Deficiency of macrophage migration inhibitory factor attenuates tau hyperphosphorylation in mouse models of Alzheimer's disease.

Background: Pathological features of Alzheimer's disease (AD) include aggregation of amyloid beta (Aβ) and tau protein. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has been implicated in the toxicity of aggregated Aβ. It remains unclear whether MIF affects hyperphosphorylation and aggregation of tau.

Safety, pharmacokinetics, pharmacodynamics, and bioavailability of GSK2018682, a sphingosine-1-phosphate receptor modulator, in healthy volunteers.

The tolerability, pharmacokinetics, and pharmacodynamics of single (SD) and repeat (RD) doses of GSK2018682, a selective S1P1 receptor modulator, were evaluated in healthy volunteers. The bioavailability (BA) of different formulations and effects of food were also evaluated. SD of up to 24 mg and RD of up to 6 mg/day for 28 days were reasonably tolerated, despite higher incidences of gastrointestinal and cardiovascular adverse events compared to placebo.

Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms.

We identified three retinoid-related orphan receptor gamma t (RORγt)-specific inhibitors that suppress T helper 17 (Th17) cell responses, including Th17-cell-mediated autoimmune disease. We systemically characterized RORγt binding in the presence and absence of drugs with corresponding whole-genome transcriptome sequencing. RORγt acts as a direct activator of Th17 cell signature genes and a direct repressor of signature genes from other T cell lineages; its strongest transcriptional effects are on cis-regulatory sites containing the RORα binding motif.

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges.

Multiple sclerosis (MS) is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, many disease-modifying therapies that primarily target adaptive immunity have been shown to prevent exacerbations and new lesions in patients with relapsing-remitting MS. However, these therapies only have limited efficacy on the progression of disability.

Drug targets in the cytokine universe for autoimmune disease.

In autoimmune disease, a network of diverse cytokines is produced in association with disease susceptibility to constitute the 'cytokine milieu' that drives chronic inflammation. It remains elusive how cytokines interact in such a complex network to sustain inflammation in autoimmune disease. This has presented huge challenges for successful drug discovery because it has been difficult to predict how individual cytokine-targeted therapy would work.

Combined phosphatase and tensin homolog (PTEN) loss and fatty acid synthase (FAS) overexpression worsens the prognosis of Chinese patients with hepatocellular carcinoma.

We aimed to investigate the expression pattern of phosphatase and tensin homolog (PTEN), to evaluate the relationship between PTEN expression and clinicopathological characteristics, including fatty acid synthase (FAS) expression, and to determine the correlations of PTEN and FAS expression with survival in Chinese patients with hepatocellular carcinoma (HCC). The expression patterns of PTEN and FAS were determined using tissue microarrays and immunohistochemistry. The expression of PTEN was compared with the clinicopathological characteristics of HCC, including FAS expression.

The cytokine milieu in the interplay of pathogenic Th1/Th17 cells and regulatory T cells in autoimmune disease.

The propagation and regulation of an immune response is driven by a network of effector and regulatory T (Treg) cells. The interplay of effector T and Treg cells determines the direction of the immune response towards inflammation or its resolution in an autoimmune disease setting. In autoimmune diseases, this interplay shifts the balance in favor of the development of autoreactive effector T cells, resulting in inflammatory pathology.

Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease.

Interleukin-7 receptor (IL-7R) is genetically associated with susceptibility to multiple sclerosis. Here we describe that IL-7 is essential for survival and expansion of pathogenic T helper type 17 (T(H)17) cells in experimental autoimmune encephalomyelitis (EAE). IL-7 directly expanded effector T(H)17 cells in EAE and human T(H)17 cells from subjects with multiple sclerosis, whereas it was not required for T(H)17 differentiation.