Beneficial Effects of Deoxyshikonin on Delayed Wound Healing in Diabetic Mice

Shiunko ointment is composed of five ingredients including Lithospermi Radix (LR), Angelicae Gigantis Radix, sesame seed oil, beeswax, and swine oil. It is externally applied as a treatment for a wide range of skin conditions such as eczema, psoriasis, hair loss, burns, topical wounds, and atopic dermatitis. Deoxyshikonin is the major angiogenic compound extracted from LR. In this study, we investigated the efficacy of LR extract and deoxyshikonin on impaired wound healing in streptozotocin (STZ)-induced diabetic mice. Treatment with LR extract elevated tube formation in human umbilical vein endothelial cells (HUVECs) and exerted antioxidant activity. An open skin wound was produced on the backs of diabetic mice and was then topically treated with deoxyshikonin or vehicle. In addition, deoxyshikonin promoted tube formation in high glucose conditions exposed to HUVECs, and which may be regulated by increased VEGFR2 expression and phosphorylation of Akt and p38. Our results demonstrate that deoxyshikonin application promoted wound repair in STZ-induced diabetic mice. Collectively, these data suggest that deoxyshikonin is an active ingredient of LR, thereby contributing to wound healing in patients with diabetes.

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Improvement of Cutaneous Wound Healing via Topical Application of Heat-Killed Lactococcus chungangensis CAU 1447 on Diabetic Mice

Nutrients ◽

10.3390/nu13082666 ◽

2021 ◽

Vol 13 (8) ◽

pp. 2666

Author(s):

YoHan Nam ◽

Jong-Hwa Kim ◽

Jihye Baek ◽

Wonyong Kim

Keyword(s):

Wound Healing ◽

Wound Repair ◽

Therapeutic Agents ◽

Skin Wound ◽

Skin Microbiome ◽

Cutaneous Wound Healing ◽

Diabetic Mice ◽

Cutaneous Wound ◽

Beneficial Effects ◽

Systemic Network

Cutaneous wound healing comprises a complex systemic network. Probiotics, naturally extracted substances, medicine, and chemical compounds have been used for wound healing, but the application of postbiotics as therapeutic agents has yet to be explored. Our study shows potential beneficial effects of heat-killed Lactococcus chungangensis CAU 1447 on type 1 diabetic mice. The postbiotic strain significantly decreased the skin wound size. The activity of myeloperoxidase secreted from neutrophils also decreased. The molecular mechanism of wound healing was adjusted by important mediators, growth factors, chemokines, and cytokines. These elements regulated the anti-inflammatory activity and accelerated wound healing. To determine the role of the postbiotic in wound repair, we showed a similar taxonomic pattern as compared to the diabetic mice using skin microbiome analysis. These findings demonstrated that heat-killed Lactococcus chungangensis CAU 1447 had beneficial effects on wound healing and can be utilized as postbiotic therapeutic agents.

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Keratin Scaffolds Containing Casomorphin Stimulate Macrophage Infiltration and Accelerate Full-Thickness Cutaneous Wound Healing in Diabetic Mice

Molecules ◽

10.3390/molecules26092554 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2554

Author(s):

Marek Konop ◽

Anna K. Laskowska ◽

Mateusz Rybka ◽

Ewa Kłodzińska ◽

Dorota Sulejczak ◽

...

Keyword(s):

Wound Healing ◽

Wound Dressing ◽

Healing Process ◽

Skin Wound ◽

Wound Healing Process ◽

Diabetic Mice ◽

Full Thickness ◽

Skin Wound Healing ◽

Impaired Wound Healing

Impaired wound healing is a major medical challenge, especially in diabetics. Over the centuries, the main goal of tissue engineering and regenerative medicine has been to invent biomaterials that accelerate the wound healing process. In this context, keratin-derived biomaterial is a promising candidate due to its biocompatibility and biodegradability. In this study, we evaluated an insoluble fraction of keratin containing casomorphin as a wound dressing in a full-thickness surgical skin wound model in mice (n = 20) with iatrogenically induced diabetes. Casomorphin, an opioid peptide with analgesic properties, was incorporated into keratin and shown to be slowly released from the dressing. An in vitro study showed that keratin-casomorphin dressing is biocompatible, non-toxic, and supports cell growth. In vivo experiments demonstrated that keratin-casomorphin dressing significantly (p < 0.05) accelerates the whole process of skin wound healing to the its final stage. Wounds covered with keratin-casomorphin dressing underwent reepithelization faster, ending up with a thicker epidermis than control wounds, as confirmed by histopathological and immunohistochemical examinations. This investigated dressing stimulated macrophages infiltration, which favors tissue remodeling and regeneration, unlike in the control wounds in which neutrophils predominated. Additionally, in dressed wounds, the number of microhemorrhages was significantly decreased (p < 0.05) as compared with control wounds. The dressing was naturally incorporated into regenerating tissue during the wound healing process. Applied keratin dressing favored reconstruction of more regular skin structure and assured better cosmetic outcome in terms of scar formation and appearance. Our results have shown that insoluble keratin wound dressing containing casomorphin supports skin wound healing in diabetic mice.

