Publications by authors named "Seong Kyu Han"

89 Publications

Anthocyanins attenuate endothelial dysfunction through regulation of uncoupling of nitric oxide synthase in aged rats.

Aging Cell 2020 12 3;19(12):e13279. Epub 2020 Dec 3.

Non-Clinical Evaluation Center, Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju, Korea.

Endothelial dysfunction is one of the main age-related arterial phenotypes responsible for cardiovascular disease (CVD) in older adults. This endothelial dysfunction results from decreased bioavailability of nitric oxide (NO) arising downstream of endothelial oxidative stress. In this study, we investigated the protective effect of anthocyanins and the underlying mechanism in rat thoracic aorta and human vascular endothelial cells in aging models. In vitro, cyanidin-3-rutinoside (C-3-R) and cyanidin-3-glucoside (C-3-G) inhibited the d-galactose (d-gal)-induced senescence in human endothelial cells, as indicated by reduced senescence-associated-β-galactosidase activity, p21, and p16 . Anthocyanins blocked d-gal-induced reactive oxygen species (ROS) formation and NADPH oxidase activity. Anthocyanins reversed d-gal-mediated inhibition of endothelial nitric oxide synthase (eNOS) serine phosphorylation and SIRT1 expression, recovering NO level in endothelial cells. Also, SIRT1-mediated eNOS deacetylation was shown to be involved in anthocyanin-enhanced eNOS activity. In vivo, anthocyanin-rich mulberry extract was administered to aging rats for 8 weeks. In vivo, mulberry extract alleviated endothelial senescence and oxidative stress in the aorta of aging rats. Consistently, mulberry extract also raised serum NO levels, increased phosphorylation of eNOS, increased SIRT1 expression, and reduced nitrotyrosine in aortas. The eNOS acetylation was higher in the aging group and was restored by mulberry extract treatment. Similarly, SIRT1 level associated with eNOS decreased in the aging group and was restored in aging plus mulberry group. These findings indicate that anthocyanins protect against endothelial senescence through enhanced NO bioavailability by regulating ROS formation and reducing eNOS uncoupling.
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http://dx.doi.org/10.1111/acel.13279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744959PMC
December 2020

Network-based machine learning in colorectal and bladder organoid models predicts anti-cancer drug efficacy in patients.

Nat Commun 2020 10 30;11(1):5485. Epub 2020 Oct 30.

Department of Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Korea.

Cancer patient classification using predictive biomarkers for anti-cancer drug responses is essential for improving therapeutic outcomes. However, current machine-learning-based predictions of drug response often fail to identify robust translational biomarkers from preclinical models. Here, we present a machine-learning framework to identify robust drug biomarkers by taking advantage of network-based analyses using pharmacogenomic data derived from three-dimensional organoid culture models. The biomarkers identified by our approach accurately predict the drug responses of 114 colorectal cancer patients treated with 5-fluorouracil and 77 bladder cancer patients treated with cisplatin. We further confirm our biomarkers using external transcriptomic datasets of drug-sensitive and -resistant isogenic cancer cell lines. Finally, concordance analysis between the transcriptomic biomarkers and independent somatic mutation-based biomarkers further validate our method. This work presents a method to predict cancer patient drug responses using pharmacogenomic data derived from organoid models by combining the application of gene modules and network-based approaches.
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http://dx.doi.org/10.1038/s41467-020-19313-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599252PMC
October 2020

Single-cell RNA sequencing identifies shared differentiation paths of mouse thymic innate T cells.

Nat Commun 2020 08 31;11(1):4367. Epub 2020 Aug 31.

Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.

Invariant natural killer T (iNKT), mucosal-associated invariant T (MAIT), and γδ T cells are innate T cells that acquire memory phenotype in the thymus and share similar biological characteristics. However, how their effector differentiation is developmentally regulated is still unclear. Here, we identify analogous effector subsets of these three innate T cell types in the thymus that share transcriptional profiles. Using single-cell RNA sequencing, we show that iNKT, MAIT and γδ T cells mature via shared, branched differentiation rather than linear maturation or TCR-mediated instruction. Simultaneous TCR clonotyping analysis reveals that thymic maturation of all three types is accompanied by clonal selection and expansion. Analyses of mice deficient of TBET, GATA3 or RORγt and additional in vivo experiments corroborate the predicted differentiation paths, while human innate T cells from liver samples display similar features. Collectively, our data indicate that innate T cells share effector differentiation processes in the thymus.
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http://dx.doi.org/10.1038/s41467-020-18155-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459300PMC
August 2020

Inhibitory actions of borneol on the substantia gelatinosa neurons of the trigeminal subnucleus caudalis in mice.

Korean J Physiol Pharmacol 2020 Sep;24(5):433-440

Department of Oral Physiology, School of Dentistry & Institute of Oral Bioscience, Jeonbuk National University, Jeonju 54896, Korea.

The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) is the first relay site for the orofacial nociceptive inputs the thin myelinated Aδ and unmyelinated C primary afferent fibers. Borneol, one of the valuable timehonored herbal ingredients in traditional Chinese medicine, is a popular treatment for anxiety, anesthesia, and antinociception. However, to date, little is known as to how borneol acts on the SG neurons of the Vc. To close this gap, the whole-cell patch-clamp technique was applied to elucidate the antinociceptive mechanism responding for the actions of borneol on the SG neurons of the Vc in mice. In the voltage-clamp mode, holding at -60 mV, the borneol-induced non-desensitizing inward currents were not affected by tetrodotoxin, a voltage-gated Na channel blocker, 6-cyano-7-nitro-quinoxaline-2,3-dione, a non--methyl-D-aspartate (NMDA) glutamate receptor antagonist and DL-2-amino-5-phosphonopentanoic acid, an NMDA receptor antagonist. However, borneol-induced inward currents were partially decreased in the presence of picrotoxin, a γ-aminobutyric acid (GABA) receptor antagonist, or strychnine, a glycine receptor antagonist, and was almost suppressed in the presence of picrotoxin and strychnine. Though borneol did not show any effect on the glycine-induced inward currents, borneol enhanced GABA-mediated responses. Beside, borneol enhanced the GABA-induced hyperpolarization under the current-clamp mode. Altogether, we suggest that borneol contributes in part toward mediating the inhibitory GABA and glycine transmission on the SG neurons of the Vc and may serve as an herbal therapeutic for orofacial pain ailments.
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http://dx.doi.org/10.4196/kjpp.2020.24.5.433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445480PMC
September 2020

Melatonin Suppresses the Kainate Receptor-Mediated Excitation on Gonadotropin-Releasing Hormone Neurons in Female and Male Prepubertal Mice.

