Publications by authors named "Eui Kyun Park"

121 Publications

Sulforaphane Alleviates Particulate Matter-Induced Oxidative Stress in Human Retinal Pigment Epithelial Cells.

Front Med (Lausanne) 2021 17;8:685032. Epub 2021 Jun 17.

College of Pharmacy, Kyungpook National University, Daegu, South Korea.

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly, and oxidative damage to retinal pigment epithelial (RPE) cells plays a major role in the pathogenesis of AMD. Exposure to high levels of atmospheric particulate matter (PM) with an aerodynamic diameter of <2.5 μm (PM) causes respiratory injury, primarily due to oxidative stress. Recently, a large community-based cohort study in the UK reported a positive correlation between PM exposure and AMD. Sulforaphane (SFN), a natural isothiocyanate found in cruciferous vegetables, has known antioxidant effects. However, the protective effects of SNF in the eye, especially in the context of AMD, have not been evaluated. In the present study, we evaluated the effect of SFN against PM-induced toxicity in human RPE cells (ARPE-19) and elucidated the molecular mechanism of action. Exposure to PM decreased cell viability in ARPE-19 cells in a time- and dose-dependent manner, potentially due to elevated intracellular reactive oxygen species (ROS). SFN treatment increased ARPE-19 cell viability and decreased PM-induced oxidative stress in a dose-dependent manner. PM-induced downregulation of serum- and glucocorticoid-inducible kinase 1 (SGK1), a cell survival factor, was recovered by SFN. PM treatment decreased the enzymatic activities of the antioxidant enzymes including superoxide dismutase and catalase, which were restored by SFN treatment. Taken together, these findings suggest that SFN effectively alleviates PM-induced oxidative damage in human ARPE-19 cells via its antioxidant effects, and that SFN can potentially be used as a therapeutic agent for AMD, particularly in cases related to PM exposure.
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http://dx.doi.org/10.3389/fmed.2021.685032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247919PMC
June 2021

S100 Calcium-Binding Protein P Secreted from Megakaryocytes Promotes Osteoclast Maturation.

Int J Mol Sci 2021 Jun 7;22(11). Epub 2021 Jun 7.

Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea.

Megakaryocytes (MKs) differentiate from hematopoietic stem cells and produce platelets at the final stage of differentiation. MKs directly interact with bone cells during bone remodeling. However, whether MKs are involved in regulating bone metabolism through indirect regulatory effects on bone cells is unclear. Here, we observed increased osteoclast differentiation of bone marrow-derived macrophages (BMMs) cultured in MK-cultured conditioned medium (MK CM), suggesting that this medium contains factors secreted from MKs that affect osteoclastogenesis. To identify the MK-secreted factor, DNA microarray analysis of the human leukemia cell line K562 and MKs was performed, and S100 calcium-binding protein P (S100P) was selected as a candidate gene affecting osteoclast differentiation. S100P was more highly expressed in MKs than in K562 cells, and showed higher levels in MK CM than in K562-cultured conditioned medium. In BMMs cultured in the presence of recombinant human S100P protein, osteoclast differentiation was promoted and marker gene expression was increased. The resorption area was significantly larger in S100P protein-treated osteoclasts, demonstrating enhanced resorption activity. Overall, S100P secreted from MKs promotes osteoclast differentiation and resorption activity, suggesting that MKs indirectly regulate osteoclast differentiation and activity through the paracrine action of S100P.
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http://dx.doi.org/10.3390/ijms22116129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201154PMC
June 2021

Demineralized Dentin Matrix Particle-Based Bio-Ink for Patient-Specific Shaped 3D Dental Tissue Regeneration.

Polymers (Basel) 2021 Apr 15;13(8). Epub 2021 Apr 15.

Department of Biomedical Engineering, Ulsan National Institute of Science and Technology 50, UNIST-gil, Ulju-gun, Ulsan 44919, Korea.

Demineralized dentin matrix (DDM)-based materials have been actively developed and are well-known for their excellent performance in dental tissue regeneration. However, DDM-based bio-ink suitable for fabrication of engineered dental tissues that are patient-specific in terms of shape and size, has not yet been developed. In this study, we developed a DDM particle-based bio-ink (DDMp bio-ink) with enhanced three-dimensional (3D) printability. The bio-ink was prepared by mixing DDM particles and a fibrinogen-gelatin mixture homogeneously. The effects of DDMp concentration on the 3D printability of the bio-ink and dental cell compatibility were investigated. As the DDMp concentration increased, the viscosity and shear thinning behavior of the bio-ink improved gradually, which led to the improvement of the ink's 3D printability. The higher the DDMp content, the better were the printing resolution and stacking ability of the 3D printing. The printable minimum line width of 10% / DDMp bio-ink was approximately 252 μm, whereas the fibrinogen-gelatin mixture was approximately 363 μm. The ink's cytocompatibility test with dental pulp stem cells (DPSCs) exhibited greater than 95% cell viability. In addition, as the DDMp concentration increased, odontogenic differentiation of DPSCs was significantly enhanced. Finally, we demonstrated that cellular constructs with 3D patient-specific shapes and clinically relevant sizes could be fabricated through co-printing of polycaprolactone and DPSC-laden DDMp bio-ink.
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http://dx.doi.org/10.3390/polym13081294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071469PMC
April 2021

PF-3845, a Fatty Acid Amide Hydrolase Inhibitor, Directly Suppresses Osteoclastogenesis through ERK and NF-κB Pathways In Vitro and Alveolar Bone Loss In Vivo.

Int J Mol Sci 2021 Feb 15;22(4). Epub 2021 Feb 15.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 41940, Korea.

Alveolar bone loss, the major feature of periodontitis, results from the activation of osteoclasts, which can consequently cause teeth to become loose and fall out; the development of drugs capable of suppressing excessive osteoclast differentiation and function is beneficial for periodontal disease patients. Given the difficulties associated with drug discovery, drug repurposing is an efficient approach for identifying alternative uses of commercially available compounds. Here, we examined the effects of PF-3845, a selective fatty acid amide hydrolase (FAAH) inhibitor, on receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclastogenesis, its function, and the therapeutic potential for the treatment of alveolar bone destruction in experimental periodontitis. PF-3845 significantly suppressed osteoclast differentiation and decreased the induction of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and the expression of osteoclast-specific markers. Actin ring formation and osteoclastic bone resorption were also reduced by PF-3845, and the anti-osteoclastogenic and anti-resorptive activities were mediated by the suppression of phosphorylation of rapidly accelerated fibrosarcoma (RAF), mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase, (ERK) and nuclear factor κB (NF-κB) inhibitor (IκBα). Furthermore, the administration of PF-3845 decreased the number of osteoclasts and the amount of alveolar bone destruction caused by ligature placement in experimental periodontitis in vivo. The present study provides evidence that PF-3845 is able to suppress osteoclastogenesis and prevent alveolar bone loss, and may give new insights into its role as a treatment for osteoclast-related diseases.
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http://dx.doi.org/10.3390/ijms22041915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919013PMC
February 2021

Impacts of Drug Interactions on Pharmacokinetics and the Brain Transporters: A Recent Review of Natural Compound-Drug Interactions in Brain Disorders.

