Chemical Inhibitors Targeting the Histone Lysine Demethylase Families with Potential for Drug Discovery.

The dynamic regulation of histone methylation and demethylation plays an important role in the regulation of gene expression. Aberrant expression of histone lysine demethylases has been implicated in various diseases including intractable cancers, and thus lysine demethylases serve as promising therapeutic targets. Recent studies in epigenomics and chemical biology have led to the development of a series of small-molecule demethylase inhibitors that are potent, specific, and have in vivo efficacy.

Factors and Mechanisms That Influence Chromatin-Mediated Enhancer-Promoter Interactions and Transcriptional Regulation.

Eukaryotic gene expression is regulated through chromatin conformation, in which enhancers and promoters physically interact (E-P interactions). How such chromatin-mediated E-P interactions affect gene expression is not yet fully understood, but the roles of histone acetylation and methylation, pioneer transcription factors, and architectural proteins such as CCCTC binding factor (CTCF) and cohesin have recently attracted attention. Moreover, accumulated data suggest that E-P interactions are mechanistically involved in biophysical events, including liquid-liquid phase separation, and in biological events, including cancers.

Effectiveness of Intracavernous Delivery of Recombinant Human Hepatocyte Growth Factor on Erectile Function in the Streptozotocin-Induced Diabetic Mouse.

Introduction: Diabetic erectile dysfunction is a disease mostly of vascular origin and men with diabetic erectile dysfunction respond poorly to oral phosphodiesterase-5 inhibitors. Hepatocyte growth factor (HGF) is a pleiotropic factor that plays an essential role in the regulation of cell proliferation, survival, and angiogenesis.

Aim: To determine the effectiveness of recombinant human (rh)-HGF in restoring erectile function in diabetic mice.

Dual transcriptome sequencing reveals resistance of TLR4 ligand-activated bone marrow-derived macrophages to inflammation mediated by the BET inhibitor JQ1.

Persistent macrophage activation is associated with the expression of various pro-inflammatory genes, cytokines and chemokines, which may initiate or amplify inflammatory disorders. A novel synthetic BET inhibitor, JQ1, was proven to exert immunosuppressive activities in macrophages. However, a genome-wide search for JQ1 molecular targets has not been undertaken.

The pericyte as a cellular regulator of penile erection and a novel therapeutic target for erectile dysfunction.

Pericytes are known to play critical roles in vascular development and homeostasis. However, the distribution of cavernous pericytes and their roles in penile erection is unclear. Herein we report that the pericytes are abundantly distributed in microvessels of the subtunical area and dorsal nerve bundle of mice, followed by dorsal vein and cavernous sinusoids.

JMJD2A attenuation affects cell cycle and tumourigenic inflammatory gene regulation in lipopolysaccharide stimulated neuroectodermal stem cells.

JMJD2A is a lysine trimethyl-specific histone demethylase that is highly expressed in a variety of tumours. The role of JMJD2A in tumour progression remains unclear. The objectives of this study were to identify JMJD2A-regulated genes and understand the function of JMJD2A in p53-null neuroectodermal stem cells (p53(-/-) NE-4Cs).

Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse.

Penile erection is a neurovascular phenomenon, and erectile dysfunction (ED) is caused mainly by vascular risk factors or diseases, neurologic abnormalities, and hormonal disturbances. Men with diabetic ED often have severe endothelial dysfunction and peripheral nerve damage, which result in poor response to oral phosphodiesterase-5 inhibitors. Nerve injury-induced protein 1 (Ninjurin 1, Ninj1) is known to be involved in neuroinflammatory processes and to be related to vascular regression during the embryonic period.

Xenogenic transplantation of human breast adipose-derived stromal vascular fraction enhances recovery of erectile function in diabetic mice.

The adipose tissue-derived stromal vascular fraction (SVF) is an ideal source of stem and stromal cells. The aim of this study was to examine whether and how xenogenic transplantation of human breast SVF restores erectile function in diabetic mice. Human SVF was isolated from five patients (age, 20-45 yr) undergoing reduction mammoplasty.

Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque.

Epigenetic modifications, such as histone acetylation/deacetylation, have been shown to play a role in the pathogenesis of fibrotic disease. Peyronie's disease (PD) is a localized fibrotic process of the tunica albuginea, which leads to penile deformity. This study was undertaken to determine the anti-fibrotic effect of small interfering RNA (siRNA)-mediated silencing of histone deacetylase 2 (HDAC2) in primary fibroblasts derived from human PD plaque.

Proteomic changes induced by histone demethylase JMJD3 in TNF alpha-treated human monocytic (THP-1) cells.

JMJD3, a Jumonji C family histone demethylase, plays an important role in the regulation of inflammation induced by the transcription factor nuclear factor-kappa B (NF-κB) in response to various stimuli. JMJD3 is a histone-3 lysine-27 trimethylation (H3K27me3) demethylase, a histone mark associated with transcriptional repression and activation of a diverse set of genes. The present study assessed stable JMJD3 knockdown (KD)-dependent proteomic profiling in human leukemia monocyte (THP-1) cells to analyze the JMJD3-mediated differential changes of marker expression in inflammatory cells.

Nerve injury-induced protein 1 (Ninjurin-1) is a novel therapeutic target for cavernous nerve injury-induced erectile dysfunction in mice.

Introduction: Radical prostatectomy for prostate cancer can not only induce cavernous nerve injury (CNI) but also result in structural changes in the cavernous tissues. Nerve injury-induced protein 1, Ninjurin-1 (Ninj1), is known to be involved in neuroinflammatory processes and to be related to vascular regression during the embryonic period.

Aim: The study aims to determine whether and how Ninj1 neutralizing antibody (Ninj1-Ab) restores erectile function in mice with CNI.

Erectile dysfunction precedes other systemic vascular diseases due to incompetent cavernous endothelial cell-cell junctions.

Purpose: Erectile dysfunction is often a harbinger of cardiovascular disease. We sought to gain mechanistic insight at the cellular and molecular levels into why erectile dysfunction precedes the clinical consequences of cardiovascular disease.

Materials And Methods: Diabetes was induced by intraperitoneal streptozotocin injection in 8-week-old C57BL/6J mice.

Functional analysis of histone demethylase Jmjd2b on lipopolysaccharide-treated murine neural stem cells (NSCs).

Neural stem cell (NSC) neurogenesis is the formation of new neurons by which the brain maintains its lifelong plasticity in response to extrinsic and intrinsic changes. Here, we show the effect of lipopolysaccharides (LPS) as an in vitro model of inflammation on NSCs to determine whether the inflammatory mediators can epigenetically affect NSCs and alter their proliferation and differentiation abilities. To study the effect of LPS on NSCs, we used an immortalized mouse neuroectodermal stem cell line, NE-4C.

Fluoxetine increases the expression of NCAM140 and pCREB in rat C6 glioma cells.

Objective: Dysfunction of neural plasticity in the brain is known to alter neural networks, resulting in depression. To understand how fluoxetine regulates molecules involved in neural plasticity, the expression levels of NCAM, NCAM140, CREB and pCREB, in rat C6 glioma cells after fluoxetine treatment were examined.

Methods: C6 cells were cultured after 20 min or after 6, 24 or 72 h treatments with 10 µM fluoxetine.

Proteomic analysis of Terminalia chebula extract-dependent changes in human lymphoblastic T cell protein expression.

Terminalia chebula is a native plant from southern Asia to southwestern China that is used in traditional medicine for the treatment of malignant tumors and diabetes. This plant also has antibacterial and immunomodulatory properties. The present study assessed T.

Effect of fluoxetine on the expression of tryptophan hydroxylase and 14-3-3 protein in the dorsal raphe nucleus and hippocampus of rat.

The serotonergic system is one of the major systems targeted in the pharmacological treatment of mood disorders including depression. Fluoxetine, one of the selective serotonin reuptake inhibitors (SSRIs), has been reported to induce the expression of tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin. The 14-3-3 protein family not only activates neuronal enzymes, including TPH, but also plays a role in a wide variety of cell signaling.

