Publications by authors named "Ji-Sun Shin"

113 Publications

Keystroke Dynamics-Based Authentication Using Unique Keypad.

Sensors (Basel) 2021 Mar 23;21(6). Epub 2021 Mar 23.

Department of Computer and Information Security, Sejong University, Seoul 05006, Korea.

Authentication methods using personal identification number (PIN) and unlock patterns are widely used in smartphone user authentication. However, these authentication methods are vulnerable to shoulder-surfing attacks, and PIN authentication, in particular, is poor in terms of security because PINs are short in length with just four to six digits. A wide range of research is currently underway to examine various biometric authentication methods, for example, using the user's face, fingerprint, or iris information. However, such authentication methods provide PIN-based authentication as a type of backup authentication to prepare for when the maximum set number of authentication failures is exceeded during the authentication process such that the security of biometric authentication equates to the security of PIN-based authentication. In order to overcome this limitation, research has been conducted on keystroke dynamics-based authentication, where users are classified by analyzing their typing patterns while they are entering their PIN. As a result, a wide range of methods for improving the ability to distinguish the normal user from abnormal ones have been proposed, using the typing patterns captured during the user's PIN input. In this paper, we propose unique keypads that are assigned to and used by only normal users of smartphones to improve the user classification performance capabilities of existing keypads. The proposed keypads are formed by randomly generated numbers based on the Mersenne Twister algorithm. In an attempt to demonstrate the superior classification performance of the proposed unique keypad compared to existing keypads, all tests except for the keypad type were conducted under the same conditions in earlier work, including collection-related features and feature selection methods. Our experimental results show that when the filtering rates are 10%, 20%, 30%, 40%, and 50%, the corresponding equal error rates (EERs) for the proposed keypads are improved by 4.15%, 3.11%, 2.77%, 3.37% and 3.53% on average compared to the classification performance outcomes in earlier work.
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http://dx.doi.org/10.3390/s21062242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004962PMC
March 2021

Discovery of N-amido-phenylsulfonamide derivatives as novel microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors.

Bioorg Med Chem Lett 2021 06 26;41:127992. Epub 2021 Mar 26.

Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Our previous research showed that N-carboxy-phenylsulfonyl hydrazide (scaffold A) could reduce LPS-stimulated PGE levels in RAW 264.7 macrophage cells by an inhibition of mPGES-1 enzyme. However, a number of scaffold A derivatives showed the drawbacks such as the formation of regioisomers and poor liver metabolic stability. In order to overcome these synthetic and metabolic problems, therefore, we decided to replace N-carboxy-phenylsulfonyl hydrazide (scaffold A) with N-carboxy-phenylsulfonamide (scaffold B) or N-amido-phenylsulfonamide frameworks (scaffold C) as a bioisosteric replacement. Among them, MPO-0186 (scaffold C) inhibited the production of PGE (IC: 0.24 μM) in A549 cells via inhibition of mPGES-1 (IC: 0.49 μM in a cell-free assay) and was found to be approximately 9- and 8-fold more potent than MK-886 as a reference inhibitor, respectively. A molecular docking study theoretically suggests that MPO-0186 could inhibit PGE production by blocking the PGH binding site of mPGES-1 enzyme. Furthermore, MPO-0186 demonstrated good liver metabolic stability and no significant inhibition observed in clinically relevant CYP isoforms except CYP2C19. This result provides a potential starting point for the development of selective and potent mPGES-1 inhibitor with a novel scaffold.
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http://dx.doi.org/10.1016/j.bmcl.2021.127992DOI Listing
June 2021

Protective effect of exopolysaccharide fraction from Bacillus subtilis against dextran sulfate sodium-induced colitis through maintenance of intestinal barrier and suppression of inflammatory responses.

Int J Biol Macromol 2021 May 27;178:363-372. Epub 2021 Feb 27.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea; Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea. Electronic address:

We previously reported that an exopolysaccharide-enriched fraction from Bacillus subtilis J92 (B-EPS) could improve immune functions by regulating the immunological parameters of IFN-γ-primed macrophages, CD3/CD28-stimulated splenocytes, and in cyclophosphamide-induced immunosuppressed mice. In the present study, we investigated whether B-EPS contributes to the maintenance of intestinal barrier integrity in a dextran sodium sulfate (DSS)-induced colitis mouse model that mimics human inflammatory bowel disease (IBD). B-EPS treatment improved histological characteristics and common features including a high disease activity index (DAI), an increased spleen weight, and colon shortening in DSS-induced colitis. B-EPS also effectively restored intestinal barrier function by modulating tight junction-related proteins (claudin-1, claudin-2, and occludin) and epithelial-mesenchymal transition (EMT) marker proteins (E-cadherin, N-cadherin, and vimentin). Moreover, B-EPS downregulated immune cell infiltration and inflammatory responses including the production of inflammatory cytokines, such as IL-6 and IL-1β, and activation of nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3). Taken together, these results suggest that B-EPS could serve as a functional food ingredient for improving intestinal barrier function and alleviating colonic inflammation in IBD.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.02.186DOI Listing
May 2021

Immunostimulatory Effects of Live K040706 on the CYP-Induced Immunosuppression Mouse Model.

Nutrients 2020 Nov 22;12(11). Epub 2020 Nov 22.

Department of Pharmaceutical Biochemistry, College of Pharmacy Kyung Hee University, Seoul 02447, Korea.

Our previous studies have shown that heat-killed K040706 exerts immunostimulatory and anti-inflammatory activities in macrophages, cyclophosphamide (CYP)-treated mice, and dextran sulfate sodium-induced colitis mice. However, the immunostimulatory effects of live K040706 (live K040706) against CYP-induced immunosuppression and its underlying molecular mechanisms remain unknown. Therefore, we investigated the immunostimulatory effects of live K040706 (10 or 10 colony forming unit (CFU)/day, p.o.) in CYP-induced immunosuppressed mice. Oral administration of live K040706 prevented the CYP-induced decreases in body weight, thymus index, natural killer (NK) cell activity, T and B cell proliferation, and cytokine (interferon (IFN)-γ, interleukin (IL)-2, and IL-12) production. The administration of live K040706 also exerted positive effects on the gut microbiota of CYP-induced mice, resulting in a microbiota composition similar to that of normal mice. Moreover, live K040706 significantly enhanced IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in the splenocytes and Peyer's patch (PP) cells of mice and increased bone marrow (BM) cell proliferation. Taken together, our data indicate that live K040706 may effectively accelerate recovery from CYP-induced immunosuppression, leading to activation of the immune system. Therefore, live K040706 may serve as a potential immunomodulatory agent against immunosuppression.
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http://dx.doi.org/10.3390/nu12113573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700367PMC
November 2020

Anti-inflammatory potential of Patrineolignan B isolated from Patrinia scabra in LPS-stimulated macrophages via inhibition of NF-κB, AP-1, and JAK/STAT pathways.

