Publications by authors named "Hak Cheol Kwon"

70 Publications

Natural photosensitizers from Tripterygium wilfordii and their antimicrobial photodynamic therapeutic effects in a Caenorhabditis elegans model.

J Photochem Photobiol B 2021 May 29;218:112184. Epub 2021 Mar 29.

Natural Product Informatics Research Center, Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangwon-do 25451, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology (UST), Gangneung, Gangwon-do 25451, Republic of Korea. Electronic address:

Tripterygium wilfordii Hook. f. is a traditional medicinal plant and has long been used in East Asia to treat many diseases. However, the extract and active components have never been investigated as potential photosensitizers for photodynamic treatment to kill pathogenic microorganisms. Here, the antimicrobial photodynamic treatment (APDT) effects of the extract, fractions, and compounds of T. wilfordii were evaluated in vitro and in vivo. Ethanolic extract (TWE) and the photosensitizer-enriched fraction (TW-F5) were prepared from dried T. wilfordii. Six active compounds were isolated from TW-F5 by semipreparative high-performance liquid chromatography, and their chemical structures were characterized through spectroscopic and spectrometric analysis. The singlet oxygen from extracts, fractions, and compounds was measured by using the imidazole-N,N-dimethyl-4-nitrosoaniline method. These extracts, fractions, and compounds were used as photosensitizers for the inactivation of bacteria and fungi by red light at 660 nm. The in vitro APDT effects were also evaluated in the model animal Caenorhabditis elegans. APDT with TWE showed effective antimicrobial activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), and Candida albicans. TW-F5, consisting of six pheophorbide compounds, also showed strong APDT activity. The photosensitizers were taken up into the bacterial cells and induced intracellular ROS production by APDT. TWE and TW-F5 also induced a strong APDT effect in vitro against skin pathogens, including Staphylococcus epidermidis and Streptococcus pyogenes. We evaluated the APDT effects of TWE and TW-F5 in C. elegans infected with various pathogens and found that PDT effectively controlled pathogenic bacteria without strong side effects. APDT reversed the growth retardation of worms induced by pathogen infection and decreased the viable pathogenic bacterial numbers associated with C. elegans. Finally, APDT with TWE increased the survivability of C. elegans infected with S. pyogenes. In summary, TWE and TW-F5 were found to be effective antimicrobial photosensitizers in PDT.
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http://dx.doi.org/10.1016/j.jphotobiol.2021.112184DOI Listing
May 2021

New Eudesmane-Type Sesquiterpene Glycosides from the Leaves of .

Plants (Basel) 2020 Dec 21;9(12). Epub 2020 Dec 21.

Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Korea.

Four new eudesmane-type sesquiterpenoids, (1,5,6,7,9,10)-1,6,9-trihydroxy-eudesm-3-ene-1,6-di---d-glucopyranoside (), (1,5,6S,7,9,10)-1,6,9,11-tetrahydroxy-eudesm-3-ene-1,6-di---d-glucopyranoside (), (1,5,6,7,9,10)-9--(--coumaroyl)-1,6,9-trihydroxy-eudesm-3-ene-6---d-glucopyranoside (), and (1,5,6,7,9,10)-9--(-feruloyl)-1,6,9-trihydroxy-eudesm-3-ene-6---d-glucopyranoside (), were isolated from a 95% EtOH extract of the leaves of by repeated chromatography. Moreover, three sesquiterpenoids (, , and ) and two caffeoylquinic acids ( and ) having previously known chemical structures were isolated during the isolation procedure. The four new compounds (, , , and ) were elucidated by spectroscopic data (1D- and 2D-NMR, MS, and ECD) interpretation and hydrolysis. Moreover, the absolute configurations of , , and were determined for the first time in this study. The compounds isolated were tested for their viability on nitric oxide (NO) and prostaglandin E (PGE) production on LPS-stimulated RAW 264.7 cells. Among them, only presented weak inhibitory effects on both NO and PGE production.
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http://dx.doi.org/10.3390/plants9121811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766762PMC
December 2020

Downregulation of dihydrolipoyl dehydrogenase by UVA suppresses melanoma progression via triggering oxidative stress and altering energy metabolism.

Free Radic Biol Med 2021 Jan 3;162:77-87. Epub 2020 Dec 3.

College of Pharmacy, Gachon University, 191, Hambakmoero, Yeonsu-gu, Incheon, 21936, Republic of Korea; Gachon Institute of Pharmaceutical Science, Gachon University, Yeonsu-gu, Incheon, 21565, Republic of Korea. Electronic address:

Melanoma, the most severe form of skin cancer, has poor prognosis and is resistant to chemotherapy. Targeting cancer metabolism is a promising approach in cancer therapeutics. Dihydrolipoyl dehydrogenase (DLD) is a mitochondrial enzyme with diaphorase activity. Here we report a pivotal role of DLD in melanoma cell progression and proliferation. Suppression DLD expression by low intensity UVA (125 mJ/cm) increased intracellular ROS production and decreased mitochondrial membrane potential thereby inducing autophagy cell death which were confirmed by increased LC3BII and decreased p62 expression in melanoma cells. Knockdown of DLD in melanoma cells also showed similar results. More so, suppression of DLD significantly inhibits in vivo melanoma growth and tumor proliferation. In addition, suppression of DLD increased the NAD+/NADH ratio in melanoma cells and also inhibits TCA cycle related metabolites. DLD downregulation markedly increased α-ketoglutarate and decreased succinic acid suggesting that DLD suppression may have decreased TCA cycle downstream metabolites, resulting in the alteration of mitochondrial energy metabolism Thus the downregulation of DLD induced autophagic cell death in melanoma cells and inhibits in vivo tumor growth and proliferation by increasing ROS production and altering energy metabolism. Our findings suggest that DLD plays a pivotal role in melanoma progression and proliferation.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.11.037DOI Listing
January 2021

Chemical Constituents of the Leaves of (Korean Bellflower) and Their Inhibitory Effects on LPS-induced PGE Production.