Int J Mol Sci 2021 Feb 11;22(4). Epub 2021 Feb 11.

College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.

Natural compounds such as herbal medicines and/or phyto-compounds from foods, have frequently been used to exert synergistic therapeutic effects with anti-brain disorder drugs, supplement the effects of nutrients, and boost the immune system. However, co-administration of natural compounds with the drugs can cause synergistic toxicity or impeditive drug interactions due to changes in pharmacokinetic properties (e.g., absorption, metabolism, and excretion) and various drug transporters, particularly brain transporters. In this review, natural compound-drug interactions (NDIs), which can occur during the treatment of brain disorders, are emphasized from the perspective of pharmacokinetics and cellular transport. In addition, the challenges emanating from NDIs and recent approaches are discussed.
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http://dx.doi.org/10.3390/ijms22041809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917745PMC
February 2021

Fruit Has Anti-Inflammatory Effect and Induces Osteogenic Differentiation by Regulating Nrf2/HO-1 Signaling Pathway in In Vitro and In Vivo Models of Periodontitis.

Antioxidants (Basel) 2020 Dec 3;9(12). Epub 2020 Dec 3.

College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Daegu 42601, Korea.

Periodontitis is an infectious inflammatory disease of tissues around teeth that destroys connective tissues and is characterized by the loss of periodontal ligaments and alveolar bone. A new treatment strategy is needed owing to the limitations of the current surgical treatment method and the side effects of anti-inflammatory drugs. Therefore, here, we assessed whether fruit extract (PGFE) is a new therapeutic agent for periodontitis in vitro and in vivo. According to the results, PGFE suppressed pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, and pro-inflammatory mediators such as inducible nitric oxide synthase and cyclooxygenase-2 through heme oxygenase-1 expression in human periodontal ligament cells stimulated with lipopolysaccharide (PG-LPS). In addition, the osteogenic induction of human periodontal ligament cells was inhibited by PG-LPS, and protein and mRNA levels of osteogenic markers such as alkaline phosphatase, collagen type 1 (COL1), osteopontin (OPN), and runt-related transcription factor 2 (RUNX2) were increased. The efficacy of PGFE for inhibiting periodontitis in vitro was demonstrated in a representative in vitro model of periodontitis induced by ligature and PG-LPS. Subsequently, hematoxylin and eosin staining and micro-computed tomography of the euthanized experimental animal model confirmed suppressed periodontal inflammation, which is an important strategy for treating periodontitis and for recovering the resulting alveolar bone loss. Therefore, PGFE is a potential, novel therapeutic agent for periodontal diseases.
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http://dx.doi.org/10.3390/antiox9121221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761716PMC
December 2020

Secretoneurin, a Neuropeptide, Enhances Bone Regeneration in a Mouse Calvarial Bone Defect Model.

Tissue Eng Regen Med 2021 04 3;18(2):315-324. Epub 2020 Nov 3.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University, 2177 Dalgubeol-daero, Jung-gu, Daegu, 41940, Republic of Korea.

Background: This study investigates the effects of a neuropeptide, secretoneurin (SN), on bone regeneration in an experimental mouse model.

Methods: The effects of SN on cell proliferation, osteoblast marker genes expression, and mineralization were evaluated using the CCK-8 assay, quantitative reverse transcriptase polymerase chain reaction (RT-PCR), and alizarin red S staining, respectively. To examine the effects of SN on bone regeneration in vivo, bone defects were created in the calvaria of ICR mice, and 0.5 or 1 µg/ml SN was applied. New bone formation was analyzed by micro-computed tomography (micro-CT) and histology. New blood vessel formation was assessed by CD34 immunohistochemistry.

Results: SN had no significant effect on proliferation and mineralization of MC3T3-E1 cells. However, SN partially induced the gene expression of osteoblast differentiation markers such as runt-related transcription factor 2, alkaline phosphatase, collagen type I alpha 1, and osteopontin. A significant increase of bone regeneration was observed in SN treated calvarial defects. The bone volume (BV), BV/tissue volume, trabecular thickness and trabecular number values were significantly increased in the collagen sponge plus 0.5 or 1 µg/ml SN group (p < 0.01) compared with the control group. Histologic analysis also revealed increased new bone formation in the SN-treated groups. Immunohistochemical staining of CD34 showed that the SN-treated groups contained more blood vessels compared with control in the calvarial defect area.

Conclusion: SN increases new bone and blood vessel formation in a calvarial defect site. This study suggests that SN may enhance new bone formation through its potent angiogenic activity.
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http://dx.doi.org/10.1007/s13770-020-00304-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012437PMC
April 2021

Developmental Roles of FUSE Binding Protein 1 () in Tooth Morphogenesis.

Int J Mol Sci 2020 Oct 29;21(21). Epub 2020 Oct 29.

Department of Biochemistry, School of Dentistry, IHBR, Kyungpook National University, 2177, Dalgubeol-daero, Jung-gu, Daegu 41940, Korea.

FUSE binding protein 1 (), a regulator of the c-Myc transcription factor and a DNA/RNA-binding protein, plays important roles in the regulation of gene transcription and cellular physiology. In this study, to reveal the precise developmental function of , we examined the detailed expression pattern and developmental function of during tooth morphogenesis by RT-qPCR, in situ hybridization, and knock-down study using in vitro organ cultivation methods. In embryogenesis, is obviously expressed in the enamel organ and condensed mesenchyme, known to be important for proper tooth formation. Knocking down at E14 for two days, showed the altered expression patterns of tooth development related signalling molecules, including and . In addition, transient knock-down of at E14 revealed changes in the localization patterns of c-Myc and cell proliferation in epithelium and mesenchyme, related with altered tooth morphogenesis. These results also showed the decreased amelogenin and dentin sialophosphoprotein expressions and disrupted enamel rod and interrod formation in one- and three-week renal transplanted teeth respectively. Thus, our results suggested that plays a modulating role during dentinogenesis and amelogenesis by regulating the expression pattern of signalling molecules to achieve the proper structural formation of hard tissue matrices and crown morphogenesis in mice molar development.
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http://dx.doi.org/10.3390/ijms21218079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663687PMC
October 2020

Cytoprotective effects of fermented oyster extracts against oxidative stress-induced DNA damage and apoptosis through activation of the Nrf2/HO-1 signaling pathway in MC3T3-E1 osteoblasts.