Int Immunopharmacol 2020 Sep 24;86:106726. Epub 2020 Jun 24.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Patrineolignan B (PB), a lignan compound isolated from the radix and rhizomes of Patrinia scabra, was previously reported to possess a strong tumor-specific cytotoxic activity and beneficial effects on nitric oxide (NO) levels in macrophages induced by lipopolysaccharide (LPS). In this study, we assessed the effects of PB on LPS-induced inflammation in RAW 264.7 cells and clarified its molecular mechanisms. PB reversed LPS-induced increase in NO levels and prostaglandin E (PGE) production, as well as inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and mRNA levels in macrophages. Besides, PB prevented the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 in a concentration-dependent manner. The regulatory effects of PB on LPS-induced inflammatory mediators and overproduction of pro-inflammatory cytokines were shown to depend partly on the suppression of nuclear factor kappa B (NF-κB)-mediated transcription and AP-1 activation regulated by a c-Jun amino-terminal kinase (JNK) and extracellular signal-regulated kinases (ERK). Its anti-inflammatory activity was also mediated by regulating the phosphorylation of Janus kinase (JAK)/signal transducers and activators of transcription 1/3 (STAT1/3) signaling pathway. Taken together, our results suggest that PB exhibits anti-inflammatory potency through interfering with the NF-κB, AP-1, and JAK/STAT signaling pathway in LPS-stimulated macrophages.
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http://dx.doi.org/10.1016/j.intimp.2020.106726DOI Listing
September 2020

Patriscabrin F from the roots of Patrinia scabra attenuates LPS-induced inflammation by downregulating NF-κB, AP-1, IRF3, and STAT1/3 activation in RAW 264.7 macrophages.

Phytomedicine 2020 Mar 23;68:153167. Epub 2020 Jan 23.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, South Korea; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, South Korea. Electronic address:

Background: The roots of Partrinia scabra have been used as a medicinal herb in Asia. We previously reported that the inhibitory effect of patriscabrin F on lipopolysaccharide (LPS)-induced nitric oxide (NO) production was the most potent than that of other isolated iridoids from the roots of P. scabra.

Purpose: We investigated the anti-inflammatory activity of patriscabrin F as an active compound of P. scabra and related signaling cascade in LPS-activated macrophages.

Method: The anti-inflammatory activities of patriscabrin F were determined according to its inhibitory effects on NO, prostaglandin E (PGE), and pro-inflammatory cytokines. The molecular mechanisms were revealed by analyzing nuclear factor-κB (NF-κB), activator protein-1 (AP-1), interferon regulatory factor 3 (IRF3), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway.

Results: Patriscabrin F inhibited the LPS-induced production of NO, PGE tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 in both bone-marrow derived macrophages (BMDMs) and RAW 264.7 macrophages. Patriscabrin F downregulated LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), TNF-α, IL-1β, and IL-6 at the transcriptional level. Patriscabrin F suppressed LPS-induced NF-κB activation by decreasing p65 nuclear translocation, inhibitory κBα (IκBα) phosphorylation, and IκB kinase (IKK)α/β phosphorylation. Patriscabrin F attenuated LPS-induced AP-1 activity by inhibiting c-Fos phosphorylation. Patriscabrin F suppressed the LPS-induced phosphorylation of IRF3, JAK1/JAK2, and STAT1/STAT3.

Conclusion: Taken together, our findings suggest patriscabrin F may exhibit anti-inflammatory properties via the inhibition of NF-κB, AP-1, IRF3, and JAK-STAT activation in LPS-induced macrophages.
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http://dx.doi.org/10.1016/j.phymed.2019.153167DOI Listing
March 2020

Inhibitory effects of triarylpyrazole derivatives on LPS-induced nitric oxide and PGE productions in murine RAW 264.7 macrophages.

Bioorg Med Chem Lett 2020 02 10;30(4):126884. Epub 2019 Dec 10.

Department of Beauty Science, Hanseo University, Seosan 31962, Republic of Korea. Electronic address:

In this article, a series of 22 triarylpyrazole derivatives were evaluated for in vitro antiinflammatory activity as inhibitors of nitric oxide (NO) and prostaglandin E (PGE) release induced by lipopolysaccharide (LPS) in murine RAW 264.7 macrophages. The synthesized compounds 1a-h, 2a-f and 3a-h were first examined for their cytotoxicity for determination of the non-toxic concentration for antiinflammatory screening, so that the inhibitory effects against NO and PGE production were not caused by non-specific cytotoxicity. Compounds 1h and 2f were the most active PGE inhibitors with IC values of 2.94 μM and 4.21 μM, respectively. Western blotting and cell-free COX-2 screening revealed that their effects were due to inhibition of COX-2 protein expression. Moreover, compound 1h exerted strong inhibitory effect on the expression of COX-2 mRNA in LPS-induced murine RAW 264.7 macrophages.
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http://dx.doi.org/10.1016/j.bmcl.2019.126884DOI Listing
February 2020

The Anti-Proliferative Activity of the Hybrid TMS-TMF-4f Compound Against Human Cervical Cancer Involves Apoptosis Mediated by STAT3 Inactivation.

Cancers (Basel) 2019 Dec 3;11(12). Epub 2019 Dec 3.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea.

