Lupeol, a Dietary Triterpene, Enhances Wound Healing in Streptozotocin-Induced Hyperglycemic Rats with Modulatory Effects on Inflammation, Oxidative Stress, and Angiogenesis

Impaired wound healing is a debilitating complication of diabetes that leads to significant morbidity, particularly foot ulcers. Natural products have shown to be effective in treating skin wounds. Lupeol is known to stimulate angiogenesis, fibroblast proliferation, and expressions of cytokines and growth factors involved in wound healing. The study is performed to evaluate the wound healing activity of lupeol in streptozotocin-induced hyperglycemic rats by macroscopical, histological, immunohistochemical, immunoenzymatic, and molecular methods. Percentage of wound closure and contraction was increased in the lupeol-treated group when compared to the Lanette group. Histopathological observation revealed decreased inflammatory cell infiltration and increased proliferation of fibroblasts, vascularization, and deposition of collagen fibers after lupeol treatment. Immunohistochemical analyses showed decreased intensity of NF-κB and increased intensity of FGF-2, TGF-β1, and collagen III. ELISA results revealed downregulated IL-6 levels and upregulated IL-10 levels in response to lupeol. The mRNA expression levels of Hif-1α, Sod-2, and Ho-1 were significantly increased in response to lupeol as compared to Lanette whereas Nf-κb and Vegf-A levels were decreased in relation to insulin and lupeol treatment. These findings indicate that lupeol possesses wound healing potential in hyperglycemic conditions and may be useful as a treatment for chronic wounds in diabetic patients.

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Adipose Stem Cells from Type 2 Diabetic Mice Exhibit Therapeutic Potential in Wound Healing

10.21203/rs.3.rs-16134/v1 ◽

2020 ◽

Author(s):

Yongfa Sun ◽

Lili Song ◽

Yong Zhang ◽

Hongjun Wang ◽

Xiao Dong

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Transforming Growth Factor ◽

Therapeutic Potential ◽

Diabetic Patients ◽

Therapeutic Effects ◽

Skin Damage ◽

Impaired Wound Healing ◽

Collagen Iii

Abstract BACKGROUND: Diabetic patients suffer from impaired wound healing. Mesenchymal stem cell (MSC) therapy represents a promising approach toward improving skin wound healing through release of soluble growth factors and cytokines that stimulate new vessel formation and modulate inflammation. Whether adipose-derived MSCs (ASCs) from type 2 diabetes donors are suitable for skin damage repair remains largely unknown. METHODS: In this study, we compared the phenotype and functionality of ASCs harvested from high fat diet (HFD) and streptozotocin (STZ)-induced T2D or control mice, and assessed their abilities to promote wound healing in an excisional wound splinting mouse model with T2D. RESULTS: T2D ASCs expressed similar cellular markers as control ASCs, but secreted less hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β). T2D ASCs were somewhat less effective in promoting healing of the wound, as manifested by slightly reduced re-epithelialization, cutaneous appendage regeneration, and collagen III deposition in wound tissues. In vitro, T2D ASCs promoted proliferation and migration of skin fibroblasts to a comparable extent as control ASCs via suppression of inflammation and macrophage infiltration. CONCLUSIONS: From these findings, we conclude that, although ASCs from T2D mice are marginally inferior to control ASCs, they possess comparable therapeutic effects in wound healing.

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The potential of human induced pluripotent stem cells for modelling diabetic wound healing in vitro

Clinical Science ◽

10.1042/cs20171483 ◽

2018 ◽

Vol 132 (15) ◽

pp. 1629-1643 ◽

Cited By ~ 4

Author(s):