Plants (Basel) 2020 Sep 18;9(9). Epub 2020 Sep 18.

Department of Life and Nanopharmaceutical Sciences, Graduate School Kyung Hee University, Seoul 02447, Korea.

Nakai (Campanulaceae; Korean bellflower) is one of the endemic herbs of Korea. The plant has been used as traditional medicines for treating asthma, tonsillitis, and sore throat in Korea. A hot water extract of the leaves of exhibited a significant inhibitory effect on lipopolysaccharide (LPS)-stimulated prostaglandin E (PGE) production. Repetitive chromatographic separation of the hot water extract led to the isolation of three new neolignan glucosides, campanulalignans A-C (-), with 15 known compounds (-). The structures of new compounds - were elucidated by analyzing nuclear magnetic resonance (NMR) spectroscopic data, along with high resolution quadrupole time of flight mass (HR-Q-TOF-MS) spectrometric data. Among the isolates, simplidin (), 5-hydroxyconiferaldehyde (), icariside F (), benzyl--l-arabinopyranosyl-(1″→6')--d-glucopyranoside (), and kaempferol 3---d-apiosyl (1→2)--d-glucopyranoside () were isolated from the Campanulaceae family for the first time. The isolates (, , and -) were assessed for their anti-inflammatory effects on LPS-stimulated PGE production on RAW 264.7 cells. 7,8-Dihydrodehydrodiconiferyl alcohol (), 3',4--dimethylcedrusin 9---glucopyranoside (), pinoresinol di---d-glucoside (), ferulic acid (), 5-hydroxyconiferaldehyde (), and quercetin () showed significant inhibitory effects on LPS-stimulated PGE production.
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http://dx.doi.org/10.3390/plants9091232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570004PMC
September 2020

Bioactive Phytochemicals Isolated from Enhances Glucose-Stimulated Insulin Secretion by Inducing PDX-1.

Plants (Basel) 2020 Aug 24;9(9). Epub 2020 Aug 24.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Chocolate vine () is consumed as a fruit and is also used in traditional medicine. In order to identify the bioactive components of , a phytosterol glucoside stigmasterol-3--β-d-glucoside (1), three triterpenoids maslinic acid (2), scutellaric acid (3), and hederagenin (4), and three triterpenoidal saponins akebia saponin PA (5), hederacoside C (6), and hederacolchiside F (7) were isolated from a 70% EtOH extract of the fruits of (AKQU). The chemical structures of isolates 1-7 were determined by analyzing the 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data. Here, we evaluated the effects of AKQU and compounds 1-7 on insulin secretion using the INS-1 rat pancreatic β-cell line. Glucose-stimulated insulin secretion (GSIS) was evaluated in INS-1 cells using the GSIS assay. The expression levels of the proteins related to pancreatic β-cell function were detected by Western blotting. Among the isolates, stigmasterol-3--β-d-glucoside (1) exhibited strong GSIS activity and triggered the overexpression of pancreas/duodenum homeobox protein-1 (PDX-1), which is implicated in the regulation of pancreatic β-cell survival and function. Moreover, isolate 1 markedly induced the expression of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), insulin receptor substrate-2 (IRS-2), phosphoinositide 3-kinase (PI3K), and Akt, which regulate the transcription of PDX-1. The results of our experimental studies indicated that stigmasterol-3--β-d-glucoside (1) isolated from the fruits of can potentially enhance insulin secretion, and might alleviate the reduction in GSIS during the development of T2DM.
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http://dx.doi.org/10.3390/plants9091087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570369PMC
August 2020

Constituents of and Their Neuroprotective Effects in HT22 Hippocampal Neuronal, R28 Retinal Cells, and BV2 Microglial Cells.

Plants (Basel) 2020 Aug 18;9(8). Epub 2020 Aug 18.

KIST Gangneung Institute of Natural Products, Korea Institute of Science and Technology (KIST), Gangneung 25451, Korea.

is widely used in traditional medicine and contains various types of metabolites with pharmacological activity. In the course of searching for neuroprotective molecules associated with the potential of in the treatment of neurodegenerative disorders, two new phenolic compounds ( and ) and a new tripeptide (), together with 16 known compounds (-), were isolated from the rhizomes of . The structures of the compounds were determined by the interpretation of spectroscopic data, including nuclear magnetic resonance and mass spectrometry data. All obtained compounds were assessed for their ability to protect neuronal cells against neurotoxicity and neuroinflammation. Of these, and were found to possess moderate activities in HT22 hippocampal neuronal cells, whereas , , and showed weak activities in R28 retinal cells. Additionally, compound showed moderate inhibitory activity on lipopolysaccharide-induced nitric oxide production in BV2 microglial cells.
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http://dx.doi.org/10.3390/plants9081051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465223PMC
August 2020

Differential Effects of Saikosaponins A, B2, B4, C and D on Alcohol and Chocolate Self-Administration in Rats.

