• Journal of the Korean Society of Food Science and Nutrition
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• v.46 no.2
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• pp.169-176
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• 2017

Non-alcoholic fatty liver disease (NAFLD) is caused by chronic lipid accumulation due to dysregulation of lipid metabolism in the liver, and it is associated with various human diseases such as obesity, dyslipidemia, hypertension, and diabetes. Histone acetylation is a representative epigenetic mechanism regulated by histone acetyltransferases (HATs) and deacetylases. We observed that tartary buckwheat sprout (TBS) suppressed lipid accumulation in HepG2 cells through its anti-HAT activity. We showed that TBS was a novel HAT inhibitor with specificity for the major HAT enzyme p300. Importantly, TBS reduced acetylation of total and histone proteins, H3K9, H3K36, and H4K8, resulting in decreased transcriptional activities of sterol regulatory element-binding protein 1c, ATP citrate lyase, and fatty acid synthase. These results suggest that TBS inhibits the NAFLD transcription-modulating activity of lipogenesis-related genes through modification of histone acetylation.

• Animal Bioscience
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• v.35 no.10
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• pp.1461-1478
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• 2022

The maintenance of poultry gut health is complex depending on the intricate balance among diet, the commensal microbiota, and the mucosa, including the gut epithelium and the superimposing mucus layer. Changes in microflora composition and abundance can confer beneficial or detrimental effects on fowl. Antibiotics have devastating impacts on altering the landscape of gut microbiota, which further leads to antibiotic resistance or spread the pathogenic populations. By eliciting the landscape of gut microbiota, strategies should be made to break down the regulatory signals of pathogenic bacteria. The optional strategy of conferring dietary fibers (DFs) can be used to counterbalance the gut microbiota. DFs are the non-starch carbohydrates indigestible by host endogenous enzymes but can be fermented by symbiotic microbiota to produce short-chain fatty acids (SCFAs). This is one of the primary modes through which the gut microbiota interacts and communicate with the host. The majority of SCFAs are produced in the large intestine (particularly in the caecum), where they are taken up by the enterocytes or transported through portal vein circulation into the bloodstream. Recent shreds of evidence have elucidated that SCFAs affect the gut and modulate the tissues and organs either by activating G-protein-coupled receptors or affecting epigenetic modifications in the genome through inducing histone acetylase activities and inhibiting histone deacetylases. Thus, in this way, SCFAs vastly influence poultry health by promoting energy regulation, mucosal integrity, immune homeostasis, and immune maturation. In this review article, we will focus on DFs, which directly interact with gut microbes and lead to the production of SCFAs. Further, we will discuss the current molecular mechanisms of how SCFAs are generated, transported, and modulated the pro-and anti-inflammatory immune responses against pathogens and host physiology and gut health.

• Molecules and Cells
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• v.38 no.6
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• pp.518-527
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• 2015

Controlled release of medications remains the most convenient way to deliver drugs. In this study, we precipitated gold nanoparticles with quercetin. We loaded gold-quercetin into poly(DL-lactide-co-glycolide) nanoparticles (NQ) and tested the biological activity of NQ on HepG2 hepatocarcinoma cells to acquire the sustained release property. We determined by circular dichroism spectroscopy that NQ effectively caused conformational changes in DNA and modulated different proteins related to epigenetic modifications and c ell cycle control. The mitochondrial membrane potential (MMP), reactive oxygen species (ROS), cell cycle, apoptosis, DNA damage, and caspase 3 activity were analyzed by flow cytometry, and the expression profiles of different anti- and pro-apoptotic as well as epigenetic signals were studied by immunoblotting. A cytotoxicity assay indicated that NQ preferentially killed cancer cells, compared to normal cells. NQ interacted with HepG2 cell DNA and reduced histone deacetylases to control cell proliferation and arrest the cell cycle at the sub-G stage. Activities of cell cycle-related proteins, such as $p21^{WAF}$, cdk1, and pAkt, were modulated. NQ induced apoptosis in HepG2 cells by activating p53-ROS crosstalk and induces epigenetic modifications leading to inhibited proliferation and cell cycle arrest.

• BMB Reports
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• v.36 no.1
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• pp.95-109
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• 2003

Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance. The sources of the increased oxidative stress in patients with chronic inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) derive from the increased burden of inhaled oxidants, and from the increased amounts of reactive oxygen species (ROS) generated by several inflammatory, immune and various structural cells of the airways. Increased levels of ROS produced in the airways is reflected by increased markers of oxidative stress in the airspaces, sputum, breath, lungs and blood in patients with lung diseases. ROS, either directly or via the formation of lipid peroxidation products such as 4-hydroxy-2-nonenal may play a role in enhancing the inflammation through the activation of stress kinases (JNK, MAPK, p38) and redox sensitive transcription factors such as NF-${\kappa}B$ and AP-1. Recent evidences have indicated that oxidative stress and pro-inflammatory mediators can alter nuclear histone acetylation/deacetylation allowing access for transcription factor DNA binding leading to enhanced pro-inflammatory gene expression in various lung cells. Understanding of the mechanisms of redox signaling, NF-${\kappa}B$/AP-1 regulation, the balance between histone acetylation and deacetylation and the release and expression of pro- and anti-inflammatory mediators may lead to the development of novel therapies based on the pharmacological manipulation of antioxidants in lung inflammation and injury. Antioxidants that have effective wide spectrum activity and good bioavailability, thiols or molecules which have dual antioxidant and anti-inflammatory activity, may be potential therapeutic agents which not only protect against the direct injurious effects of oxidants, but may fundamentally alter the underlying inflammatory processes which play an important role in the pathogenesis of chronic inflammatory lung diseases.