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Abstract 13373: Exercise Improves Angiogenic Function of Circulating Exosomes in Type 2 Diabetes: Role of Extracellular SOD

Circulation ◽

10.1161/circ.142.suppl_3.13373 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Kareem Abdelsaid ◽

Sudhahar Varadarajan ◽

Archita Das ◽

Yutao Liu ◽

Xuexiu Fang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Wound Healing ◽

Endothelial Dysfunction ◽

Wound Repair ◽

Cell Communication ◽

Tube Formation ◽

Skin Wound ◽

Skin Wound Healing

Background: Exosomes, key mediators of cell-cell communication, derived from type 2 diabetes mellitus (T2DM) have detrimental effects. Exercise not only improves endothelial dysfunction and angiogenesis in T2DM but also induces secretion of exosomes into circulation. Extracellular superoxide dismutase (ecSOD) is a major secretory Cu containing antioxidant enzyme that catalyzes dismutation of O 2 •- to H 2 O 2 and its full activity requires Cu transporter ATP7A. We reported that ecSOD-derived H 2 O 2 in endothelial cells (ECs) enhances angiogenesis while impaired ATP7A-ecSOD axis in diabetes induces endothelial dysfunction. Here we examined whether exercise-derived exosomes (Exe-Exo) may have pro-angiogenic effects via regulating ATP7A-ecSOD axis in T2DM. Results: Two weeks of voluntary wheel exercise of control C57Bl6 mice increased plasma exosome levels (6.2-fold) characterized by Nanosight, TEM and exosome markers (CD63, CD81, Tsg101). Treatment of HUVECs with equal number of exosomes revealed that angiogenic responses such as EC migration (1.8-fold) and tube formation (1.7-fold) were significantly enhanced by Exe-Exo compared to sedentary-derived exosomes (Sed-Exo). This was associated with increased ATP7A (2.9-fold) and ecSOD (1.4-fold) expression in Exe-Exo. Sed-Exo from high fat-induced T2DM mice significantly decreased EC migration (40%) and tube formation (10%) as well as ATP7A expression (28%) compared to Sed-Exo from control mice, which were restored by T2DM Exe-Exo, but not by T2DM/ecSOD KO Exe-Exo. Furthermore, exosomes overexpressing ecSOD (ecSOD-Exo) which mimic exercise increased angiogenesis and H2O2 levels in ECs, which were inhibited by overexpression of catalase. In vivo, skin wound healing model showed that direct application of T2DM Sed-Exo delayed while T2DM Exe-Exo enhanced wound healing of control mice. Furthermore, defective wound healing in T2DM mice or ecSOD KO mice were rescued by ecSOD-Exo application. Conclusion: Exercise training improves pro-angiogenic function of circulating exosomes in T2DM via increasing ATP7A-ecSOD axis, which may provide an effective therapy for promoting angiogenesis and wound repair in metabolic and cardiovascular diseases.

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Activator Protein-1 Transcriptional Activity Drives Soluble Micrograft-Mediated Cell Migration and Promotes the Matrix Remodeling Machinery

Stem Cells International ◽

10.1155/2019/6461580 ◽

2019 ◽

Vol 2019 ◽

pp. 1-19 ◽

Cited By ~ 1

Author(s):

Martina Balli ◽

Jonathan Sai-Hong Chui ◽

Paraskevi Athanasouli ◽

Willy Antoni Abreu de Oliveira ◽

Youssef El Laithy ◽

...