Alcohol Alcohol 2020 Jun;55(4):367-373

Neuroscience Institute, Section of Cagliari, National Research Council of Italy, Monserrato (CA), Italy.

Aims: Treatment with saikosaponin A (SSA)-an ingredient of the medicinal herb, Bupleurum falcatum-has been reported to suppress several addictive-like behaviors, including morphine, cocaine, alcohol and chocolate self-administration in male rats. The aim of this investigation was to investigate whether saikosaponins of B. falcatum other than SSA affect alcohol and chocolate self-administration in rats.

Methods: Ovariectomized female Sardinian alcohol-preferring (sP) and Wistar rats were trained to self-administer alcohol (15%, v/v) and a chocolate solution [5% (w/v) Nesquik® in water], respectively, under fixed ratio schedules of reinforcement. The following saikosaponins were compared to SSA: saikosaponin D (SSD; epimer of SSA), saikosaponin C (SSC), saikosaponin B2 (SSB2) and saikosaponin B4 (SSB4). All saikosaponins were tested acutely at the doses of 0, 0.25, 0.5 and 1 mg/kg (i.p.).

Results: Treatment with SSA and SSD resulted in highly similar, marked reductions in alcohol self-administration; SSC failed to alter lever-responding for alcohol, while SSB2 and SSB4 produced intermediate reductions. Only SSA and SSD reduced chocolate self-administration, with SSC, SSB2 and SSB4 being ineffective.

Conclusions: The wide spectrum of efficacy of saikosaponins in reducing alcohol and chocolate self-administration suggests that even relatively small structural differences are sufficient to produce remarkable changes in their in vivo pharmacological profile. Together, these results confirm that roots of B. falcatum may be an interesting source of compounds with anti-addictive potential.
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http://dx.doi.org/10.1093/alcalc/agaa049DOI Listing
June 2020

Genomic Survey of Salt Acclimation-Related Genes in the Halophilic Cyanobacterium Euhalothece sp. Z-M001.

Sci Rep 2020 01 20;10(1):676. Epub 2020 Jan 20.

Department of Biological Sciences, Chungnam National University, Daejeon, 34134, Korea.

Like other halophilic cyanobacterial genomes, the de novo-assembled genome of Euhalothece sp. Z-M001 lacks genes encoding keto-carotenoid biosynthesis enzymes, despite the presence of genes encoding carotenoid-binding proteins (CBPs). Consistent with this, HPLC analysis of carotenoids identified β-carotene and zeaxanthin as the dominant carotenoids. CBPs coexpressed with the zeaxanthin biosynthesis gene increased the survival rates of Escherichia coli strains by preventing antibiotic-induced accumulation of reactive oxygen species (ROS). RNA-seq analysis of Euhalothece revealed that among various salt resistance-related genes, those encoding the Na transporting multiple resistance and pH adaptation (Mrp) systems, glycine betaine biosynthesis enzymes, exopolysaccharide metabolic enzymes, and CBPs were highly upregulated, suggesting their importance in hypersaline habitats. During the early phase of salt deprivation, the amounts of β-carotene and zeaxanthin showed a negative correlation with ROS content. Overall, we propose that in some halophilic cyanobacteria, β-carotene and zeaxanthin, rather than keto-carotenoids, serve as the major chromophores for CBPs, which in turn act as effective antioxidants.
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http://dx.doi.org/10.1038/s41598-020-57546-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971039PMC
January 2020

An Autophagy Inducing Triterpene Saponin Derived from .

Molecules 2019 Dec 7;24(24). Epub 2019 Dec 7.

Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute, Gangneung 25451, Korea.

Autophagy is an important self-degradative mechanism that plays a key role in treating neurodegeneration diseases. This research aimed at discovering bioactive compounds from . A new triterpene saponin, astersaponin I (), was isolated from the EtOH extract of . The structure of 1 was characterized by spectroscopic methods, ECD calculation, and acid hydrolysis. The biochemical analysis showed that compound significantly increased the expression of microtubule-associated protein 1A/1B light chain 3B (LC3-II) expression in SH-SY5Y cells, which indicates the induction of autophagy. Thus, further study may be needed to clarify whether compound exerts beneficial effects on neurodegeneration diseases like Parkinson's disease through autophagy induction.
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http://dx.doi.org/10.3390/molecules24244489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943805PMC
December 2019

Antimicrobial Biophotonic Treatment of Ampicillin-Resistant with Hypericin and Ampicillin Cotreatment Followed by Orange Light.

Pharmaceutics 2019 Dec 1;11(12). Epub 2019 Dec 1.

Natural Products Informatics Research Center, Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangwon-do 25451, Korea.

Bacterial antibiotic resistance is an alarming global issue that requires alternative antimicrobial methods to which there is no resistance. Antimicrobial photodynamic therapy (APDT) is a well-known method to combat this problem for many pathogens, especially Gram-positive bacteria and fungi. Hypericin and orange light APDT efficiently kill , methicillin-resistant (MRSA), and the yeast . Although Gram-positive bacteria and many fungi are readily killed with APDT, Gram-negative bacteria are difficult to kill due to their different cell wall structures. is one of the most important opportunistic, life-threatening Gram-negative pathogens. However, it cannot be killed successfully by hypericin and orange light APDT. is ampicillin resistant, but we hypothesized that ampicillin could still damage the cell wall, which can promote photosensitizer uptake into Gram-negative cells. Using hypericin and ampicillin cotreatment followed by orange light, a significant reduction (3.4 log) in PAO1 was achieved. PAO1 inactivation and gut permeability improvement by APDT were successfully shown in a model.
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http://dx.doi.org/10.3390/pharmaceutics11120641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956302PMC
December 2019

-Derived Drimane Sesquiterpenoids That Inhibit Osteoclast Differentiation.