• Biomolecules & Therapeutics
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• v.20 no.1
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• pp.81-88
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• 2012

Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. Histone deacetylase (HDAC) inhibitors are emerging as an exciting new class of potential anti-cancer agents. In recent years, a number of structurally diverse HDAC inhibitors have been identifi ed and these HDAC inhibitors induce growth arrest, differentiation and/or apoptosis of cancer cells in vitro and in vivo. However, the underlying molecular mechanisms remain unclear. This study aimed at investigating the anti-tumor activity of various HDAC inhibitors, IN-2001, using T47D human breast cancer cells. Moreover, the possible mechanism by which HDAC inhibitors exhibit anti-tumor activity was also explored. In estrogen receptor positive T47D cells, IN-2001, HDAC inhibitor showed anti-proliferative effects in dose-and time-dependent manner. In T47D human breast cancer cells showed anti-tumor activity of IN-2001 and the growth inhibitory effects of IN-2001 were related to the cell cycle arrest and induction of apoptosis. Flow cytometry studies revealed that IN-2001 showed accumulation of cells at $G_2$/M phase. At the same time, IN-2001 treatment time-dependently increased sub-$G_1$ population, representing apoptotic cells. IN-2001-mediated cell cycle arrest was associated with induction of cdk inhibitor expression. In T47D cells, IN-2001 as well as other HDAC inhibitors treatment significantly increased $p21^{WAF1}$ and $p27^{KIP1}$ expression. In addition, thymidylate synthase, an essential enzyme for DNA replication and repair, was down-regulated by IN-2001 and other HDAC inhibitors in the T47D human breast cancer cells. In summary, IN-2001 with a higher potency than other HDAC inhibitors induced growth inhibition, cell cycle arrest, and eventual apoptosis in human breast cancer possibly through modulation of cell cycle and apoptosis regulatory proteins, such as cdk inhibitors, cyclins, and thymidylate synthase.

• Molecular & Cellular Toxicology
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• v.2 no.3
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• pp.166-169
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• 2006

Accumulated evidences have established that aberrant regulation of histone deacetylases (HDACs) is one of major causes for development of human malignancies. Mammalian HDACs can be divided into three subclasses consisting of 11 homologous of HDACs and 7 of sirtuins, but little is known about HDAC2 causes for carcinogenesis in solid tumors. Here, in order to investigate the roles of HDAC2 in carcinogenesis of liver cancer progression, we analyzed the expression of HDAC2 in 62 human hepatocellular carcinomas by utilizing Immunohistochemistry. Moderate to strong expression of HDAC2 was found in 54 (87%) out of total 62 tumors. The majority of positive tumors were detected in nucleous, but normal hepatocytes did not express of HDAC2 or showed weak positive staining. Interestingly, we were also noted that HDAC2 expression was appeared to be associated with aggressiveness of the tumors by the fact that HDAC2 expression was observed with significances in high grade tumors (Edmonson grade II, III). Taken together, we found the aberrant expression of HDAC2 in hepatocellular carcinomas, and this suggests that HDAC2 may play an important role in the development of liver cancer.

• The Korean Journal of Physiology and Pharmacology
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• v.20 no.5
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• pp.477-485
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• 2016

CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.323.3-324
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• 2002

Histone deacetylases (HDAC) activity is associated generally with transcriptional repression. We have reported previously that apicidin. a histione deacetylase inhibitor. inhibited the proliferation of tumor cells via induction of p21 WAF/C1P1. We extended our study to identify the effect of apicidin on the expression of other cell cycle regulatory protein. such as cyclin E. a critical regulator of the transition from G1 into S phase. (omitted)

• Molecules and Cells
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• v.39 no.2
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• pp.87-95
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• 2016

Sirt1 is the most prominent and extensively studied member of sirtuins, the family of mammalian class III histone deacetylases heavily implicated in health span and longevity. Although primarily a nuclear protein, Sirt1's deacetylation of Peroxisome proliferator-activated receptor Gamma Coactivator-$1{\alpha}$ (PGC-$1{\alpha}$) has been extensively implicated in metabolic control and mitochondrial biogenesis, which was proposed to partially underlie Sirt1's role in caloric restriction and impacts on longevity. The notion of Sirt1's regulation of PGC-$1{\alpha}$ activity and its role in mitochondrial biogenesis has, however, been controversial. Interestingly, Sirt1 also appears to be important for the turnover of defective mitochondria by mitophagy. I discuss here evidences for Sirt1's regulation of mitochondrial biogenesis and turnover, in relation to PGC-$1{\alpha}$ deacetylation and various aspects of cellular physiology and disease.

• Molecules and Cells
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• v.28 no.1
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• pp.1-5
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• 2009

Vascular endothelial growth factor (VEGF) is essential for many angiogenic processes both in normal and pathological conditions. However, the signaling pathways involved in VEGF-induced angiogenesis are incompletely understood. The protein kinase D1 (PKD1), a newly described calcium/calmodulin-dependent serine/threonine kinase, has been implicated in cell migration, proliferation and membrane trafficking. Increasing evidence suggests critical roles for PKD1-mediated signaling pathways in endothelial cells, particularly in the regulation of VEGF-induced angiogenesis. Recent studies show that class IIa histone deacetylases (HDACs) are PKD1 substrates and VEGF signal-responsive repressors of myocyte enhancer factor-2 (MEF2) transcriptional activation in endothelial cells. This review provides a guide to PKD1 signaling pathways and the direct downstream targets of PKD1 in VEGF signaling, and suggests important functions of PKD1 in angiogenesis.