• The Korean Journal of Physiology and Pharmacology
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• v.26 no.2
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• pp.95-111
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• 2022

Chronic obstructive pulmonary disease (COPD) is an important healthcare problem worldwide. Often, glucocorticoid (GC) resistance develops during COPD treatment. As a classic hypoglycemic drug, metformin (MET) can be used as a treatment strategy for COPD due to its anti-inflammatory and antioxidant effects, but its specific mechanism of action is not known. We aimed to clarify the role of MET on COPD and cigarette smoke extract (CSE)-induced GC resistance. Through establishment of a COPD model in rats, we found that MET could improve lung function, reduce pathological injury, as well as reduce the level of inflammation and oxidative stress in COPD, and upregulate expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), multidrug resistance protein 1 (MRP1), and histone deacetylase 2 (HDAC2). By establishing a model of GC resistance in human bronchial epithelial cells stimulated by CSE, we found that MET reduced secretion of interleukin-8, and could upregulate expression of Nrf2, HO-1, MRP1, and HDAC2. MET could also increase the inhibition of MRP1 efflux by MK571 significantly, and increase expression of HDAC2 mRNA and protein. In conclusion, MET may upregulate MRP1 expression by activating the Nrf2/HO-1 signaling pathway, and then regulate expression of HDAC2 protein to reduce GC resistance.

• Clinical and Experimental Pediatrics
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• v.65 no.4
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• pp.172-181
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• 2022

Pubertal onset is known to result from reactivation of the hypothalamic-pituitary-gonadal (HPG) axis, which is controlled by complex interactions of genetic and nongenetic factors. Most cases of precocious puberty (PP) are diagnosed as central PP (CPP), defined as premature activation of the HPG axis. The cause of CPP in most girls is not identifiable and, thus, referred to as idiopathic CPP (ICPP), whereas boys are more likely to have an organic lesion in the brain. ICPP has a genetic background, as supported by studies showing that maternal age at menarche is associated with pubertal timing in their offspring. A gain of expression in the kisspeptin gene (KISS1), gain-of-function mutation in the kisspeptin receptor gene (KISS1R), loss-of-function mutation in makorin ring finger protein 3 (MKRN3), and loss-of-function mutations in the delta-like homolog 1 gene (DLK1) have been associated with ICPP. Other genes, such as gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1), lin-28 homolog B (LIN28B), neuropeptide Y (NPYR), tachykinin 3 (TAC3), and tachykinin receptor 3 (TACR3), have been implicated in the progression of ICPP, although their relationships require elucidation. Environmental and socioeconomic factors may also be correlated with ICPP. In the progression of CPP, epigenetic factors such as DNA methylation, histone posttranslational modifications, and non-coding ribonucleic acids may mediate the relationship between genetic and environmental factors. CPP is correlated with short- and long-term adverse health outcomes, which forms the rationale for research focusing on understanding its genetic and nongenetic factors.

• BMB Reports
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• v.55 no.10
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• pp.506-511
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• 2022

Advanced hepatocellular carcinoma (HCC) is among the most challenging cancers to overcome, and there is a need for better therapeutic strategies. Among the different cancer drugs that have been used in clinics, sorafenib is considered the standard first-line drug for advanced HCC. Here, to identify a chemical compound displaying a synergistic effect with sorafenib in HCC, we screened a focused chemical library and found that MG149, a histone acetyltransferase inhibitor targeting the MYST family, exhibited the most synergistic anticancer effect with sorafenib on HCC cells. The combination of sorafenib and MG149 exerted a synergistic anti-proliferation effect on HCC cells by inducing apoptotic cell death. We revealed that cotreatment with sorafenib and MG149 aggravated endoplasmic reticulum (ER) stress to promote the death of HCC cells rather than adaptive cell survival. In addition, combined treatment with sorafenib and MG149 significantly increased the intracellular levels of unfolded proteins and reactive oxygen species, which upregulated ER stress. Collectively, these results suggest that MG149 has the potential to improve the efficacy of sorafenib in advanced HCC via the upregulation of cytotoxic ER stress.

• Journal of Medicine and Life Science
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• v.18 no.3
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• pp.41-48
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• 2021

The prevalence of attention deficit hyperactivity disorder (ADHD), a developmental neuropsychiatric disorder, is high among children and adolescents. The pathogenesis of ADHD is mediated with genetic, biological, and environmental factors. Most therapeutic drugs for ADHD have so far targeted biological causes, primarily by regulating catecholaminergic neurotransmitters. However, ADHD drugs that are clinically treated have various problems in their addictiveness and drug stability; thus, it is recommended that efficacy and safety should be secured through simultaneous prescription of multiple drugs rather than a single drug treatment. Accordingly, it is necessary to develop drugs that newly target pathogenic mechanisms of ADHD. In this study, we attempt to confirm the possibility of developing new drugs by reviewing dopamine-related developmental mechanisms of neurons and their correlation with ADHD. Histone deacetylase inhibitors (HDACi) can regulate the concentration of intracellular dopamine in neurons by expressing vesicular monoamine transporter 2 and inducing the exocytosis of neurotransmitters to the synaptic cleft, thereby promoting the development of neurons and signal transmission. This cellular modulation of HDACi is expected to treat ADHD by regulating endogenous catecholamines such as dopamine. Although studies are still in the preclinical stage, HDAC inhibitors clearly have potential as a therapeutic agent with low addictiveness and high efficacy for ADHD treatment.