J Nat Prod 2019 10 10;82(10):2835-2841. Epub 2019 Oct 10.

Laboratory Animal Resource Center , Korea Research Institute of Bioscience and Biotechnology , Cheongju 28116 , Republic of Korea.

The presence of excessive osteoclasts is a major factor in skeletal diseases. The present study aimed to discover osteoclast differentiation inhibitors from the basidiomycete . Seven new drimane sesquiterpenoids (-) and 7-ketoisodrimenin-5-ene () were obtained and characterized by various spectroscopic methods. The isolated compounds were evaluated for their inhibitory effects against receptor activator of nuclear factor-kappa-B ligand-induced osteoclastogenesis in mouse bone marrow macrophages. Compounds , , and showed potent activities with IC values of 1.6, 0.9, and 2.1 μM, respectively, while , , and exhibited relatively weak activities with IC values of 10.7, 10.1, and 8.5 μM, respectively.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00559DOI Listing
October 2019

Nakai Has Synergetic Effects on Doxorubicin-Induced Apoptosis.

Biomed Res Int 2018 1;2018:6716547. Epub 2018 Aug 1.

Department of Advanced Technology Fusion, Konkuk University, Neungdong-ro 120, Gwangjin-gu, Seoul 05029, Republic of Korea.

Natural products are valuable sources for drug discovery because they have a wide variety of useful chemical components and biological properties. A quick reevaluation of the potential therapeutic properties of established natural products was made possible by the recent development of the methodology and improvement in the accuracy of an automated high-throughput screening system. In this study, we screened natural product libraries to detect compounds with anticancer effects using HeLa cells. Of the 420 plant extracts screened, the extract of Nakai (AGN) was the most effective in reducing cell viability of HeLa cells. Markers of apoptosis, such as exposure of phosphatidylserine and cleavage of caspase-7 and PARP, were increased by treatment with the AGN extract. Treatment of the AGN extract increased expression of PKR as well as ATF4 and CHOP, the unfolded protein response genes. In addition, cotreatment of doxorubicin and the AGN extract significantly increased doxorubicin-induced apoptosis in HeLa cells. Decursin and decursinol angelate, which were known to have anticancer effects, were the main components of the AGN extract. These results suggest that the extract of AGN containing, decursin and decursinol angelate, increases doxorubicin susceptibility.
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http://dx.doi.org/10.1155/2018/6716547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093040PMC
January 2019

Reducing Effect of Saikosaponin A, an Active Ingredient of , on Intake of Highly Palatable Food in a Rat Model of Overeating.

Front Psychiatry 2018 13;9:369. Epub 2018 Aug 13.

Neuroscience Institute, Section of Cagliari, National Research Council of Italy, Monserrato, Italy.

Recent lines of experimental evidence have indicated that saikosaponin A (SSA)-a bioactive ingredient of the medicinal plant, .-potently and effectively reduced operant self-administration of chocolate and reinstatement of chocolate-seeking behavior in rats. The present study was designed to assess whether the protective properties of SSA on addictive-like, food-related behaviors generalize to a rat model of overeating of palatable food. To this end, rats were habituated to feed on a standard rat chow for 3 h/day; every 4 days, the 3-h chow-feeding session was followed by a 1-h availability of highly palatable, calorie-rich Danish butter cookies or Oreo chocolate cookies. Even though fed, rats consumed large amounts of cookies; intake of calories from cookies (consumed in 1 h) was even larger than that of calories from chow (consumed in 3 h). SSA (0, 0.25, 0.5, and 1 mg/kg, i.p.) was administered 10 min before cookie presentation. Treatment with SSA resulted in a dose-related decrease in intake of both butter and chocolate cookies. Administration of the cannabinoid CB receptor antagonist/inverse agonist, rimonabant (0, 0.3, 1, and 3 mg/kg, i.p.; tested as reference compound), produced a similar reduction in intake of butter cookies. These results (a) contribute to the set-up and validation of a rat model of overeating, characterized by the intake of large amounts of unnecessary calories and (b) provide an additional piece of evidence to the anorectic profile of SSA in rats.
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http://dx.doi.org/10.3389/fpsyt.2018.00369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099156PMC
August 2018

Apoptotic and Anti-Inflammatory Effects of Thunb. in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

Biomed Res Int 2018 9;2018:1383697. Epub 2018 Jul 9.

Department of Advanced Technology Fusion, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by synovitis, hyperplasia, and the destruction of bone and cartilage. A variety of immunosuppressive biological agents have been developed because the pathogenesis of RA is related predominantly to the inflammatory response. However, rheumatoid arthritis fibroblast-like synovial cells (RAFLS), which are known to play an important role in RA progression, exhibit resistance to immunosuppressants through cancer-like properties. In this study, we identified a novel therapeutic compound for RA, which reduced inflammation and the abnormal proliferation of RAFLS in natural product library made from Korean native plants. Thunb. (EJT) extract, a component of the natural product library, most effectively reduced viability through the induction of ROS-mediated apoptosis in a dose-dependent manner. In addition, the increased ROS induced the expression of ATF4 and CHOP, key players in ER stress-mediated apoptosis. Interestingly, EJT extract treatment dose-dependently reduced the expression of IL-1 and the transcription of MMP-9, which were induced by TNF- treatment, through the inhibition of NF-B and p38 activation. Collectively, we found that EJT extract exerted apoptotic effects through increases in ROS production and CHOP expression and exerted anti-inflammatory effects through the suppression of NF-B activation, IL-1 expression, and MMP-9 transcription.
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http://dx.doi.org/10.1155/2018/1383697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077679PMC
January 2019

Cytotoxic Drimane Sesquiterpenoids Isolated from Perenniporia maackiae.

