Berberine accelerated wound healing by restoring TrxR1/JNK in diabetes

Abstract The high disability, mortality and morbidity of diabetic ulcers make it urgent to explore effective strategies for diabetic wound repair. TrxR1 plays a vital role in regulating redox homeostasis in various pathologies. In the present study, the effect of berberine (BBR) on diabetic wounds was investigated in streptozotocin (STZ)-induced diabetic rats and a high glucose (HG)-induced cell model, and the mechanism of BBR on TrxR1 was elucidated. BBR treatment remarkably accelerated wound healing and enhanced extracellular matrix (ECM) synthesis and significantly inhibited HG-induced HaCaT cell damage. Further analysis indicated that BBR activated TrxR1, suppressed its downstream JNK signaling, thereby inhibiting oxidative stress and apoptosis, promoted cell proliferation, down-regulated matrix metalloproteinase (MMP) 9 (MMP9) and up-regulated transforming growth factor-β1 (TGF-β1) and tissue inhibitors of MMP 1 (TIMP1), resulting in accelerated wound healing. Importantly, the enhancement of BBR on wound repair was further abolished by TrxR1 inhibitor. Moreover, in diabetic wounds induced by a combination of STZ injection and high-fat diet, BBR significantly increased wound closure rate and TrxR1 expression, and this was reversed by TrxR1 inhibitor. These data indicated that topical BBR treatment accelerated diabetic wound healing by activating TrxR1. Targeting TrxR1 may be a novel, effective strategy for restoring redox homeostasis and promoting diabetic wound healing.

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Healing Effects of Photobiomodulation on Diabetic Wounds

Applied Sciences ◽

10.3390/app9235114 ◽

2019 ◽

Vol 9 (23) ◽

pp. 5114

Author(s):

Nicolette Houreld

Keyword(s):

Wound Healing ◽

Wound Repair ◽

Chronic Wounds ◽

Diabetic Patients ◽

Diabetic Wound ◽

Recurrence Rates ◽

Speed Up ◽

Diabetic Wound Healing ◽

Underlying Mechanisms ◽

Diabetic Wounds

Diabetic patients frequently develop chronic ulcers of the lower extremities, which are a frequent cause for hospitalization and amputation, placing strain on patients, their families, and healthcare systems. Present therapies remain a challenge, with high recurrence rates. Photobiomodulation (PBM), which is the non-invasive application of light at specific wavelengths, has been shown to speed up healing of chronic wounds, including diabetic foot ulcers (DFUs). PBM produces photophysical and photochemical changes within cells without eliciting thermal damage. It has been shown to promote tissue regeneration and speed up wound repair by reducing inflammation and oxidative stress, accelerating cell migration and proliferation, and promoting extracellular matrix production and release of essential growth factors. The shortage of rigorous, well-designed clinical trials makes it challenging to assess the scientific impact of PBM on DFUs, and lack of understanding of the underlying mechanisms also hinders the conventional use of this therapy. This review gives a glimpse into diabetic wound healing and PBM, and the effects of PBM on diabetic wound healing.

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Hypoxia adipose stem cell-derived exosomes promote high-quality healing of diabetic wound involves activation of PI3K/Akt pathways

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00942-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Jie Wang ◽

Hao Wu ◽

Yixuan Peng ◽

Yue Zhao ◽

Youyou Qin ◽

...

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Molecular Mechanisms ◽

High Throughput Sequencing ◽

Transforming Growth Factor ◽

Adipose Stem Cells ◽

Diabetic Wound ◽

Skin Wound Healing ◽

Diabetic Wound Healing ◽

Diabetic Wounds

AbstractRefractory diabetic wounds can cause persistent inflammation and delayed healing due to hypoxia. Currently, no optimal solution is available. Exosomes of adipose stem cells (ADSCs-exo) may promote skin wound healing, however, molecular mechanisms remains mysterious. We found significantly enhanced survival and proliferation of adipose stem cells after hypoxia induction compared to normoxia. Here, we aimed to investigate if hypoxic adipose stem cells exosomes (HypADSCs-exo) participate in hypoxia adaptability and accelerate diabetic wound healing. Based on high-throughput sequencing, 215 microRNAs (miRNAs) were upregulated and 369 miRNAs downregulated in HypADSCs-exo compared to ADSCs-exo. Up-regulated miR-21-3p, miR-126-5p, miR-31-5p whereas down-regulated gene miR-99b and miR-146-a correlated with wound healing. According to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), miRNAs might regulate cell metabolism, differentiation and Transforming growth factor-β (TGF-β) function. Consistently, HpyADSCs-exo could promote diabetic wounds healing and inhibit inflammation through PI3K/AKT signaling pathway. Collectively, HpyADSCs-exo can promote diabetic wound healing as an alternative strategy to improve wound healing.

