sirolimus and Diabetic-Foot

Diabetic foot ulcer (DFU) is a kind of common and disabling complication of Diabetes Mellitus (DM). Emerging studies have demonstrated that tendon fibroblasts play a crucial role in remodeling phase of wound healing. However, little is known about the mechanism underlying high glucose (HG)-induced decrease in tendon fibroblasts viability. In the present study, the rat models of DFU were established, and collagen deposition, autophagy activation and cell apoptosis in tendon tissues were assessed using Hematoxylin-Eosin (HE) staining, immunohistochemistry (IHC), and TdT-mediated dUTP Nick-End Labeling (TUNEL) assay, respectively. Tendon fibroblasts were isolated from Achilles tendon of the both limbs, and the effect of HG on autophagy activation in tendon fibroblasts was assessed using Western blot analysis, Cell Counting Kit-8 (CCK-8) assay, and flow cytometry. We found that cell apoptosis was increased significantly and autophagy activation was decreased in foot tendon tissues of DFU rats compared with normal tissues. The role of HG in regulating tendon fibroblasts viability was then investigated in vitro, and data showed that HG repressed cell viability and increased cell apoptosis. Furthermore, HG treatment reduced LC3-II expression and increased p62 expression, indicating that HG repressed autophagy activation of tendon fibroblasts. The autophagy activator rapamycin reversed the effect. More importantly, rapamycin alleviated the suppressive role of HG in tendon fibroblasts viability. Taken together, our data demonstrate that HG represses tendon fibroblasts proliferation by inhibiting autophagy activation in tendon injury.

Topics: Animals; Apoptosis; Autophagy; Cell Proliferation; Diabetic Foot; Fibroblasts; Glucose; Rats; Sirolimus; Tendon Injuries; Tendons

Recent studies suggest that patients on mammalian target of rapamycin (mTOR) inhibitors experience a reduction in cutaneous carcinogenesis by an estimated 50% or more compared with calcineurin inhibitors. While randomized trials are running, organ transplant recipients are frequently switched from calcineurin inhibitors to mTOR inhibitors when cutaneous carcinogenesis increases.. To slow carcinogenesis in our patient, a heart transplant recipient with a neuropathic diabetic foot syndrome who had developed cutaneous carcinogenesis at a rate of more than 20 squamous cell carcinomas (SCC) annually.. The patient's immunosuppression was switched from the calcineurin inhibitor ciclosporin to the mTOR inhibitor everolimus.. Carcinogenesis slowed to six SCC annually; however, he developed recalcitrant diabetic foot ulcers which were purely neuropathic and nonangiopathic, and a limb-threatening fistulating necrotic erysipelas of the right leg. Both sites responded poorly to antibiotic therapy, offloading and debridement. This skin fistula became chronic and some toes were at risk for minor amputation. In view of the propensity for mTOR inhibitors to impair would healing, immunosuppression was switched back to ciclosporin. All wounds healed rapidly, but skin carcinogenesis rose to former levels.. This case impressively illustrates the clinical dilemma for mTOR inhibitor use where benefit in carcinogenesis is counterbalanced by impairment in wound healing. Changes in immunosuppressive regimens should thus be made on an individual basis with careful consideration of the relative risks.

Topics: Aged; Calcineurin Inhibitors; Cardiomyopathy, Dilated; Cell Transformation, Neoplastic; Diabetic Foot; Drug Substitution; Everolimus; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Sirolimus; Skin Neoplasms; Toes; TOR Serine-Threonine Kinases; Wound Healing