We previously reported the potential anti-proliferative activity of 3-(5,6,7-trimethoxy-4-oxo-4-chromen-2-yl)--(3,4,5-trimethoxyphenyl) benzamide (TMS-TMF-4f) against human cancer cells; however, the underlying molecular mechanisms have not been investigated. In the present study, TMS-TMF-4f showed the highest cytotoxicity in human cervical cancer cells (HeLa and CaSki) and low cytotoxicity in normal ovarian epithelial cells. Annexin V-FITC and propidium iodide (PI) double staining revealed that TMS-TMF-4f-induced cytotoxicity was caused by the induction of apoptosis in both HeLa and CaSki cervical cancer cells. The compound TMS-TMF-4f enhanced the activation of caspase-3, caspase-8, and caspase-9 and regulated Bcl-2 family proteins, which led to mitochondrial membrane potential (MMP) loss and resulted in the release of cytochrome and Smac/DIABLO into the cytosol. Also, TMS-TMF-4f suppressed both constitutive and IL-6-inducible levels of phosphorylated STAT3 (p-STAT3) and associated proteins such as Mcl-1, cyclin D1, survivin, and c-Myc in both cervical cancer cells. STAT-3 overexpression completely ameliorated TMS-TMF-4f-induced apoptotic cell death and PARP cleavage. Docking analysis revealed that TMS-TMF-4f could bind to unphosphorylated STAT3 and inhibit its interconversion to the activated form. Notably, intraperitoneal administration of TMS-TMF-4f (5, 10, or 20 mg/kg) decreased tumor growth in a xenograft cervical cancer mouse model, demonstrated by the increase in TUNEL staining and PARP cleavage and the reduction in p-STAT3, Mcl-1, cyclin D1, survivin, and c-Myc expression levels in tumor tissues. Taken together, our results suggest that TMS-TMF-4f may potentially inhibit human cervical tumor growth through the induction of apoptosis via STAT3 suppression.
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http://dx.doi.org/10.3390/cancers11121927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966466PMC
December 2019

Chemical Constituents from the Aerial Parts of and Their Inhibitory Activities on Prostaglandin E Production in Lipopolysaccharide-Treated RAW 264.7 Macrophages.

J Nat Prod 2019 12 20;82(12):3379-3385. Epub 2019 Nov 20.

Herbal Medicine Resources Research Center , Korea Institute of Oriental Medicine (KIOM) , Naju 58245 , Republic of Korea.

A new flavone glucoside, acacetin-7--(3″--acetyl-6″--malonyl)-β-d-glucopyranoside (), two new phenolic glucosides, (3,7)-tuberonic acid-12--[6'--()-feruloyl]-β-d-glucopyranoside () and salicylic acid-2--[6'--()-feruloyl]-β-d-glucopyranoside (), and two new phenylpropanoid glucosides, chavicol-1--(6'--methylmalonyl)-β-d-glucopyranoside () and chavicol-1--(6'--acetyl)-β-d-glucopyranoside(), as well as 26 known compounds, -, , and -, were isolated from the aerial parts of . The structures of the new compounds were established by spectroscopic/spectrometric methods such as HRESIMS, NMR, and ECD. The anti-inflammatory effect of the isolated compounds was evaluated by measuring their inhibitory activities on prostaglandin E (PGE) in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. New compounds , , , and inhibited LPS-induced PGE production with IC values of 16.8 ± 0.8, 33.9 ± 4.8, 14.3 ± 2.1, and 48.8 ± 4.4 μM, respectively. Compounds , , -, , , , , and - showed potent inhibitory activities with IC values of 1.7-8.4 μM.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00697DOI Listing
December 2019

Immunostimulatory effects of polysaccharides isolated from young barley leaves (Hordeum vulgare L.) with dual activation of Th1 and Th2 in splenic T cells and cyclophosphamide-induced immunosuppressed mice.

Int J Biol Macromol 2020 Mar 12;147:954-964. Epub 2019 Nov 12.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Botanical polysaccharides have been widely known to possess immunological activity. The objective of this study was to investigate the molecular mechanisms underlying the immunostimulatory properties of polysaccharides isolated from barley leaf (Hordeum vulgare L.) (BLE0) in splenocytes and cyclophosphamide (CYP)-induced immunosuppressed mice. BLE0 showed cell proliferative activity and markedly increased the secretion of both Th1-cytokines (IFN-γ and IL-2) and Th2-cytokines (IL-4 and IL-10) in CD3/CD28-activated splenocytes. Molecular data revealed that BLE0 up-regulated the expression of T-bet with enhanced phosphorylation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) 1 signaling pathway. BLE0 also increase the phosphorylation of GATA3 via toll-like receptor (TLR) 2-mediated signaling pathway with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1) activation. Oral administration of BLE0 effectively improved CYP-induced decrease of body weight, splenocyte proliferation, and natural killer (NK) cell cytotoxic activity and significantly increased Th1 and Th2 cytokines, T-bet, and GATA3 mRNA expression. Dietary intake of BLE0 improves the immunological manifestations by stimulating both Th1 and Th2 responses via JAK/STAT1/T-bet and TLR2/GATA3, respectively.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.10.062DOI Listing
March 2020

Hydrangenol Isolated from the Leaves of Attenuates Wrinkle Formation and Repairs Skin Moisture in UVB-Irradiated Hairless Mice.

Nutrients 2019 Oct 2;11(10). Epub 2019 Oct 2.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

Our previous study showed that hydrangenol isolated from leaves exerts antiphotoaging activity in vitro. In this study, we determined its antiphotoaging effect in UVB-irradiated HR-1 hairless mice. We evaluated wrinkle formation, skin thickness, histological characteristics, and mRNA and protein expression using qRT-PCR and Western blot analysis in dorsal skins. Hydrangenol mitigated wrinkle formation, dorsal thickness, dehydration, and collagen degradation. Hydrangenol increased the expression of involucrin, filaggrin, and aquaporin-3 (AQP3) as well as hyaluronic acid (HA) production via hyaluronidase (HYAL)-1/-2 downregulation. Consistent with the recovery of collagen composition, the expression of Pro-COL1A1 was increased by hydrangenol. Matrix metalloproteinase (MMP)-1/-3, cyclooxygenase-2 (COX-2), and interleukin-6 (IL-6) expression was reduced by hydrangenol. Hydrangenol attenuated the phosphorylation of mitogen-activated protein kinases (MAPKs) including ERK and p38, activator protein 1 (AP-1) subunit, and signal transduction and activation of transcription 1 (STAT1). Hydrangenol upregulated the expression of nuclear factor-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO-1), glutamate cysteine ligase modifier subunit (GCLM), and glutamate cysteine ligase catalysis subunit (GCLC). Taken together, our data suggest that hydrangenol can prevent wrinkle formation by reducing MMP and inflammatory cytokine levels and increasing the expression of moisturizing factors and antioxidant genes.
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http://dx.doi.org/10.3390/nu11102354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835603PMC
October 2019

Anti-Inflammatory Mechanisms of Koreanaside A, a Lignan Isolated from the Flower of , against LPS-Induced Macrophage Activation and DSS-Induced Colitis Mice: The Crucial Role of AP-1, NF-κB, and JAK/STAT Signaling.