Patricia E. Martin ◽

Erin M. O’Shaughnessy ◽

Catherine S. Wright ◽

Annette Graham

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Chronic Wounds ◽

Healing Process ◽

Diabetic Patients ◽

Impaired Wound Healing ◽

Induced Pluripotent

Impaired wound healing and ulceration caused by diabetes mellitus, is a significant healthcare burden, markedly impairs quality of life for patients, and is the major cause of amputation worldwide. Current experimental approaches used to investigate the complex wound healing process often involve cultures of fibroblasts and/or keratinocytes in vitro, which can be limited in terms of complexity and capacity, or utilisation of rodent models in which the mechanisms of wound repair differ substantively from that in humans. However, advances in tissue engineering, and the discovery of strategies to reprogramme adult somatic cells to pluripotency, has led to the possibility of developing models of human skin on a large scale. Generation of induced pluripotent stem cells (iPSCs) from tissues donated by diabetic patients allows the (epi)genetic background of this disease to be studied, and the ability to differentiate iPSCs to multiple cell types found within skin may facilitate the development of more complex skin models; these advances offer key opportunities for improving modelling of wound healing in diabetes, and the development of effective therapeutics for treatment of chronic wounds.

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Current Aspects in the Pathophysiology and Treatment of Chronic Wounds in Diabetes Mellitus

BioMed Research International ◽

10.1155/2013/385641 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6 ◽

Cited By ~ 76

Author(s):

Elena Tsourdi ◽

Andreas Barthel ◽

Hannes Rietzsch ◽

Andreas Reichel ◽

Stefan R. Bornstein

Keyword(s):

Diabetes Mellitus ◽

Wound Healing ◽

Chronic Wounds ◽

Standard Treatment ◽

Diabetic Patients ◽

Diabetic Foot Ulcers ◽

Severe Problem ◽

Impaired Wound Healing ◽

Patients With Diabetes ◽

Extensive Debridement

Impaired wound healing is a frequent and very severe problem in patients with diabetes mellitus, yet little is known about the underlying pathomechanisms. In this paper we review the biology of wound healing with particular attention to the pathophysiology of chronic wounds in diabetic patients. The standard treatment of diabetic ulcers includes measures to optimize glycemic control as well as extensive debridement, infection elimination by antibiotic therapy based on wound pathogen cultures, the use of moisture dressings, and offloading high pressure from the wound bed. In this paper we discuss novel adjuvant therapies with particular reference to the use of autologous skin transplants for the treatment of diabetic foot ulcers which do not respond to standard care.

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Parameter-Dependency of Low-Intensity Vibration for Wound Healing in Diabetic Mice

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.654920 ◽

2021 ◽

Vol 9 ◽

Author(s):

Rita E. Roberts ◽

Onur Bilgen ◽

Rhonda D. Kineman ◽

Timothy J. Koh

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Wound Closure ◽

Chronic Wounds ◽

Low Frequency ◽

Whole Body ◽

Diabetic Patients ◽

Diabetic Mice ◽

Low Intensity ◽

Low Intensity Vibration

Chronic wounds in diabetic patients represent an escalating health problem, leading to significant morbidity and mortality. Our group previously reported that whole body low-intensity vibration (LIV) can improve angiogenesis and wound healing in diabetic mice. The purpose of the current study was to determine whether effects of LIV on wound healing are frequency and/or amplitude dependent. Wound healing was assessed in diabetic (db/db) mice exposed to one of four LIV protocols with different combinations of two acceleration magnitudes (0.3 and 0.6 g) and two frequencies (45 and 90 Hz) or in non-vibration sham controls. The low acceleration, low frequency protocol (0.3 g and 45 Hz) was the only one that improved wound healing, increasing angiogenesis and granulation tissue formation, leading to accelerated re-epithelialization and wound closure. Other protocols had little to no impact on healing with some evidence that 0.6 g accelerations negatively affected wound closure. The 0.3 g, 45 Hz protocol also increased levels of insulin-like growth factor-1 and tended to increase levels of vascular endothelial growth factor in wounds, but had no effect on levels of basic fibroblast growth factor or platelet derived growth factor-bb, indicating that this LIV protocol induces specific growth factors during wound healing. Our findings demonstrate parameter-dependent effects of LIV for improving wound healing that can be exploited for future mechanistic and therapeutic studies.

