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D-Tryptophan Promotes Skin Wound Healing via Extracellular Matrix Remodeling in Normal and Diabetic Models
Dawit Adisu Tadese1,2,3, James Mwangi1,2,3, Brenda B Michira1,2,3
1Key Laboratory of Genetic Evolution & Animal Models, Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, and Sino-African Joint Research Center, New Cornerstone Science Laboratory, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming 650201, China.
Abstract:
Diabetic wounds are a devastating complication that cause chronic pain, recurrent infections, and limb amputations due to impaired healing. Despite advances in wound care, existing therapies often fail to address the underlying molecular dysregulation, highlighting the need for innovative and safe therapeutic approaches. Among these, D-amino acids such as D-tryptophan (D-Trp) have emerged as key regulators of cellular processes; however, their therapeutic potential in diabetic wounds remains largely unexplored. Here, we investigate the therapeutic potential of D-Trp in streptozotocin (STZ)-induced diabetic mice, comparing it with phosphate-buffered saline (PBS) controls and vascular endothelial growth factor (VEGF) as a positive control. Wound healing, inflammation, and histopathology were assessed. Protein and gene expression were analyzed via Western blot and RT-qPCR, respectively. Biolayer interferometry (BLI) measured the binding of D-Trp to hypoxia-inducible factor-1α (HIF-1α). D-Trp accelerated wound healing by modulating extracellular matrix (ECM) remodeling, signaling, and apoptosis. It upregulated matrix metalloproteinases (MMP1, MMP3, MMP-9), Janus kinase 2 (JAK2), and mitogen-activated protein kinase (MAPK) proteins while reducing pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], IL-6). D-Trp also suppressed caspase-3 and enhanced angiogenesis through HIF-1α activation. These findings suggest that D-Trp promotes healing by boosting ECM turnover, reducing inflammation, and activating MAPK/JAK pathways. Thus, D-Trp is a promising therapeutic for diabetic wounds.
Insights
D-tryptophan (D-Trp) significantly accelerates diabetic wound healing by enhancing extracellular matrix remodeling and reducing inflammation. This study highlights D-Trp as a promising therapeutic agent for diabetic wound complications.
Area of Science:
- Biochemistry
- Molecular Biology
- Wound Healing Research
Background:
- Diabetic wounds present a significant clinical challenge due to impaired healing, leading to chronic pain, infections, and amputations.
- Current therapies often fall short in addressing the complex molecular mechanisms underlying poor diabetic wound healing.
- D-amino acids, specifically D-tryptophan (D-Trp), show potential as regulators of cellular processes, but their role in diabetic wound repair is underexplored.
Purpose of the Study:
- To investigate the therapeutic efficacy of D-tryptophan (D-Trp) in promoting diabetic wound healing.
- To elucidate the molecular mechanisms by which D-Trp influences wound repair, inflammation, and angiogenesis in a diabetic mouse model.
- To compare the effects of D-Trp with phosphate-buffered saline (PBS) and vascular endothelial growth factor (VEGF) controls.
Main Methods:
- Streptozotocin (STZ)-induced diabetic mice were used to model diabetic wounds.
- Wound healing progression, inflammation, and histopathological changes were assessed.
- Protein expression (Western blot) and gene expression (RT-qPCR) of key signaling molecules and cytokines were analyzed.
- Biolayer interferometry (BLI) was employed to determine the binding interaction between D-Trp and hypoxia-inducible factor-1α (HIF-1α).
Main Results:
- D-tryptophan (D-Trp) significantly accelerated wound closure compared to controls.
- D-Trp modulated extracellular matrix (ECM) remodeling by upregulating matrix metalloproteinases (MMP1, MMP3, MMP-9).
- It enhanced pro-healing signaling pathways, including Janus kinase 2 (JAK2) and mitogen-activated protein kinase (MAPK), while reducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-6).
- D-Trp suppressed apoptosis (caspase-3) and promoted angiogenesis via HIF-1α activation.
Conclusions:
- D-tryptophan (D-Trp) demonstrates significant therapeutic potential for accelerating diabetic wound healing.
- The mechanism involves enhanced ECM turnover, reduced inflammation, and activation of MAPK/JAK signaling pathways.
- D-Trp's ability to promote angiogenesis through HIF-1α activation further supports its role as a promising treatment for diabetic wounds.
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