Int J Mol Sci 2020 Aug 20;21(17). Epub 2020 Aug 20.

Department of Oral Physiology, School of Dentistry & Institute of Oral Bioscience, Jeonbuk National University, Jeonju 54896, Korea.

Melatonin, a pineal gland secretion, is an amphiphilic neurohormone involved in the biological and physiologic regulation of bodily functions. Numerous studies have shown the effects of melatonin on the release of gonadotropins and their actions at one or several levels of the hypothalamic-pituitary-gonadal axis. However, direct melatonin action on gonadotropin-releasing hormone (GnRH) neurons and its mechanism of action remain unclear. Here, plasma melatonin levels were measured and the effect of melatonin on GnRH neurons was assessed using brain slice patch clamp techniques. The plasma melatonin levels in prepubertal mice were higher than those in the adults. Melatonin itself did not change the firing activity of GnRH neurons. Interestingly, the kainate receptor-mediated responses but not the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)- and N-methyl-D-aspartic acid (NMDA)-induced responses were suppressed by melatonin in both the voltage clamp and current clamp modes. The inhibitory effects of the kainate-induced response by melatonin tended to increase with higher melatonin concentrations and persisted in the presence of tetrodotoxin, a voltage-sensitive Na channel blocker, or luzindole, a non-selective melatonin receptor antagonist. However, the response was completely abolished by pretreatment with pertussis toxin. These results suggest that melatonin can regulate GnRH neuronal activities in prepubertal mice by partially suppressing the excitatory signaling mediated by kainate receptors through pertussis toxin-sensitive G-protein-coupled receptors.
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http://dx.doi.org/10.3390/ijms21175991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504472PMC
August 2020

Potentiation of the Glycine Response by Bisphenol A, an Endocrine Disrupter, on the Substantia Gelatinosa Neurons of the Trigeminal Subnucleus Caudalis in Mice.

Chem Res Toxicol 2020 03 14;33(3):782-788. Epub 2020 Feb 14.

Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Jeonbuk National University, Jeonju, 54896, Republic of Korea.

Lamina II, also called the substantia gelatinosa (SG) of the medullary dorsal horn (the trigeminal subnucleus caudalis, Vc), is thought to play an essential role in the control of orofacial nociception because it receives the nociceptive signals from primary afferents, including thin myelinated Aδ- and unmyelinated C-fibers. Glycine, the main inhibitory neurotransmitter in the central nervous system, plays an essential role in the transference of nociceptive messages from the periphery to higher brain regions. Bisphenol A (BPA) is reported to alter the morphological and functional characteristics of neuronal cells and to be an effector of a great number of ion channels in the central nervous system. However, the electrophysiological effects of BPA on the glycine receptors of SG neurons in the Vc have not been well studied. Therefore, in this study, we used the whole-cell patch-clamp technique to determine the effect of BPA on the glycine response in SG neurons of the Vc in male mice. We demonstrated that in early neonatal mice (0-3 postnatal day mice), BPA did not affect the glycine-induced inward current. However, in the juvenile and adult groups, BPA enhanced the glycine-mediated responses. Heteromeric glycine receptors were involved in the modulation by BPA. The interaction between BPA and glycine appears to have a significant role in regulating transmission in the nociceptive pathway.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00405DOI Listing
March 2020

Domain-mediated interactions for protein subfamily identification.

Sci Rep 2020 01 14;10(1):264. Epub 2020 Jan 14.

Department of Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Korea.

Within a protein family, proteins with the same domain often exhibit different cellular functions, despite the shared evolutionary history and molecular function of the domain. We hypothesized that domain-mediated interactions (DMIs) may categorize a protein family into subfamilies because the diversified functions of a single domain often depend on interacting partners of domains. Here we systematically identified DMI subfamilies, in which proteins share domains with DMI partners, as well as with various functional and physical interaction networks in individual species. In humans, DMI subfamily members are associated with similar diseases, including cancers, and are frequently co-associated with the same diseases. DMI information relates to the functional and evolutionary subdivisions of human kinases. In yeast, DMI subfamilies contain proteins with similar phenotypic outcomes from specific chemical treatments. Therefore, the systematic investigation here provides insights into the diverse functions of subfamilies derived from a protein family with a link-centric approach and suggests a useful resource for annotating the functions and phenotypic outcomes of proteins.
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http://dx.doi.org/10.1038/s41598-019-57187-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959277PMC
January 2020

Phylogenetic analysis of ABCG subfamily proteins in plants: functional clustering and coevolution with ABCGs of pathogens.

Physiol Plant 2019 Dec 11. Epub 2019 Dec 11.

Department of Life Science, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Korea.

ABCG subfamily proteins are highly enriched in terrestrial plants. Many of these proteins secrete secondary metabolites that repel or inhibit pathogens. To establish why the ABCG subfamily proteins proliferated extensively during evolution, we constructed phylogenetic trees from a broad range of eukaryotic organisms. ABCG proteins were massively duplicated in land plants and in oomycetes, a group of agronomically important plant pathogens, which prompted us to hypothesize that plant and pathogen ABCGs coevolved. Supporting this hypothesis, full-size ABCGs in host plants (Arabidopsis thaliana and Glycine max) and their pathogens (Hyaloperonospora arabidopsidis and Phytophthora sojae, respectively) had similar divergence times and patterns. Furthermore, generalist pathogens with broad ranges of host plants have diversified more ABCGs than their specialist counterparts. The hypothesis was further tested using an example pair of ABCGs that first diverged during multiplication in a host plant and its pathogen: AtABCG31 of A. thaliana and HpaP802307 of H. arabidopsidis. AtABCG31 expression was activated following infection with H. arabidopsidis, and disrupting AtABCG31 led to increased susceptibility to H. arabidopsidis. Together, our results suggest that ABCG genes in plants and their oomycete pathogens coevolved in an arms race, to extrude secondary metabolites involved in the plant's defense response against pathogens.
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http://dx.doi.org/10.1111/ppl.13052DOI Listing
December 2019

Action of citral on the substantia gelatinosa neurons of the trigeminal subnucleus caudalis in juvenile mice.

