SIRT1 is decreased during relapses in patients with multiple sclerosis.

SIRT1 is a member of the histone deacetylase (HDAC) class III family of proteins and is an NAD-dependent histone and protein deacetylase. SIRT1 can induce chromatin silencing through the deacetylation of histones and can modulate cell survival by regulating the transcriptional activities. We investigated the expression of SIRT1 in multiple sclerosis (MS) brains and in peripheral blood mononuclear cells (PBMCs) obtained from patients with relapsing-remitting multiple sclerosis. We found that SIRT1 was expressed by a significant number of cells in both acute and chronic active lesions. We also found that CD4(+), CD68(+), oligodendrocytes (OLG), and glial fibrillar acidic protein (GFAP)(+) cells in MS plaques co-localized with SIRT1. Our results show a statistically significant decrease in SIRT1 mRNA and protein expression in PBMCs during relapses when compared to the levels in controls and stable MS patients. On the other hand, HDAC3 expression was not significantly changed during relapses in MS patients. SIRT1 expression correlated with that of histone H3 lysine 9 acetylation (H3K9ac) and methylation (H3K9me2). SIRT1 mRNA expression was significantly reduced after RGC-32 silencing, indicating a role for RGC-32 in the regulation of SIRT1 expression. Furthermore, we investigated the role of SIRT1 in the expression of FasL and found a significant increase in FasL expression and apoptosis after inhibition of SIRT1 expression. Our data suggest that SIRT1 may represent a biomarker of relapses and a potential new target for therapeutic intervention in MS.

Dual role of Response gene to complement-32 in multiple sclerosis.

Response gene to complement (RGC)-32 is a novel molecule that plays an important role in cell proliferation. We investigated the expression of RGC-32 in multiple sclerosis (MS) brain and in peripheral blood mononuclear cells (PBMCs) obtained from patients with relapsing-remitting multiple sclerosis. We found that CD3(+), CD68(+), and glial fibrillar acidic protein (GFAP)(+) cells in MS plaques co-localized with RGC-32. Our results show a statistically significant decrease in RGC-32 mRNA expression in PBMCs during relapses when compared to the levels in stable MS patients. This decrease might be useful in predicting disease activity in patients with relapsing-remitting MS. RGC-32 expression was also correlated with that of FasL mRNA during relapses. FasL mRNA expression was significantly reduced after RGC-32 silencing, indicating a role for RGC-32 in the regulation of FasL expression. In addition, the expression of Akt1, cyclin D1, and IL-21 mRNA was significantly increased during MS relapses when compared to levels in healthy controls. Furthermore, we investigated the role of RGC-32 in TGF-ß-induced extracellular matrix expression in astrocytes. Blockage of RGC-32 using small interfering RNA significantly inhibits TGF-ß induction of procollagen I, fibronectin and of the reactive astrocyte marker α-smooth muscle actin (α-SMA). Our data suggest that RGC-32 plays a dual role in MS, both as a regulator of T-cells mediated apoptosis and as a promoter of TGF-ß-mediated profibrotic effects in astrocytes.

Selenium transport and metabolism in plants: Phytoremediation and biofortification implications.

The aim of this review is to synthesize current knowledge of selenium (Se) transport and metabolism in plants, with a focus on implications for biofortification and phytoremediation. Selenium is a necessary human micronutrient, and around a billion people worldwide may be Se deficient. This can be ameliorated by Se biofortification of staple crops. Selenium is also a potential toxin at higher concentrations, and multiple environmental disasters over the past 50 years have been caused by Se pollution from agricultural and industrial sources. Phytoremediation by plants able to take up large amounts of Se is an important tool to combat pollution issues. Both biofortification and phytoremediation applications require a thorough understanding of how Se is taken up and metabolized by plants. Selenium uptake and translocation in plants are largely accomplished via sulfur (S) transport proteins. Current understanding of these transporters is reviewed here, and transporters that may be manipulated to improve Se uptake are discussed. Plant Se metabolism also largely follows the S metabolic pathway. This pathway is reviewed here, with special focus on genes that have been, or may be manipulated to reduce the accumulation of toxic metabolites or enhance the accumulation of nontoxic metabolites. Finally, unique aspects of Se transport and metabolism in Se hyperaccumulators are reviewed. Hyperaccumulators, which can accumulate Se at up to 1000 times higher concentrations than normal plants, present interesting specialized systems of Se transport and metabolism. Selenium hyperaccumulation mechanisms and potential applications of these mechanisms to biofortification and phytoremediation are presented.

Membrane attack by complement: the assembly and biology of terminal complement complexes.

Complement system activation plays an important role in both innate and acquired immunity. Activation of the complement and the subsequent formation of C5b-9 channels (the membrane attack complex) on the cell membranes lead to cell death. However, when the number of channels assembled on the surface of nucleated cells is limited, sublytic C5b-9 can induce cell cycle progression by activating signal transduction pathways and transcription factors and inhibiting apoptosis. This induction by C5b-9 is dependent upon the activation of the phosphatidylinositol 3-kinase/Akt/FOXO1 and ERK1 pathways in a Gi protein-dependent manner. C5b-9 induces sequential activation of CDK4 and CDK2, enabling the G1/S-phase transition and cellular proliferation. In addition, it induces RGC-32, a novel gene that plays a role in cell cycle activation by interacting with Akt and the cyclin B1-CDC2 complex. C5b-9 also inhibits apoptosis by inducing the phosphorylation of Bad and blocking the activation of FLIP, caspase-8, and Bid cleavage. Thus, sublytic C5b-9 plays an important role in cell activation, proliferation, and differentiation, thereby contributing to the maintenance of cell and tissue homeostasis.