Gene networking and inflammatory pathway analysis in a JMJD3 knockdown human monocytic cell line.

JMJD3, a Jumonji C family histone demethylase, is induced by transcription factor, nuclear factor-kappa B (NF-κB), in response to various stimuli. JMJD3 is crucial for erasing histone-3 lysine-27 trimethylation (H3K27me3), a modification associated with transcriptional repression and is responsible for the activation of a diverse set of genes. Here, we identify the genes in human leukaemia monocyte (THP-1) human monocytic cells that are significantly affected by the stable knockdown (kd) of JMJD3.

Sodium arsenite dependent protein expression analysis on human embryonic carcinoma (NCCIT) cell line.

Due to their pluripotent nature, embryonic carcinoma (EC) cell lines are useful for the study of basic and applied aspects of medical therapeutics, disease management and environmental mutagenesis. We evaluated the teratogenic like effects of inorganic arsenic during the early stages of cellular development in NCCIT cells, a type of human EC cells. Using matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and MetaCore pathway analysis software (GeneGo), the proteomic expression profiles of NCCIT cells after either short- or long-term sodium arsenite (NaAsO(2)) treatment and of NCCIT cell-derived embryoid bodies (EBs) after short-term NaAsO(2) treatment were studied to determine the toxic effects on the process of normal growth and differentiation.

Terminalia chebula extract acts as a potential NF-κB inhibitor in human lymphoblastic T cells.

Terminalia chebula (TC) is native to southern Asia to southwestern China and is used in traditional medicine for the treatment of human ailments including malignant tumors and diabetes. This plant also has antibacterial and immunomodulatory properties. Nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) is responsible for the expression of numerous genes involved in cell survival, proliferation, angiogenesis, inflammation, invasion and metastasis, among other processes.

Changes in the expression of transthyretin and protein kinase Cγ genes in the prefrontal cortex in response to naltrexone.

Naltrexone, an opioid receptor antagonist, has been approved for clinical use in the treatment of alcohol dependence. In the present study, we examined the underlying mechanisms of naltrexone by investigating the pharmacogenomic variations in the brain regions associated with alcohol consumption. A complementary DNA microarray analysis was used to profile gene expression changes in the hippocampus and prefrontal cortex (PFC) of C57BL/6 mice injected with naltrexone following ethanol treatment.

Ethanol-induced small heat shock protein genes in the differentiation of mouse embryonic neural stem cells.

Neural stem cells (NSCs) of the neuroepithelium differentiate into one of three central nervous system (CNS) cell lineages: neurons, astrocytes, or oligodendrocytes. In this study, the differentiation potential of NSCs from the forebrain of embryonic day 15 (E15) mouse embryos was analyzed using immunocytochemistry. NSCs were differentiated early in the presence or absence of ethanol (50 mM), and gene expression patterns among NSCs, differentiated cells and ethanol-treated differentiated cells were assessed by microarray and real-time PCR analysis.

Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs).

This study used human embryonic carcinoma (NCCIT) cells to evaluate genotoxicity and other effects of ethanol in earlier stages of cellular development. This undifferentiated pluripotent cell line has unlimited self-renewal capacity and has been shown to differentiate in vitro. We analyzed proteome expression profile of ethanol-treated NCCIT cells and NCCIT cell-derived embryoid bodies (EBs) by MALDI-TOF MS.

The role of NF-kappaB and H3K27me3 demethylase, Jmjd3, on the anthrax lethal toxin tolerance of RAW 264.7 cells.

Background: In Bacillus anthracis, lethal toxin (LeTx) is a critical virulence factor that causes immune suppression and toxic shock in the infected host. NF-kappaB is a key mediator of the inflammatory response and is crucial for the plasticity of first level immune cells such as macrophages, monocytes and neutrophils. In macrophages, this inflammatory response, mediated by NF-kappaB, can regulate host defense against invading pathogens.