Chin J Physiol 2019 Sep-Oct;62(5):175-181

Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Jeonbuk National University, Jeonju, Republic of Korea.

The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) is admitted as a pivotal site of integrating and regulating orofacial nociceptive inputs. Although citral (3,7-dimethyl-2,6-octadienal) is involved in antinociception, the action mechanism of citral on the SG neurons of the Vc has not been fully clarified yet. In this study, we examined the direct membrane effects of citral and how citral mediates responses on the SG neurons of the Vc in juvenile mice using a whole-cell patch-clamp technique. Under high chloride pipette solution, citral showed repeatable inward currents that persisted in the presence of tetrodotoxin, a voltage-gated Na channel blocker, and 6-cyano-7-nitro-quinoxaline-2,3-dione, a non-N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, D-2-amino-5-phosphonopentanoic acid, an NMDA receptor antagonist. However, the citral-induced inward currents were partially blocked by picrotoxin, a gamma-aminobutyric acid (GABA)-receptor antagonist, or by strychnine, a glycine receptor antagonist. Further, the citral-induced responses were almost blocked by picrotoxin with strychnine. We also found that citral exhibited additive effect with GABA-induced inward currents and glycine-induced inward currents were potentiated by citral. In addition, citral suppressed the firing activities by positive current injection on the SG neurons of the Vc. Taken together, these results demonstrate that citral has glycine- and/or GABA-mimetic actions and suggest that citral might be a potential target for orofacial pain modulation by the activation of inhibitory neurotransmission in the SG area of the Vc.
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http://dx.doi.org/10.4103/CJP.CJP_32_19DOI Listing
November 2019

Link clustering explains non-central and contextually essential genes in protein interaction networks.

Sci Rep 2019 08 12;9(1):11672. Epub 2019 Aug 12.

Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Korea.

Recent studies have shown that many essential genes (EGs) change their essentiality across various contexts. Finding contextual EGs in pathogenic conditions may facilitate the identification of therapeutic targets. We propose link clustering as an indicator of contextual EGs that are non-central in protein-protein interaction (PPI) networks. In various human and yeast PPI networks, we found that 29-47% of EGs were better characterized by link clustering than by centrality. Importantly, non-central EGs were prone to change their essentiality across different human cell lines and between species. Compared with central EGs and non-EGs, non-central EGs had intermediate levels of expression and evolutionary conservation. In addition, non-central EGs exhibited a significant impact on communities at lower hierarchical levels, suggesting that link clustering is associated with contextual essentiality, as it depicts locally important nodes in network structures.
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http://dx.doi.org/10.1038/s41598-019-48273-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690968PMC
August 2019

Variants at potential loci associated with Sjogren's syndrome in Koreans: A genetic association study.

Clin Immunol 2019 10 23;207:79-86. Epub 2019 Jul 23.

Department of Prosthodontics, College of Dentistry at Yonsei University, Seoul, Republic of Korea. Electronic address:

Sjogren's syndrome (SS), a chronic autoimmune disease, typically causes or involves inflammation in the salivary and lacrimal glands. Although recent genetic association studies have contributed to the discovery of SS susceptible genes, few studies have reported on the Korean population. Here, we did a genetic association study of SS in Korean patients using whole-exome sequencing data of 15 patients and 100 healthy controls. In addition to confirming previously described SS susceptibility loci MSH5 (p = 1.67 × 10-5) and RELN (p = 4.91 × 10-6), we also validated PRAMEF13 (p = 2.28 × 10-5), TARBP1 (p = 1.87 × 10-5), UGT2B28 (p = 1.33 × 10-5), TRBV5-6 (p = 2.27 × 10-5) and NAPB (p = 3.73 × 10-5) as novel susceptibility loci for SS. Furthermore, we identified UGT2B28, TARBP1 and PRAMEF13 as associated with human immune function. These findings may provide useful insight into to the pathways and pathogenesis contributing to SS susceptibility in the Korean population.
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http://dx.doi.org/10.1016/j.clim.2019.07.010DOI Listing
October 2019

Potentiation of the glycine response by serotonin on the substantia gelatinosa neurons of the trigeminal subnucleus caudalis in mice.

Korean J Physiol Pharmacol 2019 Jul 25;23(4):271-279. Epub 2019 Jun 25.

Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju 54896, Korea.

The lamina II, also called the substantia gelatinosa (SG), of the trigeminal subnucleus caudalis (Vc), is thought to play an essential role in the control of orofacial nociception. Glycine and serotonin (5-hydroxytryptamine, 5-HT) are the important neurotransmitters that have the individual parts on the modulation of nociceptive transmission. However, the electrophysiological effects of 5-HT on the glycine receptors on SG neurons of the Vc have not been well studied yet. For this reason, we applied the whole-cell patch clamp technique to explore the interaction of intracellular signal transduction between 5-HT and the glycine receptors on SG neurons of the Vc in mice. In nine of 13 neurons tested (69.2%), pretreatment with 5-HT potentiated glycine-induced current (I). Firstly, we examined with a 5-HT receptor agonist (8-OH-DPAT, 5-HT agonist, co-applied with SB-269970, 5-HT antagonist) and antagonist (WAY-100635), but 5-HT receptor agonist did not increase I and in the presence of 5-HT antagonist, the potentiation of 5-HT on I still happened. However, an agonist (α-methyl-5-HT) and antagonist (ketanserin) of the 5-HT receptor mimicked and inhibited the enhancing effect of 5-HT on I in the SG neurons, respectively. We also verified the role of the 5-HT receptor by using a 5-HT antagonist (SB-269970) but it also did not block the enhancement of 5-HT on I. Our study demonstrated that 5-HT facilitated I in the SG neurons of the Vc through the 5-HT receptor. The interaction between 5-HT and glycine appears to have a significant role in modulating the transmission of the nociceptive pathway.
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http://dx.doi.org/10.4196/kjpp.2019.23.4.271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609265PMC
July 2019

Evolutionary coupling analysis identifies the impact of disease-associated variants at less-conserved sites.

Nucleic Acids Res 2019 09;47(16):e94

Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea.