EXCLI J 2020 4;19:1102-1119. Epub 2020 Aug 4.

Anti-Aging Research Center, Dong-eui University, Busan, Republic of Korea.

Osteoblast damage by oxidative stress has been recognized as a cause of bone-related disease, including osteoporosis. Recently, we reported that fermented Pacific oyster () extracts (FO) inhibited osteoclastogenesis and osteoporosis, while promoting osteogenesis. However, since the beneficial potential of FO on osteoblasts is not well known, in the present study, we investigated the cytoprotective effect of FO against oxidative stress in MC3T3-E1 osteoblasts. Our results demonstrated that FO inhibited hydrogen peroxide (HO)-induced DNA damage and cytotoxicity through the rescue of mitochondrial function by blocking abnormal ROS accumulation. FO also prevented apoptosis by suppressing loss of mitochondrial membrane potential and cytosolic release of cytochrome , decreasing the rate of Bax/Bcl-2 expression and reducing the activity of caspase-9 and caspase-3 in HO-stimulated MC3T3-E1 osteoblasts, suggesting that FO protected MC3T3-E1 osteoblasts from the induction of caspase dependent- and mitochondria-mediated apoptosis by oxidative stress. In addition, FO markedly promoted the activation of nuclear factor-erythroid-2-related factor 2 (Nrf2), which was associated with the enhanced expression of heme oxygenase-1 (HO-1). However, inhibiting the expression of HO-1 by artificially blocking the expression of Nrf2 using siRNA significantly eliminated the protective effect of FO, indicating that FO activates the Nrf2/HO-1 signaling pathway in MC3T3-E1 osteoblasts to protect against oxidative stress. Based on the present data, FO is thought to be useful as a potential therapeutic agent for the inhibition of oxidative stress in osteoblasts.
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http://dx.doi.org/10.17179/excli2020-2376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527492PMC
August 2020

Gamma Aminobutyric Acid-Enriched Fermented Oyster () Increases the Length of the Growth Plate on the Proximal Tibia Bone in Sprague-Dawley Rats.

Molecules 2020 Sep 23;25(19). Epub 2020 Sep 23.

Anti-Aging Research Center, Dong-eui University, Busan 47340, Korea.

Bone growth during childhood and puberty determines an adult's final stature. Although several prior studies have reported that fermented oyster (FO) consisting of a high amount of gamma aminobutyric acid can be attributed to bone health, there is no research on the efficacy of FO on growth regulation and the proximal tibial growth plate. Therefore, in this study, we investigated the effect of FO oral administration on hepatic and serum growth regulator levels and the development of the proximal tibial growth plate in young Sprague-Dawley rats. Both oral administration of FO (FO 100, 100 mg/kg FO and FO 200, 200 mg/kg FO) and subcutaneous injection of recombinant human growth hormone (rhGH, 200 μg/kg of rhGH) for two weeks showed no toxicity. Circulating levels of growth hormone (GH) significantly increased in the FO 200 group. The expression and secretion of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) were enhanced by FO administration. FO administration promoted the expression of bone morphogenic proteins IGF-1 and IGFBP-3 in the proximal tibial growth plate. This positive effect of FO resulted in incremental growth of the entire plate length by expanding the proliferating and hypertrophic zones in the proximal tibial growth plate. Collectively, our results suggested that oral administration of FO is beneficial for bone health, which may ultimately result in increased height.
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http://dx.doi.org/10.3390/molecules25194375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582314PMC
September 2020

Fermented Oyster Extract Promotes Insulin-Like Growth Factor-1-Mediated Osteogenesis and Growth Rate.

Mar Drugs 2020 Sep 18;18(9). Epub 2020 Sep 18.

Department of Marine Life Science, Jeju National University, Jeju 63243, Korea.

Fermented oyster () extract (FO) prevents ovariectomy-induced osteoporosis by inhibiting osteoclastogenesis and activating osteogenesis. However, the molecular mechanisms underlying FO-mediated bone formation and growth rate are unclear. In the current study, we found that FO significantly upregulated the expression of growth-promoting genes in zebrafish larvae including insulin-like growth factor 1 (), insulin-like growth factor binding protein 3 (), growth hormone-1 (), growth hormone receptor-1 (), growth hormone receptor alpha (), glucokinase (), and cholecystokinin (). In addition, zebrafish larvae treated with 100 μg/mL FO increased in total body length (3.89 ± 0.13 mm) at 12 days post fertilization (dpf) compared to untreated larvae (3.69 ± 0.02 mm); this effect was comparable to that of the β-glycerophosphate-treated zebrafish larvae (4.00 ± 0.02 mm). Furthermore, FO time- and dose-dependently increased the extracellular release of IGF-1 from preosteoblast MC3T3-E1 cells, which was accompanied by high expression of . Pharmacological inhibition of IGF-1 receptor (IGF-1R) using picropodophyllin (PPP) significantly reduced FO-mediated vertebrae formation (from 9.19 ± 0.31 to 5.53 ± 0.35) and growth performance (from 3.91 ± 0.02 to 3.69 ± 0.01 mm) in zebrafish larvae at 9 dpf. Similarly, PPP significantly decreased FO-induced calcium deposition in MC3T3-E1 cells by inhibiting GSK-3β phosphorylation at Ser9. Additionally, DOI hydrochloride, a potent stabilizer of GSK-3β, reduced FO-induced nuclear translocation of RUNX2. Transient knockdown of / using specific silencing RNA also resulted in a significant decrease in calcium deposition and reduction in GSK-3β phosphorylation at Ser9 in MC3T3-E1 cells. Altogether, these results indicate that FO increased phosphorylated GSK-3β at Ser9 by activating the autocrine IGF-1-mediated IGF-1R signaling pathway, thereby promoting osteogenesis and growth performance. Therefore, FO is a potential nutritional supplement for bone formation and growth.
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http://dx.doi.org/10.3390/md18090472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551862PMC
September 2020

Inhibitory effect of oolonghomobisflavan B on osteoclastogenesis by suppressing p38 MAPK activation.

