Multifunctional Elastin-Like Polypeptide Fusion Protein Coacervates Inhibit Receptor-Mediated Proinflammatory Signals and Promote Angiogenesis in Mouse Diabetic Wounds

Kang, Hwan June; Kumar, Suneel; Dash, Biraja C.; Hsia, Henry C.; Yarmush, Martin L.; Berthiaume, François

doi:10.1089/wound.2021.0102

Cited by 6 publications

(4 citation statements)

References 32 publications

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“…1 d) showed the top 12 signalling pathways, many of which were closely associated with a variety of chronic wounds, such as apoptosis 70 , HIF-1 signalling pathways 71 and ROS 72 . Additionally, the AGE-RAGE signalling pathway in diabetic complications 73 was involved in diabetic wound healing; hepatitis B 74 , human cytomegalovirus infection and hepatitis C 75 signalling pathways might participate in chronic infectious wounds 76 . As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Integrated network pharmacology and experimental validation to explore the mechanisms underlying naringenin treatment of chronic wounds

Sun

Liu

et al. 2023

Sci Rep

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Naringenin is a citrus flavonoid with various biological functions and a potential therapeutic agent for skin diseases, such as UV radiation and atopic dermatitis. The present study investigates the therapeutic effect and pharmacological mechanism of naringenin on chronic wounds. Using network pharmacology, we identified 163 potential targets and 12 key targets of naringenin. Oxidative stress was confirmed to be the main biological process modulated by naringenin. The transcription factor p65 (RELA), alpha serine/threonine-protein kinase (AKT1), mitogen-activated protein kinase 1 (MAPK1) and mitogen-activated protein kinase 3 (MAPK3) were identified as common targets of multiple pathways involved in treating chronic wounds. Molecular docking verified that these four targets stably bound naringenin. Naringenin promoted wound healing in mice in vivo by inhibiting wound inflammation. Furthermore, in vitro experiments showed that a low naringenin concentration did not significantly affect normal skin cell viability and cell apoptosis; a high naringenin concentration was cytotoxic and reduced cell survival by promoting apoptosis. Meanwhile, comprehensive network pharmacology, molecular docking and in vivo and in vitro experiments revealed that naringenin could treat chronic wounds by alleviating oxidative stress and reducing the inflammatory response. The underlying mechanism of naringenin in chronic wound therapy involved modulating the RELA, AKT1 and MAPK1/3 signalling pathways to inhibit ROS production and inflammatory cytokine expression.

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Section: Resultsmentioning

confidence: 99%

Integrated network pharmacology and experimental validation to explore the mechanisms underlying naringenin treatment of chronic wounds

Sun

Liu

et al. 2023

Sci Rep

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“…Furthermore, several studies have con rmed conclusively the role of AGEs-RAGE in DFU development [29,30]. Hyperglycemia made induction of non-enzymatic glycosylation of proteins and lipids for AGEs formation, which, following binding to their receptor RAGE, further causing pro-in ammatory signaling and vascular endothelial damage, thereby delaying diabetic wound healing [30]. The application of ibrutinib by Yang et al [29] [29] revealed that it led to lower RAGE, IL-1β, TNF-α, and IL-6 expression, whereas upregulated VEGF levels, which caused higher wound healing rate and wound healing promotion of DFU rats, matching ndings of the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Li et al [25] [25] demonstrated that hesperidin treatment resulted in an increase in SOD and GSH levels, whereas a decrease in MDA and NO levels, while reversing down-regulation of VEGF-c, Ang-1, and Tie-2 expression occurred in wound tissues of DFU rats, in high accordance with our study. Furthermore, several studies have con rmed conclusively the role of AGEs-RAGE in DFU development [29,30]. Hyperglycemia made induction of non-enzymatic glycosylation of proteins and lipids for AGEs formation, which, following binding to their receptor RAGE, further causing pro-in ammatory signaling and vascular endothelial damage, thereby delaying diabetic wound healing [30].…”

Section: Discussionmentioning

confidence: 99%

Dang-Gui-Si-Ni decoction facilitates wound healing in diabetic foot ulcers by regulating expression of AGEs/RAGE/TGF-β/Smad2/3