Cells 2019 09 27;8(10). Epub 2019 Sep 27.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

The current treatment options for inflammatory bowel disease (IBD) are unsatisfactory. Therefore, novel and safer therapies are needed. We previously reported that koreanaside A (KA) showed high radical scavenging activity and suppressed vascular cell adhesion molecule 1 (VCAM-1) expression in vascular smooth muscle cells. However, the molecular mechanisms involved in its anti-inflammatory effect have not been reported. KA inhibited pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nitric oxide (NO), and prostaglandin E (PGE). KA inhibited the production and mRNA expression of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) induced by LPS. KA downregulated the myeloid differentiation primary response 88 (MyD88)-dependent inflammatory gene expressions in the MyD88-overexpressed cells. KA suppressed the LPS-induced transcriptional and DNA-binding activities of activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB). KA was found to inhibit the phosphorylation of Janus kinase 1/2 (JAK1/2) and signal transducers and activators of transcription 1/3 (STAT1/3). In DSS-induced colitis mice, KA relieved the symptoms of colitis by suppressing inflammatory cell infiltration, restoring tight junction (TJ)- and epithelial-mesenchymal transition (EMT)-related protein expression, and inactivating AP-1, NF-κB, and STAT1/3. Therefore, KA reduced inflammatory responses by downregulating AP-1, NF-κB, and JAK/STAT signaling in LPS-induced macrophages and DSS-induced colitis mice.
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http://dx.doi.org/10.3390/cells8101163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829247PMC
September 2019

Repurposing mosloflavone/5,6,7-trimethoxyflavone-resveratrol hybrids: Discovery of novel p38-α MAPK inhibitors as potent interceptors of macrophage-dependent production of proinflammatory mediators.

Eur J Med Chem 2019 Oct 9;180:253-267. Epub 2019 Jul 9.

Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea. Electronic address:

Herein, we address repurposing hybrids of mosloflavone or 5,6,7-trimethoxyflavone with amide analogs of resveratrol from anticancer leads to novel potent anti-inflammatory chemical entities. To unveil the potent anti-inflammatory molecules, biological evaluations were initiated in LPS-induced RAW 264.7 macrophages at 1 μM concentration. Promising compounds were further evaluated at various concentrations. Multiple proinflammatory mediators were assessed including NO, PGE, IL-6, TNF-α and IL-1β. Compound 5z inhibited the induced production of NO, PGE, IL-6, TNF-α and IL-1β at the low 1 μM concentration by 44.76, 35.71, 53.48, 29.39 and 41.02%, respectively. Compound 5z elicited IC values as low as 2.11 and 0.98 μM against NO and PGE production respectively. Compounds 5q and 5g showed potent submicromolar IC values of 0.31 and 0.59 μM respectively against PGE production. Reverse docking of compound 5z suggested p38-α MAPK, which is a key signaling molecule within the pathways controlling the transcription of proinflammatory mediators, as the molecular target. Biochemical testing confirmed these compounds as p38-α MAPK inhibitors explaining its potent inhibition of proinflammatory mediators' production. Collectively, the results presented 5z as a promising compound for further development of anti-inflammatory agents for treatment of macrophages-and/or immune mediated inflammatory diseases.
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http://dx.doi.org/10.1016/j.ejmech.2019.07.030DOI Listing
October 2019

A novel mPGES-1 inhibitor alleviates inflammatory responses by downregulating PGE in experimental models.

Prostaglandins Other Lipid Mediat 2019 10 20;144:106347. Epub 2019 Jun 20.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea. Electronic address:

We previously reported the strong inhibitory potency of N-phenyl-N'-(4- benzyloxyphenoxycarbonyl)-4-chlorophenylsulfonyl hydrazide (PBCH) on lipopolysaccharide (LPS)-induced prostaglandin E (PGE) production in macrophages. Herein, we characterized PBCH as a microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor and evaluated its anti-inflammatory effects using in vivo experimental models. PBCH inhibited PGE production in various activated cells in addition to inhibiting the mPGES-1 activity. In the ear edema and paw edema rat models, PBCH significantly reduced ear thickness and paw swelling, respectively. Besides, in adjuvant-induced arthritis (AIA) rat model, PBCH decreased paw swelling, plasma rheumatoid factor (RF), and receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio. Furthermore, while PBCH reduced the plasma prostaglandin E metabolite (PGEM) levels, it did not affect the plasma levels of prostacyclin (PGI) and thromboxane A (TXA). Our data suggest that PBCH downregulates PGE production by interfering with the mPGES-1 activity, thus reducing edema and arthritis in rat models.
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http://dx.doi.org/10.1016/j.prostaglandins.2019.106347DOI Listing
October 2019

Caffeoyloxy-5,6-dihydro-4-methyl-(2H)-pyran-2-one isolated from the leaves of Olinia usambarensis attenuates LPS-induced inflammatory mediators by inactivating AP-1 and NF-κB.

Chem Biol Interact 2019 Aug 15;309:108718. Epub 2019 Jun 15.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea. Electronic address:

We have previously reported the isolation of four compounds, caffeoyloxy-5,6-dihydro-4-methyl-(2H)-pyran-2-one (CDMP), olinioside, caffeic acid and 3-hydroxylup-12-en-28-oic acid, from the leaves of Olinia usambarensis. Here, we evaluated the inhibitory effects of these compounds on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and prostaglandin E (PGE) in RAW 264.7 macrophages, and found that CDMP is the most potent of these two pro-inflammatory mediators (IC; 12.12 μM and 10.78 μM, respectively). Consistent with these results, CDMP also down-regulated inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6) at the protein and mRNA levels in LPS-treated RAW 264.7 macrophages. Furthermore, CDMP suppressed LPS-induced nuclear factor κB (NF-κB) activation by decreasing p65 nuclear translocation through the phosphorylation and degradation of the inhibitory κBα (IκBα). CDMP also attenuated LPS-induced transcriptional and DNA-binding activities of activator protein 1 (AP-1) by suppressing the phosphorylation and expression of c-Fos and c-Jun. Finally, CDMP considerably suppressed the LPS-induced phosphorylation of c-Jun N-terminal kinase (JNK), but did not affect the phosphorylation of p38 or extracellular signal-regulated kinase (ERK). Taken together, our data suggest that CDMP down-regulates genes encoding pro-inflammatory mediators and cytokines, such as iNOS, COX-2, TNF-α, IL-1β, and IL-6 via NF-κB and JNK/AP-1 inactivation in LPS-induced RAW 264.7 macrophages.
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http://dx.doi.org/10.1016/j.cbi.2019.06.031DOI Listing
August 2019

Chemical Constituents from Leaves of Hydrangea serrata and Their Anti-photoaging Effects on UVB-Irradiated Human Fibroblasts.

