Circulating Hypoxia Responsive microRNAs (HRMs) and Wound Healing Potentials of Green Tea in Diabetic and Nondiabetic Rat Models

Abstract

Green tea (Camellia sinensis) has many biological activities and may promote diabetic wound healing by regulation of circulating hypoxia responsive microRNAs (HRMs) which triggers the wound repairing process in diabetic and nondiabetic wounds. Thus, in this study, the potential effects of green tea extract (GTE) on the expression of miRNAs; miR-424, miR-199a, miR-210, miR-21, and fibrogenitic markers; hydroxyproline (HPX), fibronectin (FN), and nitric oxide (NO) were evaluated in wounds of diabetic and nondiabetic rats. The animals were topically treated with vaseline, 0.6% GTE, and 5%w/w povidone iodine (standard control). HPX, FN, and NO levels and microRNAs, miR-424, miR-210, miR-199a, and miR-21, were estimated in wound tissues using colorimetric, immunoassay, and molecular PCR analysis. In vitro analysis was performed to estimate active constituents and their antioxidant activities in methanolic green teat extract (GTE). Wounds treated with green tea, a dose of 0.6, healed significantly earlier than those treated with standard vehicle and vaseline treated diabetic wounds. Higher expressions of HRMs, miR-199a, and miR-21, and lower expression of HRMs, miR-424 and miR-210, were significantly reported in tissues following treatment with green tea extract compared to standard control vehicle. The tissues also contained more collagen expressed as measures of HPX, FN, and NO and more angiogenesis, compared to wounds treated with standard control vehicle. Diabetic and nondiabetic wounds treated with green tea (0.6%) for three weeks had lesser scar width and greater re-epithelialization in shorter periods when compared to standard control vehicle. Expression of HRMs, miR-199a, miR-21, and HRMs and miR-424 and miR-210 correlated positively with HPX, fibronectin, NO, better scar formation, and tensile strength and negatively with diabetes. In addition to antidiabetic and antioxidant activities of green tea components, GTE showed angiogenesis promoting activity in diabetic wound healing. In conclusion, Camellia sinensis extracts in a dose of 0.6% significantly promote more collagen and fibronectin deposition with higher expression of NO, promoting angiogenesis process via molecular controlling of circulating hypoxia responsive microRNAs: miR-424, miR-210, miR-199a, and miR-21 in diabetic and nondiabetic wounds. Our results support a functional role of circulating hypoxia responsive microRNAs: miR-424, miR-210, miR-199a, and miR-21 as potential therapeutic targets in angiogenesis and vascular remodeling in diabetic wound healing.

Roles of MicroRNA-21 in Skin Wound Healing: A Comprehensive Review

“…In addition, miR-21 mimic MVs augmented the endotheliocyte angiogenic activity and promoted the fibroblast differentiation compared to miR-21 inhibitor MVs and vector MVs ( Li et al, 2019 ). This is consistent with a previous study ( Al-Rawaf et al, 2019 ). The in vivo studies demonstrated that treatment with miR-21 mimic MVs significantly accelerated wound healing compared to treatments with vector MVs and miR-21 inhibitor MVs ( Li et al, 2019 ).…”

Assessment of plasma and tissue fibronectin EIIIB splice variant expressions measured serially with RT-PCR in a wound model of rabbits

“…Based on the cause, wounds can be classified as an incision, crush, laceration, and perforation, without tissue loss, or wounds with tissue loss. [8,9] Many biological particles, molecules, and different cell types have a part that is involved during all the wound healing phases. Besides, hemostasis, inflammation, cell proliferation, re-epithelialization, and remodeling are in succession take placed in the phases of normal wound healing.…”

“…Besides, hemostasis, inflammation, cell proliferation, re-epithelialization, and remodeling are in succession take placed in the phases of normal wound healing. [9,10] In the literature, there are many studies revealing new therapeutic approaches or molecular-based recovery period to overcome the difficulty and slow healing processes of chronic wounds, such as diabetic foot, decubitus, and venous leg ulcer. [9,[11][12][13][14][15] In clinical practice, to patients with a cutaneous wound, systemic drugs as orally and parenterally can be administered; however, this may result in the development of several side effects limiting their long-term use.…”

“…[9,10] In the literature, there are many studies revealing new therapeutic approaches or molecular-based recovery period to overcome the difficulty and slow healing processes of chronic wounds, such as diabetic foot, decubitus, and venous leg ulcer. [9,[11][12][13][14][15] In clinical practice, to patients with a cutaneous wound, systemic drugs as orally and parenterally can be administered; however, this may result in the development of several side effects limiting their long-term use. Toxic effects of systemically administered drugs and less predictable drug delivery to the damaged tissue because of possible tissue perfusion problems, there has been an important changing in the clinical tendency toward the local application of chemical agents to improve wound healing.…”

“…It has been previously reported that topical administration of pFN in chronic wounds positively affects wound healing by affecting fibroblast activity, transforming growth factor-ß1. [9] Recently, it has been reported that the application of the chimeric fibronectin protein to diabetic wounds and corneal epithelial wounds of topical fibronectin-derived peptides accelerates wound healing in the experimental studies. [18,29,30] In this study, both isoforms were detected in the wound, and the healing process was identical to early embryogenesis.…”