Publications by authors named "Hee Soo Han"

19 Publications

  • Page 1 of 1

Relationship between ankle varus moment during gait and radiographic measurements in patients with medial ankle osteoarthritis.

PLoS One 2021 24;16(6):e0253570. Epub 2021 Jun 24.

Department of Orthopaedic Surgery, Seoul National University Bundang Hospital, Seongnam-si, South Korea.

Background: Kinetic data obtained during gait can be used to clarify the biomechanical pathogenesis of osteoarthritis of the lower extremity. This study aimed to investigate the difference in ankle varus moment between the varus angulation and medial translation types of medial ankle osteoarthritis, and to identify the radiographic measurements associated with ankle varus moment.

Methods: Twenty-four consecutive patients [mean age 65.8 (SD) 8.0 years; 9 men and 15 women] with medial ankle osteoarthritis were included. Fourteen and 10 patients had the varus angulation (tibiotalar tilt angle≥3 degrees) and medial translation (tibiotalar tilt angle<3 degrees) types, respectively. All patients underwent three-dimensional gait analysis, and the maximum varus moment of the ankle was recorded. Radiographic measurement included tibial plafond inclination, tibiotalar tilt angle, talar dome inclination, and lateral talo-first metatarsal angle. Comparison between the two types of medial ankle osteoarthritis and the relationship between the maximum ankle varus moment and radiographic measurements were analyzed.

Results: The mean tibial plafond inclination, tibiotalar tilt angle, talar dome inclination, lateral talo-first metatarsal angle, and maximum ankle varus moment were 6.4 degrees (SD 3.3 degrees), 5.0 degrees (SD 4.6 degrees), 11.4 degrees (SD 5.2 degrees), -6.5 degrees (SD 11.7 degrees), and 0.185 (SD 0.082) Nm/kg, respectively. The varus angulation type showed a greater maximum ankle varus moment than the medial translation type (p = .005). The lateral talo-first metatarsal angle was significantly associated with the maximum ankle varus moment (p = .041) in the multiple regression analysis.

Conclusion: The varus angulation type of medial ankle osteoarthritis is considered to be more imbalanced biomechanically than the medial displacement type. The lateral talo-first metatarsal angle, being significantly associated with the ankle varus moment, should be considered for correction during motion-preserving surgeries for medial ankle osteoarthritis to restore the biomechanical balance of the ankle.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253570PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224910PMC
June 2021

Comparison of Bone Mineral Density and Markers of Bone Turnover in Osteoporotic Women after 6-Month Treatment with Alendronate or Bazedoxifene: A Randomized Controlled Trial.

J Bone Metab 2021 May 31;28(2):131-137. Epub 2021 May 31.

Department of Orthopedic Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Background: In a randomized controlled trial, we compared the bone mineral densities (BMDs) and blood markers of bone turnover during short-term treatment of osteoporotic women with bisphosphonate alendronate or bazedoxifene, a selective estrogen receptor modulator.

Methods: Ten and eleven patients were randomized to the alendronate and bazedoxifene groups, respectively. BMDs were measured before and after 6 months of treatment. Blood tests were used to measure the levels of osteocalcin (OC), C-terminal telopeptide of type I collagen (CTX), vitamin D3, and parathyroid hormone pretreatment and after 3 and 6 months of treatment. The variables were compared statistically.

Results: The alendronate group showed decreases in blood levels of both OC and CTX during the study period (P<0.001 and P=0.002, respectively), while the bazedoxifene group had a decrease only in OC levels (P=0.012). After 6 months of treatment, BMDs significantly increased in the alendronate group at multiple bone sites, including the L1-4 lumbar vertebrae, femur trochanter, and total femur. However, there was no significant increase in BMD in the bazedoxifene group. BMDs were not significantly different between the 2 groups.

Conclusions: Patients treated with alendronate showed more rapid suppression of markers of bone turnover and higher BMD than those treated with bazedoxifene during a short-term regime. Considering the effects and complications of each medication, the relationship between bone turnover rate and bone quality will need to be investigated in future studies.
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http://dx.doi.org/10.11005/jbm.2021.28.2.131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206607PMC
May 2021

Standardized hot water extract from the leaves of Hydrangea serrata (Thunb.) Ser. alleviates obesity via the AMPK pathway and modulation of the gut microbiota composition in high fat diet-induced obese mice.

Food Funct 2021 Mar 3;12(6):2672-2685. Epub 2021 Mar 3.

