Background Neuronal structure is disrupted after spinal cord injury (SCI), causing functional impairment. The effectiveness of exercise therapy (ET) in clinical settings for nerve remodeling post-SCI and its underlying mechanisms remain unclear. This study aims to explore the effects and related mechanisms of ET on nerve remodeling in SCI rats. Methods We randomly assigned rats to various groups: sham-operated group, sham-operated + ET, SCI alone, SCI + H89, SCI + ET, and SCI + ET + H89. Techniques including motor-evoked potential (MEP), video capture and analysis, the Basso–Beattie–Bresnahan (BBB) scale, western blotting, transmission electron microscopy, hematoxylin and eosin staining, Nissl staining, glycine silver staining, immunofluorescence, and Golgi staining were utilized to assess signal conduction capabilities, neurological deficits, hindlimb performance, protein expression levels, neuron ultrastructure, and tissue morphology. H89—an inhibitor that targets the protein kinase A (PKA)/cAMP response element-binding (CREB) signaling pathway—was employed to investigate molecular mechanisms. Results This study found that ET can reduce neuronal damage in rats with SCI, protect residual tissue, promote the remodeling of motor neurons, neurofilaments, dendrites/axons, synapses, and myelin sheaths, reorganize neural circuits, and promote motor function recovery. In terms of mechanism, ET mainly works by mediating the PKA/CREB signaling pathway in neurons. Conclusions Our findings indicated that: (1) ET counteracted the H89-induced suppression of the PKA/CREB signaling pathway following SCI; (2) ET significantly alleviated neuronal injury and improved motor dysfunction; (3) ET facilitated neuronal regeneration by mediating the PKA/CREB signaling pathway; (4) ET enhanced synaptic and dendritic spine plasticity, as well as myelin sheath remodeling, post-SCI through the PKA/CREB signaling pathway.
{"title":"Exercise therapy facilitates neural remodeling and functional recovery post-spinal cord injury via PKA/CREB signaling pathway modulation in rats","authors":"Xinwang Ying, Qingfeng Xie, Yanfang Zhao, Jiamen Shen, Junqing Huang, Zhiyi Feng, Liuxi Chu, Junpeng Xu, Dawei Jiang, Ping Wu, Yanming Zuo, Shengcun Li, Chang Jiang, Xiaokun Li, Zhouguang Wang","doi":"10.1093/burnst/tkae058","DOIUrl":"https://doi.org/10.1093/burnst/tkae058","url":null,"abstract":"Background Neuronal structure is disrupted after spinal cord injury (SCI), causing functional impairment. The effectiveness of exercise therapy (ET) in clinical settings for nerve remodeling post-SCI and its underlying mechanisms remain unclear. This study aims to explore the effects and related mechanisms of ET on nerve remodeling in SCI rats. Methods We randomly assigned rats to various groups: sham-operated group, sham-operated + ET, SCI alone, SCI + H89, SCI + ET, and SCI + ET + H89. Techniques including motor-evoked potential (MEP), video capture and analysis, the Basso–Beattie–Bresnahan (BBB) scale, western blotting, transmission electron microscopy, hematoxylin and eosin staining, Nissl staining, glycine silver staining, immunofluorescence, and Golgi staining were utilized to assess signal conduction capabilities, neurological deficits, hindlimb performance, protein expression levels, neuron ultrastructure, and tissue morphology. H89—an inhibitor that targets the protein kinase A (PKA)/cAMP response element-binding (CREB) signaling pathway—was employed to investigate molecular mechanisms. Results This study found that ET can reduce neuronal damage in rats with SCI, protect residual tissue, promote the remodeling of motor neurons, neurofilaments, dendrites/axons, synapses, and myelin sheaths, reorganize neural circuits, and promote motor function recovery. In terms of mechanism, ET mainly works by mediating the PKA/CREB signaling pathway in neurons. Conclusions Our findings indicated that: (1) ET counteracted the H89-induced suppression of the PKA/CREB signaling pathway following SCI; (2) ET significantly alleviated neuronal injury and improved motor dysfunction; (3) ET facilitated neuronal regeneration by mediating the PKA/CREB signaling pathway; (4) ET enhanced synaptic and dendritic spine plasticity, as well as myelin sheath remodeling, post-SCI through the PKA/CREB signaling pathway.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"75 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020357","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}
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.
{"title":"Elucidating the dual roles of apoptosis and necroptosis in diabetic wound healing: implications for therapeutic intervention","authors":"Xingqian Wu, Rifang Gu, Ming Tang, Xingrui Mu, Wenjie He, Xuqiang Nie","doi":"10.1093/burnst/tkae061","DOIUrl":"https://doi.org/10.1093/burnst/tkae061","url":null,"abstract":"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.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"52 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020359","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}
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.
{"title":"Multi-omics perspective: mechanisms of gastrointestinal injury repair","authors":"Haibin Zhao, Zhigang Zhang, Hongyu Liu, Mingxiu Ma, Peng Sun, Yang Zhao, Xun Liu","doi":"10.1093/burnst/tkae057","DOIUrl":"https://doi.org/10.1093/burnst/tkae057","url":null,"abstract":"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.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"105 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992160","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}
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.
{"title":"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","authors":"Ru Song, Jiaxu Ma, Siyuan Yin, Zhenjie Wu, Chunyan Liu, Rui Sun, Guoqi Cao, Yongpan Lu, Jian Liu, Linqi Su, Yibing Wang","doi":"10.1093/burnst/tkae068","DOIUrl":"https://doi.org/10.1093/burnst/tkae068","url":null,"abstract":"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.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"137 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991904","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}
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.
{"title":"Masterful macrophages: understanding and targeting activation dysfunction in diabetic wounds","authors":"Linian Peng, Gaoxing Luo, Weifeng He, Guangping Liang","doi":"10.1093/burnst/tkaf003","DOIUrl":"https://doi.org/10.1093/burnst/tkaf003","url":null,"abstract":"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.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"11 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992575","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}
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.
{"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}
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.
{"title":"Basic helix–loop–helix ARNT like 1 regulates the function of immune cells and participates in the development of immune-related diseases","authors":"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","doi":"10.1093/burnst/tkae075","DOIUrl":"https://doi.org/10.1093/burnst/tkae075","url":null,"abstract":"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.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"49 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988609","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}
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.
{"title":"Understanding the pathophysiology of Pseudomonas aeruginosa colonization as a guide for future treatment for chronic leg ulcers","authors":"Gabriela Gonzalez Matheus, Michelle N Chamoun, Kiarash Khosrotehrani, Yogeesan Sivakumaran, Timothy J Wells","doi":"10.1093/burnst/tkae083","DOIUrl":"https://doi.org/10.1093/burnst/tkae083","url":null,"abstract":"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.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"99 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988610","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}
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.
{"title":"Haemodynamic management of septic shock","authors":"Yuki Kotani, Nicholas Ryan, Andrew A Udy, Tomoko Fujii","doi":"10.1093/burnst/tkae081","DOIUrl":"https://doi.org/10.1093/burnst/tkae081","url":null,"abstract":"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.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"75 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986354","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}
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。
{"title":"CYP24A1 is overexpressed in keloid keratinocytes and its inhibition alters profibrotic gene expression","authors":"Jennifer M Hahn, Kelly A Combs, Caitlin M Phillips, Petra M Warner, Uzair A Qazi, Heather M Powell, Dorothy M Supp","doi":"10.1093/burnst/tkae063","DOIUrl":"https://doi.org/10.1093/burnst/tkae063","url":null,"abstract":"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.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"29 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987579","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}
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