Bioorg Med Chem Lett 2020 09 21;30(18):127429. Epub 2020 Jul 21.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 41940, Republic of Korea. Electronic address:

Suppression of differentiation and/or function of osteoclasts is considered an effective therapeutic strategy for osteolytic bone diseases such as periodontitis and osteoporosis. Evidence regarding the health benefits of oolong tea consumption is accumulating, and tea polyphenols have various pharmacological properties such as anti-cancer and anti-diabetes effects. In this study, we investigated the effect of oolonghomobisflavan B (OFB), a polyphenolic compound in oolong tea, on osteoclast differentiation. OFB suppressed receptor activator of nuclear factor-κB (RANKL)-induced formation of tartate-resistant acid phosphatase-positive multinuclear cells without cytotoxicity. OFB also significantly attenuated p38 phosphorylation, which is essential for RANKL-induced osteoclastogenesis, and inhibited the expressions of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and osteoclast-specific target genes, including dendritic cell-specific transmembrane protein and cathepsin K. Our findings suggest that OFB exhibits an anti-osteoclastogenic activity by inhibiting RANKL-mediated p38 activation, which is useful for the prevention and treatment of osteolytic bone diseases.
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http://dx.doi.org/10.1016/j.bmcl.2020.127429DOI Listing
September 2020

Bobby sox homolog regulates tooth root formation through modulation of dentin sialophosphoprotein.

J Cell Physiol 2021 Jan 14;236(1):480-488. Epub 2020 Jun 14.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Institute for Hard Tissue and Biotooth Regeneration, Kyungpook National University, Daegu, Republic of Korea.

Tooth root development occurs through the interaction of multiple growth factors and transcription factors expressed in Hertwig's epithelial root sheath (HERS) and dental mesenchyme. Previously, we demonstrated that bobby sox homolog (Bbx) regulates odontoblast differentiation of human dental pulp stem cells. Here, we generated Bbx knockout (Bbx ) mice to address the functional role of Bbx in tooth formation. During tooth development, Bbx was expressed in both dental epithelium and mesenchyme. However, molar and incisor morphology in Bbx mice at postnatal Day 0 (P0) exhibited no prominent abnormalities compared with their wild-type (Bbx ) littermates. Until P28, the crown morphology in Bbx mice was not distinctively different from Bbx littermates. Meanwhile, the length of the mandibular base in Bbx mice was notably less at P28. Compared with Bbx mice, the mesial and distal root lengths of the first molar were reduced by 21.33% and 16.28% at P14 and 16.28% and 16.24% at P28, respectively, in Bbx mice. The second molar of Bbx mice also showed 10.16% and 6.4% reductions at P28 in the mesial and distal lengths, compared with Bbx mice, respectively. The gene expression analysis during early tooth root formation (P13) showed that the expression of dentin sialophosphoprotein (Dspp) was significantly decreased in Bbx mice. Collectively, our data suggest that Bbx participates in tooth root formation and might be associated with the regulation of Dspp expression.
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http://dx.doi.org/10.1002/jcp.29875DOI Listing
January 2021

Effect of fermented oyster extract on growth promotion in Sprague-Dawley rats.

Integr Med Res 2020 Dec 7;9(4):100412. Epub 2020 Apr 7.

Anti-Aging Research Center, Dong-eui University, Busan, Republic of Korea.

Background: Oysters () are a popular marine product worldwide and have the advantage of nutritional benefits. This study aimed to investigate the effect of fermented oyster extract (FO) on growth promotion, including analysis of body size, bone microarchitecture, hematology and biochemistry .

Methods: The amount of nutrients and gamma aminobutyric acid (GABA) were determined. Sprague-Dawley rats were randomly divided into four groups: the control group, FO 50 group (FO 50 mg/kg), and FO 100 group (FO 100 mg/kg) were administered orally once daily and the recombinant human growth hormone (rhGH) group (200 μg/kg) was intraperitoneally injected once daily for 14 days.

Results: Oral administration of FO 100 significantly increased body length and had no effect on organ damage or hematological profiles. However, administration of rhGH significantly induced hypertrophy of the liver, kidney and spleen along with a marked increase in body length. Tibia length and the growth plate were increased, and bone morphometric parameters were slightly improved by FO and rhGH administration. Serum analysis showed that the levels of GH and insulin like growth factor-1 (IGF-1) were slightly upregulated by FO administration. Nevertheless, the protein expression of hepatic IGF-1 was markedly increased by FO 100 and rhGH administration.

Conclusions: FO have high content of GABA, and induced positive effects on body length, tibial length, growth-plate length and hepatic IGF-1 synthesis in SD rats with no toxicity or alterations of hematological profile. Therefore, these results suggest that GABA-enriched FO could be considered a potential alternative treatment for growth stimulation.
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http://dx.doi.org/10.1016/j.imr.2020.100412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264051PMC
December 2020

Inhibitory functions of maslinic acid, a natural triterpene, on HMGB1-mediated septic responses.

Phytomedicine 2020 Apr 4;69:153200. Epub 2020 Mar 4.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea. Electronic address:

Background: Maslinic acid (MA), a natural triterpenoid from Olea europaea, prevents oxidative stress and pro-inflammatory cytokine generation. High mobility group box 1 (HMGB1) has been recognized as a late mediator of sepsis, and the inhibition of the release of HMGB1 and the recovery of vascular barrier integrity have emerged as attractive therapeutic strategies for the management of sepsis.

Methods: We tested the hypothesis that MA induces sirtuin 1 and heme oxygenase-1, which inhibit the release of HMGB1 in lipopolysaccharide (LPS)-stimulated cells, thus inhibiting HMGB1-induced hyperpermeability and increasing the survival of septic mice. MA was administered after LPS or HMGB1 challenge, and the antiseptic activity of MA was determined based on permeability, the activation of pro-inflammatory proteins, and the production of markers for tissue injury in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model.

Results: MA significantly reduced the release of HMGB1 in LPS-activated HUVECs and attenuated the CLP-induced release of HMGB1. Additionally, MA alleviated HMGB1-mediated vascular disruption and inhibited hyperpermeability in mice, and in vivo analysis revealed that MA reduced sepsis-related mortality and tissue injury.

Conclusion: Taken together, the present results suggest that MA reduced HMGB1 release and septic mortality and thus may be useful in the treatment of sepsis.
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http://dx.doi.org/10.1016/j.phymed.2020.153200DOI Listing
April 2020

Inhibitory functions of maslinic acid on particulate matter-induced lung injury through TLR4-mTOR-autophagy pathways.

