外,本文还讨论了针对BMAL1紊乱的免疫相关疾病的治疗方法。了解BMAL1对免疫功能的影响,有助于深入了解免疫相关疾病的发病机制,并有助于制定更有效的治疗策略。靶向BMAL1已被证明在免疫相关疾病中具有良好的疗效,表明其作为这些疾病的可靶向治疗靶点具有很大的潜力。
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引用次数: 0
Understanding the pathophysiology of Pseudomonas aeruginosa colonization as a guide for future treatment for chronic leg ulcers 了解铜绿假单胞菌定植的病理生理学,为今后治疗慢性腿部溃疡提供指导
IF 5.3 1区 医学 Q1 DERMATOLOGY Pub Date : 2025-01-17 DOI: 10.1093/burnst/tkae083
Gabriela Gonzalez Matheus, Michelle N Chamoun, Kiarash Khosrotehrani, Yogeesan Sivakumaran, Timothy J Wells
Chronic leg wounds represent a major burden of disease worldwide, costing health care systems billions of dollars each year. Aside from the financial implications, they also impose a significant physical and psychosocial burden on the patient, their relatives and/or carers, and the community. Whilst measures such as maintenance of wound hygiene, debridement, dressings and compression are the current standard of care, complete healing is not always achievable and ulcer recurrence is common. Thus, there is still a gap to breach in terms of understanding the intricate pathophysiology of chronic wounds and the role this plays on treatment and management. Pseudomonas aeruginosa has been linked to poor wound healing, with the pathogen being frequently isolated from chronic leg ulcers. Characterized by its multi-drug resistance, targeting P. aeruginosa requires the development of novel therapeutic options. Thus, the aim of this literature review is to describe the pathophysiology of P. aeruginosa in chronic leg ulcers and discuss novel treatment strategies. Here, we describe the key molecular mechanisms driving the observed clinical effect of P. aeruginosa on wounds and discuss novel strategies of molecular targeting of this common bacteria, establishing new approaches that could benefit patients with chronic hard to heal wounds.
慢性腿部伤口是世界范围内疾病的主要负担,每年使卫生保健系统损失数十亿美元。除了经济方面的影响外,它们还对患者、其亲属和/或照顾者以及社区造成重大的身体和心理负担。虽然维持伤口卫生、清创、敷料和压迫等措施是目前的护理标准,但完全愈合并不总是可以实现的,溃疡复发也很常见。因此,在了解慢性伤口复杂的病理生理及其在治疗和管理中的作用方面,仍然存在空白。铜绿假单胞菌与伤口愈合不良有关,病原体经常从慢性腿部溃疡中分离出来。铜绿假单胞菌具有多药耐药的特点,需要开发新的治疗方案。因此,这篇文献综述的目的是描述铜绿假单胞菌在慢性腿部溃疡中的病理生理,并讨论新的治疗策略。在这里,我们描述了驱动P. aeruginosa在伤口中观察到的临床效果的关键分子机制,并讨论了这种常见细菌的分子靶向新策略,建立了新的方法,可以使慢性难以愈合的伤口患者受益。
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引用次数: 0
Haemodynamic management of septic shock 感染性休克的血流动力学处理
IF 5.3 1区 医学 Q1 DERMATOLOGY Pub Date : 2025-01-16 DOI: 10.1093/burnst/tkae081
Yuki Kotani, Nicholas Ryan, Andrew A Udy, Tomoko Fujii
Septic shock is a significant challenge in the management of patients with burns and traumatic injuries when complicated by infection, necessitating prompt and effective haemodynamic support. This review provides a comprehensive overview of current strategies for vasopressor and fluid management in septic shock, with the aim to optimize patient outcomes. With regard to vasopressor management, we elaborate on the pharmacologic profiles and clinical applications of catecholamines, vasopressin derivatives, angiotensin II, and other vasoactive agents. Noradrenaline remains central to septic shock management. The addition of vasopressin, when sequentially added to noradrenaline, offers a non-catecholaminergic vasoactive effect with some clinical benefits and risks of adverse effects. Emerging agents such as angiotensin II and hydroxocobalamin are highlighted for their roles in catecholamine-resistant vasodilatory shock. Next, for fluid management, crystalloids are currently preferred for initial resuscitation, with balanced crystalloids showing benefits over saline. The application of albumin in septic shock warrants further research. High-quality evidence does not support large-volume fluid resuscitation, and an individualized strategy based on haemodynamic parameters, including lactate clearance and capillary refill time, is recommended. The existing knowledge suggests that early vasopressor initiation, particularly noradrenaline, may be critical in cases where fluid resuscitation takes inadequate effect. Management of refractory septic shock remains challenging, with novel agents like angiotensin II and methylene blue showing potential in recent studies. In conclusion, Further research is needed to optimize haemodynamic management of septic shock, particularly in developing novel vasopressor usage and fluid management approaches.