Genome-wide association studies have discovered a large number of genetic variants in human patients with the disease. Thus, predicting the impact of these variants is important for sorting disease-associated variants (DVs) from neutral variants. Current methods to predict the mutational impacts depend on evolutionary conservation at the mutation site, which is determined using homologous sequences and based on the assumption that variants at well-conserved sites have high impacts. However, many DVs at less-conserved but functionally important sites cannot be predicted by the current methods. Here, we present a method to find DVs at less-conserved sites by predicting the mutational impacts using evolutionary coupling analysis. Functionally important and evolutionarily coupled sites often have compensatory variants on cooperative sites to avoid loss of function. We found that our method identified known intolerant variants in a diverse group of proteins. Furthermore, at less-conserved sites, we identified DVs that were not identified using conservation-based methods. These newly identified DVs were frequently found at protein interaction interfaces, where species-specific mutations often alter interaction specificity. This work presents a means to identify less-conserved DVs and provides insight into the relationship between evolutionarily coupled sites and human DVs.
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http://dx.doi.org/10.1093/nar/gkz536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895274PMC
September 2019

Exomic and transcriptomic alterations of hereditary gingival fibromatosis.

Oral Dis 2019 Jul 15;25(5):1374-1383. Epub 2019 Apr 15.

Department of Prosthodontics, College of Dentistry, Yonsei University, Seoul, Korea.

Objective: Hereditary gingival fibromatosis (HGF) is a rare oral disease characterized by either localized or generalized gradual, benign, non-hemorrhagic enlargement of gingivae. Although several genetic causes of HGF are known, the genetic etiology of HGF as a non-syndromic and idiopathic entity remains uncertain.

Subjects And Methods: We performed exome and RNA-seq of idiopathic HGF patients and controls, and then devised a computational framework that specifies exomic/transcriptomic alterations interconnected by a regulatory network to unravel genetic etiology of HGF. Moreover, given the lack of animal model or large-scale cohort data of HGF, we developed a strategy to cross-check their clinical relevance through in silico gene-phenotype mapping with biomedical literature mining and semantic analysis of disease phenotype similarities.

Results: Exomic variants and differentially expressed genes of HGF were connected by members of TGF-β/SMAD signaling pathway and craniofacial development processes, accounting for the molecular mechanism of fibroblast overgrowth mimicking HGF. Our cross-check supports that genes derived from the regulatory network analysis have pathogenic roles in fibromatosis-related diseases.

Conclusions: The computational approach of connecting exomic and transcriptomic alterations through regulatory networks is applicable in the clinical interpretation of genetic variants in HGF patients.
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http://dx.doi.org/10.1111/odi.13093DOI Listing
July 2019

Exercise training normalizes elevated firing rate of hypothalamic presympathetic neurons in heart failure rats.

Am J Physiol Regul Integr Comp Physiol 2019 02 28;316(2):R110-R120. Epub 2018 Nov 28.

Department of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University , Seoul , Republic of Korea.

Exercise training (ExT) normalizes elevated sympathetic nerve activity in heart failure (HF), but the underlying mechanisms are not well understood. In this study, we examined the effects of 3 wk of ExT on the electrical activity of the hypothalamic presympathetic neurons in the brain slice of HF rats. HF rats were prepared by ligating the left descending coronary artery. The electrophysiological properties of paraventricular nucleus neurons projecting to the rostral ventrolateral medulla (PVN-RVLM) were examined using the slice patch-clamp technique. The neuronal firing rate was elevated in HF rats, and ExT induced a reduction in the firing rate ( P < 0.01). This ExT-induced decrease in the firing rate was associated with an increased frequency of spontaneous and miniature inhibitory postsynaptic current (IPSCs; P < 0.05). There was no significant change in excitatory postsynaptic current. Replacing Ca with Mg in the recording solution reduced the elevated IPSC frequency in HF rats with ExT ( P < 0.01) but not in those without ExT, indicating an increase in the probability of GABA release. In contrast, ExT did not restore the reduced GABA receptor-mediated tonic inhibitory current in HF rats. A GABA receptor blocker (bicuculline, 20 μM) increased the firing rate in HF rats with ExT ( P < 0.01) but not in those without ExT. Collectively, these results show that ExT normalized the elevated firing activity by increasing synaptic GABA release in PVN-RVLM neurons in HF rats. Our findings provide a brain mechanism underlying the beneficial effects of ExT in HF, which may shed light on the pathophysiology of other diseases accompanied by sympathetic hyperactivation.
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http://dx.doi.org/10.1152/ajpregu.00225.2018DOI Listing
February 2019

The Role of Interleukin-10 in Mediating the Effect of Immune Challenge on Mouse Gonadotropin-Releasing Hormone Neurons .

eNeuro 2018 Sep-Oct;5(5). Epub 2018 Oct 15.

MTA NAP-B Molecular Neuroendocrinology Research Group, Institute of Physiology, Medical School, Centre for Neuroscience, Szentágothai Research Institute, University of Pécs, 7624 Pécs, Hungary.

Immune challenge alters neural functioning via cytokine production. Inflammation has profound impact on the central regulation of fertility, but the mechanisms involved are not clearly defined. The anti-inflammatory cytokine interleukin (IL)-10 is responsible for balancing the immune response in the brain. To examine whether IL-10 has an effect on the function of the gonadotropin-releasing hormone (GnRH) neurons, we first examined the effect of immune responses with distinct cytokine profiles, such as the T cell-dependent (TD) and T cell-independent (TI) B-cell response. We investigated the effect of the TD and TI immune responses on ERK1/2 phosphorylation in GnRH neurons by administering fluorescein isothiocyanate/keyhole limpet hemocyanin (KLH-FITC) or dextran-FITC to female mice. Although dextran-FITC had no effect, KLH-FITC induced ERK1/2 phosphorylation in GnRH neurons after 6 d. KLH-FITC treatment increased the levels of IL-10 in the hypothalamus (HYP), but this treatment did not cause lymphocyte infiltration or an increase in the levels of proinflammatory cytokines. In IL-10 knock-out (KO) mice, KLH-FITC-induced ERK1/2 phosphorylation in the GnRH neurons was absent. We also showed that in IL-10 KO mice, the estrous cycle was disrupted. Perforated patch-clamp recordings from GnRH-GFP neurons, IL-10 immunohistochemistry, and in vitro experiments on acute brain slices revealed that IL-10 can directly alter GnRH neuron firing and induce ERK1/2 phosphorylation. These observations demonstrate that IL-10 plays a role in influencing signaling of GnRH neurons in the TD immune response. These results also provide the first evidence that IL-10 can directly alter the function of GnRH neurons and may help the maintenance of the integrity of the estrous cycle.
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http://dx.doi.org/10.1523/ENEURO.0211-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220573PMC
April 2019

Botulinum toxin type A enhances the inhibitory spontaneous postsynaptic currents on the substantia gelatinosa neurons of the subnucleus caudalis in immature mice.

