Salivary Immunoglobulin Gamma-3 Chain C Is a Promising Noninvasive Biomarker for Systemic Lupus Erythematosus.

We aimed to characterize the salivary protein components and identify biomarkers in patients with systemic lupus erythematosus (SLE). A proteomic analysis using two-dimensional gel electrophoresis and mass spectrometry was performed to determine the alterations of salivary proteins between patients with SLE and healthy controls, and the concentrations of the candidate proteins were measured through Western blot analysis and the enzyme-linked immunosorbent assay. The 10 differentially expressed protein spots were immunoglobulin gamma-3 chain C region (IGHG3), immunoglobulin alpha-1 chain C region, protein S100A8, lactoferrin, leukemia-associated protein 7, and 8-oxoguanine DNA glycosylase. The patients with SLE exhibited enhanced salivary IGHG3 (3.9 ± 2.15 pg/mL) and lactoferrin (4.7 ± 1.8 pg/mL) levels compared to patients with rheumatoid arthritis (1.8 ± 1.01 pg/mL and 3.2 ± 1.6 pg/mL, respectively; p < 0.001 for both) or healthy controls (2.2 ± 1.64 pg/mL and 2.2 ± 1.7 pg/mL, respectively; p < 0.001 for both). The salivary IGHG3 levels correlated with the erythrocyte sedimentation rate (r = 0.26, p = 0.01), anti-double-stranded DNA (dsDNA) antibody levels (r = 0.25, p = 0.01), and nephritis (r = 0.28, p = 0.01). The proteomic analysis revealed that the salivary IGHG3 levels were associated with SLE and lupus disease activity, suggesting that salivary IGHG3 may be a promising noninvasive biomarker for SLE.

Hypoxic ischemia and proteasome dysfunction alter tau isoform ratio by inhibiting exon 10 splicing.

Alternative splicing of tau exon 10 influences microtubule assembly and stability during development and in pathological processes of the central nervous system. However, the cellular events that underlie this pre-mRNA splicing remain to be delineated. In this study, we examined the possibility that ischemic injury, known to change the cellular distribution and expression of several RNA splicing factors, alters the splicing of tau exon 10. Transient occlusion of the middle cerebral artery reduced tau exon 10 inclusion in the ischemic cortical area within 12 h, resulting in the induction of three-repeat (3R) tau in cortical neurons. Ubiquitinated protein aggregates and reduced proteasome activity were also observed. Administration of proteasome inhibitors such as MG132, proteasome inhibitor I and lactacystin reduced tau exon 10 splicing in cortical cell cultures. Decreased levels of Tra2beta, an RNA splicing factor responsible for tau exon 10 inclusion, were detected both in cortical cell cultures exposed to MG132 and in cerebral cortex after ischemic injury. Taken together, these findings suggest that transient focal cerebral ischemia reduces tau exon 10 splicing through a mechanism involving proteasome-ubiquitin dysfunction and down-regulation of Tra2beta.

Tissue inhibitor of metalloproteinases-3 (TIMP-3) expression is increased during serum deprivation-induced neuronal apoptosis in vitro and in the G93A mouse model of amyotrophic lateral sclerosis: a potential modulator of Fas-mediated apoptosis.

Cortical neurons deprived of serum undergo apoptosis that is sensitive to inhibitors of macromolecule synthesis. Proteomic analysis revealed differential expression of 49 proteins in cortical neurons 8 h after serum deprivation. Tissue inhibitor of metalloproteinases-3 (TIMP-3), a pro-apoptotic protein in various cancer cells, was increased during serum deprivation-induced apoptosis (SDIA), but not during necrosis induced by excitotoxicity or oxidative stress. Levels of TIMP-3 were markedly increased in degenerating motor neurons in a transgenic model of familial amyotrophic lateral sclerosis. The TIMP-3 expression was accompanied by increase in Fas-FADD interaction, activated caspase-8, and caspase-3 during SDIA and in vulnerable spinal cord of the ALS mouse. SDIA and activation of the Fas pathway were prevented by addition of an active MMP-3. Timp-3 deletion by RNA interference attenuated SDIA in N2a cells. These findings provide evidence that TIMP-3 is an upstream mediator of neuronal apoptosis and likely contributes to neuronal loss in neurodegenerative diseases such as amyotrophic lateral sclerosis.