Selective inhibition of PCAF suppresses microglial-mediated ß-amyloid neurotoxicity.

Recent studies have emphasized the functional role of the P300/CBP-associated factor (PCAF) enzyme in resistance to ß-amyloid (Aß)-mediated neurotoxicity; however, the underlying mechanisms through which PCAF regulates inflammation and neurotoxicity have not yet been elucidated. In this study, we used computer-based molecular docking simulations to perform structure-based artificial screening for PCAF-specific inhibitors. Our results revealed that one of the compounds from the screened library, compound C-11, selectively inhibited PCAF, but not p300 or GCN5, with a half-maximal inhibitory concentration (IC50) of approximately 0.25 µM. Furthermore, C-11 had no effects on the activities of other epigenetic enzymes. Western blot analysis using an antibody against acetyl-nuclear factor-κB (NF-κB) demonstrated that PCAF mediated the Aß-induced activation of NF-κB by acetylation at Lys-122. We also found that the knockdown of PCAF completely inhibited Aß-induced cytokine production in BV-2 cells in a similar manner to C-11 treatment. Finally, PCAF inhibition suppressed both Aß-induced cytokine production and Aß-mediated neuronal cell death. Therefore, our results suggest that in neuronal cells, PCAF is a promising therapeutic target for alleviating the inflammatory progression of Alzheimer's disease.

Gallic acid, a histone acetyltransferase inhibitor, suppresses ß-amyloid neurotoxicity by inhibiting microglial-mediated neuroinflammation.

SCOPE: We examined the biological effect of gallic acid (GA) as a nuclear factor (NF)-κB acetyltransferase inhibitor on microglial-mediated ß-amyloid neurotoxicity and restorative effects on the Aß-induced cognitive dysfunction. METHODS AND RESULTS: The protective effects of GA on the survival of neuronal cells were assessed with an MTT assay and a co-culture system. For the co-culture experiments, both BV-2 and primary microglia cells were treated with GA prior to Aß stimulation, and conditioned media were transferred to Neuro-2A cells. The mRNA and protein levels of inflammatory cytokines in both microglia and Neuro-2A cells were assessed with real-time polymerase chain reaction and western blotting. Inhibition of nuclear factor kappa B (NF-κB) acetylation with GA treatment resulted in reduced cytokine production in microglia cells and protection of neuronal cells from Aß-induced neurotoxicity. Furthermore, we observed a restorative effect of GA on Aß-induced cognitive dysfunction in mice with Y-maze and passive avoidance tests. Finally, we found that GA treatment efficiently blocked neuronal cell death by downregulating the expression of cytokines and the in vivo levels of NF-κB acetylation. CONCLUSION: These results suggest that selective inhibition of NF-κB acetylation by the histone acetyltransferase inhibitor GA is a possible therapeutic approach for alleviating the inflammatory progression of Alzheimer disease.

Delphinidin, a specific inhibitor of histone acetyltransferase, suppresses inflammatory signaling via prevention of NF-κB acetylation in fibroblast-like synoviocyte MH7A cells.

Histone acetyltransferase (HAT) inhibitors (HATi) isolated from dietary compounds have been shown to suppress inflammatory signaling, which contributes to rheumatoid arthritis. Here, we identified a novel HATi in Punica granatum L. known as delphinidin (DP). DP did not affect the activity of other epigenetic enzymes (histone deacetylase, histone methyltransferase, or sirtuin1). DP specifically inhibited the HAT activities of p300/CBP. It also inhibited p65 acetylation in MH7A cells, a human rheumatoid arthritis synovial cell line. DP-induced hypoacetylation was accompanied by cytosolic accumulation of p65 and nuclear localization of IKBα. Accordingly, DP treatment inhibited TNFα-stimulated increases in NF-κB function and expression of NF-κB target genes in these cells. Importantly, DP suppressed lipopolysaccharide-induced pro-inflammatory cytokine expression in Jurkat T lymphocytes, demonstrating that HATi efficiently suppresses cytokine-mediated immune responses. Together, these results show that the HATi activity of DP counters anti-inflammatory signaling by blocking p65 acetylation and that this compound may be useful in preventing inflammatory arthritis.

Grape seed extract regulates androgen receptor-mediated transcription in prostate cancer cells through potent anti-histone acetyltransferase activity.

Histone acetylation, which is regulated by histone acetyltransferases (HATs) and deacetylases, is an epigenetic mechanism that influences eukaryotic transcription. Significant changes in histone acetylation are associated with cancer; therefore, manipulating the acetylation status of key gene targets is likely crucial for effective cancer therapy. Grape seed extract (GSE) has a known protective effect against prostate cancer. Here, we showed that GSE significantly inhibited HAT activity by 30-80% in vitro (P < .05). Furthermore, we demonstrated significant repression of androgen receptor (AR)-mediated transcription by GSE in prostate cancer cells by measuring luciferase activity using a pGL3-PSA construct bearing the AR element in the human prostate cancer cell line LNCaP (P < .05). GSE treatment also decreased the mRNA level of the AR-regulated genes PSA and NKX 3.1. Finally, GSE inhibited growth of LNCaP cells. These results indicate that GSE potently inhibits HAT, leading to decreased AR-mediated transcription and cancer cell growth, and implicate GSE as a novel candidate for therapeutic activity against prostate cancer.