Korean J Physiol Pharmacol 2018 Sep 27;22(5):539-546. Epub 2018 Aug 27.

Department of Oral Physiology, School of Dentistry & Institute of Oral Bioscience, Chonbuk National University, Jeonju 54896, Korea.

Botulinum toxin type A (BoNT/A) has been used therapeutically for various conditions including dystonia, cerebral palsy, wrinkle, hyperhidrosis and pain control. The substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis (Vc) receive orofacial nociceptive information from primary afferents and transmit the information to higher brain center. Although many studies have shown the analgesic effects of BoNT/A, the effects of BoNT/A at the central nervous system and the action mechanism are not well understood. Therefore, the effects of BoNT/A on the spontaneous postsynaptic currents (sPSCs) in the SG neurons were investigated. In whole cell voltage clamp mode, the frequency of sPSCs was increased in 18 (37.5%) neurons, decreased in 5 (10.4%) neurons and not affected in 25 (52.1%) of 48 neurons tested by BoNT/A (3 nM). Similar proportions of frequency variation of sPSCs were observed in 1 and 10 nM BoNT/A and no significant differences were observed in the relative mean frequencies of sPSCs among 1-10 nM BoNT/A. BoNT/A-induced frequency increase of sPSCs was not affected by pretreated tetrodotoxin (0.5 µM). In addition, the frequency of sIPSCs in the presence of CNQX (10 µM) and AP5 (20 µM) was increased in 10 (53%) neurons, decreased in 1 (5%) neuron and not affected in 8 (42%) of 19 neurons tested by BoNT/A (3 nM). These results demonstrate that BoNT/A increases the frequency of sIPSCs on SG neurons of the Vc at least partly and can provide an evidence for rapid action of BoNT/A at the central nervous system.
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http://dx.doi.org/10.4196/kjpp.2018.22.5.539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115353PMC
September 2018

Extract Supplementation Attenuates Memory Deficits by Modulating BDNF-CREB and Its Downstream Molecules, in Animal Models of Memory Impairment.

Nutrients 2018 Jul 17;10(7). Epub 2018 Jul 17.

Department of Food Science and Human Nutrition, Chonbuk National University, 664-14 Duckjin-dong, Jeonju, Jeonbuk 561-756, Korea.

Cholinergic dysfunction, impaired brain-derived neurotrophic factor and cAMP response element binding protein (BDNF-CREB) signaling are one of the major pathological hallmarks of cognitive impairment. Therefore, improving cholinergic neurotransmission, and regulating the BDNF-CREB pathway by downregulating apoptosis genes is one strategy for inhibiting the etiology of dementia. This study evaluates the potential effects of MIQ (SS) extract against cognitive dysfunction and its underlying mechanisms. SS supplementation for 33 days improved scopolamine-induced memory impairment symptoms in Morris water maze test and Y-maze test. SS reduced the acetylcholineesterase activity and significantly increase acetylcholine and cholineacetyltransferase activity in the brain. In the subsequent mechanism study, SS regulated the mRNA expression level of neuronal plasticity molecules such as (nerve growth factor) NGF, BDNF, CREB, and its downstream molecules such as Bcl-2 and Egr-1 by downregulating the neuronal apoptosis targets in both hippocampus and frontal cortex. Additionally, inward currents caused by SS in hippocampal CA1 neurons was partially blocked by the GABA receptor antagonist picrotoxin (50 μM), suggesting that SS acts on synaptic/extrasynaptic GABA receptors. These findings indicate that SS may function in a way that is similar to nootropic drugs by inhibiting cholinergic abnormalities, and neuronal apoptosis targets and ultimately increasing the expression of BDNF-CREB.
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http://dx.doi.org/10.3390/nu10070917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073797PMC
July 2018

Divergence of Noncoding Regulatory Elements Explains Gene-Phenotype Differences between Human and Mouse Orthologous Genes.

Mol Biol Evol 2018 07;35(7):1653-1667

Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea.

Mice have been widely used as a model organism to investigate human gene-phenotype relationships based on a conjecture that orthologous genes generally perform similar functions and are associated with similar phenotypes. However, phenotypes associated with orthologous genes often turn out to be quite different between human and mouse. Herein, we devised a method to quantitatively compare phenotypes annotations associated with mouse models and human. Using semantic similarity comparisons, we identified orthologous genes with different phenotype annotations, of which the similarity score is on a par with that of random gene pairs. Analysis of sequence evolution and transcriptomic changes revealed that orthologous genes with phenotypic differences are correlated with changes in noncoding regulatory elements and tissue-specific expression profiles rather than changes in protein-coding sequences. To map accurate gene-phenotype relationships using model organisms, we propose that careful consideration of the evolutionary divergence of noncoding regulatory elements and transcriptomic profiles is essential.
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http://dx.doi.org/10.1093/molbev/msy056DOI Listing
July 2018

Comparison of electrophysiological properties of two types of pre-sympathetic neurons intermingled in the hypothalamic paraventricular nucleus.

J Vet Sci 2018 Jul;19(4):483-491

Department of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute of Veterinary Science, Seoul National University, Seoul 08826, Korea.

The hypothalamic paraventricular nucleus (PVN) contains two types of neurons projecting to either the rostral ventrolateral medulla (PVN) or the intermediolateral horn (IML) of the spinal cord (PVN). These two neuron groups are intermingled in the same subdivisions of the PVN and differentially regulate sympathetic outflow. However, electrophysiological evidence supporting such functional differences is largely lacking. Herein, we compared the electrophysiological properties of these neurons by using patch-clamp and retrograde-tracing techniques. Most neurons (>70%) in both groups spontaneously fired in the cell-attached mode. When compared to the PVN neurons, the PVN neurons had a lower firing rate and a more irregular firing pattern ( < 0.05). The PVN neurons showed smaller resting membrane potential, slower rise and decay times, and greater duration of spontaneous action potentials ( < 0.05). The PVN neurons received greater inhibitory synaptic inputs (frequency, < 0.05) with a shorter rise time ( < 0.05). Taken together, the results indicate that the two pre-sympathetic neurons differ in their intrinsic and extrinsic electrophysiological properties, which may explain the lower firing activity of the PVN neurons. The greater inhibitory synaptic inputs to the PVN neurons also imply that these neurons have more integrative roles in regulation of sympathetic activity.
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http://dx.doi.org/10.4142/jvs.2018.19.4.483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070595PMC
July 2018

Korean red ginseng excitation of paraventricular nucleus neurons via non-N-methyl-D-aspartate glutamate receptor activation in mice.

