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The effect of metabolic acidosis (MA) on Na-S(sub i) cotransport activity and NaS(sub i)-1 protein and mRNA expression was investigated. In rats with MA for 24 hrs, there was substantial increase in the fractional excretion of S(sub i), which was related with a 2.4-fold reduction in brush-border membrane (BBM) Na-S(sub i) cotransport activity. Results showed that MA decreases S(sub i) reabsorption by inducing reductions in BBM Na-S(sub i) cotransport activity and that reductions in the expression of NaS(sub i)-1 protein and mRNA abundance, at least partially, have a significant role in the inhibition of Na-S(sub i) cotransport activity during MA.

Objective To determine if suppressing Nogo-A, an axonal inhibitory protein, will promote functional recovery in a murine model of multiple sclerosis (MS). Methods A small interfering RNA was developed to specifically suppress Nogo-A (siRNA-NogoA). The siRNA-NogoA silencing effect was evaluated in vitro and in vivo via immunohistochemistry. The siRNA was administered intravenously in 2 models of experimental autoimmune encephalomyelitis (EAE). Axonal repair was measured by upregulation of GAP43. Enzyme-linked immunosorbent assay, flow cytometry, and 3H-thymidine incorporation were used to determine immunological changes in myelin-specific T cells in mice with EAE. Results The siRNA-NogoA suppressed Nogo-A expression in vitro and in vivo. Systemic administration of siRNA-NogoA ameliorated EAE and promoted axonal repair, as demonstrated by enhanced GAP43+ axons in the lesions. Myelin-specific T-cell proliferation and cytokine production were unchanged in the siRNA-NogoA-treated mice. Interpretation Silencing Nogo-A in EAE promotes functional recovery. The therapeutic benefit appears to be mediated by axonal growth and repair, and is not attributable to changes in the encephalitogenic capacity of the myelin-specific T cells. Silencing Nogo-A may be a therapeutic option for MS patients to prevent permanent functional deficits caused by immune-mediated axonal damage. ANN NEUROL 2010;67:498-507 [ABSTRACT FROM AUTHOR]

The primary biological function of the endogenous cellular prion protein has remained unclear. We investigated its biological function in the generation of cellular immune responses using cellular prion protein gene-specific small interfering ribonucleic acid in vivo and in vitro. Our results were confirmed by blocking cellular prion protein with monovalent antibodies and by using cellular prion protein-deficient and -transgenic mice. In vivo prion protein gene-small interfering ribonucleic acid treatment effects were of limited duration, restricted to secondary lymphoid organs and resulted in a 70% reduction of cellular prion protein expression in leukocytes. Disruption of cellular prion protein signalling augmented antigen-specific activation and proliferation, and enhanced T cell receptor signalling, resulting in zeta-chain-associated protein-70 phosphorylation and nuclear factor of activated T cells/activator protein 1 transcriptional activity. In vivo prion protein gene-small interfering ribonucleic acid treatment promoted T cell differentiation towards pro-inflammatory phenotypes and increased survival of antigen-specific T cells. Cellular prion protein silencing with small interfering ribonucleic acid also resulted in the worsening of actively induced and adoptively transferred experimental autoimmune encephalomyelitis. Finally, treatment of myelin basic protein1–11 T cell receptor transgenic mice with prion protein gene-small interfering ribonucleic acid resulted in spontaneous experimental autoimmune encephalomyelitis. Thus, central nervous system autoimmune disease was modulated at all stages of disease: the generation of the T cell effector response, the elicitation of T effector function and the perpetuation of cellular immune responses. Our findings indicate that cellular prion protein regulates T cell receptor-mediated T cell activation, differentiation and survival. Defects in autoimmunity are restricted to the immune system and not the central nervous system. Our data identify cellular prion protein as a regulator of cellular immunological homoeostasis and suggest cellular prion protein as a novel potential target for therapeutic immunomodulation. [ABSTRACT FROM PUBLISHER]

Elucidating the cross-talk between inflammatory and cell proliferation pathways might provide important insights into the pathogenesis of inflammation-induced cancer. Here, we show that the receptor-interacting protein 1 (RIP1)—an essential mediator of inflammation-induced nuclear factor-κB (NF-κB) activation—regulates p27Kip1 levels and cell-cycle progression. RIP1 regulates p27Kip1 levels by an NF-κB-independent signal that involves activation of the phosphatidylinositol 3-kinase (PI3K)–Akt–forkhead pathway. Mouse embryonic fibroblasts (MEFs) from RIP1-knockout mice express high levels of p27Kip1. Reconstitution of MEFs with RIP1 downregulates p27Kip1 levels in a PI3K-dependent manner. RIP1 regulates p27Kip1 at the messenger RNA level by regulating the p27Kip1 promoter through the forkhead transcription factors. RIP1 expression blocks accumulation of cells in G1 in response to serum starvation and favours cell-cycle progression. Finally, we show that overexpression of p27Kip1 blocks the effects of RIP1 on the cell cycle. Thus, our study provides a new insight into how components of inflammatory and immune signalling pathways regulate cell-cycle progression. [ABSTRACT FROM AUTHOR]

Investigates whether metabolic acidosis (MA) regulates rat renal sodium-sulfate cotransport activity. Effect of acid diets on arterial blood pH and bicarbonate; Role of sodium-sulfate protein and mRNA in the regulation of sodium-sulfate cotransport activity by MA; MRNA-induced sulfate, phophate, and L-arginine transport in Xenopus oocytes injected with mRNA.