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A bioglass sustained-release scaffold with ECM-like structure for enhanced diabetic wound healing

Nanomedicine ◽

10.2217/nnm-2020-0053 ◽

2020 ◽

Vol 15 (23) ◽

pp. 2241-2253

Author(s):

Pengju Zhang ◽

Yuqi Jiang ◽

Dan Liu ◽

Yan Liu ◽

Qinfei Ke ◽

...

Keyword(s):

Wound Healing ◽

Therapeutic Option ◽

Effective Strategy ◽

Diabetic Wound ◽

Nano Structure ◽

Wound Site ◽

Diabetic Wound Healing ◽

Coaxial Fibers ◽

Diabetic Wounds ◽

Endothelial Cell Adhesion

Aim: To develop an effective strategy for increasing angiogenesis at diabetic wound sites and thereby accelerating wound healing. Materials & methods: A micropatterned nanofibrous scaffold with bioglass nanoparticles encapsulated inside coaxial fibers was prepared by electrospinning. Results: Si ions could be released in a sustained manner from the scaffolds. The hierarchical micro-/nano-structure of the scaffold was found to act as a temporary extracellular matrix to promote endothelial cell adhesion and growth. The scaffold greatly improved angiogenesis and collagen deposition at the wound site, which shortened the healing period of diabetic wounds. Conclusion: This study provides a promising therapeutic option for chronic diabetic wounds with improved angiogenesis.

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Co-Transplantation of Skin-Derived Precursors and Collagen Sponge Facilitates Diabetic Wound Healing by Promoting Local Vascular Regeneration

Cellular Physiology and Biochemistry ◽

10.1159/000438537 ◽

2015 ◽

Vol 37 (5) ◽

pp. 1725-1737 ◽

Cited By ~ 15

Author(s):

Tingyu Ke ◽

Mei Yang ◽

Duo Mao ◽

Meifeng Zhu ◽

Yongzhe Che ◽

...

Keyword(s):

Wound Healing ◽

Wound Repair ◽

Expression Patterns ◽

Collagen Sponge ◽

Health Concern ◽

Diabetic Wound ◽

Paracrine Signalling ◽

Vascular Regeneration ◽

Diabetic Wound Healing

Background/Aims: Impaired diabetes wound healing can often lead to serious complications and remains a major health concern due to the lack of effective therapeutic approaches. Compromised angiogenesis, disrupted growth factor and cytokine activity are all attributable to diabetic wound healing impairment. The skin-derived precursors (SKPs) have been shown to differentiate into vascular and nerve cells, both of which are crucial components for wound repair. Given their easy accessibility and multipotency, the SKPs were proposed as an ideal therapeutic candidate for diabetic wound healing. Since the efficacy of cell therapy is limited by poor cell survival, collagen sponge was employed for better SKPs delivery. Methods: SKPs were isolated and transplanted directly to the wound areas of diabetic mice in the absence and presence of collagen sponge. The effects of SKPs and/or collagen sponge on diabetic wound healing were examined histologically as well as immunostaining of isolectin and α-SMA. Mechanisms via which the SKPs facilitate wound healing were then investigated by transplanting SKPs that have been pre-labelled with a fluorescence dye, Dil. Expression patterns of Dil and an SKP marker, nestin, was also examined. Results and Conclusion: Accelerated wound healing and enhanced local capillary regeneration could be observed 14 days after skin ablation from both SKPs and collagen sponge co-transplanted and collagen sponge only groups. Subsequent analyses further revealed superior pro-angiogenic effects from the SKP and collagen sponge co-delivered group, which are mainly attributable to in vivo transdifferentation and paracrine signalling of the SKPs.

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Updates in Diabetic Wound Healing, Inflammation, and Scarring

Seminars in Plastic Surgery ◽

10.1055/s-0041-1731460 ◽

2021 ◽

Author(s):

Nina Dasari ◽

Austin Jiang ◽

Anna Skochdopole ◽

Jayer Chung ◽

Edward Reece ◽

...

Keyword(s):

Wound Healing ◽

Disease Process ◽

Wound Dehiscence ◽

Diabetic Patients ◽

Wound Infections ◽

Diabetic Wound ◽

Complex Process ◽

Diabetic Wound Healing ◽

Almost All ◽

Diabetic Wounds

AbstractDiabetic patients can sustain wounds either as a sequelae of their disease process or postoperatively. Wound healing is a complex process that proceeds through phases of inflammation, proliferation, and remodeling. Diabetes results in several pathological changes that impair almost all of these healing processes. Diabetic wounds are often characterized by excessive inflammation and reduced angiogenesis. Due to these changes, diabetic patients are at a higher risk for postoperative wound healing complications. There is significant evidence in the literature that diabetic patients are at a higher risk for increased wound infections, wound dehiscence, and pathological scarring. Factors such as nutritional status and glycemic control also significantly influence diabetic wound outcomes. There are a variety of treatments available for addressing diabetic wounds.

