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Park, Ka Hyon,Kim, Duck-Kyu,Huh, Yun Hyun,Lee, Gyuseok,Lee, Su-Hyeon,Hong, Yunkyung,Kim, Sun-Hun,Kook, Min-Suk,Koh, Jeong-Tae,Chun, Jang-Soo,Lee, Shee Eun,Ryu, Je-Hwang Nature Publishing Group 2017 Experimental and molecular medicine Vol.49 No.8
<P>Periodontal disease is one of the most prevalent chronic disorders worldwide. It is accompanied by inflammation of the gingiva and destruction of periodontal tissues, leading to alveolar bone loss. Here, we focused on the role of adipokines, which are locally expressed by periodontal tissues, in the regulation of catabolic gene expression leading to periodontal inflammation. The expression of the nicotinamide phosphoribosyltransferase (NAMPT) adipokine was dramatically increased in inflamed human and mouse gingival tissues. NAMPT expression was also increased in lipopolysaccharide- and proinflammatory cytokine-stimulated primary cultured human gingival fibroblasts (GF). Adenovirus-mediated NAMPT (Ad-<I>Nampt</I>) overexpression upregulated the expression and activity of COX-2, MMP1 and MMP3 in human GF. The upregulation of IL-1β- or Ad-<I>Nampt</I>-induced catabolic factors was significantly abrogated by the intracellular NAMPT (iNAMPT) inhibitor, FK866 or by the sirtuin (SIRT) inhibitor, nicotinamide (NIC). Recombinant NAMPT protein or extracellular NAMPT (eNAMPT) inhibition using a blocking antibody did not alter NAMPT target gene expression levels. Moreover, intragingival Ad-<I>Nampt</I> injection mediated periodontitis-like phenotypes including alveolar bone loss in mice. SIRT2, a part of the SIRT family, was positively associated with NAMPT actions in human GF. Furthermore, <I>in vivo</I> inhibition of the NAMPT-NAD<SUP>+</SUP>-SIRT axis by NIC injection in mice ameliorated the periodontal inflammation and alveolar bone erosion caused by intragingival injection of Ad-<I>Nampt</I>. Our findings indicate that NAMPT is highly upregulated in human GF, while its enzymatic activity acts as a crucial mediator of periodontal inflammation and alveolar bone destruction via regulation of COX-2, MMP1, and MMP3 levels.</P>
Park, Ka Hyon,Park, Yoonkyung,Park, II-Seon,Hahm, Kyung-Soo,Shin, Song Yub John Wiley Sons, Ltd. 2008 Journal of Peptide Science Vol.14 No.7
<P>To develop novel Pro-rich model AMPs with shorter length and higher bacterial selectivity/therapeutic index (TI) than natural AMP, indolicidin, we synthesized a series of undodecapeptides derived from the sequence XXPXXPWXPXX-NH<SUB>2</SUB> (X indicates Leu or Lys) with different ratios of Lys and Leu residues. Several Pro-rich model peptides (K<SUB>7</SUB>WP<SUB>3</SUB>, K<SUB>6</SUB>WL<SUB>1</SUB>P<SUB>3</SUB>, K<SUB>5</SUB>WL<SUB>2</SUB>P<SUB>3</SUB>-1, K<SUB>5</SUB>WL<SUB>2</SUB>P<SUB>3</SUB>-2, and K<SUB>4</SUB>WL<SUB>3</SUB>P<SUB>3</SUB>) had approximate 8- to 11-fold higher bacterial selectivity/TI compared to indolicidin. These peptides selectively bind to negatively charged liposomes (EYPG/EYPG; 7:3, w/w) mimicking bacterial membranes. Their high selectivity to negatively charged phospholipids corresponds well with their high bacterial selectivity. Indolicidin showed almost complete depolarization of the cytoplasmic membrane of Staphylococcus aureus and dye-leakage from negatively charged liposomes at 10 µM, whereas all of Pro-rich model peptides had very little activity in these assays even at 80 µM, as observed in buforin 2. These results suggest that the ultimate target of our designed Pro-rich model peptides is probably the intracellular components (e.g. protein, DNA or RNA) rather than the cytoplasmic membranes. Collectively, our designed Pro-rich short model peptides appear to be excellent candidates for future development as a novel antimicrobial agent. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.</P>
이선영,Park Ka Hyon,이규석,Kim Su-Jin,Song Won-Hyun,Kwon Seung-Hee,Koh Jeong-Tae,Huh Yun Hyun,Ryu Je-Hwang 생화학분자생물학회 2021 Experimental and molecular medicine Vol.53 No.-
Aging is associated with cellular senescence followed by bone loss leading to bone fragility in humans. However, the regulators associated with cellular senescence in aged bones need to be identified. Hypoxia-inducible factor (HIF)−2α regulates bone remodeling via the differentiation of osteoblasts and osteoclasts. Here, we report that HIF-2α expression was highly upregulated in aged bones. HIF-2α depletion in male mice reversed age-induced bone loss, as evidenced by an increase in the number of osteoblasts and a decrease in the number of osteoclasts. In an in vitro model of doxorubicin-mediated senescence, the expression of Hif-2 α and p21 , a senescence marker gene, was enhanced, and osteoblastic differentiation of primary mouse calvarial preosteoblast cells was inhibited. Inhibition of senescence-induced upregulation of HIF-2α expression during matrix maturation, but not during the proliferation stage of osteoblast differentiation, reversed the age-related decrease in Runx2 and Ocn expression. However, HIF-2α knockdown did not affect p21 expression or senescence progression, indicating that HIF-2α expression upregulation in senescent osteoblasts may be a result of aging rather than a cause of cellular senescence. Osteoclasts are known to induce a senescent phenotype during in vitro osteoclastogenesis. Consistent with increased HIF-2α expression, the expression of p16 and p21 was upregulated during osteoclastogenesis of bone marrow macrophages. ChIP following overexpression or knockdown of HIF-2α using adenovirus revealed that p16 and p21 are direct targets of HIF-2α in osteoclasts. Osteoblast-specific ( Hif-2α fl/fl ; Col1a1 - Cre ) or osteoclast-specific ( Hif-2α fl/fl ; Ctsk - Cre ) conditional knockout of HIF-2α in male mice reversed age-related bone loss. Collectively, our results suggest that HIF-2α acts as a senescence-related intrinsic factor in age-related dysfunction of bone homeostasis.
