Anticancer efficacy of unique pyridine-based tetraindoles.

Results of previous studies demonstrated that the tetraindole, SK228, which has a high lipid but low water solubility, displayed moderate anticancer efficacy in a xenograft model of breast cancer. This finding led to the proposal that new, pyridine based tetraindole (PBT) analogs of SK228, containing tetraindole moieties distributed about central protonated pyridine cores, would have enhanced bioavailabilities and anticancer efficacies. Among the PBTs prepared and subjected to biological studies, 3f (FCW81) was observed to display the highest antiproliferative activity against the two triple negative breast cancer (TNBCs) cell lines, MDA-MB-231 and BT549.

Interferon β is associated with type 1 interferon-inducible gene expression in dermatomyositis.

Objectives: To determine whether type 1 interferon (IFN) proteins in blood are associated with downstream type 1 IFN-inducible gene expression in blood from patients with myositis.

Methods: IFNα, IFNβ and IFNω concentrations were measured by ELISA in 129 blood samples (from 93 patients with dermatomyositis (DM), inclusion body myositis, polymyositis and other muscle diseases and from 36 healthy volunteers). Their concentrations were correlated with their ability to stimulate type 1 IFN-inducible gene transcription in a functional assay for 123 of these samples and the type 1 IFN-inducible blood gene expression from 70 of the same samples.

Vitamin D receptor negatively regulates bacterial-stimulated NF-kappaB activity in intestine.

Vitamin D receptor (VDR) plays an essential role in gastrointestinal inflammation. Most investigations have focused on the immune response; however, how bacteria regulate VDR and how VDR modulates the nuclear factor (NF)-kappaB pathway in intestinal epithelial cells remain unexplored. This study investigated the effects of VDR ablation on NF-kappaB activation in intestinal epithelia and the role of enteric bacteria on VDR expression.

Human plasmacytoid dendritic cell accumulation amplifies their type 1 interferon production.

To determine the potential consequences of plasmacytoid dendritic cell (pDC) accumulation in tissue sites observed in several autoimmune diseases, we measured type 1 interferon production from circulating human pDCs as a function of pDC concentration. The effects of interferon-alpha and blockade of the type 1 interferon receptor (IFNAR) on human pDC type 1 interferon and interferon-inducible transcription and protein production were measured. Human pDCs became far more efficient producers of interferon-alpha at concentrations beyond those normally present in blood, through an IFNAR-dependent mechanism.

Interferon-stimulated gene 15 (ISG15) conjugates proteins in dermatomyositis muscle with perifascicular atrophy.

Objective: We investigated interferon-stimulated gene 15 (ISG15), a poorly understood ubiquitin-like modifier, and its enzymatic pathway in dermatomyositis (DM), an autoimmune disease primarily involving muscle and skin.

Methods: We generated microarray data measuring transcript abundance for approximately 18,000 genes in each of 113 human muscle biopsy specimens, and studied biopsy specimens and cultured skeletal muscle using immunohistochemistry, immunoblotting proteomics, real-time quantitative polymerase chain reaction, and laser-capture microdissection.

Results: Transcripts encoding ISG15-conjugation pathway proteins were markedly upregulated in DM with perifascicular atrophy (DM-PFA) muscle (ISG15 339-fold, HERC5 62-fold, and USP18 68-fold) compared with 99 non-DM samples.

Salmonella type III effector AvrA stabilizes cell tight junctions to inhibit inflammation in intestinal epithelial cells.

Salmonella Typhimurium is a major cause of human gastroenteritis. The Salmonella type III secretory system secretes virulence proteins, called effectors. Effectors are responsible for the alteration of tight junction (TJ) structure and function in intestinal epithelial cells.

Involvement of the vitamin D receptor in the regulation of NF-kappaB activity in fibroblasts.

We have used mouse embryonic fibroblasts (MEFs) derived from VDR(+/-) and VDR(-/-) mice to determine whether the nuclear vitamin D receptor (VDR) is directly involved in the regulation of NF-kappaB activation. We found that the basal IkappaBalpha protein level was markedly decreased in VDR(-/-) MEFs compared to VDR(+/-) MEFs; however, degradation of IkappaBalpha and its phosphorylation were not altered in VDR(-/-) cells, neither were the levels of IKKalpha and IKKbeta proteins. Consistently, p65 nuclear translocation was increased in unstimulated VDR(-/-) cells.

Increased NF-kappaB activity in fibroblasts lacking the vitamin D receptor.

1,25-Dihydroxyvitamin D [1,25(OH)2D3] is known to have anti-inflammatory activity; however, the molecular mechanism remains poorly defined. Here we show that the nuclear vitamin D receptor (VDR) is directly involved in the regulation of NF-kappaB activation, a pathway essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from VDR-/- mice, the basal level of kappaB inhibitor (IkappaB) alpha protein was markedly decreased compared with VDR+/- MEFs; however, degradation of IkappaBalpha and its phosphorylation in response to TNF-alpha treatment or Salmonella infection were not altered in VDR-/- cells, neither were the levels of IkappaB kinase-alpha and IkappaB kinase-beta proteins.