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Extracellular vesicles derived from adipose-derived stem cells accelerate diabetic wound healing by suppressing the expression of matrix metalloproteinase-9

Current Pharmaceutical Biotechnology ◽

10.2174/1389201022666210719154009 ◽

2021 ◽

Vol 22 ◽

Author(s):

Jiang-wen Wang ◽

Yuan-zheng Zhu ◽

Xuan Hu ◽

Jia-ying Nie ◽

Zhao-hui Wang ◽

...

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Mouse Model ◽

Adipose Derived Stem Cells ◽

Collagen Deposition ◽

Diabetic Wound ◽

Diabetic Wound Healing ◽

Diabetic Wounds ◽

Metalloproteinase 9

Background: The healing of diabetic wounds is poor due to a collagen deposition disorder. Matrix metalloproteinase-9 (MMP-9) is closely related to collagen deposition in the process of tissue repair. Many studies have demonstrated that extracellular vesicles derived from adipose-derived stem cells (ADSC-EVs) promote diabetic wound healing by enhancing collagen deposition. Objective: In this study, we explored if ADSC-EVs could downregulate the expression of MMP-9 in diabetic wounds and promote wound healing by improving collagen deposition. The potential effects of ADSC-EVs on MMP-9 and diabetic wound healing were tested both in vitro and in vivo. Methods: We first evaluated the effect of ADSC-EVs on the proliferation and MMP-9 secretion of HaCaT cells treated with advanced glycation end product-bovine serum albumin (AGE-BSA), using CCK-8 western blot and MMP-9 enzyme-linked immunosorbent assay(ELISA). Next, the effect of ADSC-EVs on the healing, re-epithelialisation, collagen deposition, and MMP-9 concentration in diabetic wound fluids was evaluated in an immunodeficient mouse model via MMP-9 ELISA and haematoxylin and eosin, Masson’s trichrome, and immunofluorescence staining for MMP-9. Results: In vitro, ADSC-EVs promoted the proliferation and MMP-9 secretion of HaCaT cells.In vivo, ADSC-EVs accelerated diabetic wound healing by improving re-epithelialisation and collagen deposition and by inhibiting the expression of MMP-9. Conclusion: ADSC-EVs possessed the healing of diabetic wounds in a mouse model by inhibiting downregulating MMP-9 and improving collagen deposition.Thus ,ADSC-EVs are a promising candidate for the treatment of diabetic wounds .

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Notoginsenoside R1 Facilitated Wound Healing in High-Fat Diet/Streptozotocin-Induced Diabetic Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2022/2476493 ◽

2022 ◽

Vol 2022 ◽

pp. 1-15

Author(s):

Guangzhao Cao ◽

Changpei Xiang ◽

Rui Zhou ◽

Yi Zhang ◽

He Xu ◽

...

Keyword(s):

Wound Healing ◽

High Fat Diet ◽

Transforming Growth Factor ◽

Tissue Inhibitor Of Metalloproteinase ◽

Therapeutic Drug ◽

High Morbidity ◽

Diabetic Wound ◽

High Fat ◽

Diabetic Wound Healing ◽

Matrix Metallopeptidase

Diabetic ulcers bring about high morbidity and mortality in patients and cause a great economic burden to society as a whole. Since existing treatments cannot fulfil patient requirements, it is urgent to find effective therapies. In this study, the wound healing effect of topical notoginsenoside R1 (NR1) treatment on diabetic full-thickness wounds in type II diabetes mellitus (T2DM) was induced by the combination of a high-fat diet and streptozotocin (STZ) injection. NR1 significantly increased the wound closure rate, enhanced extracellular matrix (ECM) secretion, promoted collagen growth, increased platelet endothelial cell adhesion molecule-1 (CD31) expression, and decreased cleaved caspase-3 expression. RNA-Seq analysis identified ECM remodeling and inflammation as critical biological processes and Timp1 and Mmp3 as important targets in NR1-mediated wound healing. Further experiments showed that NR1-treated wounds demonstrated higher expression of tissue inhibitor of metalloproteinase 1 (TIMP1) and transforming growth factor-β1 (TGFβ1) and lower expression of matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 3 (MMP3), interleukin-1β (IL-1β), and interleukin-6 (IL-6) than diabetic wounds. These investigations promote the understanding of the mechanism of NR1-mediated diabetic wound healing and provide a promising therapeutic drug to enhance diabetic wound healing.