J Nat Prod 2018 06 7;81(6):1444-1450. Epub 2018 Jun 7.

Laboratory Animal Resource Center , Korea Research Institute of Bioscience and Biotechnology , Cheongju 28116 , Republic of Korea.

A chemical investigation of a basidiomycetes fungus, Perenniporia maackiae, led to the discovery of 12 drimane sesquiterpenoids, including seven new constituents (1-7). The elucidation of the structures was performed via interpreting extensive spectroscopic methods, including ECD calculations. Among all isolated compounds, 1, 2, and 6 exhibited cytotoxicity toward six carcinoma cells, including ACHN, HCT-15, MDA-MB-231, NCI-H23, NUGC-3, and PC-3 cells, with half-maximal inhibition of cell proliferation values of 1.2-6.0 μM.
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http://dx.doi.org/10.1021/acs.jnatprod.8b00175DOI Listing
June 2018

New Naphthoquinone Terpenoids from Marine Actinobacterium, Streptomyces sp. CNQ-509.

Mar Drugs 2018 Mar 12;16(3). Epub 2018 Mar 12.

Natural Constituents Research Center, Korea Institute of Science and Technology (KIST), Gangneung, Gangwon-do 25451, Korea.

A member of the marine streptomycete clade MAR4, sp. CNQ-509, has genetic potential for the biosynthesis of hybrid isoprenoids and produces several meroterpenoids such as naphterpin, nitropyrrolin and marinophenazine. Our research on the strain CNQ-509 led to the isolation of two new naphterpin derivatives ( and ) comprised of naphthoquinone and geranyl moieties along with the known terpenoid, debromomarinone. The two-dimensional structure of these compounds was determined through spectral data analysis using data from NMR, MS and UV spectroscopy. Furthermore, the full structures of and including absolute configurations were unequivocally established by a combination of NMR experiments and chemical modifications.
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http://dx.doi.org/10.3390/md16030090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867634PMC
March 2018

Gordonic Acid, a Polyketide Glycoside Derived from Bacterial Coculture of Streptomyces and Gordonia Species.

J Nat Prod 2017 09 28;80(9):2542-2546. Epub 2017 Aug 28.

Natural Constituents Research Center, Korea Institute of Science and Technology (KIST) , Gangneung, Gangwon-do 25451, Republic of Korea.

Despite numerous efforts to discover novel bioactive products from microorganisms, previously reported compounds are repetitively reisolated. A new polyketide glycoside, gordonic acid (1), isolated from the mixed culture of two Gram-positive bacteria, Gordonia sp. KMC005 and Streptomyces tendae KMC006, is reported. The structure of 1 was characterized as an acyclic polyene polyketide substituted with a β-d-digitoxopyranose through NMR, HR-ESI-QTOF-MS, IR, and UV spectral data. The stereochemistry for 1 was determined by Mosher's method followed by 2D NOESY analysis and by NMR chemical shift calculations supported by DP4 analysis. Gordonic acid (1) showed weak activity against Micrococcus luteus and Enterococcus hirae.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00293DOI Listing
September 2017

5,7-Dihydroxy-6-geranylflavanone improves insulin sensitivity through PPARα/γ dual activation.

Int J Mol Med 2016 May 17;37(5):1397-404. Epub 2016 Mar 17.

Natural Products Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute, Gangneung, Gangwon-do 210-340, Republic of Korea.

In the present study, we demonstrate that 5,7-dihydroxy-6-geranylflavanone (DGF) isolated from Amorpha fruticosa (A. fruticosa) is a novel peroxisome proliferator-activated receptor (PPAR)α/γ dual agonist which may be used to improve insulin sensitivity. The extract from A. fruticosa increased the transcriptional activity of both PPARα and PPARγ which was, in part, driven by the active ingredient DGF. Treatment with DGF markedly enhanced the adipogenesis of 3T3-L1 preadipocytes, which was comparable to the effect of the PPARγ agonist, troglitazone. In addition, DGF was found to enhance fatty acid oxidation and glucose utilization through the dual activation of PPARα/γ. In addition treatment with DGF led to an improvement in insulin sensitivity, resulting in enhanced glucose uptake in muscle cells. The findings of our study data suggest that DGF may be used as potential therapeutic agent in the treatment of type 2 diabetes and related metabolic disorders by enhancing glucose and lipid metabolism.
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http://dx.doi.org/10.3892/ijmm.2016.2531DOI Listing
May 2016

Protective Effect of Artemisia asiatica Extract and Its Active Compound Eupatilin against Cisplatin-Induced Renal Damage.

Evid Based Complement Alternat Med 2015 11;2015:483980. Epub 2015 Oct 11.

Department of Pathology, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung 210-711, Republic of Korea.

