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TMF and glycitin act synergistically on keratinocytes and fibroblasts to promote wound healing and anti-scarring activity

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ABSTRACT

Keratinocyte-fibroblast interactions are critical for skin repair after injury. During the proliferative phase of wound healing, proliferation, migration and differentiation of these cells are the major mechanisms leading to tissue remodeling. We have previously reported that glycitin, a major soy isoflavone, stimulates dermal fibroblast proliferation; and the phytochemical, 4′,6,7-trimethoxyisoflavone (TMF), induces migration of HaCaT keratinocyte cells. We therefore investigated whether these compounds display synergistic effects on skin cells during wound healing in vitro and in vivo. Co-treatment with TMF and glycitin synergistically promotes the proliferation and migration of both keratinocytes and dermal fibroblasts, with a 1:1 ratio of these compounds showing the greatest efficacy in our co-culture system. This keratinocyte-fibroblast interaction occurred via the secretion of TGF-β, and the induction of differentiation and proliferation was confirmed in both indirect and direct co-culture assays. In an excisional and burn wound animal model, mice treated with a 1:1 ratio of TMF and glycitin showed faster wound closure, regeneration and scar reduction than even the positive control drug. These data indicate that two isoflavones, TMF and glycitin, act synergistically to promote wound healing and anti-scarring and could potentially be developed together as a bioactive therapeutic for wound treatment.

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A 1:1 mixture of glycitin and TMF accelerates wound closure and protects against scar formation in an in vivo excisional wound model. (a, b) Wound closure in our excisional wound model after 2 weeks. Photographs were taken every 2 days, and wounds were measured using the Image J program. ‘Control' indicates the butylene glycol; *P<0.05 as compared with Madecassol, #P<0.001 as compared with Fucidin. (c) On the last day of treatment, skin tissues were isolated, fixed and stained with hematoxylin/eosin and Masson's trichrome. (d) Scar width, (e) epidermal thickness and (f) collagen content were measured 14 days after wounding using the Image J program. TMF, 4′,6,7-trimethoxyisoflavone.
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fig5: A 1:1 mixture of glycitin and TMF accelerates wound closure and protects against scar formation in an in vivo excisional wound model. (a, b) Wound closure in our excisional wound model after 2 weeks. Photographs were taken every 2 days, and wounds were measured using the Image J program. ‘Control' indicates the butylene glycol; *P<0.05 as compared with Madecassol, #P<0.001 as compared with Fucidin. (c) On the last day of treatment, skin tissues were isolated, fixed and stained with hematoxylin/eosin and Masson's trichrome. (d) Scar width, (e) epidermal thickness and (f) collagen content were measured 14 days after wounding using the Image J program. TMF, 4′,6,7-trimethoxyisoflavone.

Mentions: To further verify that co-treatment with glycitin and TMF can promote wound healing, we assessed the effects of these compounds in an in vivo excision assay using ICR mice. We first made excisional wounds on the back using a 5 mm diameter punch. Glycitin and TMF were mixed in a 1:1 ratio (200 μM each) in butylene glycol, and wound sites were treated with 200 μl of this mixture once a day, for 2 weeks. As a positive control, wounds were treated with Madecassol, a healing ointment made from an extract of the medicinal herb, Centella asiatica, which contains antibiotic and anti-inflammatory properties. It has been shown to promote collagen synthesis and regeneration and to prevent scar formation. Fucidin, an anti-infective ointment that contains the fusidic acid, was also utilized as a positive control. We observed that mice treated with G:T=1:1 showed faster wound closure, as compared with the Madecassol and Fucidin groups (Figure 5a and b). These data are consistent with previous results, demonstrating that these compounds are most effective when used in a 1:1 ratio.


TMF and glycitin act synergistically on keratinocytes and fibroblasts to promote wound healing and anti-scarring activity
A 1:1 mixture of glycitin and TMF accelerates wound closure and protects against scar formation in an in vivo excisional wound model. (a, b) Wound closure in our excisional wound model after 2 weeks. Photographs were taken every 2 days, and wounds were measured using the Image J program. ‘Control' indicates the butylene glycol; *P<0.05 as compared with Madecassol, #P<0.001 as compared with Fucidin. (c) On the last day of treatment, skin tissues were isolated, fixed and stained with hematoxylin/eosin and Masson's trichrome. (d) Scar width, (e) epidermal thickness and (f) collagen content were measured 14 days after wounding using the Image J program. TMF, 4′,6,7-trimethoxyisoflavone.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5382558&req=5

fig5: A 1:1 mixture of glycitin and TMF accelerates wound closure and protects against scar formation in an in vivo excisional wound model. (a, b) Wound closure in our excisional wound model after 2 weeks. Photographs were taken every 2 days, and wounds were measured using the Image J program. ‘Control' indicates the butylene glycol; *P<0.05 as compared with Madecassol, #P<0.001 as compared with Fucidin. (c) On the last day of treatment, skin tissues were isolated, fixed and stained with hematoxylin/eosin and Masson's trichrome. (d) Scar width, (e) epidermal thickness and (f) collagen content were measured 14 days after wounding using the Image J program. TMF, 4′,6,7-trimethoxyisoflavone.
Mentions: To further verify that co-treatment with glycitin and TMF can promote wound healing, we assessed the effects of these compounds in an in vivo excision assay using ICR mice. We first made excisional wounds on the back using a 5 mm diameter punch. Glycitin and TMF were mixed in a 1:1 ratio (200 μM each) in butylene glycol, and wound sites were treated with 200 μl of this mixture once a day, for 2 weeks. As a positive control, wounds were treated with Madecassol, a healing ointment made from an extract of the medicinal herb, Centella asiatica, which contains antibiotic and anti-inflammatory properties. It has been shown to promote collagen synthesis and regeneration and to prevent scar formation. Fucidin, an anti-infective ointment that contains the fusidic acid, was also utilized as a positive control. We observed that mice treated with G:T=1:1 showed faster wound closure, as compared with the Madecassol and Fucidin groups (Figure 5a and b). These data are consistent with previous results, demonstrating that these compounds are most effective when used in a 1:1 ratio.

View Article: PubMed Central - PubMed

ABSTRACT

Keratinocyte-fibroblast interactions are critical for skin repair after injury. During the proliferative phase of wound healing, proliferation, migration and differentiation of these cells are the major mechanisms leading to tissue remodeling. We have previously reported that glycitin, a major soy isoflavone, stimulates dermal fibroblast proliferation; and the phytochemical, 4&prime;,6,7-trimethoxyisoflavone (TMF), induces migration of HaCaT keratinocyte cells. We therefore investigated whether these compounds display synergistic effects on skin cells during wound healing in vitro and in vivo. Co-treatment with TMF and glycitin synergistically promotes the proliferation and migration of both keratinocytes and dermal fibroblasts, with a 1:1 ratio of these compounds showing the greatest efficacy in our co-culture system. This keratinocyte-fibroblast interaction occurred via the secretion of TGF-&beta;, and the induction of differentiation and proliferation was confirmed in both indirect and direct co-culture assays. In an excisional and burn wound animal model, mice treated with a 1:1 ratio of TMF and glycitin showed faster wound closure, regeneration and scar reduction than even the positive control drug. These data indicate that two isoflavones, TMF and glycitin, act synergistically to promote wound healing and anti-scarring and could potentially be developed together as a bioactive therapeutic for wound treatment.

No MeSH data available.


Related in: MedlinePlus