High Glucose Restraint of Acetylcholine-Induced Keratinocyte Epithelial-Mesenchymal Transition Is Mitigated by p38 Inhibition
| Autor: | Mark Wei Yi Tan, Erica Mei Ling Teo, Jun Hong Toh, Ze Qing Kong, Xiaomeng Wang, Wei Ren Tan, Wei Kiat Jonathan Wee, Nguan Soon Tan, Hong Sheng Cheng |
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| Přispěvatelé: | School of Biological Sciences, Lee Kong Chian School of Medicine (LKCMedicine), Interdisciplinary Graduate School (IGS), Institute of Molecular and Cell Biology, A*STAR, Singapore Eye Research Institute, NTU Institute for Health Technologies |
| Rok vydání: | 2021 |
| Předmět: |
Blood Glucose
Keratinocytes Male 0301 basic medicine MAPK/ERK pathway Epithelial-Mesenchymal Transition MAP Kinase Signaling System p38 mitogen-activated protein kinases Dermatology Pharmacology p38 Mitogen-Activated Protein Kinases Biochemistry Streptozocin Article Cell Line Diabetes Mellitus Experimental Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Epithelial–mesenchymal transition Protein Kinase Inhibitors Molecular Biology Skin Wound Healing Cell Function integumentary system Chemistry Biological sciences [Science] Cell Biology Acetylcholine Diabetic Foot 030104 developmental biology medicine.anatomical_structure Hyperglycemia 030220 oncology & carcinogenesis Cholinergic Keratinocyte Wound healing Homeostasis medicine.drug |
| Zdroj: | J Invest Dermatol |
| ISSN: | 0022-202X |
| Popis: | Non-neuronal acetylcholine (Ach) plays important roles in various aspects of cell biology and homeostasis outside the neural system. Keratinocytes (KCs) have a functional cholinergic mechanism, suggesting that they respond to Ach. However, the physiological role and mechanism by which Ach modulates wound KC behavior in both nondiabetic and diabetic conditions are unexplored. We found an enrichment in neurotransmitter-related pathways in microdissected-migrating nondiabetic and diabetic KCs. We showed that Ach upregulated TGFβRII through Src-extracellular signal‒regulated kinase 1/2 pathway to potentiate TGFβ1-mediated epithelial‒mesenchymal transition in normoglycemic condition. Unexpectedly, KCs were nonresponsive to the elevated endogenous Ach in a hyperglycemic environment. We further showed that the activation of p38 MAPK in high glucose condition interferes with Src-extracellular signal‒regulated kinase 1/2 signaling, resulting in Ach resistance that could be rescued by inhibiting p38 MAPK. A better understanding of the cholinergic physiology in diabetic KCs could improve wound management and care. The finding suggests that mitigating the inhibitory effect of diabetic wound microenvironment has a direct clinical implication on the efficacy and safety of various wound healing agents to improve chronic diabetic wounds. Ministry of Education (MOE) Submitted/Accepted version This research is supported by the Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 1 (2014-T1-002-138-03) and Tier 2 (MOE2018-T2- 1-043) to NST. |
| Databáze: | OpenAIRE |
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