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Adipose Stem Cells from Type 2 Diabetic Mice Exhibit Therapeutic Potential in Wound Healing

10.21203/rs.3.rs-16134/v2 ◽

2020 ◽

Author(s):

Yongfa Sun ◽

Lili Song ◽

Yong Zhang ◽

Hongjun Wang ◽

Xiao Dong

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Transforming Growth Factor ◽

Therapeutic Potential ◽

Diabetic Patients ◽

Therapeutic Effects ◽

Skin Damage ◽

Impaired Wound Healing ◽

Collagen Iii

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Local application reduces number of needed EPC for beneficial effects on wound healing compared to systemic treatment in mice

European Journal of Trauma and Emergency Surgery ◽

10.1007/s00068-021-01621-3 ◽

2021 ◽

Author(s):

Katharina Sommer ◽

Heike Jakob ◽

Tobias Kisch ◽

Dirk Henrich ◽

Ingo Marzi ◽

...

Keyword(s):

Wound Healing ◽

Progenitor Cells ◽

Wound Closure ◽

Chronic Wounds ◽

Systemic Treatment ◽

Treated Group ◽

Local Application ◽

Beneficial Effects ◽

Group 2

Abstract Introduction Stem cell transplantation is one of the most promising strategies to improve healing in chronic wounds as systemic administration of endothelial progenitor cells (EPC) enhances healing by promoting neovascularization and homing though a high amount of cells is needed. In the following study, we analysed whether local application can reduce the number of EPC needed achieving the same beneficial effect on wound healing. Material and Methods Wound healing after local or systemic treatment with EPC was monitored in vivo by creating standardized wounds on the dorsum of hairless mice measuring wound closure every second day. Systemic group received 2 × 106 EPC i.v. and locally treated group 2 × 105 EPC, locally injected. As control PBS injection was performed the same way. Expression of CD31, VEGF, CD90 and, SDF-1α was analysed immunohistochemically for evaluation of neovascularisation and amelioration of homing. Results Local (7.1 ± 0.45 SD) as well as systemic (6.1 ± 0.23 SD) EPC transplantation led to a significant acceleration of wound closure compared to controls (PBS local: 9.7 ± 0.5 SD, PBS systemic 10.9 ± 0.38 SD). Systemic application enhanced CD31 expression on day 6 after wounding and local EPC on 6 and 9 in comparison to control. VEGF expression was not significantly affected. Systemic and local EPC treatment resulted in a significantly enhanced SDF-1α and CD90 expression on all days investigated. Conclusion Local as well as systemic EPC treatment enhances wound healing. Moreover, beneficial effects are obtained with a tenfold decrease number of EPC when applied locally. Thus, local EPC treatment might be more convenient way to enhance wound healing as number of progenitor cells is limited.

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Comparison of the ficus for the wound healing activity in various species

International Journal of Research in Phytochemistry and Pharmacology ◽

10.26452/ijrpp.v10i4.1381 ◽

2020 ◽

Vol 10 (4) ◽

pp. 67-70

Author(s):

Mothilal K ◽

Akila CR ◽

Mahender K ◽

Chaitanya Kumar K ◽

Ravi D

Keyword(s):

Wound Healing ◽

Wound Closure ◽

Subcutaneous Tissue ◽

Significant Activity ◽

Herbal Extracts ◽

Standard Drug ◽

Excision Wound ◽

Injuries And Wounds ◽

Skin Conditions ◽

Wound Healing Activity

Injuries and wounds are any sorts of damage to the skin or subcutaneous tissue. Usually, any wounds of such sorts are self-healed. Sometimes, there may be a delay in healing, and that delay is caused due to the functional delays in various processes of wound healing. All the Ficus plants show similar activities like the antioxidant, anti-inflammatory and wound healing properties 7including skin conditions like ulcers and rheumatism. The anthelmintic property and immunomodulatory are also seen. The herbal extracts of the same family of Ficus in different plants were investigated for the wound healing activity in the excision wound method, and the extracts showed significant activity compared to the drug. All the extracts showed a better healing ability, but the extract of FBO-100 showed the highest activity followed by FMO followed by FHO and finally the FRO. Overall, the activity of the extract ointment was comparable and was significant compared to the standard drug ointment. The wound closure of the extract ointment treated groups were better and were completed in 12 days, and the activity was more than 96%. The herbal extracts of the same family of Ficus in different plants were investigated for the wound healing activity in the excision wound method, and the extracts showed significant activity compared to the drug. The plants of microcarpa, benghalensis, religiosa and hispida are compared for the activity, and the order showed for the activity was FBO>FMO>FHO>FRO.