Procyanidin B3, an inhibitor of histone acetyltransferase, enhances the action of antagonist for prostate cancer cells via inhibition of p300-dependent acetylation of androgen receptor.

Increasing evidence suggests that AR (androgen receptor) acetylation is critical for prostate cancer cell growth. In the present study, we identified Pro-B3 (procyanidin B3) as a specific HAT (histone acetyltransferase) inhibitor. Pro-B3 selectively inhibited the activity of HATs, but not other epigenetic enzymes. Pro-B3 substantially inhibited the p300-mediated AR acetylation, both in vitro and in vivo. Pro-B3 inhibited both p300-dependent and agonist-induced AR transcription. We demonstrate that the p300-mediated AR acetylation is critical for the hormone responsiveness of AR. Interestingly, B3 treatment efficiently enhanced the antagonist activity of flutamide through suppression of p300 HAT activity, demonstrating that relative p300 activity is critical for the antagonist action. Finally, Pro-B3 treatment inhibited acetylation-dependent prostate cell proliferation and expression of cell-cycle control genes, subsequently increasing cell death, indicating the functional importance of AR acetylation for prostate cancer cell growth.

Neuroprotective effects of Eriobotrya japonica against ß-amyloid-induced oxidative stress and memory impairment.

The generation of oxygen free radicals and oxidative damage is believed to be involved in the pathogenesis of neurodegenerative disorders. Eriobotrya japonica has been used to treat several diseases in East Asia. In this study, we investigated the protective effect of an E. japonica extract against Aß peptide-induced oxidative stress. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay demonstrated that the E. japonica extract scavenged approximately 40% of DPPH radicals. Also, treatment of the E. japonica extract inhibited Aß(1-42)-mediated neuronal cell death. Furthermore, treatment of E. japonica extract efficiently suppressed the increase in intracellular ROS triggered by the Aß(1-42) peptide. Importantly, mice pre-treated with the E. japonica extract showed restoration of alternation behavior and reversal of Aß(1-42)-induced memory impairment. Consequently, the E. japonica extract substantially inhibited the increase in lipid peroxidation and restored superoxide dismutase activity. These results suggest that E. japonica protects from oxidative stress and cognitive deficits induced by the Aß peptide.

Chlorogenic acid suppresses pulmonary eosinophilia, IgE production, and Th2-type cytokine production in an ovalbumin-induced allergic asthma: activation of STAT-6 and JNK is inhibited by chlorogenic acid.

Asthma is a chronic inflammatory disease of the airways characterized by reversible airway obstruction, airway hyperreactivity, and remodeling of the airways. Chlorogenic acid (CGA), an ester of caffeic acid with quinic acid, is one of the most abundant polyphenol compounds in various agricultural products. CGA shows various biological properties, such as anti-oxidant, anti-viral, anti-carcinogenic and anti-inflammatory activities. We investigated suppressive effects of CGA on ovalbumin (OVA)-induced allergic asthma in mice and underlying mechanisms of them. CGA significantly reduced pulmonary eosinophilia and expression of IL-4, IL-5 and TNF-α in the lung as well as the serum levels of total and OVA-specific IgE, while CGA enhanced those of total and OVA-specific IgG3, of which isotype switching is down-regulated by IL-4. In vitro IgE production from LPS/IL-4-stimulated splenocytes was remarkably reduced by CGA, while that of IgG3 was enhanced. The Cε germ line transcription, which is necessary for IL-4 mediated IgE isotype switching, was reduced by CGA in LPS/IL-4-stimulated splenocytes. IgE isotype switching is mediated via several transduction pathways, activating several molecules including STAT-6, NF-κB, ERK1/2, and JNK. Among the molecules, which were activated by IL-4/LPS, activation of STAT-6 and JNK was inhibited by CGA.

2,3,7,8-Tetrachlorodibenzo-p-dioxin up-regulates stathmin 1 in the eye: suggestive evidence for the involvement of stathmin 1 in accelerated eye opening in mice induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

When pregnant mice were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the average time to eye opening in the offspring was shortened by about a day. How acceleration of eye opening by TCDD occurs remains unknown. To reveal the underlying mechanisms of the accelerated eye opening, pregnant mice were intraperitoneally injected with corn oil or TCDD at GD (gestation day) 11, and tissues around the eye of neonatal mice were subject to proteome analysis and RT-PCR. Upon TCDD administration, translationally controlled tumor protein (TCTP) and 60S acidic ribosomal protein p2 (RLA2) were reduced, while stathmin 1(STMN1) was increased, at both protein and mRNA levels. One hypothetical mechanism for eye opening is the proliferation of corneal epithelial cells before eye opening. STMN1, but not TCTP and RLA2, was up-regulated in immortalized human corneal epithelial cells (HCE-T) by TCDD, which promoted proliferation of HCE-T probably by accelerating the G1/S transition. Down-regulation of STMN1 by the antisense oligonucleotide technology inhibited proliferation of HCE-T, suggesting that STMN1, of which expression is enhanced by TCDD, may be involved in accelerated eye opening, probably by stimulating proliferation of corneal epithelial cells.