The present study investigated the renoprotective effect of an Artemisia asiatica extract and eupatilin in kidney epithelial (LLC-PK1) cells. Although cisplatin is effective against several cancers, its use is limited due to severe nephrotoxicity. Eupatilin is a flavonoid compound isolated from the Artemisia plant and possesses antioxidant as well as potent anticancer properties. In the LLC-PK1 cellular model, the decline in cell viability induced by oxidative stress, such as that induced by cisplatin, was significantly and dose-dependently inhibited by the A. asiatica extract and eupatilin. The increased protein expressions of phosphorylated JNK and p38 by cisplatin in cells were markedly reduced after A. asiatica extract or eupatilin cotreatment. The elevated expression of cleaved caspase-3 was significantly reduced by A. asiatica extract and eupatilin, and the elevated percentage of apoptotic cells after cisplatin treatment in LLC-PK1 cells was markedly decreased by cotreatment with A. asiatica extract or eupatilin. Taken together, these results suggest that A. asiatica extract and eupatilin could cure or prevent cisplatin-induced renal toxicity without any adverse effect; thus, it can be used in combination with cisplatin to prevent nephrotoxicity.
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http://dx.doi.org/10.1155/2015/483980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619882PMC
November 2015

Anti-cancer Effect of Luminacin, a Marine Microbial Extract, in Head and Neck Squamous Cell Carcinoma Progression via Autophagic Cell Death.

Cancer Res Treat 2016 Apr 9;48(2):738-52. Epub 2015 Sep 9.

Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.

Purpose: The purpose of this study is to determine whether luminacin, a marine microbial extract from the Streptomyces species, has anti-tumor effects on head and neck squamous cell carcinoma (HNSCC) cell lines via autophagic cell death.

Materials And Methods: Inhibition of cell survival and increased cell death was measured using cell viability, colony forming, and apoptosis assays. Migration and invasion abilities of head and cancer cells were evaluated using wound healing, scattering, and invasion assays. Changes in the signal pathway related to autophagic cell death were investigated. Drug toxicity of luminacin was examined in in vitro HaCaT cells and an in vivo zebrafish model.

Results: Luminacin showed potent cytotoxicity in HNSCC cells in cell viability, colony forming, and fluorescence-activated cell sorting analysis. In vitro migration and invasion of HNSCC cells were attenuated by luminacin treatment. Combined with Beclin-1 and LC3B, Luminacin induced autophagic cell death in head and neck cancer cells. In addition, in a zebrafish model and human keratinocyte cell line used for toxicity testing, luminacin treatment with a cytotoxic concentration to HNSCC cells did not cause toxicity.

Conclusion: Taken together, these results demonstrate that luminacin induces the inhibition of growth and cancer progression via autophagic cell death in HNSCC cell lines, indicating a possible alternative chemotherapeutic approach for treatment of HNSCC.
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http://dx.doi.org/10.4143/crt.2015.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843729PMC
April 2016

Pontemazines A and B, phenazine derivatives containing a methylamine linkage from Streptomyces sp. UT1123 and their protective effect to HT-22 neuronal cells.

Bioorg Med Chem Lett 2015 Nov 8;25(22):5083-6. Epub 2015 Oct 8.

Natural Product Research Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do 210-340, Republic of Korea. Electronic address:

New phenazine derivatives with a methylamine linker, Pontemazines A (1) and B (2), were isolated from the culture broth of Streptomyces sp. UT1123. The structures of compounds 1 and 2 were determined by NMR spectroscopy and high-resolution mass spectrometry. These compounds consist of a 9-mehoxyphenazine connected to a benzamide functional group by a unique methylamine linker instead of the more common methyl ether. Pontemazines A and B possess a neuronal cell protective effect on glutamate-induced mouse hippocampal HT-22 cell damage.
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http://dx.doi.org/10.1016/j.bmcl.2015.10.019DOI Listing
November 2015

Salinazinones A and B: Pyrrolidinyl-Oxazinones from Solar Saltern-Derived Streptomyces sp. KMF-004.

Org Lett 2015 Oct 8;17(20):5024-7. Epub 2015 Oct 8.

Natural Products Research Center, Korea Institute of Science and Technology (KIST) , Gangneung, Gangwon-do 210-340, Republic of Korea.

Salinazinones A (1) and B (2), two unprecedented pyrrolidinyl-oxazinones, were isolated from the culture broth of Streptomyces sp. KMF-004 from a solar saltern at Aphae Island, Korea. The structures of these salinazinones, which are unusual and consist of 2-methylpropenyl-1,3-oxazin-6-one bearing 1-oxopyrrolidinyl substituents, were assigned by spectral and chemical analyses using Mosher's method, circular dichroism (CD), and calculated ECD. Salinazinones are the first examples of a natural alkaloid class composed of an oxazinone-pyrrolidone conjugate.
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http://dx.doi.org/10.1021/acs.orglett.5b02495DOI Listing
October 2015

Effect of Lycoris chejuensis and Its Active Components on Experimental Models of Alzheimer's Disease.

J Agric Food Chem 2015 Aug 28;63(31):6979-88. Epub 2015 Jul 28.

†Natural Products Research Center, Korea Institute of Science and Technology, 290 Daejeon-dong, Gangneung, Gangwon-do 210-340, Republic of Korea.