感染性休克是烧伤和创伤性损伤患者并发感染时的重大挑战,需要及时有效的血流动力学支持。这篇综述全面概述了感染性休克中血管加压剂和液体管理的当前策略,旨在优化患者的预后。关于血管加压素的管理,我们详细阐述了儿茶酚胺、血管加压素衍生物、血管紧张素II和其他血管活性药物的药理学特征和临床应用。去甲肾上腺素仍然是感染性休克治疗的核心。在去甲肾上腺素的基础上依次添加抗利尿激素,可产生非儿茶酚胺类血管活性作用,具有一定的临床益处和不良反应风险。新兴药物如血管紧张素II和羟钴胺素因其在儿茶酚胺抵抗性血管舒张性休克中的作用而受到重视。其次,对于液体管理,晶体液目前首选用于初始复苏,平衡晶体液比生理盐水更有利。白蛋白在感染性休克中的应用有待进一步研究。高质量证据不支持大容量液体复苏,建议采用基于血流动力学参数的个体化策略,包括乳酸清除率和毛细血管再充血时间。现有的知识表明,在液体复苏效果不足的情况下,早期血管加压剂,特别是去甲肾上腺素的启动可能是至关重要的。难治性感染性休克的治疗仍然具有挑战性,血管紧张素II和亚甲基蓝等新型药物在最近的研究中显示出潜力。总之,需要进一步的研究来优化脓毒性休克的血流动力学管理,特别是在开发新的血管加压剂使用和液体管理方法方面。
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引用次数: 0
CYP24A1 is overexpressed in keloid keratinocytes and its inhibition alters profibrotic gene expression CYP24A1在瘢痕疙瘩角质形成细胞中过表达,其抑制可改变促纤维化基因的表达
IF 5.3 1区 医学 Q1 DERMATOLOGY Pub Date : 2025-01-16 DOI: 10.1093/burnst/tkae063
Jennifer M Hahn, Kelly A Combs, Caitlin M Phillips, Petra M Warner, Uzair A Qazi, Heather M Powell, Dorothy M Supp
Background Keloids are disfiguring, fibrotic scar-like lesions that are challenging to treat and commonly recur after therapy. A deeper understanding of the mechanisms driving keloid formation is necessary for the development of more effective therapies. Reduced vitamin D receptor (VDR) expression has been observed in keloids, implicating vitamin D signaling in keloid pathology. Vitamin D exhibits anti-proliferative and anti-inflammatory properties, suggesting it could have therapeutic utility in keloid disorder. The current study investigated vitamin D-regulated gene expression in keloid keratinocytes and the effects of inhibiting an enzyme involved in vitamin D metabolism on the phenotype of keloid-derived keratinocytes. Methods Normal and keloid-derived primary keratinocytes were isolated from normal skin and keloid lesions, respectively, and were cultured in the absence or presence of vitamin D. In some experiments, inhibitors of the vitamin D metabolizing enzyme CYP24A1, ketoconazole or VID400 were added in the absence or presence of vitamin D. Cellular proliferation, migration and gene expression were measured. Results We observed significant overexpression of CYP24A1 mRNA in keloid versus normal keratinocytes and increased CYP24A1 protein levels in keloids versus normal skin. CYP24A1 encodes 24 hydroxylase and is induced by vitamin D in a feedback loop that regulates vitamin D levels; thus, inhibition of CYP24A1 activity may locally increase active vitamin D levels. Ketoconazole, a non-specific cytochrome P-450 inhibitor, reduced proliferation of keloid and normal keratinocytes, but VID400, a specific CYP24A1 inhibitor, only significantly affected keloid keratinocyte proliferation. Neither inhibitor significantly reduced keratinocyte migration. The two inhibitors had different effects on vitamin D target gene expression in keratinocytes. Specifically, ketoconazole treatment reduced CYP24A1 expression in normal and keloid keratinocytes, whereas VID400 increased CYP24A1 expression. Both inhibitors decreased expression of profibrotic genes, including periostin and hyaluronan synthase 2, in keloid-derived cells. Combined treatment of keloid keratinocytes with vitamin D and ketoconazole or VID400 increased the effects of vitamin D treatment on target genes, although the effects were gene- and cell type-specific. Conclusions The data suggest that reduction of vitamin D inactivation with CYP24A1 inhibitors may reduce profibrotic gene expression in keloid-derived cells. Therefore, CYP24A1 inhibitors may serve as adjunctive therapies to suppress keloid-associated gene expression changes.