Biol Pharm Bull 2019 ;42(3):424-431

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University.

Hydrangea serrata (THUNB.) SER. (Hydrangeaceae) leaves have been used as herbal teas in Korea and Japan. The objective of this study was to identify anti-photoaging compounds in aqueous EtOH extract prepared from leaves of H. serrata and their effects on UVB-irradiated Hs68 human foreskin fibroblasts. Phytochemical study on H. serrata leaves led to the isolation and characterization of ten compounds: hydrangenol, thunberginol A, thunberginol C, hydrangenoside A, hydrangenoside C, cudrabibenzyl A, 2,3,4'-trihydroxystilbene, thunberginol F, quercetin 3-O-β-D-xylopyranosyl (1-2)-β-D-galactopyranoside, quercetin 3-O-β-D-xylopyranosyl (1-2)-β-D-glucopyranoside. Cudrabibenzyl A, 2,3,4'-trihydroxystilbene, quercetin 3-O-β-D-xylopyranosyl (1-2)-β-D-galactopyranoside, quercetin 3-O-β-D-xylopyranosyl (1-2)-β-D-glucopyranoside were firstly isolated from H. serrata. We estimated the effects of 10 compounds on cell viability and production of pro-collagen Type I, matrix metalloproteinase (MMP)-1, and hyaluronic acid (HA) after UVB irradiation. Of these compounds, hydrangenol showed potent preventive activities against reduced cell viability and degradation of pro-collagen Type I in UVB-irradiated Hs68 fibroblasts. Hydrangenol had outstanding inductive activities on HA production. It suppressed mRNA expression levels of MMP-1, MMP-3, hyaluronidase (HYAL)-1, HYAL-2, cyclooxygenase-2 (COX-2), interleukin (IL)-6, IL-8, and IL-1β in UVB-irradiated Hs68 fibroblasts. When Hs68 fibroblasts were exposed to hydrangenol after UVB irradiation, UVB-induced reactive oxygen species (ROS) production was suppressed. Hydrangenol also inhibited the activation of activator protein-1 (AP-1) and signal transduction and activation of transcription 1 (STAT-1) by downregulating phosphorylation of p38 and extracellular signal-regulated kinase (ERK). Our data indicate that hydrangenol isolated from H. serrata leaves has potential protective effects on UVB-induced skin photoaging.
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http://dx.doi.org/10.1248/bpb.b18-00742DOI Listing
July 2019

(Thunb.) Ser. Extract Attenuate UVB-Induced Photoaging through MAPK/AP-1 Inactivation in Human Skin Fibroblasts and Hairless Mice.

Nutrients 2019 Mar 1;11(3). Epub 2019 Mar 1.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

Skin photoaging is mainly caused by exposure to ultraviolet (UV) light, which increases expressions of matrix metalloproteinases (MMPs) and destroys collagen fibers, consequently inducing wrinkle formation. Nutritional factors have received scientific attention for use as agents for normal skin functions. The aim of this study was to investigate the effect of hot water extracts from the leaves of (Thunb.) Ser. (WHS) against ultraviolet B (UVB)-induced skin photoaging and to elucidate the underlying molecular mechanisms in human foreskin fibroblasts (Hs68) and HR-1 hairless mice. WHS recovered UVB-reduced cell viability and ameliorated oxidative stress by inhibiting intracellular reactive oxygen species (ROS) generation in Hs68 cells. WHS rescued UVB-induced collagen degradation by suppressing MMP expression, and reduced the mRNA levels of inflammatory cytokines. These anti-photoaging activities of WHS were associated with inhibition of the activator protein 1 (AP-1), signal transduction and activation of transcription 1 (STAT1), and mitogen-activated protein kinase (MAPK) signaling pathways. Oral administration of WHS effectively alleviated dorsal skin from wrinkle formation, epidermal thickening, collagen degradation, and skin dehydration in HR-1 hairless mice exposed to UVB. Notably, WHS suppressed UVB activation of the AP-1 and MAPK signaling pathways in dorsal mouse skin tissues. Taken together, our data indicate that WHS prevents UVB-induced skin damage due to collagen degradation and MMP activation via inactivation of MAPK/AP-1 signaling pathway.
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http://dx.doi.org/10.3390/nu11030533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470489PMC
March 2019

Non-glycosidic iridoids from the roots of Patrinia scabra and their nitric oxide production inhibitory effects.

Arch Pharm Res 2019 Sep 5;42(9):766-772. Epub 2019 Feb 5.

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

Phytochemical investigation on the 70% aqueous EtOH extract from the roots of Patrinia scabra led to the isolation and characterization of five new non-glycosidic iridoids, patriscabrins F-J (1-5), along with a known iridoid 11-ethoxyviburtinal (6). The structures of the new compounds 1-5 were determined by interpretation of spectroscopic data, particularly by 1D- and 2D-NMR and ECD studies. Thereafter, the isolates 1-6 were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells. Of these, patriscabrin F (1) exhibited the most potent inhibitory effect with observed IC value of 14.1 μM. In addition, patriscabrin G (2) and 11-ethoxyviburtinal (6) showed IC values 24.6 and 35.5 μM, respectively.
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http://dx.doi.org/10.1007/s12272-019-01117-0DOI Listing
September 2019

EGFR inhibitors from cancer to inflammation: Discovery of 4-fluoro-N-(4-(3-(trifluoromethyl)phenoxy)pyrimidin-5-yl)benzamide as a novel anti-inflammatory EGFR inhibitor.

Bioorg Chem 2019 05 12;86:112-118. Epub 2019 Jan 12.

Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea. Electronic address:

EGFR inhibitors are well-known as anticancer agents. Quite differently, we report our effort to develop EGFR inhibitors as anti-inflammatory agents. Pyrimidinamide EGFR inhibitors eliciting low micromolar IC and the structurally close non-EGFR inhibitor urea analog were synthesized. Comparing their nitric oxide (NO) production inhibitory activity in peritoneal macrophages and RAW 246.7 macrophages indicated that their anti-inflammatory activity in peritoneal macrophages might be a sequence of EGFR inhibition. Further evaluations proved that compound 4d significantly and dose-dependently inhibits LPS-induced iNOS expression and IL-1β, IL-6, and TNF-α production via NF-κB inactivation in peritoneal macrophages. Compound 4d might serve as a lead compound for development of a novel class of anti-inflammatory EGFR inhibitors.
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http://dx.doi.org/10.1016/j.bioorg.2019.01.017DOI Listing
May 2019

Anti-Colitic Effects of Ethanol Extract of Mill. through Suppression of Pro-Inflammatory Mediators via NF-κB/STAT3 Inactivation in Dextran Sulfate Sodium-Induced Colitis Mice.

Int J Mol Sci 2019 Jan 5;20(1). Epub 2019 Jan 5.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.

Mill, cv. Hass, also known as avocado, has been reported to possess hypolipidemic, anti-diabetic, anti-oxidant, cardioprotective, and photoprotective potencies. However, few studies have reported its anti-colitic effects. In this study, we investigated anti-colitic effects of ethanol extract of (EEP) in dextran sulfate sodium (DSS)-induced colitic mice and the involved molecular mechanisms. EEP effectively improved clinical signs and histological characteristics of DSS-induced colitis mice. In DSS-exposed colonic tissues, EEP reduced expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines such as interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. Moreover, EEP suppressed DSS-induced activation of nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3). Consistent with in vivo results, EEP also suppressed protein and mRNA expression levels of iNOS, COX-2, and pro-inflammatory cytokines via NF-κB and STAT3 inactivation in LPS-induced RAW 264.7 macrophages. Taken together, our data indicate that ethanol extract of avocado may be used as a promising therapeutic against inflammatory bowel diseases by suppressing the NF-κB and STAT3 signaling pathway.
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http://dx.doi.org/10.3390/ijms20010177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337306PMC
January 2019

Natural products hybrids: 3,5,4'-Trimethoxystilbene-5,6,7-trimethoxyflavone chimeric analogs as potential cytotoxic agents against diverse human cancer cells.

Eur J Med Chem 2019 Jan 29;161:559-580. Epub 2018 Oct 29.

Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea. Electronic address:

Cancer still represents a major global health problem. All currently available anticancer agents have disadvantages like resistance or side effects. Therefore, introduction of novel anticancer agents is needed. Intrigued by the high success rate for natural products-based drug discovery, we designed and synthesized antiproliferative chemical entities as hybrids of two natural products; 3,5,4'-trimethoxystilbene and 5,6,7-trimethoxyflavone. To probe the spectrum of the synthesized compounds, in vitro evaluation was conducted against nine panels representing major cancer diseases. The results revealed the hybrid analogs 4f, 4h, 4k and 4q as promising broad-spectrum anticancer lead compounds eliciting high growth inhibition of several cell lines representing multiple cancers diseases. Evaluation of the promising lead compounds against normal human cell lines suggested a selective cytotoxic effect on cancer cells. Mechanistic investigation of the cytotoxic activity of compound 4f in human cervical cancer HeLa cells showed that it triggers cell death through induction of apoptosis. As a whole, this study presents the natural products hybrid analogs 4f, 4h, 4k and 4q as potential lead compounds for further development of novel anticancer therapeutics.
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http://dx.doi.org/10.1016/j.ejmech.2018.10.062DOI Listing
January 2019

Synthesis of New Triarylpyrazole Derivatives Possessing Terminal Sulfonamide Moiety and Their Inhibitory Effects on PGE₂ and Nitric Oxide Productions in Lipopolysaccharide-Induced RAW 264.7 Macrophages.

Molecules 2018 Oct 7;23(10). Epub 2018 Oct 7.

Center for Biomaterials, Korea Institute of Science and Technology, Cheongryang, Seoul 130-650, Korea.

This article describes the design, synthesis, and in vitro anti-inflammatory screening of new triarylpyrazole derivatives. A total of 34 new compounds were synthesized containing a terminal arylsulfonamide moiety and a different linker between the sulfonamide and pyridine ring at position 4 of the pyrazole ring. All the target compounds were tested for both cytotoxicity and nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Compounds 1b, 1d, 1g, 2a, and 2c showed the highest NO inhibition percentages and the lowest cytotoxic effect. The most potent derivatives were tested for their ability to inhibit prostaglandin E₂ (PGE₂) in LPS-induced RAW 264.7 macrophages. The IC for nitric oxide inhibition, PGE₂ inhibition, and cell viability were determined. In addition, 1b, 1d, 1g, 2a, and 2c were tested for their inhibitory effect on LPS-induced inducible nitric oxide synthase (iNOS) and Cyclooxygenase 2 (COX-2) protein expression as well as iNOS enzymatic activity.
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http://dx.doi.org/10.3390/molecules23102556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222820PMC
October 2018

Saikosaponin B2 Suppresses Inflammatory Responses Through IKK/IκBα/NF-κB Signaling Inactivation in LPS-Induced RAW 264.7 Macrophages.

Inflammation 2019 Feb;42(1):342-353

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Dongdaemun-Ku, Kyungheedae-ro 26, Seoul, 02447, Republic of Korea.