J Vet Sci 2018 Mar;19(2):172-178

Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju 54896, Korea.

It has been reported that Korean red ginseng (KRG), a valuable and important traditional medicine, has varied effects on the central nervous system, suggesting its activities are complicated. The paraventricular nucleus (PVN) neurons of the hypothalamus has a critical role in stress responses and hormone secretions. Although the action mechanisms of KRG on various cells and systems have been reported, the direct membrane effects of KRG on PVN neurons have not been fully described. In this study, the direct membrane effects of KRG on PVN neuronal activity were investigated by using a perforated patch-clamp in ICR mice. In gramicidin perforated patch-clamp mode, KRG extract (KRGE) induced repeatable depolarization followed by hyperpolarization of PVN neurons. The KRGE-induced responses were concentration- dependent and persisted in the presence of tetrodotoxin, a voltage sensitive Na channel blocker. The KRGE-induced responses were suppressed by 6-cyano-7-nitroquinoxaline-2,3-dione (10 μM), a non-N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, but not by picrotoxin, a type A gamma-aminobutyric acid receptor antagonist. The results indicate that KRG activates non-NMDA glutamate receptors of PVN neurons in mice, suggesting that KRG may be a candidate for use in regulation of stress responses by controlling autonomic nervous system and hormone secretion.
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http://dx.doi.org/10.4142/jvs.2018.19.2.172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879065PMC
March 2018

Existence of ATP sensitive potassium currents on human periodontal ligament cells.

Arch Oral Biol 2017 Apr 17;76:48-54. Epub 2017 Jan 17.

Department of Oral Physiology, School of Dentistry & Institute of Oral Bioscience, Chonbuk National University, Jeonju, South Korea. Electronic address:

Objective: Potassium channels of the ATP-sensitive family (K channel) are inhibited by increase in intracellular ATP. Electrophysiological studies have demonstrated that the kinetics and pharmacological properties of K channels vary among different tissues, suggesting structurally and functionally distinct types. There are studies showing human periodontal ligament (PDL) cells respond to mechanical stress by increasing ATP release, which participates in bone resorption or bone homeostasis. So, in this study we investigated the existence of K channel subunit and their single channel properties in human periodontal ligaments.

Materials & Method: The human PDL cells were isolated from healthy erupted third molar. For patch-clamp experiments, human PDL fibroblasts were seeded on 3.5cm plastic dishes. The inside-out patch clamp recordings were performed under voltage clamp mode. Reverse transcriptase polymerase chain reaction (RT-PCR) was conducted to identify the channel subunits. All pair-wise comparisons were performed by Paired t-test. A P value <0.05 was considered significant.

Results: We observed mRNA transcripts for Kir6.1, Kir6.2 and Sur2B subuits in the human PDL cells. In inside-out patch mode, the single channel conductance was 163pS at symmetrical K concentration of 140mM and inward rectification was seen in ATP-free bath solution. The reversal potential of the currents was found to be 0mV at symmetrical concentration (140mM) of K in bath solution. The single channel currents were almost blocked by adding 5mM ATP in the bath solution. However, the currents were not blocked by 100μM glibenclamide, a subunit specific K channel blocker.

Conclusions: These results indicate that human PDL cells express K channels subunit including Sur2B and Kir6.1 and Kir6.2 which are sensitive to ATP but insensitive to glibenclamide.
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http://dx.doi.org/10.1016/j.archoralbio.2017.01.006DOI Listing
April 2017

Participation of central GABA receptors in the trigeminal processing of mechanical allodynia in rats.

Korean J Physiol Pharmacol 2017 Jan 21;21(1):65-74. Epub 2016 Dec 21.

Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu 41940, Korea.

Here we investigated the central processing mechanisms of mechanical allodynia and found a direct excitatory link with low-threshold input to nociceptive neurons. Experiments were performed on male Sprague-Dawley rats weighing 230-280 g. Subcutaneous injection of interleukin 1 beta (IL-1β) (1 ng/10 µL) was used to produce mechanical allodynia and thermal hyperalgesia. Intracisternal administration of bicuculline, a gamma aminobutyric acid A (GABA) receptor antagonist, produced mechanical allodynia in the orofacial area under normal conditions. However, intracisternal administration of bicuculline (50 ng) produced a paradoxical anti-allodynic effect under inflammatory pain conditions. Pretreatment with resiniferatoxin (RTX), which depletes capsaicin receptor protein in primary afferent fibers, did not alter the paradoxical anti-allodynic effects produced by the intracisternal injection of bicuculline. Intracisternal injection of bumetanide, an Na-K-Cl cotransporter (NKCC 1) inhibitor, reversed the IL-1β-induced mechanical allodynia. In the control group, application of GABA (100 µM) or muscimol (3 µM) led to membrane hyperpolarization in gramicidin perforated current clamp mode. However, in some neurons, application of GABA or muscimol led to membrane depolarization in the IL-1β-treated rats. These results suggest that some large myelinated Aβ fibers gain access to the nociceptive system and elicit pain sensation via GABA receptors under inflammatory pain conditions.
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http://dx.doi.org/10.4196/kjpp.2017.21.1.65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214912PMC
January 2017

Constitutive activation of T cells by γ2-herpesviral GPCR through the interaction with cellular CXCR4.

Biochim Biophys Acta Mol Cell Res 2017 Jan 15;1864(1):1-11. Epub 2016 Oct 15.

Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Institute of Endemic Disease, Seoul National University Medical Research Center and Bundang Hospital, Seoul 03080, Republic of Korea. Electronic address:

Members of the herpesviral family use multiple strategies to hijack infected host cells and exploit cellular signaling for their pathogenesis and latent infection. Among the most intriguing weapons in the arsenal of pathogenic herpesviruses are the constitutively active virally-encoded G protein-coupled receptors (vGPCRs). Even though vGPCRs contribute to viral pathogenesis such as immune evasion and proliferative disorders, the molecular details of how vGPCRs continuously activate cellular signaling are largely unknown. Here, we report that the vGPCR of Herpesvirus saimiri (HVS), an oncogenic γ2-herpesvirus, constitutively activates T cells via a heteromeric interaction with cellular CXCR4. Constitutive T cell activation also occurs with expression of the vGPCR of Kaposi's sarcoma-associated herpesvirus (KSHV), but not the vGPCR of Epstein-Barr virus. Expression of HVS vGPCR down-regulated the surface expression of CXCR4 but did not induce the degradation of the chemokine receptor, suggesting that vGPCR/CXCR4 signaling continues in cytosolic compartments. The physical association of vGPCR with CXCR4 was demonstrated by proximity ligation assay as well as immunoprecipitation. Interestingly, the constitutive activation of T cells by HVS vGPCR is independent of proximal T cell receptor (TCR) signaling molecules, such as TCRβ, Lck, and ZAP70, whereas CXCR4 silencing by shRNA abolished T cell activation by vGPCRs of HVS and KSHV. Furthermore, previously identified inactive vGPCR mutants failed to interact with CXCR4. These findings on the positive cooperativity of vGPCR with cellular CXCR4 in T cell activation extend our current understanding of the molecular mechanisms of vGPCR function and highlight the importance of heteromerization for GPCR activity.
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http://dx.doi.org/10.1016/j.bbamcr.2016.10.008DOI Listing
January 2017

Effects of hypotaurine on substantia gelatinosa neurons of the trigeminal subnucleus caudalis in immature mice.

Amino Acids 2016 12 29;48(12):2843-2853. Epub 2016 Aug 29.

Department of Oral Physiology and Institute of Oral Bioscience, School of Dentistry, Chonbuk National University, 664-14, 1 Ga, Deokjin-Dong, Jeonbuk, Jeonju, 561-756, Republic of Korea.

To understand the action and mechanism of hypotaurine, an immediate precursor of taurine, on orofacial nociceptive processing, we examined the direct effects and receptor types involved in hypotaurine-induced responses using the whole-cell patch clamp technique in the substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis (Vc) of immature mice. Under the condition of high-chloride pipette solution, hypotaurine elicited inward currents or upward deflections of membrane potential, which increased in a concentration-dependent manner (30-3000 μM) with the EC of 663.8 and 337.6 μM, respectively. The responses to 300 µM hypotaurine were reproducible and recovered upon washout. The 300 µM hypotaurine-induced currents were maintained in the presence of TTX, CNQX, and AP5, indicating direct postsynaptic action of hypotaurine on SG neurons. Responses to both low (300 µM) and high (1 or 3 mM) concentrations of hypotaurine were completely and reversibly blocked by the glycine receptor antagonist strychnine (2 µM), but unaffected by the GABA receptor antagonist gabazine (3 µM) which blocks synaptic GABA receptors at low concentration. Furthermore, responses to 300 µM hypotaurine and a maximal concentration of glycine (3 mM) were not additive, indicating that hypotaurine and glycine act on the same receptor. Hypotaurine-induced currents were partially antagonized by picrotoxin (50 µM) which blocks homomeric glycine receptors and by bicuculline (10 µM) which is an antagonist of α2 subunit-containing glycine receptors. These results suggest that hypotaurine-induced responses were mediated by glycine receptor activation in the SG neurons and hypotaurine might be used as an effective therapeutics for orofacial pain.
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http://dx.doi.org/10.1007/s00726-016-2321-1DOI Listing
December 2016

OASIS 2: online application for survival analysis 2 with features for the analysis of maximal lifespan and healthspan in aging research.

Oncotarget 2016 Aug;7(35):56147-56152

Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea.

Online application for survival analysis (OASIS) has served as a popular and convenient platform for the statistical analysis of various survival data, particularly in the field of aging research. With the recent advances in the fields of aging research that deal with complex survival data, we noticed a need for updates to the current version of OASIS. Here, we report OASIS 2 (http://sbi.postech.ac.kr/oasis2), which provides extended statistical tools for survival data and an enhanced user interface. In particular, OASIS 2 enables the statistical comparison of maximal lifespans, which is potentially useful for determining key factors that limit the lifespan of a population. Furthermore, OASIS 2 provides statistical and graphical tools that compare values in different conditions and times. That feature is useful for comparing age-associated changes in physiological activities, which can be used as indicators of "healthspan." We believe that OASIS 2 will serve as a standard platform for survival analysis with advanced and user-friendly statistical tools for experimental biologists in the field of aging research.
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http://dx.doi.org/10.18632/oncotarget.11269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302902PMC
August 2016

Non-genomic action of vitamin D3 on N-methyl-D-aspartate and kainate receptor-mediated actions in juvenile gonadotrophin-releasing hormone neurons.

Reprod Fertil Dev 2017 Jun;29(6):1231-1238

Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Duckjin Dong, Jeonju, Jeonbuk 561-756, South Korea.

Vitamin D is a versatile signalling molecule that plays a critical role in calcium homeostasis. There are several studies showing the genomic action of vitamin D in the control of reproduction; however, the quick non-genomic action of vitamin D at the hypothalamic level is not well understood. Therefore, to investigate the effect of vitamin D on juvenile gonadotrophin-releasing hormone (GnRH) neurons, excitatory neurotransmitter receptor agonists N-methyl-D-aspartate (NMDA, 30μM) and kainate (10μM) were applied in the absence or in the presence of vitamin D3 (VitaD3, 10nM). The NMDA-mediated responses were decreased by VitaD3 in the absence and in the presence of tetrodotoxin (TTX), a sodium-channel blocker, with the mean relative inward current being 0.56±0.07 and 0.66±0.07 (P<0.05), respectively. In addition, VitaD3 induced a decrease in the frequency of gamma-aminobutyric acid mediated (GABAergic) spontaneous postsynaptic currents and spontaneous postsynaptic currents induced by NMDA application with a mean relative frequency of 0.595±0.07 and 0.56±0.09, respectively. Further, VitaD3 decreased the kainate-induced inward currents in the absence and in the presence of TTX with a relative inward current of 0.64±0.06 and 0.68±0.06, respectively (P<0.05). These results suggest that VitaD3 has a non-genomic action and partially inhibits the NMDA and kainate receptor-mediated actions of GnRH neurons, suggesting that VitaD3 may regulate the hypothalamic-pituitary-gonadal (HPG) axis at the time of pubertal development.
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http://dx.doi.org/10.1071/RD15357DOI Listing
June 2017

Baicalin Activates Glycine and γ-Aminobutyric Acid Receptors on Substantia Gelatinosa Neurons of the Trigeminal Subsnucleus Caudalis in Juvenile Mice.

