Non-Healing Wounds: should we call it mTORture?

Here’s a manuscript from our group in collaboration with leadership from our Cuban colleagues Jorge Berlanga and crew from CIGB. 

Early work seems to suggest that a focus on the AKT/mTOR/cyclin axis might point to a mechanism for both detection and intervention in helping out our patients’ fibroblasts to prosper. 

mTOR = mammalian target of rapamycin
Akt (aka Protein Kinase B)
Cyclins

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Expression of cell proliferation cycle negative regulators in fibroblasts of an ischemic diabetic foot ulcer.

Berlanga-Acosta J, Mendoza-Mari Y, Daniela Martínez M, Valdés-Perez C, Ojalvo AG, Armstrong DG.
Source
J Berlanga-Acosta, DVM, PhD, Tissue repair and cytoprotection project, Biomedical Direction, Center for Genetic Engineering and Biotechnology, 10 600 Havana, Cuba Y Mendoza-Mari, MSc, Tissue repair and cytoprotection project, Biomedical Direction, Center for Genetic Engineering and Biotechnology, 10 600 Havana, Cuba M Daniela Martínez, MSc, Tissue repair and cytoprotection project, Biomedical Direction, Center for Genetic Engineering and Biotechnology, 10 00 Havana, Cuba C Valdés-Perez, MD, Diabetic Foot Wounds, National Institute of Angiology and Vascular Surgery, Avenida Calzada del Cerro SN esquina Hospital, Centro Habana, Havana, Cuba AG Ojalvo, PhD, Tissue repair and cytoprotection project, Biomedical Direction, Center for Genetic Engineering and Biotechnology, 10 600 Havana, Cuba DG Armstrong, MD, PhD, Southern Arizona Limb Salvage Alliance (SALSA), Department of Surgery, University of Arizona College of Medicine, Tucson, AZ, USA.
Abstract
Wound chronification and opportunistic infections stand as major factors leading to lower extremities amputations in diabetes. The molecular mechanisms underlying diabetic’s torpid healing have not been elucidated. We present the case of a female diabetic patient that after a plantar abscess surgical drainage, tight glycaemia control and infection clearance; the wound bed evolved to chronification with poor matrix accumulation, scant angiogenesis and no evidence of dermo-epidermal contours contraction. Ulcer fibroblasts yet cultured under ‘physiological’ conditions exhibited a slow and declining proliferative response. Diabetic fibroblasts cycle arrest occurred earlier than non-diabetic counterparts. This in vitro premature arrest-senescence phenotype appeared related to the transcriptional upregulation of p53 and the proto-oncogene c-myc; with a concomitant expression reduction of the survival and cellular growth promoters Akt and mTOR. Importantly, immunocytochemistry of the diabetic ulcer-derived fibroblasts proved nuclear over expression of potent proliferation inhibitors and pro-senescence proteins as p53 phosphorylated on serine-15 and p21(Cip) (1). In line with this, cyclin D1 appeared substantially underexpressed in these cells. We postulate that the downregulation of the Akt/mTOR/cyclin D1 axis by the proximal activation of p53 and p21 due to stressor factors, impose an arrest/pro-senescence programme that translated in a torpid and slow healing process.
© 2012 The Authors. International Wound Journal © 2012 Blackwell Publishing Ltd and Medicalhelplines.com Inc.

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Here’s a nausea-inducing view of some sample interactions.
File:MTOR-pathway-v1.7.svg

David G. Armstrong

Dedicated to amputation prevention, wound healing, diabetic foot, biotechnology and the intersection between medical devices and consumer electronics.

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