cyclin-d1 and Peripheral-Nerve-Injuries

Icariside II (ICA II), an active flavonoid monomer, has been proven to restore post-prostatectomy erectile dysfunction in rats; however, the high cost of extraction from natural plants limits the application of ICA II.. To investigate the therapeutic effect and possible mechanism of action of YS-10, a new flavonoid compound, which was designed and synthesized based on the structure of ICA II in a rat model in of cavernous nerve injury.. Eight of 32 adult male Sprague-Dawley rats were selected as the normal control (NC) group and received vehicle treatment. The remaining rats were subjected to bilateral cavernous nerve injury (BCNI) and randomized into three groups: BCNI group, BCNI + ICA II group (2.5 mg/kg/day), and BCNI + YS-10 group (2.5 mg/kg/day). The total procedure lasted for 21 days, followed by a washout period of 3 days. All animals were evaluated for erectile function, and tissues were harvested for histopathological analyses.. It was observed that in YS-10 group, the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP) and the area under the ICP/MAP curve were effectively enhanced. The maximum ICP/MAP increased by 30% in the YS-10 group (0.86 ± 0.085) compared with the BCNI group (0.66 ± 0.058), which is close to 82% of the NC group (1.05 ± 0.033). Histopathological changes demonstrated significant reduction of smooth muscle atrophy, collagen deposition, and endothelial and neural dysfunction after YS-10 treatment, which have no statistical differences compared with ICA II group. Additionally, high-protein expression levels of β-Catenin and cyclin D1 were observed in the treatment groups.. YS-10, a novel synthesized flavonoid compound, could effectively improve erectile dysfunction in rats after BCNI by alleviating pathological impairments; this effect may associate with the upregulation of β-Catenin and cyclin D1 in Wnt signaling pathway.

Topics: Animals; beta Catenin; Cyclin D1; Disease Models, Animal; Erectile Dysfunction; Flavonoids; Male; Penile Erection; Penis; Peripheral Nerve Injuries; Rats; Rats, Sprague-Dawley; Up-Regulation; Wnt Signaling Pathway

Severe peripheral nerve injury leads to skeletal muscle atrophy and impaired limb function that is not sufficiently improved by existing treatments. Fibroblast growth factor 6 (FGF6) is involved in tissue regeneration and is dysregulated in denervated rat muscles. However, the way that FGF6 affects skeletal muscle repair after peripheral nerve injury has not been fully elucidated.. In this study, we investigated the role of FGF6 in the regeneration of denervated muscles using myoblast cells and an in vivo model of peripheral nerve injury.. FGF6 promoted the viability and migration of C2C12 and primary myoblasts in a dose-dependent manner through FGFR1-mediated upregulation of cyclin D1. Low concentrations of FGF6 promoted myoblast differentiation through FGFR4-mediated activation of ERK1/2, which upregulated expression of MyHC, MyoD, and myogenin. FGFR-1, FGFR4, MyoD, and myogenin were not upregulated when FGF6 expression was inhibited in myoblasts by shRNA-mediated knockdown. Injection of FGF6 into denervated rat muscles enhanced the MyHC-IIb muscle fiber phenotype and prevented muscular atrophy.. These findings indicate that FGF6 reduces skeletal muscle atrophy by relying on the ERK1/2 mechanism and enhances the conversion of slow muscle to fast muscle fibers, thereby promoting functional recovery of regenerated skeletal muscle after innervation.

Topics: Animals; Cell Differentiation; Cell Line; Cell Movement; Cell Proliferation; Cyclin D1; Fibroblast Growth Factor 6; Gene Expression Regulation; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle Denervation; Muscle, Skeletal; Myoblasts; MyoD Protein; Myogenin; Myosin Heavy Chains; Peripheral Nerve Injuries; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Fibroblast Growth Factor, Type 4; Regeneration; RNA, Small Interfering; Sciatic Nerve

Following damage to peripheral nerves, a remarkable process of clearance and regeneration takes place. Axons downstream of the injury degenerate, while the nerve is remodeled to direct axonal regrowth. Schwann cells are important for this regenerative process. "Sensing" damaged axons, they dedifferentiate to a progenitor-like state, in which they aid nerve regeneration. Here, we demonstrate that activation of an inducible Raf-kinase transgene in myelinated Schwann cells is sufficient to control this plasticity by inducing severe demyelination in the absence of axonal damage, with the period of demyelination/ataxia determined by the duration of Raf activation. Remarkably, activation of Raf-kinase also induces much of the inflammatory response important for nerve repair, including breakdown of the blood-nerve barrier and the influx of inflammatory cells. This reversible in vivo model identifies a central role for ERK signaling in Schwann cells in orchestrating nerve repair and is a powerful system for studying peripheral neuropathies and cancer.

Topics: Animals; Animals, Newborn; Benzamides; Cell Movement; Cyclin D1; Cytokines; Diphenylamine; Estrogen Antagonists; Gene Expression Regulation; Leukocytes; Male; MAP Kinase Signaling System; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Confocal; Microscopy, Electron, Transmission; Microscopy, Immunoelectron; Motor Activity; Myelin Sheath; Nerve Regeneration; Neutrophils; Peripheral Nerve Injuries; Proto-Oncogene Proteins c-raf; Reaction Time; Receptor, Nerve Growth Factor; Receptors, Estrogen; Recovery of Function; Schwann Cells; T-Lymphocytes; Tamoxifen; Time Factors

Neurons regulate Schwann cell proliferation, but little is known about the molecular basis of this interaction. We have examined the possibility that cyclin D1 is a key regulator of the cell cycle in Schwann cells. Myelinating Schwann cells express cyclin D1 in the perinuclear region, but after axons are severed, cyclin D1 is strongly upregulated in parallel with Schwann cell proliferation and translocates into Schwann cell nuclei. During development, cyclin D1 expression is confined to the perinuclear region of proliferating Schwann cells and the analysis of cyclin D1-null mice indicates that cyclin D1 is not required for this type of Schwann cell proliferation. As in the adult, injury to immature peripheral nerves leads to translocation of cyclin D1 to Schwann cell nuclei and injury-induced proliferation is impaired in both immature and mature cyclin D1-deficient Schwann cells. Thus, our data indicate that the molecular mechanisms regulating proliferation of Schwann cells during development or activated by axonal damage are fundamentally different.

Topics: Aging; Animals; Animals, Newborn; Cell Compartmentation; Cell Differentiation; Cell Division; Cell Nucleus; Cells, Cultured; Cyclin D1; Cytoplasm; Gene Expression Regulation; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Sheath; Nerve Crush; Nerve Regeneration; Peripheral Nerve Injuries; Peripheral Nerves; Rats; Rats, Inbred Strains; Schwann Cells; Sciatic Nerve; Wallerian Degeneration