Nan, Yong Hai,Park, Ka Hyon,Park, Yoonkyung,Jeon, Young Jin,Kim, Yangmee,Park, Il-Seon,Hahm, Kyung-Soo,Shin, Song Yub Published by Elsevier/North Holland on behalf of t 2009 FEMS microbiology letters Vol.292 No.1
<P>To investigate the effects of positive charge and hydrophobicity on the cell selectivity, mechanism of action and anti-inflammatory activity of a Trp-rich antimicrobial peptide indolicidin (IN), a series of IN analogs with Trp-->Lys substitution were synthesized. All IN analogs displayed an approximately 7- to 18-fold higher cell selectivity, compared with IN. IN, IN-1 and IN-2 depolarized (50-90%) the cytoplasmic membrane potential of Staphylococcus aureus close to minimal inhibitory concentration (5-10 microg mL(-1)). However, other IN analogs (IN-3 and IN-4) displayed very low ability in membrane depolarization even at 40 microg mL(-1). Confocal laser-scanning microscopy revealed that IN-3 and IN-4 penetrated the Escherichia coli cell membrane, whereas IN, IN-1 and IN-2 did not enter the cell membrane. In the gel retardation assay, IN-3 and IN-4 bound more strongly to DNA compared with IN, IN-1 and IN-2. These findings suggest that the mechanism of antimicrobial action of IN-3 and IN-4 may be involved in the inhibition of intracellular functions via interference with DNA/RNA synthesis. Unlike IN, all IN analogs did not inhibit nitric oxide production or inducible nitric oxide synthase mRNA expression in lipopolysaccharide-stimulated mouse macrophage RAW264.7 cells, indicating that the hydrophobicity of IN is more important for anti-inflammatory activity in lipopolysaccharide-treated macrophage cells than the positive charge.</P>
Cell Selectivity of Arenicin-1 and Its Derivative with Two Disulfide Bonds
Ju-Un Lee,Ka Hyon Park,이지영,Jinkyoung Kim,신송엽,Yoonkyung Park,Kyung-Soo Hahm,Yangmee Kim* 대한화학회 2008 Bulletin of the Korean Chemical Society Vol.29 No.6
Antibiotics has become more important in modern health care system. Antimicrobial peptide is one of the attractive candidates for new mechanism of antibiotics. Arenicin-1 (AR-1) is 21-residue antimicrobial peptide isolated from marine polychaeta Arenicola marina with single disulfide bond forming an 18-residue ring [Ovchinnikova, T. V. et al., FEBS Lett. 2004, 577, 209-214]. Our previous study on AR-1 and its linear derivative showed that disulfide bridge and the amphipathic â-sheet structure of the AR-1 play important roles in their biological activities. AR-1 has high antibacterial activity but it also displays hemolytic activity against human red blood cells. In order to develop more potent and more bacterial cell selective peptide, we designed and synthesized a new derivative, AR-1-C (RWCVYAYCRVRGVLCRYRRCW) by substitution of Val8,15 with Cys8,15. AR-1-C has higher antibacterial activity but displayed less hemolytic activity against human red blood cells than the parent AR-1. AR-1 has a two-stranded antiparallel â-sheet structures forming a large and flexible ring while AR-1-C with two disulfide bonds forming a 12-residue ring has higher structural rigidity and higher hydrophobic-hydrophilic balance than AR-1. Peptide rigidity and optimum balance between the hydrophobic and hydrophilic phase in amphipathic â-sheet structure are important in biological activities of arenicin and its derivative.