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Platelet-Rich Plasma with Endothelial Progenitor Cells Accelerates Diabetic Wound Healing in Rats by Upregulating the Notch1 Signaling Pathway

Journal of Diabetes Research ◽

10.1155/2019/5920676 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 4

Author(s):

Cheng Zhang ◽

Yu Zhu ◽

Shengdi Lu ◽

Wanrun Zhong ◽

Yanmao Wang ◽

...

Keyword(s):

Wound Healing ◽

Growth Factors ◽

Signaling Pathway ◽

Platelet Rich Plasma ◽

Diabetic Wound ◽

Endothelial Progenitor ◽

Notch1 Signaling ◽

Diabetic Wound Healing ◽

Notch1 Signaling Pathway ◽

Diabetic Wounds

Diabetic wounds, as a kind of refractory wound, are very difficult to heal. Both endothelial progenitor cell (EPC) transplantation and platelet-rich plasma (PRP) can improve diabetic wound healing to some extent. However, PRP application cannot provide reparative cells, while EPC transplantation cannot replenish the required growth factors for wound healing. Thus, when applied alone, neither of these factors is sufficient for effective wound healing. Furthermore, the proliferation, differentiation, and fate of the transplanted EPCs are not well known. Therefore, in this study, we examined the efficacy of combined PRP application with EPC transplantation in diabetic wound healing. Our results indicated that PRP application improved EPC proliferation and migration. The Notch signaling pathway plays a key role in the regulation of the proliferation and differentiation of stem cells and angiogenesis in wound healing. The application of PRP upregulated the Notch pathway-related gene and protein expression in EPCs. Furthermore, experiments with shNotch1-transfected EPCs indicated that PRP enhanced the function of EPCs by upregulating the Notch1 signaling pathway. In vivo studies further indicated that the combination of PRP and EPC transplantation increased neovascularization, reduced wound size, and improved healing in rat wound models. Thus, PRP application can provide the necessary growth factors for wound healing, while EPC transplantation offers the required cells, indicating that the combination of both is a potent novel approach for treating diabetic wounds.

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γ-PGA hydrogel loaded with cell-free fat extract promotes the healing of diabetic wounds

Journal of Materials Chemistry B ◽

10.1039/d0tb01190h ◽

2020 ◽

Vol 8 (36) ◽

pp. 8395-8404

Author(s):

Mengting Yin ◽

Xiangsheng Wang ◽

Ziyou Yu ◽

Yun Wang ◽

Xiansong Wang ◽

...

Keyword(s):

Wound Healing ◽

Diabetic Wound ◽

Diabetic Wound Healing ◽

Diabetic Wounds

Schematic of Ceffe–γ-PGA hydrogel treatment for diabetic wound healing.

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Enhanced Healing of Diabetic Wounds by Subcutaneous Administration of Human Umbilical Cord Derived Stem Cells and Their Conditioned Media

International Journal of Endocrinology ◽

10.1155/2013/592454 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 26

Author(s):

Chandrama Shrestha ◽

Liling Zhao ◽

Ke Chen ◽

Honghui He ◽

Zhaohui Mo

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Umbilical Cord ◽

Subcutaneous Administration ◽

Conditioned Media ◽

Human Umbilical Cord ◽

Diabetic Wound ◽

Significant Difference ◽

Diabetic Wound Healing ◽

Diabetic Wounds

Objective. Mesenchymal stem cells (MSCs) isolated from the umbilical cord and their conditioned media (CM) can be easily obtained and refined compared with stem cells from other sources. Here, we explore the possibility of the benefits of these cells in healing diabetic wounds.Methodology and Results. Delayed wound healing animal models were established by making a standard wound on the dorsum of eighteen db/db mice, which were divided into three groups with six mice in each: groups I, II, and III received PBS, UC-MSC, and CM, respectively. UC-MSC and their CM significantly accelerated wound closure compared to PBS-treated wounds, and it was most rapid in CM-injected wounds. In day-14 wounds, significant difference in capillary densities among the three groups was noted (n=6;P<0.05), and higher levels of VEGF, PDGF, and KGF expression in the CM- and UC-MSC-injected wounds compared to the PBS-treated wounds were seen. The expression levels of PDGF-βand KGF were higher in CM-treated wounds than those in UC-MSC-treated wounds.Conclusion. Both the transplantation of UC-MSC and their CM are beneficial to diabetic wound healing, and CM has been shown to be therapeutically better than UC-MSC, at least in the context of diabetic wound healing.

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