背景瘢痕疙瘩是一种毁容性纤维化瘢痕样病变,治疗难度大,治疗后常复发。要开发更有效的疗法,就必须深入了解瘢痕疙瘩的形成机制。在瘢痕疙瘩中观察到维生素 D 受体(VDR)表达减少,这表明维生素 D 信号转导与瘢痕疙瘩病理有关。维生素 D 具有抗增殖和抗炎特性,这表明它对瘢痕疙瘩疾病有治疗作用。本研究调查了瘢痕疙瘩角质形成细胞中维生素 D 调节基因的表达,以及抑制一种参与维生素 D 代谢的酶对瘢痕疙瘩角质形成细胞表型的影响。方法 分别从正常皮肤和瘢痕疙瘩病变处分离出正常和瘢痕疙瘩源性原代角质形成细胞,在无维生素 D 或有维生素 D 的情况下进行培养;在某些实验中,在无维生素 D 或有维生素 D 的情况下加入维生素 D 代谢酶 CYP24A1、酮康唑或 VID400 的抑制剂。结果 我们观察到 CYP24A1 mRNA 在瘢痕疙瘩与正常角质细胞中明显过表达,CYP24A1 蛋白水平在瘢痕疙瘩与正常皮肤中明显升高。CYP24A1 编码 24羟化酶,在调节维生素 D 水平的反馈回路中由维生素 D 诱导;因此,抑制 CYP24A1 的活性可能会在局部增加活性维生素 D 的水平。酮康唑是一种非特异性细胞色素 P-450 抑制剂,可减少瘢痕疙瘩和正常角质细胞的增殖,但 VID400(一种特异性 CYP24A1 抑制剂)只对瘢痕疙瘩角质细胞的增殖有显著影响。两种抑制剂都不能明显减少角质细胞的迁移。这两种抑制剂对角质细胞中维生素 D 靶基因的表达有不同的影响。具体来说,酮康唑能降低正常和瘢痕疙瘩角质形成细胞中 CYP24A1 的表达,而 VID400 能提高 CYP24A1 的表达。这两种抑制剂都能降低瘢痕疙瘩衍生细胞中组织坏死基因的表达,包括包膜组织蛋白和透明质酸合成酶 2。用维生素 D 和酮康唑或 VID400 联合处理瘢痕疙瘩角质形成细胞,可增强维生素 D 处理对靶基因的影响,但这种影响具有基因和细胞类型特异性。结论 这些数据表明,用 CYP24A1 抑制剂减少维生素 D 的灭活可能会降低瘢痕疙瘩源性细胞中凋亡性基因的表达。因此,CYP24A1 抑制剂可作为抑制瘢痕疙瘩相关基因表达变化的辅助疗法。
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引用次数: 0
Biomarkers of sepsis in burn injury: an update 烧伤败血症的生物标志物:最新进展
IF 5.3 1区 医学 Q1 DERMATOLOGY Pub Date : 2025-01-16 DOI: 10.1093/burnst/tkae080
Tina L Palmieri, Jason Heard
Sepsis, a dysregulated response to infection, is a leading cause of death after burn injury. Changes in the immune response as well as the loss of the skin, the primary barrier to infection, contribute to the increased risk for infection and sepsis in burn patients. This higher risk is further compounded by the development of the systemic inflammatory response and hypermetabolic state, which limit the utility of commonly used infection markers. As such, the development of sepsis biomarkers after burn injury is an imperative. A sepsis biomarker would facilitate earlier diagnosis and treatment of sepsis, thus decreasing length of stay, morbidity, and mortality after burn injury. Numerous different biomarkers, ranging from acute phase reactants, cytokines, and inflammatory markers to omics analyses and extracellular vesicles have been assessed as potential biomarkers in burn sepsis. To date no single biomarker has proven useful as the sole indicator for sepsis. The future of burn sepsis biomarkers will likely require a panel of biomarkers from all categories. The purpose of this review article is to list the various biomarkers that have been studied in burn sepsis and describe their clinical utility and future use in patients with burn injury.
败血症是一种对感染的失调反应,是烧伤后死亡的主要原因。免疫反应的变化以及皮肤这一主要感染屏障的缺失导致烧伤患者感染和败血症的风险增加。全身炎症反应和高代谢状态的出现进一步加剧了这一风险,限制了常用感染指标的作用。因此,开发烧伤后败血症生物标志物势在必行。脓毒症生物标志物将有助于尽早诊断和治疗脓毒症,从而缩短烧伤后的住院时间,降低发病率和死亡率。从急性期反应物、细胞因子、炎症标志物到全局分析和细胞外囊泡,许多不同的生物标志物已被评估为烧伤败血症的潜在生物标志物。迄今为止,还没有一种生物标志物被证明可作为败血症的唯一指标。烧伤脓毒症生物标志物的未来很可能需要一个由各类生物标志物组成的小组。这篇综述文章的目的是列出在烧伤败血症中已研究过的各种生物标志物,并描述它们在烧伤患者中的临床效用和未来用途。
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引用次数: 0
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Burns & Trauma
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