Environ Res 2020 04 5;183:109230. Epub 2020 Feb 5.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu, 41566, Republic of Korea. Electronic address:

Particulate matter (PM), the collection of all liquid and solid particles suspended in air, includes both organic and inorganic particles, many of which are health-hazards. PM particles with a diameter equal to or less than 2.5 μm (PM) is a form of air pollutant that causes significant lung damage when inhaled. Maslinic acid (MA) prevents oxidative stress and pro-inflammatory cytokine generation, but there is little information available regarding its role in PM-induced lung injury. Therefore, the purpose of this study was to determine the protective activity of MA against PM-induced lung injury. The mice were divided into seven groups (n = 10 each): a mock control group, an MA control (0.8 mg/kg mouse body weight) group, an opted PM produced from diesel (10 mg/kg mouse body weight) group, a diesel PM+MA (0.2, 0.4, 0.6, and 0.8 mg/kg mouse body weight) groups. Mice were treated with MA via tail-vein injection 30 min after the intratracheal instillation of a diesel PM. Changes in the wet/dry weight ratio of the lung tissue, total protein/total cell and lymphocyte counts, inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were monitored in diesel PM-treated mice. The results showed that MA reduced pathological lung injury, the wet/dry weight ratio of the lung tissue, and hyperpermeability caused by diesel PM. MA also inhibited diesel PM-induced myeloperoxidase (MPO) activity in the lung tissue, decreased the levels of diesel PM-induced inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1β, reduced nitric oxide (NO) and total protein in the BALF, and effectively attenuated diesel PM-induced increases in the number of lymphocytes in the BALF. In addition, MA increased the protein phosphorylation of the mammalian target of rapamycin (mTOR) and dramatically suppressed diesel PM-stimulated expression of toll-like receptor 4 (TLR4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1. In conclusion, these findings indicate that MA has a critical anti-inflammatory effect due to its ability to regulate both the TLR4-MyD88 and mTOR-autophagy pathways and may thus be a potential therapeutic agent against diesel PM-induced lung injury.
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http://dx.doi.org/10.1016/j.envres.2020.109230DOI Listing
April 2020

Maslinic Acid Ameliorates Inflammation via the Downregulation of NF-κB and STAT-1.

Antioxidants (Basel) 2020 Jan 25;9(2). Epub 2020 Jan 25.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Korea.

Maslinic acid (MA), a natural compound of the triterpenoid group derived from olive, prevents the generation of pro-inflammatory cytokines and oxidative stress. In human umbilical vein endothelial cells (HUVECs) treated with lipopolysaccharide (LPS), we characterized the effects of MA on the regulation of heme oxygenase (HO)-1, cyclooxygenase (COX-)2, and inducible nitric oxide synthase (iNOS). MA was tested in the lung tissues of LPS-treated mice, to determine its effect on levels of iNOS expression and representative inflammatory mediators such as interleukin (IL)-1 and tumor necrosis factor (TNF)-. We show that MA induced the expression of HO-1, reduced LPS-induced NF-κB-luciferase activity, and inhibited iNOS/NO and COX-2/PGE2, resulting in the downregulation of STAT-1 phosphorylation. Furthermore, our data show that MA induced the nuclear translocation of Nrf2, increased the binding of Nrf2 to ARE, and decreased IL-1 production in LPS-treated HUVECs. The MA-induced reduction in iNOS/NO expression was reversed by RNAi suppression of HO-1. In mice treated with LPS, MA significantly downregulated levels of iNOS in lung tissue and TNF- in the bronchoalveolar lavage fluid. Taken together, our findings indicate that MA exerts a critical anti-inflammatory effect by modulating iNOS via the downregulation of NF-κB and p-STAT-1. Thus, we propose that MA may be an ideal substance to treat inflammatory diseases.
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http://dx.doi.org/10.3390/antiox9020106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070941PMC
January 2020

GSK-3β-Targeting Fisetin Promotes Melanogenesis in B16F10 Melanoma Cells and Zebrafish Larvae through β-Catenin Activation.

Int J Mol Sci 2020 Jan 2;21(1). Epub 2020 Jan 2.

Department of Marine Life Sciences, Jeju National University, Jeju 63243, Korea.

Fisetin is found in many fruits and plants such as grapes and onions, and exerts anti-inflammatory, anti-proliferative, and anticancer activity. However, whether fisetin regulates melanogenesis has been rarely studied. Therefore, we evaluated the effects of fisetin on melanogenesis in B16F10 melanoma cell and zebrafish larvae. The current study revealed that fisetin slightly suppressed in vitro mushroom tyrosinase activity; however, molecular docking data showed that fisetin did not directly bind to mushroom tyrosinase. Unexpectedly, fisetin significantly increased intracellular and extracellular melanin production in B16F10 melanoma cells regardless of the presence or absence of α-melanocyte stimulating hormone (α-MSH). We also found that the expression of melanogenesis-related genes such as and (), were highly increased 48 h after fisetin treatment. Pigmentation of zebrafish larvae by fisetin treatment also increased at the concentrations up to 200 µM and then slightly decreased at 400 µM, with no alteration in the heart rates. Molecular docking data also revealed that fisetin binds to glycogen synthase kinase-3β (GSK-3β). Therefore, we evaluated whether fisetin negatively regulated GSK-3β, which subsequently activates β-catenin, resulting in melanogenesis. As expected, fisetin increased the expression of β-catenin, which was subsequently translocated into the nucleus. In the functional assay, FH535, a Wnt/β-catenin inhibitor, significantly inhibited fisetin-mediated melanogenesis in zebrafish larvae. Our data suggested that fisetin inhibits GSK-3β, which activates β-catenin, resulting in melanogenesis through the revitalization of MITF and tyrosinase.
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http://dx.doi.org/10.3390/ijms21010312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982351PMC
January 2020

Fermented Oyster Extract Promotes Osteoblast Differentiation by Activating the Wnt/β-Catenin Signaling Pathway, Leading to Bone Formation.

Biomolecules 2019 11 6;9(11). Epub 2019 Nov 6.

Department of Marine Life Science, Jeju National University, Jeju 63243, Korea.