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Type 2 immunity induced by bladder extracellular matrix enhances corneal wound healing

Science Advances ◽

10.1126/sciadv.abe2635 ◽

2021 ◽

Vol 7 (16) ◽

pp. eabe2635

Author(s):

Xiaokun Wang ◽

Liam Chung ◽

Joshua Hooks ◽

David R. Maestas ◽

Andriana Lebid ◽

...

Keyword(s):

Wound Healing ◽

Immune Responses ◽

Smooth Muscle Actin ◽

Treated Group ◽

Interleukin 4 ◽

Impaired Wound Healing ◽

Urinary Bladder Matrix ◽

Incomplete Healing ◽

Haze Formation

The avascular nature of cornea tissue limits its regenerative potential, which may lead to incomplete healing and formation of scars when damaged. Here, we applied micro- and ultrafine porcine urinary bladder matrix (UBM) particulate to promote type 2 immune responses in cornea wounds. Results demonstrated that UBM particulate substantially reduced corneal haze formation as compared to the saline-treated group. Flow cytometry and gene expression analysis showed that UBM particulate suppressed the differentiation of corneal stromal cells into α-smooth muscle actin–positive (αSMA+) myofibroblasts. UBM treatments up-regulated interleukin-4 (IL-4) produced primarily by eosinophils in the wounded corneas and CD4+ T cells in draining lymph nodes, suggesting a cross-talk between local and peripheral immunity. Gata1−/− mice lacking eosinophils did not respond to UBM treatment and had impaired wound healing. In summary, stimulating type 2 immune responses in the wounded cornea can promote proregenerative environments that lead to improved wound healing for vision restoration.

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Surgical Strategies to Promote Cutaneous Healing

Medical Sciences ◽

10.3390/medsci9020045 ◽

2021 ◽

Vol 9 (2) ◽

pp. 45

Author(s):

Ines Maria Niederstätter ◽

Jennifer Lynn Schiefer ◽

Paul Christian Fuchs

Keyword(s):

Wound Healing ◽

Wound Closure ◽

Chronic Wounds ◽

Treatment Algorithm ◽

Surgical Site Infections ◽

Repair Process ◽

Suture Technique ◽

The Body ◽

Wound Debridement ◽

Reconstructive Ladder

Usually, cutaneous wound healing does not get impeded and processes uneventfully, reaching wound closure easily. The goal of this repair process is to restore the integrity of the body surface by creating a resilient and stable scar. Surgical practice and strategies have an impact on the course of wound healing and the later appearance of the scar. By considering elementary surgical principles, such as the appropriate suture material, suture technique, and timing, optimal conditions for wound healing can be created. Wounds can be differentiated into clean wounds, clean–contaminated wounds, contaminated, and infected/dirty wounds, based on the degree of colonization or infection. Furthermore, a distinction is made between acute and chronic wounds. The latter are wounds that persist for longer than 4–6 weeks. Care should be taken to avoid surgical site infections in the management of wounds by maintaining sterile working conditions, using antimicrobial working techniques, and implementing the principles of preoperative antibiotics. Successful wound closure is influenced by wound debridement. Wound debridement removes necrotic tissue, senescent and non-migratory cells, bacteria, and foreign bodies that impede wound healing. Additionally, the reconstructive ladder is a viable and partially overlapping treatment algorithm in plastic surgery to achieve successful wound closure.

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A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

Nature Communications ◽

10.1038/s41467-021-23448-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Guodong Li ◽

Chung-Nga Ko ◽

Dan Li ◽

Chao Yang ◽

Wanhe Wang ◽

...

Keyword(s):

Wound Healing ◽

Small Molecule ◽

Hypoxia Inducible Factor ◽

Diabetic Patients ◽

Diabetic Mice ◽

Impaired Wound Healing ◽

Von Hippel Lindau ◽

Design And Synthesis

AbstractImpaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

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