Novel neutrophil extracellular trap-related mechanisms in diabetic wounds inspire a promising treatment strategy with hypoxia-challenged small extracellular vesicles

Chu, Ziqiang; Huang, Qilin; Ma, Kui; Liu, Xi; Zhang, Wenhua; Cui, Shengnan; Wei, Qian; Gao, Huanhuan; Hu, Wenzhi; Wang, Zihao; Meng, Sheng; Tian, Lige; Li, Haihong; Fu, Xiaobing; Zhang, Cuiping

doi:10.1016/j.bioactmat.2023.04.007

Cited by 21 publications

(14 citation statements)

References 60 publications

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“…24 Some of the mechanisms that sustain NET release have been clarified, including oxidative stress, epigenetic changes driven by microRNAs and activation of the inflammasome. 25 We found that, in patients with diabetes, neutrophils are prone to release NETs. Specifically, NET components were enriched in samples collected from non-healing DFUs, and high levels of neutrophil elastase in the wounds were associated with infection and worsened ulcer outcomes.…”

Section: Disarming Neutrophilsmentioning

confidence: 78%

Recent developments in targets for ischemic foot disease

Golledge

Thanigaimani

Barratt

et al. 2023

Diabetes Metabolism Res

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Diabetes is a key risk factor for ischaemic foot disease, which causes pain, tissue loss, hospital admission, and major amputation. Currently, treatment focuses on revascularisation, but many patients are unsuitable for surgery and revascularisation is frequently unsuccessful. The authors describe recent research in animal models and clinical trials investigating novel medical targets for ischaemia, including theories about impaired wound healing, animal models for limb ischaemia and recent randomised controlled trials testing novel medical therapies. Novel targets identified in animal models included stimulating mobilisation of CD34+ progenitor cells through upregulating oncostatin M or microRNA‐181, downregulating tumour necrosis factor superfamily member 14, or activating the Wingless pathway. Within the ischaemic limb vasculature, upregulation of apolipoprotein L domain containing 1, microRNA‐130b or long noncoding RNA that enhances endothelial nitric oxide synthase expression promoted limb blood supply recovery, angiogenesis, and arteriogenesis. Similarly, administration of soluble guanylate cyclase stimulators riociguat or praliciguat or 3‐ketoacyl‐CoA thiolase inhibitor trimetazidine promoted blood flow recovery. Translating pre‐clinical findings to patients has been challenging, mainly due to limitations in clinically translatable animal models of human disease. Promising results have been reported for administering plasmids encoding hepatocyte growth factor or intra‐arterial injection of bone marrow derived cells in small clinical trials. It remains to be seen whether these high resource therapies can be developed to be widely applicable. In conclusion, an ever‐expanding list of potential targets for medical revascularisation is being identified. It is hoped that through ongoing research and further larger clinical trials, these will translate into new broadly applicable therapies to improve outcomes.

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Section: Disarming Neutrophilsmentioning

confidence: 78%

Recent developments in targets for ischemic foot disease

Golledge

Thanigaimani

Barratt

et al. 2023

Diabetes Metabolism Res

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“…Metformin with antioxidant and anti-inflammatory activity is loaded onto mesoporous silicon nanoparticles and gene delivery combined with antibacterial dressing carriers to heal diabetic wounds through dual controlled release of polarized macrophages and inhibition of NETosis. 22,221 Nano-targeted neutrophils interfere with their function to inhibit NETosis. Nanoparticles decorated with sialic acid residue dimer can to easily bind to the neutrophil siglec-5 to reduce ROS production.…”

Section: Nanodelivery Systemsmentioning

confidence: 99%

“…Many stimuli that cause inflammation induce NETosis, whereas NETs promote the onset and worsening of inflammation, as seen in sepsis, diabetes, and rheumatoid arthritis (RA). [21][22][23] Therefore, the inhibition of NETosis is an important approach for the treatment of inflammatory diseases. Although many recent reviews have described the inhibition of NETs formation, an evaluation of their advantages and disadvantages and effective therapeutic targeting strategies is lacking.…”

Section: Introductionmentioning

confidence: 99%

Role and Therapeutic Targeting Strategies of Neutrophil Extracellular Traps in Inflammation

Li,

Xiao,

Filipczak

et al. 2023

IJN

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Neutrophil extracellular traps (NETs) are large DNA reticular structures secreted by neutrophils and decorated with histones and antimicrobial proteins. As a key mechanism for neutrophils to resist microbial invasion, NETs play an important role in the killing of microorganisms (bacteria, fungi, and viruses). Although NETs are mostly known for mediating microbial killing, increasing evidence suggests that excessive NETs induced by stimulation of physical and chemical components, microorganisms, and pathological factors can exacerbate inflammation and organ damage. This review summarizes the induction and role of NETs in inflammation and focuses on the strategies of inhibiting NETosis and the mechanisms involved in pathogen evasion of NETs. Furthermore, herbal medicine inhibitors and nanodelivery strategies improve the efficiency of inhibition of excessive levels of NETs.

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“…[ 3 ] MiR‐17‐5p was a crucial regulator by enhancing the angiogenic effect of endothelial cells, [ 3 ] and exerting protective effects on fibroblasts in vitro and in vivo. [ 20 ] This suggests that engineered sEVs modified for the efficient loading of miR‐17‐5p may provide a promising and novel therapy for diabetic wounds.…”

Section: Introductionmentioning

confidence: 99%

MiR‐17‐5p‐engineered sEVs Encapsulated in GelMA Hydrogel Facilitated Diabetic Wound Healing by Targeting PTEN and p21

Wei,

Su,

Meng

et al. 2024

Advanced Science

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Delayed wound healing is a major complication of diabetes, and is associated with impaired cellular functions. Current treatments are unsatisfactory. Based on the previous reports on microRNA expression in small extracellular vesicles (sEVs), miR‐17‐5p‐engineered sEVs (sEVs17‐OE) and encapsulated them in gelatin methacryloyl (GelMA) hydrogel for diabetic wounds treatment are fabricated. SEVs17‐OE are successfully fabricated with a 16‐fold increase in miR‐17‐5p expression. SEVs17‐OE inhibited senescence and promoted the proliferation, migration, and tube formation of high glucose‐induced human umbilical vein endothelial cells (HG‐HUVECs). Additionally, sEVs17‐OE also performs a promotive effect on high glucose‐induced human dermal fibroblasts (HG‐HDFs). Mechanism analysis showed the expressions of p21 and phosphatase and tensin homolog (PTEN), as the target genes of miR‐17‐5p, are downregulated significantly by sEVs17‐OE. Accordingly, the downstream genes and pathways of p21 and PTEN, are activated. Next, sEVs17‐OE are loaded in GelMA hydrogel to fabricate a novel bioactive wound dressing and to evaluate their effects on diabetic wound healing. Gel‐sEVs17‐OE effectively accelerated wound healing by promoting angiogenesis and collagen deposition. The cellular mechanism may be associated with local cell proliferation. Therefore, a novel bioactive wound dressing by loading sEVs17‐OE in GelMA hydrogel, offering an option for chronic wound management is successfully fabricated.

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Novel neutrophil extracellular trap-related mechanisms in diabetic wounds inspire a promising treatment strategy with hypoxia-challenged small extracellular vesicles

Cited by 21 publications

References 60 publications

Recent developments in targets for ischemic foot disease

Recent developments in targets for ischemic foot disease

Role and Therapeutic Targeting Strategies of Neutrophil Extracellular Traps in Inflammation

MiR‐17‐5p‐engineered sEVs Encapsulated in GelMA Hydrogel Facilitated Diabetic Wound Healing by Targeting PTEN and p21

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