The Pacific oyster, , is well-known as a nutritious food. Recently, we revealed that fermented extract of (FO) inhibited ovariectomy-induced osteoporosis, resulting from suppression of osteoclastogenesis. However, since the beneficial effect of FO on osteogenesis is poorly understood, it was examined in mouse preosteoblast MC3T3-E1 cells, human osteosarcoma MG-63 osteoblast-like cells, and zebrafish larvae in this study. We found that FO increased mitochondrial activity from days 1 to 7; however, total cell number of MC3T3-E1 cells gradually decreased without any change in cell viability, which suggests that FO stimulates the differentiation of MC3T3-E1 cells. FO also promoted the expression of osteoblast marker genes, including , , , , , , and in MC3T3-E1 cells accompanied by a significant increase in ALP activity. FO also increased nuclear translocation of RUNX2 and OSX transcription factors, ALP activity, and calcification in vitro along with the upregulated expression of osteoblast-specific marker proteins such as RUNX2, ALP, Col1α1, OCN, OSX, and BMP4. Additionally, FO enhanced bone mineralization (calcein intensity) in zebrafish larvae at 9 days post-fertilization comparable to that in the β-glycerophosphate (GP)-treated group. All the tested osteoblast marker genes, including , , , , , , and , were also remarkably upregulated in the zebrafish larvae in response to FO. It also promoted tail fin regeneration in adult zebrafish as same as the GP-treated groups. Furthermore, not only FO positively regulate β-catenin expression and Wnt/β-catenin luciferase activity, but pretreatment with a Wnt/β-catenin inhibitor (FH535) also significantly decreased FO-mediated bone mineralization in zebrafish larvae, which indicates that FO-induced osteogenesis depends on the Wnt/β-catenin pathway. Altogether, the current study suggests that the supplemental intake of FO has a beneficial effect on osteogenesis.
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http://dx.doi.org/10.3390/biom9110711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920898PMC
November 2019

Flumequine-Mediated Upregulation of p38 MAPK and JNK Results in Melanogenesis in B16F10 Cells and Zebrafish Larvae.

Biomolecules 2019 10 11;9(10). Epub 2019 Oct 11.

Department of Marine Life Sciences, Jeju National University, Jeju 63243, Korea.

Flumequine is a well-known second generation quinolone antibiotic that induces phototoxicity. However, the effect of flumequine on skin melanogenesis is unclear. Therefore, we, for the first time, investigated whether flumequine regulates melanogenesis. The present study showed that flumequine slightly inhibited mushroom tyrosinase activity but significantly increased extracellular and intracellular melanin content in B16F10 cells and promoted the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase. Additionally, flumequine remarkably increased melanin pigmentation in zebrafish larvae without any toxicity. We also found that flumequine stimulated p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation; inhibition of p38 MAPK and JNK resulted in significant downregulation of extracellular and intracellular melanin content in B16F10 cells and pigmentation of zebrafish larvae accompanied with suppression of MITF and tyrosinase expression, indicating that flumequine-mediated p38 and JNK promote melanogenesis and . According to the molecular docking prediction, flumequine targeted dual-specificity MAPK phosphatase 16 (DUSP16), which is a major negative regulator of p38 MAPK and JNK. Our findings demonstrate that flumequine induces an increase in melanin content in B16F10 cells and zebrafish larvae by activating p38 MAPK and JNK. These data show the potential of flumequine for use as an anti-vitiligo agent.
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http://dx.doi.org/10.3390/biom9100596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843389PMC
October 2019

Stimulatory Effects of KPR-A148 on Osteoblast Differentiation and Bone Regeneration.

Tissue Eng Regen Med 2019 08 17;16(4):405-413. Epub 2019 Jul 17.

1Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Institute for Hard Tissue and Bio-tooth Regeneration (IHBR), Kyungpook National University, 2177 Dalgubeol-daero, Jung-gu, Daegu, 41940 Republic of Korea.

Background: Xanthine derivatives have been used to treat a variety of medical conditions including respiratory disease and neural degeneration. However, few studies have reported their effects on bone regeneration. Therefore, we investigated the effects of KPR-A148, a synthetic xanthine derivative on osteoblast differentiation and bone regeneration .

Methods: The cytotoxicity of KPR-A148 was evaluated using MC3T3-E1 cells by the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltertrazolium bromide assay. The effects of KPR-A148 on osteoblast differentiation were examined by alkaline phosphatase staining, Alizarin red S staining, and real-time PCR of osteoblast differentiation marker genes. To investigate the effects of KPR-A148 on bone regeneration, a KPR-A148-containing collagen sponge was implanted into a mouse calvarial defect and KPR-A148 was injected twice, weekly. Bone regeneration was evaluated quantitatively by micro-CT and qualitatively by hematoxylin and eosin, as well as Masson's Trichrome staining.

Results: KPR-A148 did not show toxicity in the MC3T3-E1 cells and promoted osteoblast differentiation in a concentration-dependent manner. 10 μM of KPR-A148 showed the most significant effect on alkaline phospatase staining and matrix mineralization. KPR-A148 increased the expression of osteoblast marker genes in both the early and late stages of differentiation. In addition, KPR-A148 significantly induced new bone formation in the calvarial defect model.

Conclusion: These results demonstrate that KPR-A148 strongly induces osteoblast differentiation and new bone formation. Therefore, it could be used as a potential therapeutic agent for regenerating bone following its destruction by disease or trauma.
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http://dx.doi.org/10.1007/s13770-019-00200-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675851PMC
August 2019

Inhibitory effects of cudratricusxanthone O on particulate matter-induced pulmonary injury.

Int J Environ Health Res 2021 Apr 13;31(3):271-284. Epub 2019 Aug 13.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University , Daegu, Republic of Korea.

Particulate matter 2.5 (PM), aerodynamic diameter ≤ 2.5 μm, is the primary air pollutant that plays the key role for lung injury resulted from the loss of vascular barrier integrity. Cudratricusxanthone O (CTXO) is a novel xanthone compound isolated from the root of Bureau. Here, we investigated the beneficial effects of CTXO against PM-induced lung endothelial cell (EC) barrier disruption and pulmonary inflammation. Permeability, leukocyte migration, activation of proinflammatory proteins, generation of reactive oxygen species (ROS), and histology were examined in PM-treated ECs and mice. CTXO significantly scavenged PM-induced ROS and inhibited the ROS-induced activation of p38 mitogen-activated protein kinase (MAPK). Concurrently, CTXO activated Akt, which helped maintain endothelial integrity. Furthermore, CTXO reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in the bronchoalveolar lavage fluid in PM-induced lung tissues. These results indicated that CTXO may exhibit protective effects against PM-induced inflammatory lung injury and vascular hyperpermeability.
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http://dx.doi.org/10.1080/09603123.2019.1652252DOI Listing
April 2021

Fermented Sea Tangle ( Aresch) Suppresses RANKL-Induced Osteoclastogenesis by Scavenging ROS in RAW 264.7 Cells.

Foods 2019 Jul 26;8(8). Epub 2019 Jul 26.

Department of Biochemistry, Dong-eui University College of Korean Medicine, Busan 47227, Korea.

