The underlying mechanisms of colorectal carcinoma (CRC) metastasis remain to be elucidated. The aim of this study is to investigate clinical significance and the expression of eIF4E, VEGF-C, MMP-2, and E-cadherin in the CRC metastasis. We investigated their expressions in 108 patients, analyzed the relationships between their expressions in CRC and evaluated the relationships between their expressions and clinical pathogenic parameters. Furthermore, their roles in patient survival and in CRC metastasis were also investigated. We found that eIF4E, VEGF-C and MMP-2 were up-regulated in CRC, and their expression frequencies (EFs) were higher in cancerous tissues than in adjacent normal tissues. The EF of E-cadherin is lower in cancerous tissues than in adjacent normal tissues. Totally, their EFs were not associated with sex and age of patient, however, their EFs were associated with tumor differentiation, the depth of invasion, lymph node metastasis and tumor stages. Furthermore, eIF4E, VEGF-C, and MMP-2 shortened and E-cadherin prolonged survival in patient-derived CRC xenografts. Similarly, eIF4E, VEGF-C, and MMP-2 promoted and E-cadherin suppressed the lung metastasis of CRC cells. In addition, knockdown of eIF4E inhibited migration of CRC cells, downregulated VEGF-C, MMP-2 and upregulated E-cadherin. In conclusion, eIF4E promoted CRC metastasis via up-regulating the expression of VEGF-C, MMP-2 and suppressing E-cadherin.
Microglia-mediated inflammation is an important step in the progression of cerebral ischemia/reperfusion injury and the associated production of receptors of immunomoudulation, including Toll-like receptors (TLRs). Peroxiredoxin 6 (Prdx6) has been demonstrated as the endogenous antioxidant protein for its peroxidase properties. However, the role of the independent phospholipase A2 (iPLA2) activity of Prdx6 in stroke has not been well studied. In this study, we evaluated whether blocking the calcium-iPLA2 activity of Prdx6 using siRNA and inhibitors (1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol, MJ33) would have a critical effect on inflammatory brain damage. We conducted oxygen-glucose deprivation (OGD)/recovery (R) in vitro and middle cerebral artery occlusion (MCAO) in vivo in a microglia/neuron co-culture system and in rats. In vitro, we found that Prdx6-iPLA2 activity was associated with the secretion of neurotoxic inflammatory mediators interleukin1β (IL-1β), interleukin-17 (IL-17) and interleukin-23 (IL-23) and elevated expression of Toll-like receptor 2/4 (TLR2/4), leading to the formation of nuclear factor-kappa B (NF-κB), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in microglial cells. In vivo, combined treatment with Prdx6-iPLA2 activity inhibitor MJ33 showed a greater diminution in neurologic deficits, cerebral infarction, brain water content and inflammatory molecules than Prdx6-siRNA treatment alone. Our findings provide new insight into Prdx6-iPLA2 function in the brain. Inhibition of Prdx6-iPLA2 activity by gene therapy and/or pharmacology may constitute a promising new therapeutic approach to the treatment of stroke.
INTRODUCTION Macroautophagy, or simply autophagy, maintains cell viability, particularly under stress, by recycling the constituent components of damaged macromolecules and organelles through a specific autophagic vesiclelysosome degradation pathway [1-4]. In neurons, nascent autophagic vesicles (autophagosomes) are mainly formed in distal axons and thus require longdistance retrograde transport to merge with degradative www.aging-us.com
The accumulation of autophagosomes and dysfunction at the axonal terminal of neurons play crucial roles in the genesis and development of Alzheimer’s disease (AD). Abnormalities in neuron axonal transport-related proteins prevent autophagosome maturation in AD. Curcumin, a polyphenol plant compound, has been shown to exert neuroprotective effects by increasing autophagy in AD, but the underlying mechanism of its effect on autophagy axon transport remains elusive. This study investigated the effects of curcumin on autophagosome formation and axonal transport in N2a/APP695swe cells (AD cell model) as well as the mechanism underlying those effects. Curcumin treatment significantly increased the expression of Beclin1, Atg5, and Atg16L1, induced the formation of autophagosomes, and promoted autophagosome–lysosome fusion in N2a/APP695swe cells. At the same time, curcumin promoted the expression of dynein, dynactin, and BICD2 as well as their binding to form the retrograde axonal transport molecular motor complex. Moreover, curcumin also increased the expression of the scaffolding proteins Rab7- interacting lysosomal protein (RILP) and huntingtin in N2a/APP695swe cells. Taken together, our findings indicate that curcumin increases autophagic flux by promoting interactions among autophagic axonal transport-related proteins and inducing lysosome–autophagosome fusion. This study provides evidence suggesting the potential use of curcumin as a novel treatment for AD.
Gao et al.: Neuroprotective effect of Curcumin involved in increasing the protein levels of UCP2 and inhibiting oxidative stress induced by chronic cerebral ischemia in vitro. Molecular Neurodegeneration 2012 7(Suppl 1):S26.
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