A Negative Regulatory Mechanism Involving 14-3-3ζ Limits Signaling Downstream of ROCK to Regulate Tissue Stiffness in Epidermal Homeostasis.

ROCK signaling causes epidermal hyper-proliferation by increasing ECM production, elevating dermal stiffness, and enhancing Fak-mediated mechano-transduction signaling. Elevated dermal stiffness in turn causes ROCK activation, establishing mechano-reciprocity, a positive feedback loop that can promote tumors. We have identified a negative feedback mechanism that limits excessive ROCK signaling during wound healing and is lost in squamous cell carcinomas (SCCs).

Mechanotransduction pathways promoting tumor progression are activated in invasive human squamous cell carcinoma.

Cutaneous squamous cell carcinomas (SCCs) are commonly diagnosed skin cancers that may progress to invasiveness in the absence of early intervention. Using a murine model of SCC, we have previously demonstrated that activation of the Rho-associated kinase (ROCK) signaling pathway promotes rapid progression of pre-neoplastic lesions to invasive SCC. Herein we demonstrate that in human cutaneous SCC, ROCK signaling is increasingly up-regulated with tumor progression in both tumor cells and cells of the tumor microenvironment and is accompanied by key tumor-promoting changes in the extracellular matrix protein composition.

Macrophage presence is essential for the regeneration of ascending afferent fibres following a conditioning sciatic nerve lesion in adult rats.

Background: Injury to the peripheral branch of dorsal root ganglia (DRG) neurons prior to injury to the central nervous system (CNS) DRG branch results in the regeneration of the central branch. The exact mechanism mediating this regenerative trigger is not fully understood. It has been proposed that following peripheral injury, the intraganglionic inflammatory response by macrophage cells plays an important role in the pre-conditioning of injured CNS neurons to regenerate.

Sciatic nerve conditioning lesion increases macrophage response but it does not promote the regeneration of injured optic nerves.

Unlabelled: Injured optic nerves in the matured central nervous system (CNS), alike injured neurons in other CNS regions, fail to regenerate. Interestingly, activation of inflammatory cells (macrophages) following optic lens injury or implantation of peripheral nerve fragments into the vitreous body, have been previously reported to stimulate retinal ganglion cells (RGCs) to regenerate axons across the injury site and into the distal optic nerve. In addition, the beneficial role of macrophage cells has also been demonstrated in the regeneration of lesioned spinal neurons following sciatic nerve injury.

Intramuscular delivery of a single chain antibody gene prevents brain Aβ deposition and cognitive impairment in a mouse model of Alzheimer's disease.

Anti-beta-amyloid (Aβ) immunotherapy is effective in removing brain Aβ, but has shown to be associated with detrimental effects. We have demonstrated that Adeno-associated virus (AAV)-mediated delivery of an anti-Aβ single chain antibody (scFv) gene was effective in clearing brain Aβ without eliciting any inflammatory side effects in old APP(Swe)/PS1dE9 transgenic mice. In the present study, we tested the efficacy and safety of intramuscular delivery of the scFv gene in preventing brain Aβ deposition.

Effects of proNGF on neuronal viability, neurite growth and amyloid-beta metabolism.

Alzheimer's disease (AD) is characterized pathologically by the deposition of amyloid-beta peptides (Abeta), neurofibrillary tangles, distinctive neuronal loss and neurite dystrophy. Nerve growth factor (NGF) has been suggested to be involved in the pathogenesis of AD, however, the role of its precursor (proNGF) in AD remains unknown. In this study, we investigated the effect of proNGF on neuron death, neurite growth and Abeta production, in vitro and in vivo.

Consumption of grape seed extract prevents amyloid-beta deposition and attenuates inflammation in brain of an Alzheimer's disease mouse.

Polyphenols extracted from grape seeds are able to inhibit amyloid-beta (Abeta) aggregation, reduce Abeta production and protect against Abeta neurotoxicity in vitro. We aimed to investigate the therapeutic effects of a polyphenol-rich grape seed extract (GSE) in Alzheimer's disease (AD) mice. APP(Swe)/PS1dE9 transgenic mice were fed with normal AIN-93G diet (control diet), AIN-93G diet with 0.

Intramuscular delivery of a single chain antibody gene reduces brain Abeta burden in a mouse model of Alzheimer's disease.

Anti-beta-amyloid (Abeta) immunotherapy has been well documented to effectively elicit amyloid plaque clearance and slow cognitive decline in experimental and clinical studies. However, anti-Abeta immunotherapy was associated with detrimental effects of brain inflammation and microhemorrhage, presumably induced by T-cell-mediated and/or Fc-mediated inflammatory responses. In the present study, a single chain antibody (scFv) against Abeta could effectively inhibit the aggregation of Abeta and promote the disaggregation of preformed Abeta fibrils.

Mutational analysis of 105 mucopolysaccharidosis type VI patients.

Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome) is a lysosomal storage disorder caused by mutations in the N-acetylgalactosamine-4-sulfatase (arylsulfatase B, ARSB) gene. ARSB is a lysosomal enzyme involved in the degradation of the glycosaminoglycans (GAG) dermatan and chondroitin sulfate. ARSB mutations reduce enzyme function and GAG degradation, causing lysosomal storage and urinary excretion of these partially degraded substrates.

Mutational analysis of mucopolysaccharidosis type VI patients undergoing a phase II trial of enzyme replacement therapy.

Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome) is a lysosomal storage disorder caused by mutations in the N-acetylgalactosamine-4-sulfatase (ARSB) gene. These mutations result in a deficiency of ARSB activity. Ten MPS VI patients were involved in a phase II clinical study of enzyme replacement therapy.