Sea tangle ( Aresch), a brown alga, has been used for many years as a functional food ingredient in the Asia-Pacific region. In the present study, we investigated the effects of fermented sea tangle extract (FST) on receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-stimulated osteoclast differentiation, using RAW 264.7 mouse macrophage cells. FST was found to inhibit the RANKL-stimulated activation of tartrate-resistance acid phosphatase (TRAP) and F-actin ring structure formation. FST also down-regulated the expression of osteoclast marker genes like TRAP, matrix metalloproteinase-9, cathepsin K and osteoclast-associated receptor by blocking RANKL-induced activation of NF-κB and expression of nuclear factor of activated T cells c1 (NFATc1), a master transcription factor. In addition, FST significantly abolished RANKL-induced generation of reactive oxygen species (ROS) by activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and its transcriptional targets. Hence, it seems likely that FST may have anti-osteoclastogenic potential as a result of its ability to inactivate the NF-κB-mediated NFATc1 signaling pathway and by reducing ROS production through activation of the Nrf2 pathway. Although further studies are needed to inquire its efficacy in vivo, FST appears to have potential use as an adjunctive or as a prophylactic treatment for osteoclastic bone disease.
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http://dx.doi.org/10.3390/foods8080290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723172PMC
July 2019

Inhibitory effects of compounds isolated from Decne peel on particulate matter-induced pulmonary injury in mice.

J Toxicol Environ Health A 2019 25;82(12):727-740. Epub 2019 Jul 25.

a College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University , Daegu , Republic of Korea.

Particulate matter 2.5 (PM), with an aerodynamic diameter of ≤2.5 μm, is the primary air pollutant that plays a key role associated with lung injury produced by loss of vascular barrier integrity. Decne (Chinese yam), a perennial plant belonging to Dioscoreaceae family, is widely cultivated in tropical and subtropical regions across Asia. Both aerial parts and root of are consumed for nutritional and medicinal purposes. The aim of this study was to (1) identify the bioactive compounds present in peel which may be responsible for inhibition of PM-induced pulmonary inflammation in mice and (2) examine mechanisms underlying the observed effects of these compounds on mouse lung microvascular endothelial cells. The measured parameters include permeability, leukocyte migration, proinflammatory protein activation, reactive oxygen species (ROS) generation, and histology. Two phenanthrene compounds, 2,7-dihydroxy-4,6-dimethoxyphenanthrene (1) and 6,7-dihydroxy-2,4-dimethoxyphenanthrene (2) were isolated from peels. Both these phenanthrene compounds exhibited significant scavenging activity against PM-induced ROS and inhibited ROS-induced activation of p38 mitogen-activated protein kinase. In addition, enhancement of Akt pathway, involved in the maintenance of endothelial integrity, was noted. These phenanthrene compounds also reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in the bronchoalveolar lavage fluid obtained from PM-induced lung tissues. Evidence thus indicates that phenanthrene compounds derived from may exhibit protective effects against PM-induced inflammatory lung injury and vascular hyperpermeability in mice.
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http://dx.doi.org/10.1080/15287394.2019.1646174DOI Listing
May 2020

Fermented Oyster Extract Prevents Ovariectomy-Induced Bone Loss and Suppresses Osteoclastogenesis.

Nutrients 2019 Jun 21;11(6). Epub 2019 Jun 21.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 41940, Korea.

There is growing interest in bioactive substances from marine organisms for their potential use against diverse human diseases. Osteoporosis is a skeletal disorder associated with bone loss primarily occurring through enhanced osteoclast differentiation and resorption. Recently, we reported the anti-osteoclastogenic activity of fermented Pacific oyster () extract (FO) in vitro. The present study focused on investigating the anti-osteoporotic efficacy of FO in bone loss prevention in an experimental animal model of osteoporosis and elucidating the mechanism underlying its effects. Oral administration of FO significantly decreased ovariectomy-induced osteoclast formation and prevented bone loss, with reduced serum levels of bone turnover biomarkers including osteocalcin and C-terminal telopeptide fragment of type I collagen C-terminus (CTX). FO significantly suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced differentiation of bone marrow-derived macrophages (BMMs) into osteoclasts and attenuated the induction of osteoclast-specific genes required for osteoclastogenesis and bone resorption. Furthermore, FO inhibited RANKL-mediated IκBα and p65 phosphorylation in BMMs. Taken together, these results demonstrate that FO effectively suppresses osteoclastogenesis in vivo and in vitro, and that FO can be considered as a potential therapeutic option for the treatment of osteoporosis and osteoclast-mediated skeletal diseases.
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http://dx.doi.org/10.3390/nu11061392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627411PMC
June 2019

Pentamidine Inhibits Titanium Particle-Induced Osteolysis and Receptor Activator of Nuclear Factor-κB Ligand-Mediated Osteoclast Differentiation .

Tissue Eng Regen Med 2019 06 2;16(3):265-273. Epub 2019 Apr 2.

2Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, 2177 Dalgubeol-daero, Jung-gu, Daegu, 41940 Republic of Korea.

Background: Wear debris-induced osteolysis leads to periprosthetic loosening and subsequent prosthetic failure. Since excessive osteoclast formation is closely implicated in periprosthetic osteolysis, identification of agents to suppress osteoclast formation and/or function is crucial for the treatment and prevention of wear particle-induced bone destruction. In this study, we examined the potential effect of pentamidine treatment on titanium (Ti) particle-induced osteolysis, and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis.

Methods: The effect of pentamidine treatment on bone destruction was examined in Ti particle-induced osteolysis mouse model. Ti particles were implanted onto mouse calvaria, and vehicle or pentamidine was administered for 10 days. Then, calvarial bone tissue was analyzed using micro-computed tomography and histology. We performed osteoclastogenesis assay using bone marrow-derived macrophages (BMMs) to determine the effect of pentamidine on osteoclast formation. BMMs were treated with 20 ng/mL RANKL and 10 ng/mL macrophage colony-stimulating factor in the presence or absence of pentamidine. Osteoclast differentiation was determined by tartrate-resistant acid phosphatase staining, real-time polymerase chain reaction, and immunofluorescence staining.

Results: Pentamidine administration decreased Ti particle-induced osteoclast formation significantly and prevented bone destruction compared to the Ti particle group . Pentamidine also suppressed RANKL-induced osteoclast differentiation and actin ring formation markedly, and inhibited the expression of nuclear factor of activated T cell c1 and osteoclast-specific genes . Additionally, pentamidine also attenuated RANKL-mediated phosphorylation of IκBα in BMMs.

Conclusion: These results indicate that pentamidine is effective in inhibiting osteoclast formation and significantly attenuates wear debris-induced bone loss in mice.
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http://dx.doi.org/10.1007/s13770-019-00186-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542890PMC
June 2019

2-O-digalloyl-1,3,4,6-tetra-O-galloyl-β-D-glucose isolated from Galla Rhois suppresses osteoclast differentiation and function by inhibiting NF-κB signaling.

BMB Rep 2019 Jun;52(6):409-414

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 41940, Korea.

