• Journal of Life Science
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• v.27 no.8
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• pp.879-887
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• 2017

It is well established that brain-derived neurotrophic factor (BDNF) is expressed not only in the brain but also in skeletal muscle, and is required for normal neuromuscular system function. Histone deacetylases (HDACs) and insulin-like growth factor-I (IGF-I) are potent regulators of skeletal muscle myogenesis and muscle gene expression, but the mechanisms of HDAC and IGF-I in skeletal muscle-derived BDNF expression have not been examined. In this study, we examined the effect of IGF-I and suberoylanilide hydroxamic acid (SAHA), a pan-HDAC inhibitor, on BDNF induction. Proliferating or differentiating C2C12 skeletal muscle cells were treated with increasing concentrations (0-50 ng/ml) of IGF-I in the absence or presence of $5{\mu}M$ SAHA for various time periods (3-24 hr). Treatment of C2C12 cells with IGF-I resulted in a dose- and time-dependent decrease in BDNF mRNA expression. However, inhibition of HDAC led to a significant increase in the expression of BDNF mRNA levels. In addition, immunocytochemistry revealed high BDNF protein levels in undifferentiated C2C12 skeletal muscle cells, whether untreated, IGF-I-treated, or exposed to SAHA. These results represent the first evidence that IGF-I can suppress the mRNA and protein expression of BDNF; conversely, SAHA attenuates the effects of IGF-I. Consequently, SAHA upregulates BDNF expression in C2C12 skeletal muscle cells.

• Proceedings of the KSAR Conference
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• 2003.06a
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• pp.27-27
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• 2003

A diversified and concentrative approach of methylation player can be one of the most powerful studies in the understanding of global epigenetic modifications. Previous studies have suggested that DNA methylation contributes to transcriptional silencing through the several DNA methylation-mediated repression systems by hypermethylation, including methyltransferases (DNMTs), DNA methyltransferase association protein 1 (DMAPl), methyl-CpG binding domain (MBD), and histone deacetylases (HDACs). Assembly of these regulatory protein complexes act sequentially, reciprocally, and interdependently on the newly composed DNA strand through S phase. Therefore, these protein complexes have a role in coupling DNA replication to the designed turn-off system in genome. In this study, we attempted to address the role of DNA methylation by the functional analysis of the methyltransferase molecule, we described the involvement of DMAP1 and DNMTs in cell divistion and the effect of their loss. We also described distinct patterns that DMAP1 and DNMTs are spatially reorganized and displaced from condensing chromosomes as cells progress through mitosis in HeLa cell, COS7, and HIH3T3 cell cycle progressions. DNMT1, DNMT3b, and DMAP1 do not stably contact the genetic material during chromosome compaction and repressive expression. These finding show that the loss of activities of DNMTs and DMAP1 occure stage specifically during the cell cycle, may contribute to the integral balance of global DNA methylation. This is consistent with previous studies resulted in decreased histone acetyltransferases and HDACs, and differs from studies resulted in increased histone methyltransferases. Our results suggest that DNA methylation by DNMTs and DMAP1 during mitosis acts to antagonize hypermethylation by which this mark is epigenetical mitotic-specific methylation.

• 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.

• Proceedings of the Plant Resources Society of Korea Conference
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• 2018.04a
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• pp.67-67
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• 2018

Trichoderma species are a rich source of metabolites, but less known for biomedical potential. This work deals with antibacterial and antioxidant potentials of intracellular non-cytotoxic metabolites, extracted from Trichoderma atroviride (KNUP001). A total of 53 fractions was collected by column chromatography and tested for cytotoxicity by MTT assay. Only one fraction (F41) was found to be non-toxic to Vero cells with $95.4{\pm}0.61%$ of survival. The F41 was then subjected to chemical analysis, antibacterial and antioxidant assays. The F41 at $500{\mu}g.ml^{-1}$ showed the total antioxidant of $48.70{\pm}2.90%$, DPPH radical scavenging activity of $37.25{\pm}2.25$, nitric oxide (NO) radical scavenging activity of $54.55{\pm}1.95$ and $H_2O_2$ radical scavenging activity of $43.75{\pm}3.21$. The F41 at $25{\mu}g.ml^{-1}$ displayed antibacterial activity against E. coli ($14.25{\pm}0.2mm$), P. mirabilis ($10.4{\pm}0.6mm$), S. dysenteriae ($18.6{\pm}03mm$), S. paratyphi A ($14.1{\pm}1.1mm$), E. aerogenes ($5.6{\pm}0.4mm$) and S. marcescens ($14.25{\pm}0.2mm$). GC-MS analysis revealed the dominant presence of oleic acid C 18.1 (63.18%), n-hexadecanoic acid (6.17%), and ethyl oleate (4.93%) and potent molecules such as 8-[(2E)-2-(3-hydroxybenzylidene)hydrazinyl]-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione, 2-(Dimethylamino)ethyl (1Z)-N-hydroxy-2-(4-morpholinyl)-2-oxoethanimidothioate, Fluorene in the F41, and virtual study revealed that these molecules are likely responsible for the antibacterial activities of F41. Hence, further investigation deserves on purification and characterization of the active metabolites from T. atroviride strain KNUP001 towards developing molecular leads to effective antibacterial drugs, and non-toxic to host cells.

