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Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and Prss56-Nf1 knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified NF1 -deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas NF1 -deficient SSPCs adopted a fibrotic fate, NF1 -deficient Schwann cells produced critical paracrine factors including transforming growth factor-β and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both NF1 -deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.

Ischemic stroke is the second leading cause of death worldwide. The major limitation of stroke management is the lack of clinically effective therapy. Antioxidants have been demonstrated as potent neuroprotective agents by enhancing the defense mechanism(s), whereas reducing the oxidative stress in the ischemic stroke models. In the present study, we evaluated neuroprotective potential of solasodine, an antioxidant glycoalkaloid of Solanum species, against global model of ischemia in rats. Ischemia/reperfusion (I/R)-injury produced marked elevation in lipid peroxidation (LPO) and nitric oxide (NO), whereas superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels were decreased in experimental animals. Prior administration of solasodine (100 and 200mg/kg, p.o.) significantly heightened SOD, CAT, GSH and total thiols, whereas reduced LPO and NO levels in the brain. Interestingly, brain coronal sectioning and histopathology studies revealed a marked reversal of I/R-provoked neuronal damage in the solasodine treatment groups. Taken together, our study, for the first time, demonstrates neuroprotective potential of solasodine against global ischemia-induced cerebral injury in experimental rats. We propose that the neuroprotection offered by solasodine could be attributed, at least in part, to its anti-oxidant property., (Copyright © 2014 Elsevier B.V. All rights reserved.)