title: Mono-epoxy-tocotrienol-α enhances wound healing in diabetic mice and stimulates in vitro angiogenesis and cell migration.
abstract: Diabetes mellitus is characterized by hyperglycemia and capillary hypoxia that causes excessive production of free radicals and impaired antioxidant defense, resulting in oxidative stress and diabetes complications such as impaired wound healing. We have previously shown that modified forms of tocotrienols possess beneficial effects on the biosynthesis of the mevalonate pathway lipids including increase in mitochondrial CoQ. The aim of this study is to investigate the effects of mono-epoxy-tocotrienol-α on in vitro and in vivo wound healing models as well as its effects on mitochondrial function. Gene profiling analysis and gene expression studies on HepG2 cells and human dermal fibroblasts were performed by microarray and qPCR, respectively. In vitro wound healing using human fibroblasts was studied by scratch assay and in vitro angiogenesis using human dermal microvascular endothelial cells was studied by the tube formation assay. In vivo wound healing was performed in the diabetic db/db mouse model. For the study of mitochondrial functions and oxygen consumption rate Seahorse XF-24 was employed. In vitro, significant increase in wound closure and cell migration (p<0.05) both in normal and high glucose and in endothelial tube formation (angiogenesis) (p<0.005) were observed. Microarray profiling analysis showed a 20-fold increase of KIF26A gene expression and 11-fold decrease of lanosterol synthase expression. Expression analysis by qPCR showed significant increase of the growth factors VEGFA and PDGFB. The epoxidated compound induced a significantly higher basal and reserve mitochondrial capacity in both HDF and HepG2 cells. Additionally, in vivo wound healing in db/db mice, demonstrated a small but significant enhancement on wound healing upon local application of the compound compared to treatment with vehicle alone. Mono-epoxy-tocotrienol-α seems to possess beneficial effects on wound healing by increasing the expression of genes involved in cell growth, motility and angiogenes as well as on mitochondrial function.
authors.affiliation: The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet and Department of Endocrinology, Diabetes and Metabolism Karolinska Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xu
authors.affiliation: The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet and Department of Endocrinology, Diabetes and Metabolism Karolinska Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Bentinger
authors.affiliation: The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet and Department of Endocrinology, Diabetes and Metabolism Karolinska Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Octavian
authors.initials: O
authors.lastname: Savu
authors.affiliation: Department of Oncology-Pathology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Ali
authors.initials: A
authors.lastname: Moshfegh
authors.affiliation: The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet and Department of Endocrinology, Diabetes and Metabolism Karolinska Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Vivekananda
authors.initials: V
authors.lastname: Sunkari
authors.affiliation: The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet and Department of Endocrinology, Diabetes and Metabolism Karolinska Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Gustav
authors.initials: G
authors.lastname: Dallner
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Swiezewska
authors.affiliation: The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet and Department of Endocrinology, Diabetes and Metabolism Karolinska Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Sergiu-Bogdan
authors.initials: SB
authors.lastname: Catrina
authors.affiliation: The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet and Department of Endocrinology, Diabetes and Metabolism Karolinska Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brismar
authors.affiliation: The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet and Department of Endocrinology, Diabetes and Metabolism Karolinska Hospital, SE-171 76 Stockholm, Sweden. Electronic address: michael.tekle@ki.se.
authors.forename: Michael
authors.initials: M
authors.lastname: Tekle
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000473:pathology* / Q000503:physiopathology*; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D012867:Skin / Q000166:cytology / Q000187:drug effects; D024508:Tocotrienols / Q000737:chemistry / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D024508:Tocotrienols; C082032:tocotrienol, alpha
keywords: Angiogenesis; Diabetes; Oxidative stress; Tocotrienols; Wound healing