• Bulletin of the Korean Chemical Society
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• v.30 no.5
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• pp.1152-1156
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• 2009

Silent information regulator 2 (Sir2) or sirtuins are NAD(+)-dependent deacetylases, which hydrolyze the acetyllysine residues. In mammals, sirtuins are classified into seven different classes (SIRT1-7). SIRT1 was reported to be involved in age related disorders like obesity, metabolic syndrome, type II diabetes mellitus and Parkinson’s disease. Activation of SIRT1 is one of the promising approaches to treat these age related diseases. In this study, we have used HipHop module of CATALYST to identify a series of pharmacophore models to screen SIRT1 enhancing molecules. Three molecules from Sirtris Pharmaceuticals were selected as training set and 607 sirtuin activator molecules were used as test set. Five different hypotheses were developed and then validated using the training set and the test set. The results showed that the best pharmacophore model has four features, ring aromatic, positive ionization and two hydrogen-bond acceptors. The best hypothesis from our study, Hypo2, screened high number of active molecules from the test set. Thus, we suggest that this four feature pharmacophore model could be helpful to screen novel SIRT1 activator molecules. Hypo2-virtual screening against Maybridge database reveals seven molecules, which contains all the critical features. Moreover, two new scaffolds were identified from this study. These scaffolds may be a potent lead for the SIRT1 activation.

• Tuberculosis and Respiratory Diseases
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• v.81 no.1
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• pp.80-87
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• 2018

Background: Asthma is a disease of chronic airway inflammation with heterogeneous features. Neutrophilic asthma is corticosteroid-insensitive asthma related to absence or suppression of $T_H2$ process and increased $T_H1$ and/or $T_H17$ process. Macrolides are immunomodulatory drug that reduce airway inflammation, but their role in asthma is not fully known. The purpose of this study was to evaluate the role of macrolides in neutrophilic asthma and compare their effects with those of corticosteroids. Methods: C57BL/6 female mice were sensitized with ovalbumin (OVA) and lipopolysaccharides (LPS). Clarithromycin (CAM) and/or dexamethasone (DXM) were administered at days 14, 15, 21, 22, and 23. At day 24, the mice were sacrificed. Results: Airway resistance in the OVA+LPS exposed mice was elevated but was more attenuated after treatment with CAM+DXM compared with the monotherapy group (p<0.05 and p<0.01). In bronchoalveolar lavage fluid study, total cells and neutrophil counts in OVA+LPS mice were elevated but decreased after CAM+DXM treatment. In hematoxylin and eosin stain, the CAM+DXM-treated group showed less inflammation additively than the monotherapy group. There was less total protein, interleukin 17 (IL-17), interferon ${\gamma}$, and tumor necrosis factor ${\alpha}$ in the CAM+DXM group than in the monotherapy group (p<0.001, p<0.05, and p<0.001). More histone deacetylase 2 (HDAC2) activity was recovered in the DXM and CAM+DXM challenged groups than in the control group (p<0.05). Conclusion: Decreased IL-17 and recovered relative HDAC2 activity correlated with airway resistance and inflammation in a neutrophilic asthma mouse model. This result suggests macrolides as a potential corticosteroid-sparing agent in neutrophilic asthma.

• Journal of Life Science
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• v.26 no.8
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• pp.983-989
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• 2016

All cells composing of our body undergo their destiny such as proliferation, differentiation, necrosis, apoptosis and senescence depending on their circumstance with time. The errors occurring in these processes develop several aberrations in phenotypes including cancer, inflammation, aging and diseases. New strategy and approach are required to screen anti-aging compounds derived from natural products. Therefore, here we explain the target proteins to play a key role in aging mechanism. In the first place, matrix metalloproteinases (MMPs) are involved in metastasis, chronic inflammation and skin aging as an aging marker. In particular, histone deacetylases (HDACs) give a great attention to aging researchers who try to extend the life span of animal model. In addition, we describe the signaling pathway related to senescence which p53, IGF-1 and SIRT1 play an important role in. Furthermore, autophagy is involved in the signaling pathway associated with aging. Several new compounds modulating the signaling pathway of senescence are introduced in this review. Here, we try to provide a new insight in the molecular basis for the aging mechanism and development of aging marker. In addition, the compounds introduced here could be available for pharmaceutical applications for the prevention and the treatment of diseases related to aging.