Evaluating Novel RXR Agonists That Induce ApoE and Tyrosine Hydroxylase in Cultured Human Glioblastoma Cells.

There is considerable interest in identifying effective and safe drugs for neurodegenerative disorders. Cell culture and animal model work have demonstrated that modulating gene expression through RXR-mediated pathways may mitigate or reverse cognitive decline. However, because RXR is a dimeric partner for several transcription factors, activating off-target transcription is a concern with RXR ligands (rexinoids).

Characterization of a PKR inhibitor from the pathogenic ranavirus, Ambystoma tigrinum virus, using a heterologous vaccinia virus system.

Ambystoma tigrinum virus (ATV) (family Iridoviridae, genus Ranavirus) was isolated from diseased tiger salamanders (Ambystoma tigrinum stebbinsi) from the San Rafael Valley in southern Arizona, USA in 1996. Genomic sequencing of ATV, as well as other members of the genus, identified an open reading frame that has homology to the eukaryotic translation initiation factor, eIF2α (ATV eIF2α homologue, vIF2αH). Therefore, we asked if the ATV vIF2αH could also inhibit PKR.

SIRT1 enzymatically potentiates 1,25-dihydroxyvitamin D signaling via vitamin D receptor deacetylation.

The hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25D), binds to the vitamin D receptor (VDR) and promotes heterodimerization of VDR with a retinoid-X-receptor (RXR) to genomically regulate diverse cellular processes. Herein, it is revealed for the first time that VDR is post-translationally acetylated, and that VDR immunoprecipitated from human embryonic kidney (HEK293) cells displays a dramatic decrease in acetylated receptor in the presence of 1,25D-ligand, sirtuin-1 (SIRT1) deacetylase, or the resveratrol activator of SIRT1. To elucidate the functional significance of VDR deacetylation, vitamin-d-responsive-element (VDRE)-based transcriptional assays were performed to determine if deacetylase overexpression affects VDR/VDRE-driven transcription.

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN).

Sulfonic acid analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene, 1) as well as seven novel and two reported analogues of 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN) were synthesized and assessed for selective retinoid X receptor (RXR) agonism. Compound 1 is FDA-approved for treatment of cutaneous T-cell lymphoma (CTCL); however, 1 can provoke side effects by impacting RXR-dependent receptor pathways. All of the analogues in this study were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXR-responsive element (RXRE)-mediated transcriptional experiments.

Retinoid X Receptor Selective Agonists and their Synthetic Methods.

Since the isolation and identification of the retinoid X receptor (RXR) as a member of the nuclear receptor (NR) superfamily in 1990, its analysis has ushered in a new understanding of physiological regulation by nuclear receptors, and novel methods to identify other unknown and orphan receptors. Expression of one or more of the three isoforms of RXR-α, β, and γ-can be found in every human cell type. Biologically, RXR plays a critical role through its ability to partner with other nuclear receptors.

Use of a recombinant vaccinia virus expressing interferon gamma for post-exposure protection against vaccinia and ectromelia viruses.

Post-exposure vaccination with vaccinia virus (VACV) has been suggested to be effective in minimizing death if administered within four days of smallpox exposure. While there is anecdotal evidence for efficacy of post-exposure vaccination this has not been definitively studied in humans. In this study, we analyzed post-exposure prophylaxis using several attenuated recombinant VACV in a mouse model.

Vaccinia viruses with mutations in the E3L gene as potential replication-competent, attenuated vaccines: scarification vaccination.

In this study, we evaluated the efficacy of vaccinia virus (VACV) containing mutations in the E3L virulence gene to protect mice against a lethal poxvirus challenge after vaccination by scarification. VACV strains with mutations in the E3L gene had significantly decreased pathogenicity, even in immune deficient mice, yet retained the ability to produce a potent Th1-dominated immune response in mice after vaccination by scarification, while protecting against challenge with wild type, pathogenic VACV. Initial experiments were done using the mouse-adapted, neurovirulent Western Reserve (WR) strain of vaccinia virus.

Vaccinia viruses with mutations in the E3L gene as potential replication-competent, attenuated vaccines: intra-nasal vaccination.

Vaccinia virus (VACV) has been used as the vaccine to protect against smallpox, and recombinant VACVs have been used to develop vaccine candidates against numerous cancers and infectious diseases. Although relatively safe for use in humans, the strains of VACV that were used as smallpox vaccines led to several complications including, progressive infection in immune compromised individuals, eczema vaccination in individuals with a history of atopic dermatitis, and encephalitis and perimyocarditis in apparently healthy individuals. The work described in this paper focuses on attenuated strains of VACV that may have the potential for use as vaccine vectors with reduced pathogenicity.

Inhibition of PKR by RNA and DNA viruses.

Interferons were the first of the anti-viral innate immune modulators to be characterized, initially characterized solely as anti-viral proteins [reviewed in Le Page, C., Genin, P., Baines, M.

Role of RcsF in signaling to the Rcs phosphorelay pathway in Escherichia coli.

The rcs phosphorelay pathway components were originally identified as regulators of capsule synthesis. In addition to the transmembrane sensor kinase RcsC, the RcsA coregulator, and the response regulator RcsB, two new components have been characterized, RcsD and RcsF. RcsD, the product of the yojN gene, now renamed rcsD, acts as a phosphorelay between RcsC and RcsB.

The N-terminal domain of the vaccinia virus E3L-protein is required for neurovirulence, but not induction of a protective immune response.

Encephalitis is a rare, but serious complication from vaccination against smallpox using replication competent strains of vaccinia virus. In this report we describe mutants of vaccinia virus, containing N-terminal deletions of the vaccinia virus interferon resistance gene, E3L, that are attenuated for neuropathogenesis in a mouse model system. These recombinant viruses replicated to high titers in the nasal mucosa after intra-nasal infection of C57BL/6 mice but failed to spread to the lungs or brain.