Bupleurum falcatum (Umbelliferae) have been widely used to treat inflammatory diseases as traditional medicines in East Asian region. Although saikosaponins are main bioactive molecules of B. falcatum, there is little information on bioactivity of saikosaponin B (SSB2). This study was conducted to assess the anti-inflammatory activities and the involved mechanisms of SSB2 in LPS-induced RAW 264.7 macrophages. SSB2 suppressed the releases of nitric oxide (NO), prostaglandin E (PGE), tumor necrosis factor α (TNF-α), interleukins (IL)-6, and IL-1β by suppressing mRNA levels of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, IL-1β, and IL-6 in LPS-induced macrophages. SSB2 blocked LPS-induced DNA binding and nuclear factor kappa B (NF-κB) transcriptional activity by inhibiting nuclear translocation p65 and p50, inhibitory κBα (IκBα) degradation, and IκB kinase β (IKKβ) phosphorylation and activity. In IKKβ-overexpressing cells, SSB2 significantly suppressed IKKβ-dependent NF-κB transcriptional activity. Moreover, SSB2 reduced phosphorylation of p38 and extracellular signal-regulated kinase1/2 (ERK1/2). SSB2 effectively inhibits LPS-induced pro-inflammatory mediator releases by interfering with IKKβ and IκBα activation, thus preventing NF-κB activation. Our data indicates that SSB2 could be a potential therapeutic application for inflammation-associated diseases.
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http://dx.doi.org/10.1007/s10753-018-0898-0DOI Listing
February 2019

Cirsimarin, a flavone glucoside from the aerial part of Cirsium japonicum var. ussuriense (Regel) Kitam. ex Ohwi, suppresses the JAK/STAT and IRF-3 signaling pathway in LPS-stimulated RAW 264.7 macrophages.

Chem Biol Interact 2018 Sep 25;293:38-47. Epub 2018 Jul 25.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, 02447, South Korea; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, 02447, South Korea. Electronic address:

Cirsium japonicum var. ussuriense (Regel) Kitam. ex Ohwi (C. ussuriense) is known as "Dae-Gye" or "Korean milk thistle". C. ussuriense have long been used as a folk medicinal plant for inflammatory diseases such as hepatitis, nephritis, and mastitis in Korea, China, and Japan. To reveal the anti-inflammatory components of C. ussuriense, we isolated three flavone glycosides (linarin, cirsimarin, and hispidulin-7-O-neohesperidoside) from the aerial part of C. ussuriense and evaluated their inhibitory effects on LPS-induced pro-inflammatory mediators in macrophages. We also investigated the involving molecular mechanisms of cirsimarin. Among three flavone glycosides, cirsimarin showed vastly superior inhibitory potency in LPS-induced nitric oxide (NO) and prostaglandin E (PGE) production. Cirsimarin concentration-dependently inhibited LPS-induced inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein and mRNA levels in macrophages. Cirsimarin suppressed the production and mRNA expression of tumor necrosis factor- α (TNF-α) and interleukin (IL)-6 in LPS-stimulated RAW 264.7 and bone marrow-derived macrophages. Moreover, molecular data presented that cirsimarin down-regulated the phosphorylation of Janus kinase (JAK)/signal transducer and activator of transcriptions (STATs) and p38 mitogen-activated protein kinase (MAPK), and nuclear translocation of interferon regulatory factor (IRF)-3. Collectively, cirsimarin may be an active ingredient responsible for anti-inflammatory effects of C. ussuriense and it may act as a promising therapeutic against inflammatory diseases by suppressing the JAK/STAT and IRF-3 signaling pathway.
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http://dx.doi.org/10.1016/j.cbi.2018.07.024DOI Listing
September 2018

Iridoids from the Roots of Patrinia scabra and Their Inhibitory Potential on LPS-Induced Nitric Oxide Production.

J Nat Prod 2018 06 25;81(6):1468-1473. Epub 2018 May 25.

Department of Life and Nanopharmaceutical Sciences, Graduate School , Kyung Hee University , Seoul 136-713 , Korea.

An activity-guided fractionation procedure of the 70% aqueous EtOH extract from the roots of Patrinia scabra led to the isolation and characterization of five new iridoids, patriscabrins A-E (1-5), along with 13 known compounds. The structures of 1-5 were determined by interpretation of spectroscopic data, particularly by 1D and 2D NMR, ECD, and VCD studies. Thereafter, isolates were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells. Of these, the new iridoids 2 and 5 and the known lignan patrineolignan B (6) exhibited IC values of 14.7 to 17.8 μM.
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http://dx.doi.org/10.1021/acs.jnatprod.8b00229DOI Listing
June 2018

Compound K induced apoptosis via endoplasmic reticulum Ca release through ryanodine receptor in human lung cancer cells.

J Ginseng Res 2018 Apr 4;42(2):165-174. Epub 2017 Feb 4.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.

Background: Extended endoplasmic reticulum (ER) stress may initiate apoptotic pathways in cancer cells, and ER stress has been reported to possibly increase tumor death in cancer therapy. We previously reported that caspase-8 played an important role in compound K-induced apoptosis via activation of caspase-3 directly or indirectly through Bid cleavage, cytochrome release, and caspase-9 activation in HL-60 human leukemia cells. The mechanisms leading to apoptosis in A549 and SK-MES-1 human lung cancer cells and the role of ER stress have not yet been understood.

Methods: The apoptotic effects of compound K were analyzed using flow cytometry, and the changes in protein levels were determined using Western blot analysis. The intracellular calcium levels were monitored by staining with Fura-2/AM and Fluo-3/AM.

Results: Compound K-induced ER stress was confirmed through increased phosphorylation of eIF2α and protein levels of GRP78/BiP, XBP-1S, and IRE1α in human lung cancer cells. Moreover, compound-K led to the accumulation of intracellular calcium and an increase in m-calpain activities that were both significantly inhibited by pretreatment either with BAPTA-AM (an intracellular Ca chelator) or dantrolene (an RyR channel antagonist). These results were correlated with the outcome that compound K induced ER stress-related apoptosis through caspase-12, as z-ATAD-fmk (a specific inhibitor of caspase-12) partially ameliorated this effect. Interestingly, 4-PBA (ER stress inhibitor) dramatically improved the compound K-induced apoptosis.

Conclusion: Cell survival and intracellular Ca homeostasis during ER stress in human lung cancer cells are important factors in the induction of the compound K-induced apoptotic pathway.
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http://dx.doi.org/10.1016/j.jgr.2017.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926506PMC
April 2018

Dammarane-type triterpene ginsenoside-Rg18 inhibits human non-small cell lung cancer A549 cell proliferation via G phase arrest.

Oncol Lett 2018 Apr 15;15(4):6043-6049. Epub 2018 Feb 15.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.