Zhang,

Xu,

junior

et al. 2024

Preprint

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Purpose Diabetic foot ulcer (DFU) is a predominant complication of diabetes mellitus with poor prognosis accompanied by high amputation and mortality rates. Dang-Gui-Si-Ni decoction (DSD), as a classic formula with a long history in China, has been found to improve DFU symptoms. However, mechanism of DSD for DFU therapy remains unclear with no systematic elaboration. Methods In vivo, following establishment of DFU rat model, DSD intervention with low, medium and high doses was done, with Metformin (DM) as a positive control group. With wound healing detection, pathological changes by HE staining, inflammatory factor expression by ELISA and qRT-PCR, oxidative stress levels by ELISA, and AGEs/RAGE/TGF-β/Smad2/3 expression by Western blot were performed. In vitro, intervention with LY2109761 (TGF-β pathway inhibitor) based on DSD treatment in human dermal fibroblast-adult (HDF-a) cells was made. Cell viability by CCK8, migration ability by cell scratch, apoptosis by flow cytometry, and AGEs/RAGE/TGF-β/Smad2/3 expression by Western blot were measured. Results DFU rats exhibited elevated AGEs/RAGE expression, whereas decreased TGF-β1 and p-Smad3/Smad3 protein expression, accompanied by higher IL-1β, IL-6, TNF-α levels, and oxidative stress. DSD intervention reversed above effects. Glucose induction caused lower cell viability, migration, TGF-β1 and p-Smad3/Smad3 protein expression, with increased apoptosis and AGEs/RAGE expression in HDF-a cells. These effects were reversed after DSD intervention, and further LY2109761 intervention inhibited DSD effects in cells. Conclusion DSD intervention may facilitates wound healing in diabetic foot ulcers by regulating expression of AGEs/RAGE/TGF-β/Smad2/3, providing scientific experimental evidence for DSD clinical application for DFU therapy.

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“…Encouragingly, an anti-RAGE monoclonal antibody that binds a peptide sequence in the RAGE extracellular structural domain prevented receptor-ligand binding and significantly improved hindlimb perfusion in ischaemic limbs, with greater reconstruction of collateral circulation in occluded arteries [ 132 ]. Recombinant proteins containing ELP fused to the RAGE domain or to stromal cell-derived factor 1 can inhibit AGE-RAGE signal transduction and promote cell proliferation and angiogenesis [ 133 ]. Blocking the AGE-RAGE-based response involving matrix proteins is emerging as a promising approach for preventing the development of ischaemic diseases in older adults.…”

Section: Therapeutic Strategies For Promoting Angiogenesis By Targeti...mentioning

confidence: 99%

Impaired angiogenesis in ageing: the central role of the extracellular matrix

et al. 2023

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Each step in angiogenesis is regulated by the extracellular matrix (ECM). Accumulating evidence indicates that ageing-related changes in the ECM driven by cellular senescence lead to a reduction in neovascularisation, reduced microvascular density, and an increased risk of tissue ischaemic injury. These changes can lead to health events that have major negative impacts on quality of life and place a significant financial burden on the healthcare system. Elucidating interactions between the ECM and cells during angiogenesis in the context of ageing is neceary to clarify the mechanisms underlying reduced angiogenesis in older adults. In this review, we summarize ageing-related changes in the composition, structure, and function of the ECM and their relevance for angiogenesis. Then, we explore in detail the mechanisms of interaction between the aged ECM and cells during impaired angiogenesis in the older population for the first time, discussing diseases caused by restricted angiogenesis. We also outline several novel pro-angiogenic therapeutic strategies targeting the ECM that can provide new insights into the choice of appropriate treatments for a variety of age-related diseases. Based on the knowledge gathered from recent reports and journal articles, we provide a better understanding of the mechanisms underlying impaired angiogenesis with age and contribute to the development of effective treatments that will enhance quality of life.

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Multifunctional Elastin-Like Polypeptide Fusion Protein Coacervates Inhibit Receptor-Mediated Proinflammatory Signals and Promote Angiogenesis in Mouse Diabetic Wounds

Cited by 6 publications

References 32 publications

Integrated network pharmacology and experimental validation to explore the mechanisms underlying naringenin treatment of chronic wounds

Integrated network pharmacology and experimental validation to explore the mechanisms underlying naringenin treatment of chronic wounds

Dang-Gui-Si-Ni decoction facilitates wound healing in diabetic foot ulcers by regulating expression of AGEs/RAGE/TGF-β/Smad2/3

Impaired angiogenesis in ageing: the central role of the extracellular matrix

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