• Proceedings of the Korea Society of Environmental Toocicology Conference
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• 2003.10a
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• pp.181-181
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• 2003

We have studied the mechanism of action of TCDD on CYP1A1 promoter activity in both Hepa Ⅰ and MCF-7 cells using transient transfection system with p1A1-Luc reporter gene. When HDAC inhibitors, such as trichostatin A, HC toxin and a novel HDAC inhibitor, IN2001 were cotreated with TCDD to the cells transfected with plAt-Luc reporter gene, the basal promoter activity of CYP1A1 was increased by HBAC inhibitors. Also, in MCF-7 human breast cancer cells, HDAC inhibitors, such as IN2001 and trichostatin A increased the basal activity of CYP1A1 promoter but TCDD stimulated CYP1A1 promoter activity was not changed by HDAC inhibitors. And, in stably-transfected Hepa Ⅰ cells with p1A1-Luc, HDAC inhibitors increased the basal promoter activity only Also, we have investigated the effects of HDAC inhibitors on the human breast and prostate cancer cells in terms of cell proliferation and apoptosis based on SRB assay. IN2001 as well as trichostatin A inhibited the MCF-7, MDA-MB-231, MDA-MB-468, T47D, ZR75-1, PC3 cell growth dose-dependently. The growth inhibition of these cells with HDAC inhibitors was associated with profound morphological change, which suggests the HDAC inhibitors induced apoptosis of cells. The result of cell cycle analysis after 24h exposure of IN2001 showed G2/M cell cycle arrest in MCF-7 cells and apoptosis in T47D and MDA-MB-231 cells.

• Journal of Periodontal and Implant Science
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• v.52 no.6
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• pp.437-454
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• 2022

Embryonic stem cells have been a popular research topic in regenerative medicine owing to their pluripotency and applicability. However, due to the difficulty in harvesting them and their low yield efficiency, advanced cell reprogramming technology has been introduced as an alternative. Dental stem cells have entered the spotlight due to their regenerative potential and their ability to be obtained from biological waste generated after dental treatment. Cell reprogramming, a process of reverting mature somatic cells into stem cells, and transdifferentiation, a direct conversion between different cell types without induction of a pluripotent state, have helped overcome the shortcomings of stem cells and raised interest in their regenerative potential. Furthermore, the potential of these cells to return to their original cell types due to their epigenetic memory has reinforced the need to control the epigenetic background for successful management of cellular differentiation. Herein, we discuss all available sources of dental stem cells, the procedures used to obtain these cells, and their ability to differentiate into the desired cells. We also introduce the concepts of cell reprogramming and transdifferentiation in terms of genetics and epigenetics, including DNA methylation, histone modification, and non-coding RNA. Finally, we discuss a novel therapeutic avenue for using dental-derived cells as stem cells, and explain cell reprogramming and transdifferentiation, which are used in regenerative medicine and tissue engineering.

• The Korean Journal of Physiology and Pharmacology
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• v.27 no.4
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• pp.407-416
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• 2023

The regeneration of myocardium following acute circulatory events remains a challenge, despite numerous efforts. Mesenchymal stem cells (MSCs) present a promising cell therapy option, but their differentiation into cardiomyocytes is a time-consuming process. Although it has been demonstrated that PSME4 degrades acetyl-YAP1, the role of PSME4 in the cardiac commitment of MSCs has not been fully elucidated. Here we reported the novel role of PSME4 in MSCs cardiac commitment. It was found that overnight treatment with apicidin in primary-cultured mouse MSCs led to rapid cardiac commitment, while MSCs from PSME4 knock-out mice did not undergo this process. Cardiac commitment was also observed using lentivirus-mediated PSME4 knockdown in immortalized human MSCs. Immunofluorescence and Western blot experiments revealed that YAP1 persisted in the nucleus of PSME4 knockdown cells even after apicidin treatment. To investigate the importance of YAP1 removal, MSCs were treated with shYAP1 and apicidin simultaneously. This combined treatment resulted in rapid YAP1 elimination and accelerated cardiac commitment. However, overexpression of acetylation-resistant YAP1 in apicidin-treated MSCs impeded cardiac commitment. In addition to apicidin, the universal effect of histone deacetylase (HDAC) inhibition on cardiac commitment was confirmed using tubastatin A and HDAC6 siRNA. Collectively, this study demonstrates that PSME4 is crucial for promoting the cardiac commitment of MSCs. HDAC inhibition acetylates YAP1 and facilitates its translocation to the nucleus, where it is removed by PSME4, promoting cardiac commitment. The failure of YAP1 to translocate or be eliminated from the nucleus results in the MSCs' inability to undergo cardiac commitment.