We found that an extract of Lycoris chejuensis and its three isolated active components, narciclasine, 7-deoxynarciclasine, and 7-deoxy-trans-dihydronarciclasine, each significantly reduced the formation of amyloid-β peptides in HeLa cells transfected with an amyloid precursor protein carrying the Swedish mutation up to 45 ± 3.6%. The extract down-regulated amyloid precursor protein, especially the mature form by up to 88%, and reduced the ability of secretases to generate toxic amyloid-β. Double-transgenic mice treated with the extract for 4 months also showed significantly reduced levels of amyloid-β and plaques while exhibiting improved memory functions in the Morris water maze and novel object recognition tests. In conclusion, the extract and isolated active components of L. chejuensis decreased the production of amyloid-β by attenuating amyloid precursor protein levels. Furthermore, the extract improved the disrupted memory functions in animals while inhibiting amyloid plaque formation. Thus, this extract, as well as its active components, could prove beneficial in the treatment of Alzheimer's disease.
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http://dx.doi.org/10.1021/acs.jafc.5b00889DOI Listing
August 2015

Amorphastilbol exerts beneficial effects on glucose and lipid metabolism in mice consuming a high-fat-diet.

Int J Mol Med 2015 Aug 29;36(2):527-33. Epub 2015 May 29.

Natural Medicine Center, KIST Gangneung Institute, Gangneung, Gangwon 210-340, Republic of Korea.

In the present study, the anti-diabetic effects of amorphastilbol (APH) from Amorpha fruticosa (AF) were evaluated in high-fat-diet (HFD) mice. HFD-induced blood glucose and insulin levels are significantly reduced in AF extract or APH treatment groups. HFD-induced weight gain was reduced by AF treatment, which is accompanied by reduction of fat mass and adipocyte size and number in white adipose tissues. Furthermore, total cholesterol and low-density lipoprotein-cholesterol levels are decreased in AF- or APH-treated mice. In addition, AF and APH are able to improve insulin sensitivity through inhibition of protein tyrosine phosphatase 1B, a negative regulator of the insulin-signaling pathway. Taken together, the data suggest that AF has beneficial effects on glucose and lipid metabolism and its pharmacological effects are driven, in part, by its active component, APH. Therefore, AF and APH can be used as potential therapeutic agents against type 2 diabetes and associated metabolic disorders, including obesity, by enhancing glucose and lipid metabolism.
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http://dx.doi.org/10.3892/ijmm.2015.2227DOI Listing
August 2015

Nocatriones A and B, photoprotective tetracenediones from a marine-derived Nocardiopsis sp.

J Nat Prod 2014 Oct 15;77(10):2326-30. Epub 2014 Oct 15.

Natural Products Research Center, Korea Institute of Science and Technology (KIST) , Gangneung, Gangwon-do 210-340, Republic of Korea.

Two new tetracenedione derivatives, nocatriones A (1) and B (2), were discovered from the culture broth of a marine actinomycete, Nocardiopsis sp. KMF-002, which was isolated from the tissue of an unidentified dark purple marine sponge. The structures of 1 and 2, which are tetracenediones containing α-pyrone substituents, were determined to be 3,8,10,11-tetrahydroxy-2-(4-hydroxy-2-oxo-2H-pyran-6-yl)-1-methyltetracene-5,12-dione (1) and 3,8,10,12-tetrahydroxy-2-(4-hydroxy-2-oxo-2H-pyran-6-yl)-1-methyltetracene-6,11-dione (2). Ultraviolet B (UVB)-irradiated cells treated with 10 μM nocatrione A (1) significantly decreased the level of MMP-1, a protein that degrades collagen and other extracelluar matrix components that comprise dermal tissue, when compared to untreated cells. These results support that nocatriones A (1) and B (2) may show antiphotoaging activity in UVB-irradiated models.
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http://dx.doi.org/10.1021/np5006086DOI Listing
October 2014

Sargahydroquinoic acid inhibits TNFα-induced AP-1 and NF-κB signaling in HaCaT cells through PPARα activation.

Biochem Biophys Res Commun 2014 Aug 11;450(4):1553-9. Epub 2014 Jul 11.

Natural Medicine Center, KIST Gangneung Institute, Gangneung 210-340, Republic of Korea. Electronic address:

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors and expressed in various cell types in the skin, including keratinocytes, fibroblasts and infiltrating immune cells. Thus, their ligands are targets for the treatment of various skin disorders, such as photo-aging and chronological aging of skin. Intensive studies have revealed that PPARα/γ functions in photo-aging and age-related inflammation by regulating matrix metalloproteinases (MMPs) via activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB). However, the detailed mechanism of PPARα/γ's role in skin aging has not yet been elucidated. In this study, we confirmed that sargahydroquinoic acid (SHQA) as a PPARα/γ ligand significantly decreased Tumor Necrosis Factor-alpha (TNFα)-induced MMP-2/-9 expression by downregulating TNFα-induced transcription factors, subsequently reducing IκBα degradation and blocking NF-κB p65 nuclear translocation in HaCaT human epidermal keratinocyte cells. Treatment of cells with SHQA and GW6471 (PPARα antagonist) not bisphenol A diglycidyl ether (PPARγ antagonists), reversed the effect on TNFα-induced inflammatory signaling pathway activation. Taken together, our data suggest that SHQA inhibit TNFα-induced MMP-2/-9 expression and age-related inflammation by suppressing AP-1 and NF-κB pathway via PPARα.
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http://dx.doi.org/10.1016/j.bbrc.2014.07.026DOI Listing
August 2014

Isolation and characterization of a novel bacterial strain Shewanella marinisediminis sp. nov. from deep-sea sediments.