Natural compounds isolated from medicinal herbs and plants have immense significance in maintaining bone health. Hydrolysable tannins have been shown to possess a variety of medicinal properties including antiviral, anticancer, and anti-osteoclastogenic activities. As a part of a study on the discovery of alternative agent against skeletal diseases, we isolated a hydrolysable tannin, 2-O-digalloyl-1,3,4,6-tetra-Ogalloyl- β-D-glucose (DTOGG), from Galla Rhois and examined the effect on osteoclast formation and function. We found that DTOGG significantly inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation by downregulating the expression of the key regulator in osteoclastogenesis as well as osteoclast-related genes. Analysis of RANKL/RANK signaling revealed that DTOGG impaired activation of IκBα and p65 in the nuclear factor kappa-lightchain- enhancer of activated B cells (NF-κB) signaling pathway. Furthermore, DTOGG reduced bone resorbing activity of osteoclasts, compared to the vehicle-treated control. These results suggest that DTOGG could be a useful natural compound to manage osteoclast-mediated skeletal diseases. [BMB Reports 2019; 52(6): 409-414].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605525PMC
June 2019

Ablation of Stabilin-1 Enhances Bone-Resorbing Activity in Osteoclasts In Vitro.

Calcif Tissue Int 2019 08 25;105(2):205-214. Epub 2019 Apr 25.

Department of Molecular Medicine, CMRI, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea.

Stabilin-1 is a transmembrane receptor that regulates molecule recycling and cell homeostasis by controlling the intracellular trafficking and participates in cell-cell adhesion and transmigration. Stabilin-1 expression is observed in various organs, including bones; however, its function and regulatory mechanisms in the bone remain unclear. In this study, we evaluated the physiological function of stabilin-1 in bone cells and tissue using a stabilin-1 knockout (Stab1 KO) mouse model. In wild-type (WT) mice, stabilin-1 was expressed in osteoblasts and osteoclasts, and its expression was maintained during osteoblast differentiation but significantly decreased after osteoclast differentiation. There was no difference in osteoblast differentiation and function, or the expression of osteoblast differentiation markers between mesenchymal stem cells isolated from Stab1 KO and WT mice. However, osteoclast differentiation marker levels demonstrated a non-significant increase and bone-resorbing activity was significantly increased in vitro in RANKL-induced osteoclasts from Stab1-deficient bone marrow macrophages (BMMs) compared with those of WT BMMs. Microcomputed tomography showed a negligible difference between WT and Stab1 KO mice in bone volume and trabecular thickness and number. Moreover, no in vivo functional defect in bone formation by osteoblasts was observed in the Stab1 KO mice. The osteoclast surface and number showed an increased tendency in Stab1 KO mice compared to WT mice in vivo, but this difference was not statistically significant. Overall, these results indicate that Stab1 does not play an essential role in in vivo bone development and bone cell function, but it does affect in vitro osteoclast maturation and function for bone resorption.
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http://dx.doi.org/10.1007/s00223-019-00552-xDOI Listing
August 2019

Inhibitory Effect of KP-A038 on Osteoclastogenesis and Inflammatory Bone Loss Is Associated With Downregulation of Blimp1.

Front Pharmacol 2019 10;10:367. Epub 2019 Apr 10.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Institute for Hard Tissue and Bio-tooth Regeneration, Kyungpook National University, Daegu, South Korea.

Excessive osteoclastic activity results in pathological bone resorptive diseases, such as osteoporosis, periodontitis, and rheumatoid arthritis. As imidazole-containing compounds possess extensive therapeutic potential for the management of diverse diseases, we synthesized a series of imidazole derivatives and investigated their effects on osteoclast differentiation and function. In the present study, we found that a novel imidazole derivative, KP-A038, suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and bone-resorbing activity and attenuated lipopolysaccharide (LPS)-induced bone destruction . KP-A038 significantly inhibited the induction of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and the expression of its target genes, including tartrate-resistant acid phosphatase (), cathepsin K (), dendritic cell-specific transmembrane protein (), and matrix metallopeptidase 9 (). KP-A038 upregulated the expression of negative regulators of osteoclast differentiation, such as interferon regulatory factor-8 () and B-cell lymphoma 6 (). Consistently, KP-A038 downregulated the expression of B lymphocyte-induced maturation protein-1 (Blimp1 encoded by ), a repressor for and . Moreover, administration of KP-A038 reduced LPS-induced bone erosion by suppressing osteoclast formation . Thus, our findings suggest that KP-A038 may serve as an effective therapeutic agent for the treatment and/or prevention of bone loss in pathological bone diseases, including osteoporosis and periodontitis.
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http://dx.doi.org/10.3389/fphar.2019.00367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467953PMC
April 2019

Aloin Reduces HMGB1-Mediated Septic Responses and Improves Survival in Septic Mice by Activation of the SIRT1 and PI3K/Nrf2/HO-1 Signaling Axis.

Am J Chin Med 2019 9;47(3):613-633. Epub 2019 Apr 9.

* College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea.

High mobility group box 1 (HMGB1) is recognized as a late mediator of sepsis, and the inhibition of HMGB1 release and recovery of vascular barrier integrity have emerged as attractive therapeutic strategies for the management of sepsis. We tested the hypothesis that aloin induces sirtuin 1 (SIRT1) and heme oxygenase (HO)-1, which inhibit HMGB1 release in lipopolysaccharide (LPS)-stimulated cells, thereby inhibiting HMGB1-induced hyperpermeability and increasing the survival of septic mice. Aloin was administered after LPS or HMGB1 challenge, and the antiseptic activity of aloin was determined from measurements of permeability, activation of pro-inflammatory proteins and production of markers for tissue injury in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model. Aloin significantly reduced HMGB1 release in LPS-activated HUVECs via SIRT1-mediated HMGB1 deacetylation and the PI3K/Nrf2/heme oxygenase (HO)-1 signaling axis. Aloin also suppressed the production of tumor necrosis factor (TNF)- and interleukin (IL)-6, as well as the activation of nuclear factor (NF)- B and extracellular signal-regulated kinase 1/2 (ERK 1/2) by HMGB1. Moreover, aloin restored HMGB1-mediated vascular disruption and inhibited vascular hyperpermeability in mice. In addition, treatment with aloin reduced the CLP-induced release of HMGB1, sepsis-related mortality and tissue injury . Our results suggest that aloin reduces HMGB1 release and sepsis-related mortality by activating SIRT1 and PI3K/Nrf2/HO-1 signals, indicating that aloin has potential for the treatment of sepsis.
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http://dx.doi.org/10.1142/S0192415X19500320DOI Listing
October 2019