# Mechanistic study of Small-molecular Therapy in diabetic Wound Healing

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2024 · $359,688

## Abstract

Diabetic foot ulcers that lead to amputations are a major health problem affecting ~20% of the 30 million diabetic
patients in the US. The current regimen has limited success, and the amputation rates remain high. Therefore,
understanding molecular mechanisms for compounds with translational potential is a crucial step toward making
a breakthrough in wound care protocols. Endothelial cells (ECs) are indispensable cellular components for
wound angiogenesis. However, EC functions are impaired in patients with diabetes. The coformulation of two
dietary compounds - Trans-resveratrol (tRES) and hesperetin (HESP) - improves glucose metabolic profile and
arterial function in overweight and obese subjects through inducing the gene expression of glyoxalase 1 (GLO1),
an enzyme that detoxifies reactive metabolites during glycolysis and protects cells against glycation stress. Our
pilot data indicated that tRES+HESP improved wound healing in diabetic animals with an increase in GLO1
expression. However, its effects are likely far beyond inducing GLO1 expression because tRES+HESP treated
ECs produced many pro-angiogenic factors, including angiopoietin-1 (ANGPT1) that plays an essential role in
angiogenesis. Therefore, it is critical to determine proteins that are regulated by tRES+HESP in angiogenesis
and tissue repair. The objective of this project is to fill the knowledge gap of the role of tRES+HESP in rescuing
the disrupted angiogenesis in diabetes, and our long-term goal is to develop therapeutic strategies for diabetic
wound repair. We hypothesize that tRES+HESP augments angiogenesis and improves diabetic wound healing
through enhancing the expression of GLO1 and a potent pro-angiogenic factor, ANGPT1, and through novel
changes in additional proteins in pathways critical to diabetic wound repair. Aim 1: Identification of molecular
pathways and protein changes induced by tRES+HESP in human dermal microvascular ECs in vitro. Sub-aim
1: Determine to what extent tRES+HESP can rescue diabetic endothelial cell function in vitro. Sub-aim 2:
Determine how vital ANGPT1 is in tRES+HESP-induced angiogenesis in vitro. Sub-aim 3: Discover new proteins
and pathways responsible for the benefit of tRES+HESP treatment in endothelial cell function in vitro using state-
of-the-art proteomics. Aim 2: Determine the therapeutic potential of tRES+HESP and its underlying molecular
mechanisms in chronic diabetic wounds in vivo. Sub-aim 1: Determine the efficacy of tRES+HESP on wound
healing in a newly developed diabetic chronic wound model in db/db mice. Sub-aim 2: Determine the role of
ANGPT1 in the tRES+HESP-induced improvement in wound healing in vivo. Sub-aim 3: Discover new proteins
and pathways responsible for the benefit of tRES+HESP treatment in diabetic wound repair in vivo using state-
of-the-art proteomics. The outcome of the proposed research will determine the efficacy of topical application
of this formula, tRES+HESP, in diabetic wound healing, and will unveil und...

## Key facts

- **NIH application ID:** 10791784
- **Project number:** 5R01DK128937-04
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Jiemei Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $359,688
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10791784

## Citation

> US National Institutes of Health, RePORTER application 10791784, Mechanistic study of Small-molecular Therapy in diabetic Wound Healing (5R01DK128937-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10791784. Licensed CC0.

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