J Environ Biol 2013 May;34(3):501-7

A new bacterial strain designated DH39T was isolated from marine sediment collected from the East Sea, Korea. Phylogenetic analysis using the 16S rRNA gene sequence revealed that strain DH39(T) clustered with the genus Shewanella and is closely related to Shewanella canadensis HAW-EB2(T), S. woodyi MS32(T), and S. sediminis HAW-EB3(T) with 98.1, 97.8, and 97.6% sequence similarities, respectively. The isolated bacterium was Gram-negative, rod-shaped, and aerobic. Its temperature range for growth was 4-30 degrees C. The predominant fatty acids were 16:1omega7, 17:1omega8, 13:0-i, 16:0, and 15:0-i. The DNA G+C content was 45.0 mol%. DNA-DNA hybridization analysis showed that DNA-DNA relatedness values in the 165 rRNA phylogenetic tree of strain DH39(T) and its nearest neighbors S. hanedai and S. sediminis were 52.9 and 58.7%. Phylogenetic evidence and phenotypic characteristics suggest strain DH39(T) constitutes a novel Shewanella species. Therefore, we propose Shewanella marinisediminis sp. nov., with DH39(T) (KCCM 42936(T) = NCCB 100311(T)) as the type strain.
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May 2013

Glionitrin A, a new diketopiperazine disulfide, activates ATM-ATR-Chk1/2 via 53BP1 phosphorylation in DU145 cells and shows antitumor effect in xenograft model.

Biol Pharm Bull 2014 ;37(3):378-86

Natural Medicine Center, Korea Institute of Science and Technology.

In a recent study, we isolated the diketopiperazine disulfide glionitrin A from the co-culture broth of a mine drainage-derived fungus (Aspergillus fumigatus KMC901) and bacterium (Sphingomonas KMK001). Here, we investigated the antitumor activity of glionitrin A and its underlying molecular mechanisms in human prostate cancer DU145 cells. Glionitrin A showed significant cytotoxicity, promoting cell cycle arrest and apoptosis. Glionitrin A-treated cells exhibited elevated levels of phospho-histone 2AX (Ser139), a marker of DNA damage, and accumulated in both S phase and G2/M phase due to the activation of checkpoints associated with the ataxia-telangiectasia-mutated and ataxia-telangiectasia-mutated-Rad3-related Chk1/2 pathway downstream of p53-binding protein 1 phosphorylation at Ser1778. In addition, glionitrin A induced apoptosis through both caspase-dependent and -independent pathways. Glionitrin A activated caspase-8, -9 and -3 and also released endonuclease G from the mitochondria to the nucleus in a dose-dependent manner. Our in vivo study performed in nude mice bearing xenografts of DU145 cells showed that glionitrin A dramatically reduced the tumor volume by an average of 38.2% (5 mg/kg, per os (p.o.)) and 71.3% (10 mg/kg, p.o.) at 27 d after the beginning of treatment. Taken together, these findings provide a detailed description of the mechanism underlying the biological activity of the new natural product glionitrin A, which has the potential to be developed as an anti-prostate cancer agent.
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http://dx.doi.org/10.1248/bpb.b13-00719DOI Listing
October 2014

Sungsanpin, a lasso peptide from a deep-sea streptomycete.

J Nat Prod 2013 May 10;76(5):873-9. Epub 2013 May 10.

Natural Products Research Institute, College of Pharmacy, Seoul National University , 1 Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea.

Sungsanpin (1), a new 15-amino-acid peptide, was discovered from a Streptomyces species isolated from deep-sea sediment collected off Jeju Island, Korea. The planar structure of 1 was determined by 1D and 2D NMR spectroscopy, mass spectrometry, and UV spectroscopy. The absolute configurations of the stereocenters in this compound were assigned by derivatizations of the hydrolysate of 1 with Marfey's reagents and 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl isothiocyanate, followed by LC-MS analysis. Careful analysis of the ROESY NMR spectrum and three-dimensional structure calculations revealed that sungsanpin possesses the features of a lasso peptide: eight amino acids (-Gly(1)-Phe-Gly-Ser-Lys-Pro-Ile-Asp(8)-) that form a cyclic peptide and seven amino acids (-Ser(9)-Phe-Gly-Leu-Ser-Trp-Leu(15)) that form a tail that loops through the ring. Sungsanpin is thus the first example of a lasso peptide isolated from a marine-derived microorganism. Sungsanpin displayed inhibitory activity in a cell invasion assay with the human lung cancer cell line A549.
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http://dx.doi.org/10.1021/np300902gDOI Listing
May 2013

Tripartin, a histone demethylase inhibitor from a bacterium associated with a dung beetle larva.

Org Lett 2013 Apr 3;15(8):1834-7. Epub 2013 Apr 3.

Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.

Tripartin (1), a new dichlorinated indanone, was isolated from the culture broth of the Streptomyces sp. associated with a larva of the dung beetle Copris tripartitus Waterhouse. The planar structure of tripartin (1) was identified by the spectroscopic analyses of NMR, mass, UV, and IR data. The structure was confirmed, and the absolute configuration of 1 was determined by X-ray crystallography. Tripartin displayed specific activity as an inhibitor of the histone H3 lysine 9 demethylase KDM4 in HeLa cells.
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http://dx.doi.org/10.1021/ol4004417DOI Listing
April 2013