Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor.

G protein-coupled receptor 84 (GPR84) is a putative receptor for medium-chain fatty acids (MCFAs), whose pathophysiological roles have not yet been clarified. Here, we show that GPR84 was activated by MCFAs with the hydroxyl group at the 2- or 3-position more effectively than nonhydroxylated MCFAs. We also identified a surrogate agonist, 6-n-octylaminouracil (6-OAU), for GPR84.

Activation of T cell death-associated gene 8 regulates the cytokine production of T cells and macrophages in vitro.

An orphan G-protein-coupled receptor, T cell death-associated gene 8 (TDAG8) which has been reported to be a proton sensor, inhibits the production of pro-inflammatory cytokines induced by extracellular acidification. Recently, we have found that TDAG8 knockout mice showed significant exacerbation in various immune-mediated inflammation disease models. To elucidate the role of TDAG8, we screened an in-house library to find compounds which have a profile as a TDAG8 agonist using a cyclic adenosine 5'-monophosphate assay.

Activation of T cell death-associated gene 8 attenuates inflammation by negatively regulating the function of inflammatory cells.

T cell death-associated gene 8 (TDAG8) is a G-protein-coupled receptor identified by differential mRNA display during thymocyte apoptosis induced by T cell receptor engagement. To examine the physiological role of an orphan G-protein-coupled receptor TDAG8 in inflammation, we studied various immune-mediated inflammatory disease models using TDAG8-deficient mice. We found that TDAG8-deficient mice showed significant exacerbation of anti-type II collagen antibody-induced arthritis and delayed-type hypersensitivity, and showed a slight exacerbation of collagen-induced arthritis.

Caspase-independent cell death by Fas ligation in human thymus-derived T cell line, HPB-ALL cells.

In HPB-ALL cells, a human thymus-derived T-cell line, Fas (CD95)-mediated cell death was inhibited by about only 50% as a result of treatment with an amount of benzyloxycarbonyl-Val-Ala-Asp-(O-methyl)-CH(2)F (zVAD-fmk) sufficient to block the caspase activity. Fas-mediated caspase-independent cell death was not observed in other lymphoblast cell lines or mouse activated splenocytes, but this type of cell death was observed in mouse and rat thymocytes, the same as for HPB-ALL cells. This suggests that Fas-mediated caspase-independent cell death is a common feature in thymocytes.

Blockade of scavenger receptor class B type I raises high density lipoprotein cholesterol levels but exacerbates atherosclerotic lesion formation in apolipoprotein E deficient mice.

Recent accumulating evidence supports the concept that raising high-density lipoprotein (HDL) may represent an additional therapeutic target for prevention of cardiovascular disease. Scavenger receptor class B type I plays a critical role in plasma HDL cholesterol concentration and structure. This study investigated the effect of scavenger receptor class B type I blockade by a synthetic scavenger receptor class B type I blocker on plasma lipids and atherosclerosis lesion formation in apolipoprotein E (apoE)-deficient mice.

A novel compound, R-138329, increases plasma HDL cholesterol via inhibition of scavenger receptor BI-mediated selective lipid uptake.

High-density lipoprotein (HDL) has a protective effect against atherosclerosis. Therefore, a compound that elevates the plasma HDL cholesterol (HDL-C) levels is expected to be a promising anti-atherosclerotic agent. We discovered a novel compound, R-138329, that increased HDL-C by 41% in normolipidemic hamsters at a dose of 100mg/kg.

6-Ethyl-N,N'-bis(3-hydroxyphenyl)[1,3,5]triazine-2,4-diamine (RS-0466) enhances the protective effect of brain-derived neurotrophic factor on amyloid beta-induced cytotoxicity in cortical neurones.

Amyloid beta peptide in the senile plaques of patients with Alzheimer's disease is considered to be responsible for the pathology of Alzheimer's disease. We have previously reported that 6-ethyl-N,N'-bis(3-hydroxyphenyl)[1,3,5]triazine-2,4-diamine, RS-0466, is capable of significantly inhibiting amyloid beta-induced cytotoxicity in HeLa cells. To determine various profiles of RS-0466, we investigated whether RS-0466 would enhance the neuroprotective effect of brain-derived neurotrophic factor on amyloid beta(1-42)-induced cytotoxicity in rat cortical neurones.

RS-4252 inhibits amyloid beta-induced cytotoxicity in HeLa cells.

Progressive deposition of amyloid beta peptide in the senile plaques is a principal event in the neurodegenerative process of Alzheimer's disease. Several reports have demonstrated that amyloid beta is cytotoxic using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an indicator of viability in cells. With the MTT assay, we screened an in-house library to find compounds which suppress amyloid beta-induced inhibition of MTT reduction.