Keyword(s):

Wound Healing ◽

Cell Migration ◽

Wound Repair ◽

Molecular Mechanisms ◽

Cell Model ◽

Matrix Remodeling ◽

Activator Protein 1 ◽

Impaired Wound Healing ◽

Beneficial Effects

Impaired wound healing and tissue regeneration have severe consequences on the patient’s quality of life. Micrograft therapies are emerging as promising and affordable alternatives to improve skin regeneration by enhancing the endogenous wound repair processes. However, the molecular mechanisms underpinning the beneficial effects of the micrograft treatments remain largely unknown. In this study, we identified the active protein-1 (AP-1) member Fos-related antigen-1 (Fra-1) to play a central role in the extracellular signal-regulated kinase- (ERK-) mediated enhanced cell migratory capacity of soluble micrograft-treated mouse adult fibroblasts and in the human keratinocyte cell model. Accordingly, we show that increased micrograft-dependent in vitro cell migration and matrix metalloprotease activity is abolished upon inhibition of AP-1. Furthermore, soluble micrograft treatment leads to increased expression and posttranslational phosphorylation of Fra-1 and c-Jun, resulting in the upregulation of wound healing-associated genes mainly involved in the regulation of cell migration. Collectively, our work provides insights into the molecular mechanisms behind the cell-free micrograft treatment, which might contribute to future advances in wound repair therapies.

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A Synthetic Curcuminoid Analog, (2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone, Ameliorates Impaired Wound Healing in Streptozotocin-Induced Diabetic Mice by Increasing miR-146a

Molecules ◽

10.3390/molecules25040920 ◽

2020 ◽

Vol 25 (4) ◽

pp. 920

Author(s):

Jingjuan Huang ◽

Jia Fu ◽

Bing Liu ◽

Rui Wang ◽

Tianhui You

Keyword(s):

Wound Healing ◽

Umbilical Vein ◽

Interleukin 1 ◽

Diabetic Wound ◽

Diabetic Mice ◽

Skin Wound Healing ◽

Promising Alternative ◽

Impaired Wound Healing ◽

Diabetic Wound Healing

The impairment in diabetic wound healing represents a significant clinical problem, with no efficient targeted treatments for these wound disorders. Curcumin is well confirmed to improve diabetic wound healing, however, its low bioavailability and poor solubility severely limit its clinical application. This study aims to provide the pharmacological basis for the use of (2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone (C66). The results showed that topically applied C66 improved cutaneous wound healing in vivo. Further studies showed that C66 treatment increased the level of microRNA-146a (miR-146a) in the wounds in streptozotocin (STZ)-induced diabetic mice, downregulated the expression of interleukin-1 receptor-associated kinase 1 (IRAK1) and phosphorylated nuclear factor-κB (NF-κB) p65 subunit (p-p65) (both p < 0.05), and suppressed the mRNA expression of inflammation-related cytokines, tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), and interleukin-6 (IL-6). The in vitro data obtained in human umbilical vein endothelial cells (HUVECs) showed that C66 could reverse high glucose (HG)-induced NF-κB activation due to upregulation of miR-146a expression, which matched the in vivo findings. In conclusion, the present study indicates that C66 exerts anti-inflammation activity and accelerates skin wound healing of diabetic mice, probably via increasing miR-146a and inhibiting the NF-κB-mediated inflammation pathway. Therefore, C66 may be a promising alternative for the treatment of diabetic wounds.

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Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Stimulated by Deferoxamine Accelerate Cutaneous Wound Healing by Promoting Angiogenesis

BioMed Research International ◽

10.1155/2019/9742765 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 11

Author(s):

Jianing Ding ◽

Xin Wang ◽

Bi Chen ◽

Jieyuan Zhang ◽

Jianguang Xu

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Wound Healing ◽

Mesenchymal Stem Cells ◽

Wound Repair ◽

Umbilical Vein ◽

Tube Formation ◽

Diabetic Rats

The exosomes are derived from mesenchymal stem cells (MSCs) and may be potentially used as an alternative for cell therapy, for treating diabetic wounds, and aid in angiogenesis. This study, aimed to investigate whether exosomes originated from bone marrow-derived MSCs (BMSCs) preconditioned by deferoxamine (DFO-Exos) exhibited superior proangiogenic property in wound repair and to explore the underlying mechanisms involved. Human umbilical vein endothelial cells (HUVECs) were used for assays involving cell proliferation, scratch wound healing, and tube formation. To test the effects in vivo, streptozotocin-induced diabetic rats were established. Two weeks after the procedure, histological analysis was used to measure wound-healing effects, and the neovascularization was evaluated as well. Our findings demonstrated that DFO-Exos activate the PI3K/AKT signaling pathway via miR-126 mediated PTEN downregulation to stimulate angiogenesis in vitro. This contributed to enhanced wound healing and angiogenesis in streptozotocin-induced diabetic rats in vivo. Our results suggest that, in cell-free therapies, exosomes derived from DFO preconditioned stem cells manifest increased proangiogenic ability.