Am J Chin Med 2016 ;44(2):389-400

* Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju 561-756, Republic of Korea.

The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) receives nociceptive afferent inputs from thin-myelinated A[Formula: see text] fibers and unmyelinated C fibers and has been shown to be involved in the processing of orofacial nociceptive information. Scutellaria baicalensis Georgi (Huang-Qin, SbG), one of the 50 fundamental herbs of Chinese herbology, has been used historically as anti-inflammatory and antineoplastic medicine. Baicalin, one of the major compounds of SbG, has been reported to have neuroprotective, anti-inflammatory and analgesic effects. However, the receptor type activated by baicalin and its precise action mechanism on the SG neurons of Vc have not yet been studied. The whole-cell patch clamp technique was performed to examine the ion channels activated by baicalin on the SG neurons of Vc. In high Cl[Formula: see text] pipette solution, the baicalin (300[Formula: see text][Formula: see text]M) induced repeatable inward currents ([Formula: see text][Formula: see text]pA, [Formula: see text]) without desensitization on all the SG neurons tested. Further, the inward currents showed a concentration (0.1-3[Formula: see text]mM) dependent pattern. The inward current was sustained in the presence of tetrodotoxin (0.5[Formula: see text][Formula: see text]M), a voltage sensitive Na[Formula: see text] channel blocker. In addition, baicalin-induced inward currents were reduced in the presence of picrotoxin (50[Formula: see text][Formula: see text]M), a GABAA receptor antagonist, flumazenil (100[Formula: see text][Formula: see text]M), a benzodiazepine-sensitive GABAA receptor antagonist, and strychnine (2[Formula: see text][Formula: see text]M), a glycine receptor antagonist, respectively. These results indicate that baicalin has inhibitory effects on the SG neurons of the Vc, which are due to the activation of GABAA and/or the glycine receptor. Our results suggest that baicalin may be a potential target for orofacial pain modulation.
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http://dx.doi.org/10.1142/S0192415X16500221DOI Listing
December 2016

Fermented Barley Supplementation Modulates the Expression of Hypothalamic Genes and Reduces Energy Intake and Weight Gain in Rats.

J Med Food 2016 Apr;19(4):418-26

1 Department of Food Science and Human Nutrition, Chonbuk National University , Jeonju, Korea.

Dietary fiber and proteins are individually known to decrease feeding, but could result greater weight management benefit when both are combined. We hypothesized that supplementing the diet with fermented barley, being rich in both dietary fiber and proteins, could lower energy intake by modulating the mRNA expression level of hypothalamic genes associated with the regulation of feeding behavior and satiety; thereby decreasing body weight gain. To test our hypothesis, four groups of Sprague Dawley rats were arranged in a 2 × 2 factorial design (n = 6), low-fat diet with either guar gum (LFD-G) or fermented barley (LFD-FB) and high-fat diet with either guar gum (HFD-G) or fermented barley (HFD-FB). Using oral gavage, fermented barley was given at a dosage of 1500 mg/kg body weight and guar gum was supplemented in an equivalent quantity to that of the fiber in the fermented barley. After 19 weeks, the fermented barley-supplemented groups showed a significant reduction in energy intake, triglyceride, body weight gain, and serum leptin, compared to the guar gum-supplemented groups in both the low- and high-fat diet groups. Likewise, the anorexigenic gene proopiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) mRNA level were significantly higher in the fermented barley-supplemented groups compared to the guar gum-supplemented groups in rats fed on both high- and low-fat diets. In conclusion, fermented barley supplementation upregulated hypothalamic POMC/CART, decreased energy intake in both low- and high-fat diet groups, and prevented excessive weight gain in rats.
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http://dx.doi.org/10.1089/jmf.2015.3600DOI Listing
April 2016

Effects of cisplatin on potassium currents in CT26 cells.

J Cancer Res Ther 2016 Jan-Mar;12(1):248-53

Department of Oral Physiology, School of Dentistry, Institute of Oral Bioscience, Chonbuk National University, Jeonju, South Korea.

Aims: Cisplatin, a platinum-based drug, is an important weapon against many types of cancer. It is well-known that cisplatin induces apoptosis. Potassium channel plays very important role in several signaling pathways. To investigate the possibility that potassium channels also have a role in the cellular response to cisplatin, we examined the effect of cisplatin on the activity of potassium channels on CT26 cell, the colon carcinoma cell line.

Materials And Methods: The cells were cultured in DMEM, supplemented with 10< heat-inactivated fetal bovine serum. At mid-log phase, cultures were harvested, washed twice in phosphate-buffered saline, and resuspended in culture medium before use. Cells were voltage-clamped using the whole-cell patch clamp technique. Membrane current data were collected and amplified.

Statistical Analysis: Differences between two groups were assessed by paired t-test and one sample t-test to compare the relative values. One-way ANOVA was used for all experiment with more than two groups.

Results: Potassium currents were detected in CT26 cells and the currents were reduced by the application of tetraethylammonium (TEA) chloride, iberiotoxin, a big conductance calcium-activated potassium channel blocker and barium. The potassium currents were enhanced to 192< by the application of cisplatin (0.5 mM). Moreover, the increase of potassium currents by cisplatin was further inhibited by the application of TEA confirming the action of cisplatin on potassium channels. In addition, relative current induced by cisplatin in CT26 cells was bit larger than in normal IEC-6 cells.

Conclusion: Potassium currents were detected in CT26 cells and the currents were reduced by the application of tetraethylammonium (TEA) chloride, iberiotoxin, a big conductance calcium-activated potassium channel blocker and barium. The potassium currents were enhanced to 192< by the application of cisplatin (0.5 mM). Moreover, the increase of potassium currents by cisplatin was further inhibited by the application of TEA confirming the action of cisplatin on potassium channels. In addition, relative current induced by cisplatin in CT26 cells was bit larger than in normal IEC-6 cells.
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http://dx.doi.org/10.4103/0973-1482.154085DOI Listing
December 2016