• The Plant Pathology Journal
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• v.39 no.4
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• pp.384-396
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• 2023

Colletotrichum acutatum species complex is one of the most important groups in the genus Colletotrichum with a high species diversity and a wide range of host plants. C. acutatum and related species have been collected from different plants and locations in Korea and deposited into the Korean Agricultural Culture Collection (KACC), National Institute of Agricultural Sciences since the 1990s. These fungal isolates were previously identified based mainly on morphological characteristics, and a limitation of molecular data was provided. To confirm the identification of species, 64 C. acutatum species complex isolates in KACC were used in this study for DNA sequence analyses of six loci: nuclear ribosomal internal transcribed spacers (ITS), betatubulin 2 (TUB2), histone-3 (HIS3), glyceraldehyde3-phosphate dehydrogenase (GAPDH), chitin synthase 1 (CHS-1), and actin (ACT). The molecular analysis revealed that they were identified in six different species of C. fioriniae (24 isolates), C. nymphaeae (21 isolates), C. scovillei (12 isolates), C. chrysanthemi (three isolates), C. lupini (two isolates), and C. godetiae (one isolate), and a novel species candidate. We compared the hosts of KACC isolates with "The List of Plant Diseases in Korea", previous reports in Korea and global reports and found that 23 combinations between hosts and pathogens could be newly reported in Korea after pathogenicity tests, and 12 of these have not been recorded in the world.

• Genomics & Informatics
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• v.21 no.3
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• pp.31.1-31.8
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• 2023

Multiple myeloma (MM) is a hematological malignancy. It is widely believed that genetic factors play a significant role in the development of MM, as investigated in numerous studies. However, the application of genomic information for clinical purposes, including diagnostic and prognostic biomarkers, remains largely confined to research. In this study, we utilized genetic information from the Genomic-Driven Clinical Implementation for Multiple Myeloma database, which is dedicated to clinical trial studies on MM. This genetic information was sourced from the genome-wide association studies catalog database. We prioritized genes with the potential to cause MM based on established annotations, as well as biological risk genes for MM, as potential drug target candidates. The DrugBank database was employed to identify drug candidates targeting these genes. Our research led to the discovery of 14 MM biological risk genes and the identification of 10 drugs that target three of these genes. Notably, only one of these 10 drugs, panobinostat, has been approved for use in MM. The two most promising genes, calcium signal-modulating cyclophilin ligand (CAMLG) and histone deacetylase 2 (HDAC2), were targeted by four drugs (cyclosporine, belinostat, vorinostat, and romidepsin), all of which have clinical evidence supporting their use in the treatment of MM. Interestingly, five of the 10 drugs have been approved for other indications than MM, but they may also be effective in treating MM. Therefore, this study aimed to clarify the genomic variants involved in the pathogenesis of MM and highlight the potential benefits of these genomic variants in drug discovery.

• IMMUNE NETWORK
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• v.22 no.3
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• pp.21.1-21.21
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• 2022

As far the current severe coronavirus disease 2019 (COVID-19), respiratory disease is still the biggest threat to human health. In addition, infectious respiratory diseases are particularly prominent. In addition to killing and clearing the infection pathogen directly, regulating the immune responses against the pathogens is also an important therapeutic modality. Sirtuins belong to NAD+-dependent class III histone deacetylases. Among 7 types of sirtuins, silent information regulator type-1 (SIRT1) played a multitasking role in modulating a wide range of physiological processes, including oxidative stress, inflammation, cell apoptosis, autophagy, antibacterial and antiviral functions. It showed a critical effect in regulating immune responses by deacetylation modification, especially through high-mobility group box 1 (HMGB1), a core molecule regulating the immune system. SIRT1 was associated with many respiratory diseases, including COVID-19 infection, bacterial pneumonia, tuberculosis, and so on. Here, we reviewed the latest research progress regarding the effects of SIRT1 on immune system in respiratory diseases. First, the structure and catalytic characteristics of SIRT1 were introduced. Next, the roles of SIRT1, and the mechanisms underlying the immune regulatory effect through HMGB1, as well as the specific activators/inhibitors of SIRT1, were elaborated. Finally, the multitasking roles of SIRT1 in several respiratory diseases were discussed separately. Taken together, this review implied that SIRT1 could serve as a promising specific therapeutic target for the treatment of respiratory diseases.