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Vitamin D Ameliorates Impaired Wound Healing in Streptozotocin-Induced Diabetic Mice by Suppressing Endoplasmic Reticulum Stress

Journal of Diabetes Research ◽

10.1155/2018/1757925 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Yi Feng Yuan ◽

Sushant K. Das ◽

Mao Quan Li

Keyword(s):

Vitamin D ◽

Wound Healing ◽

Cell Viability ◽

Er Stress ◽

Umbilical Vein ◽

Healing Process ◽

Vitamin D Supplementation ◽

Diabetic Mice ◽

Impaired Wound Healing ◽

Apoptosis Rate

Background. This study is designed to investigate whether vitamin D promotes diabetic wound healing and explore the potential mechanism which may be involved in the healing process. Material and Methods. Human umbilical vein endothelial cells (HUVECs) were treated with 200 μg/ml of advanced glycation end product-modified human serum albumin (AGE-HSA) and 250 mg/dl of glucose with vitamin D. Cell viability was analyzed using the CCK-8 assay, and the apoptosis rate was measured using flow cytometry. Endogenous markers of ER stress were quantified using Western blot and a real-time polymerase chain reaction. Diabetic mice were treated with vitamin D (100 ng/kg per day) for 14 days. The ulcer area and ulcerative histology were detected dynamically. Results. Vitamin D administration not only decreased the apoptosis rate but also increased cell viability. Furthermore, the expression of endogenous markers of ER stress was downregulated as a result of vitamin D treatment. Vitamin D supplementation significantly accelerated wound healing of diabetic mice and improved the healing quality. Further studies showed that reduced ER stress was associated with the positive outcome. Conclusion. These results suggest that vitamin D may ameliorate impaired wound healing in diabetic mice by suppressing ER stress.

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Mealworm Oil (MWO) Enhances Wound Healing Potential through the Activation of Fibroblast and Endothelial Cells

Molecules ◽

10.3390/molecules26040779 ◽

2021 ◽

Vol 26 (4) ◽

pp. 779

Author(s):

Joung-Hee Kim ◽

Eun-Yeong Kim ◽

Kyu Jin Chung ◽

Jung-Hee Lee ◽

Hee-Jung Choi ◽

...

Keyword(s):

Wound Healing ◽

Endothelial Cells ◽

Wound Repair ◽

Smooth Muscle Actin ◽

Tube Formation ◽

Skin Wound ◽

Vegf Receptor ◽

Fibroblast Cells ◽

Alpha Smooth Muscle Actin

Mealworm and mealworm oil (MWO) have been reported to affect antioxidant, anti-coagulation, anti-adipogenic and anti-inflammatory activities. However, the function of MWO in wound healing is still unclear. In this study, we found that MWO induced the migration of fibroblast cells and mRNA expressions of wound healing factors such as alpha-smooth muscle actin (α-SMA), collagen-1 (COL-1) and vascular endothelial growth factor (VEGF) in fibroblast cells. The tube formation and migration of endothelial cells were promoted through the activation of VEGF/VEGF receptor-2 (VEGFR-2)-mediated downstream signals including AKT, extracellular signal-regulated kinase (ERK) and p38 by MWO-stimulated fibroblasts for angiogenesis. Moreover, we confirmed that MWO promoted skin wound repair by collagen synthesis, re-epithelialization and angiogenesis in an in vivo excisional wound model. These results demonstrate that MWO might have potential as a therapeutic agent for the treatment of skin wounds.

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Collagen Peptides Derived from Sipunculus nudus Accelerate Wound Healing

Molecules ◽

10.3390/molecules26051385 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1385

Author(s):

Haisheng Lin ◽

Zhihong Zheng ◽

Jianjun Yuan ◽

Chaohua Zhang ◽

Wenhong Cao ◽

...

