Impaired wound healing results from the dysfunction of the Akt/mTOR pathway in diabetic rats.

Wound healing is impaired in diabetes mellitus. The underlying mechanism involved in this process is still unknown. The Akt/mTOR signaling pathway plays a crucial role in the pathogenesis of diabetes. we investigated the role of the Akt/mTOR pathway in diabetic wounds and the mechanisms that growth factors activate this pathway to promote diabetic wound healing. Full-thickness skin excisional wounds were created on the backs of normal and streptozotocin-induced diabetic rats. The expression of key proteins in the Akt/mTOR pathway was assayed using western blotting; topical effects of granulocyte-macrophage colony stimulating factor (GM-CSF) on diabetic wounds and activation of the Akt/mTOR pathway were subsequently investigated. Activation of the Akt/mTOR pathway by GM-SCF in vitro was examined in rat primary fibroblasts. The results indicate that the Akt/mTOR pathway was activated in the wound tissue of both non-diabetic and diabetic rats, as indicated by a remarkable increase in expression of total and phosphorylated key proteins in this pathway. However, the expression level of these proteins was dramatically attenuated in diabetic wounds compared with non-diabetic wounds. Upon topical application of GM-CSF, the diabetic wound healing was remarkably improved concomitantly with increased expression and phosphorylation of key proteins in the Akt/mTOR pathway. In addition, rat fibroblast proliferation induced by GM-CSF depended on the Akt/mTOR pathway activation. Impaired wound healing results from the dysfunction of the Akt/mTOR pathway in diabetic rats. The pharmacologic elevation of this pathway may represent an attractive intervention strategy to improve prognosis of diabetic wounds.

Huang H ，Cui W ，Qiu W ，Zhu M ，Zhao R ，Zeng D ，Dong C ，Wang X ，Guo W ，Xing W ，Li X ，Li L ，Tan Y ，Wu X ，Chen L ，Fu X ，Luo D ，Xu X ... -  《-》

[Effect of granulocyte-macrophage colony-stimulating factor on the mammalian target of sirolimus signaling pathway in the wound of rat].

Cui WH ，Huang H ，Xu X ，Guo M ，Dai H ，Jian Y ，Guo W ，Xing W ，Jiang JX ，Yang R ... -  《-》

[Expressions of the key proteins of the protein kinase B/mammalian target of rapamycin signaling pathway in skin tissue and wound tissue of diabetic rats].

Huang H ，Qiu W ，Zhu M ，Zhang Y ，Cui WH ，Xing W ，Li XY ，An TC ，Chen MJ ，Guo W ，Xu X ... -  《-》

Notoginsenoside Ft1 Promotes Fibroblast Proliferation via PI3K/Akt/mTOR Signaling Pathway and Benefits Wound Healing in Genetically Diabetic Mice.

Wound healing requires the essential participation of fibroblasts, which is impaired in diabetic foot ulcers (DFU). Notoginsenoside Ft1 (Ft1), a saponin from Panax notoginseng, can enhance platelet aggregation by activating signaling network mediated through P2Y12 and induce proliferation, migration, and tube formation in cultured human umbilical vein endothelial cells. However, whether it can accelerate fibroblast proliferation and benefit wound healing, especially DFU, has not been elucidated. In the present study on human dermal fibroblast HDF-a, Ft1 increased cell proliferation and collagen production via PI3K/Akt/mTOR signaling pathway. On the excisional wound splinting model established on db/db diabetic mouse, topical application of Ft1 significantly shortened the wound closure time by 5.1 days in contrast with phosphate-buffered saline (PBS) treatment (15.8 versus 20.9 days). Meanwhile, Ft1 increased the rate of re-epithelialization and the amount of granulation tissue at day 7 and day 14. The molecule also enhanced mRNA expressions of COL1A1, COL3A1, transforming growth factor (TGF)-β1 and TGF-β3 and fibronectin, the genes that contributed to collagen expression, fibroblast proliferation, and consequent scar formation. Moreover, Ft1 facilitated the neovascularization accompanied with elevated vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor at either mRNA or protein levels and alleviated the inflammation of infiltrated monocytes indicated by reduced tumor necrosis factor-α and interleukin-6 mRNA expressions in the diabetic wounds. Altogether, these results indicated that Ft1 might accelerate diabetic wound healing by orchestrating multiple processes, including promoting fibroblast proliferation, enhancing angiogenesis, and attenuating inflammatory response, which provided a great potential application of it in clinics for patients with DFU.

Zhang E ，Gao B ，Yang L ，Wu X ，Wang Z ... -  《-》

Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephropathy.

Nagai K ，Matsubara T ，Mima A ，Sumi E ，Kanamori H ，Iehara N ，Fukatsu A ，Yanagita M ，Nakano T ，Ishimoto Y ，Kita T ，Doi T ，Arai H ... -  《KIDNEY INTERNATIONAL》