The purpose of this study was to determine the effect of isothiocyanates (ITCs) in delaying the progression of the murine immunodeficiency virus to murine AIDS, resulting in increased life span. Furthermore, we investigated the role of ITCs in modulating immune dysfunction caused by LP-BM5 retrovirus infection. Among the tested ITCs, oral administration of sulforaphane (SUL), benzyl isothiocyante (BITC), and phenethyl isothiocyanate (PEITC) showed the inhibition of premature death caused by LP-BM5 retrovirus infection, while indolo[3,2-b] carbazole (ICZ) and indole-3-carbinol (I3C) did not delay the progress of the LP-BM5 retrovirus to murine AIDS. Inhibition of premature death by BITC, PEITC, and SUL could be explained by restoration of the immune system and down regulation of free radicals. Dysfunction of T and B cell mitogenesis caused by retrovirus infection in primary cultured splenocytes has been partially recovered with administration of BITC, PEITC, and SUL. There was a shift from imbalanced cytokine production (increased Th2 and decreased Th1 cell cytokine production) into balanced Th1/Th2 cell secretion of cytokines under administration of these ITCs during the development of murine AIDS. Hepatic vitamin E level was significantly restored by administration of these ITCs, in accordance with reduced hepatic lipid peroxidation levels. This study suggests that certain types of ITCs have beneficial effects in preventing premature death during progression to murine AIDS by restoration of immune dysfunction and removal of excessive free radicals, implying that selective usage of ITCs would be helpful in retarding the progression from HIV infection to AIDS.
Previous studies have established an important role of histone acetylation in transcriptional control by nuclear hormone receptors. With chromatin immunoprecipitation assays, we have now investigated whether histone methylation and phosphorylation are also involved in transcriptional regulation by thyroid hormone receptor (TR). We found that repression by unliganded TR is associated with a substantial increase in methylation of H3 lysine 9 (H3-K9) and a decrease in methylation of H3 lysine 4 (H3-K4), methylation of H3 arginine 17 (H3-R17), and a dual modification of phosphorylation of H3 serine 10 and acetylation of lysine 14 (pS10/acK14). On the other hand, transcriptional activation by liganded TR is coupled with a substantial decrease in both H3-K4 and H3-K9 methylation and a robust increase in H3-R17 methylation and the dual modification of pS10/acK14. Trichostatin A treatment results in not only histone hyperacetylation but also an increase in methylation of H3-K4, increase in dual modification of pS10/acK14, and reduction in methylation of H3-K9, revealing an extensive interplay between histone acetylation, methylation, and phosphorylation. In an effort to understand the underlying mechanism for an increase in H3-K9 methylation during repression by unliganded TR, we demonstrated that TR interacts in vitro with an H3-K9-specific histone methyltransferase (HMT), SUV39H1. Functional analysis indicates that SUV39H1 can facilitate repression by unliganded TR and in so doing requires its HMT activity. Together, our data uncover a novel role of H3-K9 methylation in repression by unliganded TR and provide strong evidence for the involvement of multiple distinct histone covalent modifications (acetylation, methylation, and phosphorylation) in transcriptional control by nuclear hormone receptors.
We synthesized novel fluorescent magnetic silica nanoparticles (FMSNPs) containing large magnetic components for biomedical application. By employing assemblies of magnetic nanoparticles as kernels against FMSNPs, both the saturation of magnetization and the magnetic resonance (MR) signal intensity were significantly enhanced. Furthermore, the cellular binding of FMSNPs was improved by introducing a positive charge on the surface of the FMSNPs, and fluorescent dyes on the surface of FMSNPs enable optical imaging of sub-cellular regions.
Significance Programmed cell death 5 (PDCD5) plays a pivotal role in cellular apoptosis. Pathological relevance of PDCD5 is mostly found in human cancers; however, the role of PDCD5 in noncancerous diseases is not fully elucidated. Here we show that mice with endothelial PDCD5 deficiency have elevated serum nitric oxide levels and an atheroprotective effect in blood vessels. In addition, PDCD5 disrupts the HDAC3–protein kinase B (PKB/AKT) interaction and inhibits AKT-eNOS signaling and nitric oxide production in vivo and in vitro. Moreover, serum PDCD5 reflects vascular endothelial status, which is significantly correlated with cardiovascular risk. Our results demonstrate a mechanism of endothelial homeostasis and provide a potential therapeutic target for improving endothelial function.
Amyloid ${\beta}$-peptide ($A{\beta}$-peptide)-induced oxidative stress is thought to be a critical component of the pathophysiology of Alzheimer's disease (AD). New chalcone derivatives, the Chana series, were recently synthesized from the retrochalcones of licorice. In this study, we investigated the protective effects of the Chana series against neurodegenerative changes in vitro and in vivo. Among the Chana series, Chana 30 showed the highest free radical scavenging activity (90.7%) in the 1,1-diphenyl-2- picrylhydrazyl assay. Chana 30 also protected against $A{\beta}$-induced neural cell injury in vitro. Furthermore, Chana 30 reduced the learning and memory deficits of $A{\beta}_{1-42}$-peptide injected mice. Taken together, these results suggest that Chana 30 may be a promising candidate as a potent therapeutic agent against neurodegenerative diseases.
Histone acetylation depends on the activity of two enzyme families, histone acetyltransferase (HAT) and deacetylase (HDAC). In this study, we screened various plant extracts to find potent HAT inhibitors. Hot water extracts of Ampelopsis Radix inhibited HAT activity, especially p300 and CBP (40% at 100 μg/ml). The mRNA levels of two androgen receptor (AR) regulated genes, PSA and TSC22, decreased with Ampelopsis Radix treatment (100 μg/ml). Importantly, in IP western analysis, AR acetylation was dramatically decreased by Ampelopsis Radix treatment. Furthermore, chromatin immunoprecipitation indicated that the acetylation of histone H3 in the PSA and B2M promoter regions was also repressed. Finally, Ampelopsis Radix treatment reduced the growth of human prostate cancer cells, LNCaP (50% growth inhibition at 200 μg/ml). Taken together, our data indicate that the potent HAT inhibitory activity of allspice reduced AR and histone acetylation and led to decreased transcription of AR target genes, resulting in inhibition of prostate cancer cell growth. This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea gorvenment (MOST) (No. R13-2002-054-04002-0); a grant (code #20070301034007) from BioGreen 21 program, Rural Development Administration, Republic of Korea.
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