Keyword(s):

Wound Healing ◽

Wound Repair ◽

Transforming Growth Factor ◽

Umbilical Vein ◽

Smooth Muscle Actin ◽

Mrna Level ◽

Skin Wound ◽

Control Group ◽

Collagen Peptides ◽

Sipunculus Nudus

Marine collagen peptides have high potential in promoting skin wound healing. This study aimed to investigate wound healing activity of collagen peptides derived from Sipunculus nudus (SNCP). The effects of SNCP on promoting healing were studied through a whole cortex wound model in mice. Results showed that SNCP consisted of peptides with a molecular weight less than 5 kDa accounted for 81.95%, rich in Gly and Arg. SNCP possessed outstanding capacity to induce human umbilical vein endothelial cells (HUVEC), human immortalized keratinocytes (HaCaT) and human skin fibroblasts (HSF) cells proliferation and migration in vitro. In vivo, SNCP could markedly improve the healing rate and shorten the scab removal time, possessing a scar-free healing effect. Compared with the negative control group, the expression level of tumor necrosis factor-α, interleukin-1β and transforming growth factor-β1 (TGF-β1) in the SNCP group was significantly down-regulated at 7 days post-wounding (p < 0.01). Moreover, the mRNA level of mothers against decapentaplegic homolog 7 (Smad7) in SNCP group was up-regulated (p < 0.01); in contrast, type II TGF-β receptors, collagen I and α-smooth muscle actin were significantly down-regulated at 28 days (p < 0.01). These results indicate that SNCP possessed excellent activity of accelerating wound healing and inhibiting scar formation, and its mechanism was closely related to reducing inflammation, improving collagen deposition and recombination and blockade of the TGF-β/Smads signal pathway. Therefore, SNCP may have promising clinical applications in skin wound repair and scar inhibition.

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Abstract 18933: Regulation of Impaired Angiogenesis in Diabetes by Microrna26a

Circulation ◽

10.1161/circ.130.suppl_2.18933 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Basak Icli ◽

Christoph Nabzdyk ◽

Jorge Lujan Hernandez ◽

Megan Cahi ◽

Dennis Orgill ◽

...

Keyword(s):

Wound Healing ◽

Endothelial Cells ◽

High Glucose ◽

Chronic Wounds ◽

Cellular Migration ◽

M2 Macrophage ◽

Diabetic Mice ◽

Impaired Wound Healing ◽

Matrix Deposition ◽

Wide Range

Wound healing is a physiological reparative response to injury that involves hemostasis, cellular migration, proliferation, angiogenesis, extracellular matrix deposition, wound contraction and re-epithelialization. However, patients with type 2 diabetes mellitus (T2D) are frequently afflicted with impaired wound healing that progresses into chronic wounds or diabetic ulcers, and may lead to complications including limb amputation. In recent years, microRNAs (miRNAs) has been implicated in a wide-range of disease states. We have investigated the potential role of microRNA-26a (miR-26a) in a diabetic model of wound healing. Expression of miR-26a is rapidly induced in response to diabetic stimuli (e.g. high glucose, PKC activation) in endothelial cells (ECs). Punch skin biopsy wounding of db/db mice revealed increased expression of miR-26a (~2-fold) four days post wounding compared to that of WT mice. Local administration of a miR-26a inhibitor, LNA-anti-miR-26a, induced angiogenesis (up to 80%), increased granulation tissue thickness (by 2.5 fold) and accelerated wound closure (by 50% after nine days) compared to scrambled anti-miR controls using a db/db mouse model of diabetes. These effects were independent of altered M1/M2 macrophage ratios. Mechanistically, inhibition of miR-26a increased its target gene, SMAD1, both at the mRNA and protein levels in ECs. In addition, increased SMAD1 levels correlated with increased ID1, a downstream modulator or SMAD1, and decreased expression of the cell cycle inhibitor p27 nine days post-wounding of diabetic mice. Interestingly, inhibition of miR-26a increased migration and growth of both human microvascular ECs (HMVECs), human umbilical endothelial cells (HUVECs), and fibroblasts under normal glucose conditions. However, in the presence of high glucose, anti-miR-26a functional effects were abolished in fibroblasts, but not in HUVECs or HMVECs, suggesting cell-specific miR-26a regulated effects under diabetic conditions. These findings establish miR-26a as an important regulator on the progression of skin wounds of diabetic mice by specifically regulating the angiogenic response after injury, and demonstrate that neutralization of miR-26a may serve as a novel approach for therapy.

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