A previous study reported that a novel dammarane-type triterpene saponin, ginsenoside-Rg18, derived from the root , displayed hydroxyl radical scavenging, anti-bacterial and cytotoxic activities. However, the underlying molecular mechanisms of its anti-proliferative effect on non-small cell lung cancer (NSCLC) A549 cells remains unclear. In the present study, it was determined that Rg18 inhibited the proliferation of A549 cells with a half-maximal inhibitory concentration of 150 µM. Flow cytometry analysis indicated that cell cycle progression was blocked by Rg18 at G phase in A549 cells, which was accompanied by downregulation of cyclin-dependent kinase 2 (CDK2), CDK4, CDK6, cyclin D1, cyclin D2, cyclin E and phosphorylated retinoblastoma protein expression at the protein level. In addition, the CDK inhibitors (CDKNs), CDKN1A and CDKN1B, were upregulated following Rg18 treatment. Furthermore, Rg18 treatment resulted in the intracellular accumulation of reactive oxygen species (ROS), and a dose-dependent inhibition of p38 mitogen activated protein kinase (p38), c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB)/p65 phosphorylation. Taken together, Rg18-mediated G phase arrest was closely associated with the generation of intracellular ROS, and p38, JNK and NF-κB/p65 inhibition in A549 human NSCLC cells.
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http://dx.doi.org/10.3892/ol.2018.8057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844119PMC
April 2018

Kaempferol 7-O-β-D-glucoside isolated from the leaves of Cudrania tricuspidata inhibits LPS-induced expression of pro-inflammatory mediators through inactivation of NF-κB, AP-1, and JAK-STAT in RAW 264.7 macrophages.

Chem Biol Interact 2018 Mar 20;284:101-111. Epub 2018 Feb 20.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea. Electronic address:

Kaempferol 7-O-β-D-glucoside (KPG), a natural flavonol isolated from Cudrania tricuspidata, has been reported to exert anti-cancer effects; however, its anti-inflammatory effects have not yet been reported. In this study, we demonstrate the suppressive effect of KPG on the production of nitric oxide (NO), prostaglandin E (PGE), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and mouse bone marrow-derived macrophages. KPG downregulated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein level and iNOS, COX-2, TNF-α, IL-1β, and IL-6 at the mRNA level in LPS-treated RAW 264.7 macrophages. Moreover, we elucidated the underlying molecular mechanism, demonstrating that KPG attenuated LPS-induced nuclear factor-κB (NF-κB) activation by decreasing p65 nuclear translocation, inhibiting κBα (IκBα) phosphorylation/degradation and IκB kinaseα/β (IKKα/β) phosphorylation. KPG additionally reduced LPS-induced activator protein-1 (AP-1) activity by inhibiting c-Fos expression in the nucleus, though c-Jun was not affected. Furthermore, we revealed that KPG significantly abrogated the LPS-induced phosphorylation of signal transducer and activator of transcription (STAT) 1 (Ser 727, Tyr 701) and STAT3 (Tyr 705) through inhibiting the phosphorylation of Janus kinase (JAK) 1 and JAK2, its upstream activating proteins. Taken together, our data suggest that KPG induces anti-inflammatory activity by blocking NF-κB, AP-1, and JAK-STAT signaling pathways in LPS-treated RAW 264.7 macrophages, thus suppressing inflammatory mediators.
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http://dx.doi.org/10.1016/j.cbi.2018.02.022DOI Listing
March 2018

Penetrating Obturator Artery Injury after Gunshot Wounds: A Successful Multidisciplinary Trauma Team Approach to a Potentially Lethal Injury.

Cureus 2017 Nov 17;9(11):e1857. Epub 2017 Nov 17.

Trauma and Acute Care Surgery, Hurley Medical Center.

Obturator artery injury (OAI) from pelvic gunshot wounds (GSW) is a rarely reported condition. Hemorrhages from pelvic trauma (PT) are mostly venous. Arterial hemorrhages represent about 10-20% of PTs. When arterial hemorrhages from PT occur, they are a severe and deadly complication often causing significant hemodynamic instability and eventual shock.  23-year-old male presented to our emergency service via a private vehicle with multiple gunshot wounds to both thighs and to the lower back, resulted in rectal and obturator artery (OA) injuries. The patient underwent a successful coil-embolization of the right OA. Given the density of structures within the pelvis, patients who sustain gunshot wounds to the pelvic region are at high risk for injury to the small bowel, sigmoid colon, rectum, bladder, and/or vascular structures. While bleeding is the major cause of early mortality in PT, rectal injuries carry the highest mortality due to visceral injuries. A high clinical index of suspicion is needed to diagnose an iliac artery injury or injury to its branches. Prompt computed tomographic angiogram (CTA) and embolization of the OA is the best method to control and stop the bleeding and improve the mortality outcome. Clinicians caring for patients presenting with pelvic gunshot wounds should pay attention to the delayed presentation of internal hemorrhage from the OAs. A multidisciplinary team approach is crucial in the successful management of penetrating injuries to the obturator artery.
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http://dx.doi.org/10.7759/cureus.1857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773274PMC
November 2017

Kyungheechunggan-Tang-01, a New Herbal Medication, Suppresses LPS-Induced Inflammatory Responses through JAK/STAT Signaling Pathway in RAW 264.7 Macrophages.

Evid Based Complement Alternat Med 2017 29;2017:7383104. Epub 2017 Nov 29.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.

Medicinal plants have been used as alternative therapeutic tools to alleviate inflammatory diseases. The objective of this study was to evaluate anti-inflammatory properties of Kyungheechunggan-tang- (KCT-) 01, KCT-02, and Injinchunggan-tang (IJCGT) as newly developed decoctions containing 3-11 herbs in LPS-induced macrophages. KCT-01 showed the most potent inhibitory effects on LPS-induced NO, PGE, TNF-, and IL-6 production among those three herbal formulas. In addition, KCT-01 significantly inhibited LPS-induced iNOS and COX-2 at protein levels and expression of iNOS, COX-2, TNF-, and IL-6 at mRNA levels. Molecular data revealed that KCT-01 attenuated the activation of JAK/STAT signaling cascade without affecting NF-B or AP-1 activation. In ear inflammation induced by croton oil, KCT-01 significantly reduced edema, MPO activity, expression levels of iNOS and COX-2, and STAT3 phosphorylation in ear tissues. Taken together, our findings suggest that KCT-01 can downregulate the expression of proinflammatory genes by inhibiting JAK/STAT signaling pathway under inflammatory conditions. This study provides useful data for further exploration and application of KCT-01 as a potential anti-inflammatory medicine.
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http://dx.doi.org/10.1155/2017/7383104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733936PMC
November 2017
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