Kainate exacerbates beta-amyloid toxicity in rat hippocampus.

We have previously shown that beta-amyloid (Abeta) increased the excitotoxicity of ibotenate, an N-methyl-D-aspartate (NMDA) receptor agonist, to hippocampal neurons of rats. In this report, non-toxic amounts of kainate were co-injected with Abeta into rat hippocampus. Nissl-stained brain sections revealed that Abeta/kainate co-injection exerted synergistic neuronal degeneration in the hippocampus as well as that by Abeta/ibotenate co-injection.

beta-Amyloid-specific upregulation of stearoyl coenzyme A desaturase-1 in macrophages.

beta-Amyloid peptide (A beta), a major component of senile plaques, the formation of which is characteristic of Alzheimer's disease (AD), is believed to induce inflammation of the brain mediated by microglia, leading to neuronal cell loss. In this study, we performed an oligonucleotide microarray analysis to investigate the molecular events underlying the A beta-induced activation of macrophages and its specific suppression by the A beta-specific-macrophage-activation inhibitor, RS-1178. Of the approximately 36,000 genes and expressed sequence tags analyzed, eight genes were specifically and significantly upregulated by a treatment with interferon gamma (IFN gamma) and A beta compared to a treatment with IFN gamma alone (p<0.

A novel compound RS-0466 reverses beta-amyloid-induced cytotoxicity through the Akt signaling pathway in vitro.

beta-Amyloid peptide is the principal protein in the senile plaques of Alzheimer's disease and is considered to be responsible for the pathology of Alzheimer's disease. Several studies have shown that beta-amyloid is cytotoxic, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an indicator of viability in cells. Utilizing the MTT assay, we screened an in-house library to find compounds that suppress beta-amyloid-induced inhibition of MTT reduction.

Acute neuroinflammation exacerbates excitotoxicity in rat hippocampus in vivo.

Accumulating evidence suggests that inflammation may play an important part in neurodegenerative diseases such as Alzheimer's disease. Inflammation itself, however, is insufficient to produce acute neurodegeneration in vivo. In this report, we determined whether inflammation increases excitotoxicity in hippocampal neurons.

Amyloid beta-peptide alters the distribution of early endosomes and inhibits phosphorylation of Akt in the presence of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT).

Amyloid beta-peptide (Abeta) effectively inhibits the cellular reduction activity of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) in a variety of cultured cells. Although the inhibitory activity is widely used for the estimation of the biological activity of Abeta, the cellular mechanism is unclear. In the present study, we examined the effect of Abeta on the morphology of early endosomes, in which MTT is accumulated as MTT formazan after cellular reduction.

A novel beta-sheet breaker, RS-0406, reverses amyloid beta-induced cytotoxicity and impairment of long-term potentiation in vitro.

Fibril formation of amyloid beta peptide (Abeta) is considered to be responsible for the pathology of Alzheimer's disease (AD). The Abeta fibril is formed by a protein misfolding process in which intermolecular beta-sheet interactions become stabilized abnormally. Thus, to develop potential anti-AD drugs, we screened an in-house library to find compounds which have a profile as a beta-sheet breaker.

A novel compound, RS-1178, specifically inhibits neuronal cell death mediated by beta-amyloid-induced macrophage activation in vitro.

beta-Amyloid peptide (Abeta), a major component of senile plaques, the formation of which is characteristic of Alzheimer's disease (AD), is believed to induce inflammation in the brain leading to cell loss and cognitive decline. Accumulating evidence shows Abeta activates microglia, which play the role of the brain's immune system, and mediates inflammatory responses in the brain. Thus, a compound inhibiting Abeta-induced activation of microglia may lead to a novel therapy for AD.

Glutamate exacerbates amyloid beta1-42-induced impairment of long-term potentiation in rat hippocampal slices.

Amyloid beta (A beta) is the principal constituent of senile plaques in Alzheimer's disease patients. We investigated whether A beta and glutamate affect long-term potentiation (LTP) in rat hippocampal slices. Pretreatment with 1 microM A beta1-42 alone for 3 h slightly inhibited LTP; however, the potentiation was maintained for 60 min.

Troglitazone inhibits both post-glutamate neurotoxicity and low-potassium-induced apoptosis in cerebellar granule neurons.

Both excitotoxicity and apoptosis contribute to neuronal loss in various neurodegenerative diseases such as Alzheimer's disease as well as stroke, and a drug inhibiting both types of cell death may lead to practical treatment for these diseases. Post-treatment with troglitazone, a potent and specific activator of peroxisome proliferator-activated receptor (PPAR)-gamma attenuated the cell death of cerebellar granule neurons, triggered by glutamate exposure. The inhibitory effect of troglitazone against glutamate excitotoxicity, in vitro, was observed even when added 2.