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

Obesity is an increasing health problem worldwide as it is the major risk factor for metabolic diseases. In the present study, we investigated the anti-obesity effects of WHS by examining its effects on high fat diet (HFD)-induced obese mice. Male C57BL/6 mice were fed either a normal diet (ND) or a high fat diet (HFD) with or without WHS. At the end of the experiment, we observed the changes in their body weight and white adipose tissue (WAT) weight and lipid profiles in plasma. We performed western blot and histological analyses of WAT and liver to elucidate the molecular mechanisms of action. We also conducted fecal 16S rRNA analysis for investigating the gut microbiota. Our results indicated that pre- and post-oral administration of WHS significantly prevented body weight gain and reduced body fat weight in HFD-induced obese mice. In addition, WHS was found to improve adipocyte hypertrophy and liver fat accumulation by regulating the AMPK and AKT/mTOR pathways. WHS ameliorated hyperlipidemia by reducing total cholesterol and low-density lipoprotein (LDL) and decreased the energy metabolism-related hormones, leptin and insulin, in mouse plasma. Furthermore, we found that WHS modulated gut dysbiosis by normalizing HFD-induced changes. Taken together, our in vivo data implicate that WHS can be considered as a potential dietary supplement for alleviating obesity.
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http://dx.doi.org/10.1039/d0fo02185gDOI Listing
March 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

Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative-lipid complex.

Drug Deliv 2020 Dec;27(1):1501-1513

Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Mokpo National University, Muan-gun, Republic of Korea.

In this study, a system for oral delivery of etoposide (ETP) was designed to avoid the problems associated with low and variable bioavailability of a commercially available ETP emulsion comprised of polyethylene glycol, glycerol, and citric acid anhydrous. ETP was complexed with low-molecular-weight methylcellulose (ETP/LMC) and loaded into a water-in-oil-in-water multiple nanoemulsion to formulate an ETP/LMC-nanoemulsion (ELNE). To further enhance the oral bioavailability, an ionic complex formed by anionic lipid 1,2-didecanoyl-sn-glycero-3-phosphate (sodium salt) and cationic -deoxycholyl-l-lysyl-methylester was incorporated into ELNE, yielding ELNE#7. As expected, ELNE#7 showed 4.07- and 2.25-fold increases in artificial membrane and Caco-2/HT29-MTX-E12 permeability ( ), respectively, resulting in 224% greater oral bioavailability compared with the commercially available ETP emulsion. In contrast, inhibition of clathrin- and caveola-mediated endocytosis, macropinocytosis, and bile acid transporters by chlorpromazine, genistein, amiloride, and actinomycin D in Caco-2/HT-29-MTX-E12 monolayers reduced the by 45.0%, 20.5%, 28.8%, and 31.1%, respectively. These findings suggest that these routes play important roles in enhancing the oral absorption of ELNE#7. In addition, our mechanistic study suggested that P-glycoprotein did not have an inhibitory effect on the permeation of ELNE#7. Notably, ELNE#7 showed significantly enhanced toxicity in LLC and A549 cells compared with ETP-E. These observations support the improved oral absorption of ETP in ELNE#7, suggesting that it is a better alternative than ETP emulsion.
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http://dx.doi.org/10.1080/10717544.2020.1837293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594851PMC
December 2020

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

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

Oral Intake of Hydrangea serrata (Thunb.) Ser. Leaves Extract Improves Wrinkles, Hydration, Elasticity, Texture, and Roughness in Human Skin: A Randomized, Double-Blind, Placebo-Controlled Study.

Nutrients 2020 May 28;12(6). Epub 2020 May 28.

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

Previously, we reported that the hot water extract of leaves (WHS) and its active component, hydrangenol, possess in vitro and in vivo effects on skin wrinkles and moisturization. We conducted a randomized, double-blind, placebo-controlled trial to clinically evaluate the effect of WHS on human skin. Participants ( = 151) were randomly assigned to receive either WHS 300 mg, WHS 600 mg, or placebo, once daily for 12 weeks. Skin wrinkle, hydration, elasticity, texture, and roughness parameters were assessed at baseline and after 4, 8, and 12 weeks. Compared to the placebo, skin wrinkles were significantly reduced in both WHS groups after 8 and 12 weeks. In both WHS groups, five parameters (R1-R5) of skin wrinkles significantly improved and skin hydration was significantly enhanced when compared to the placebo group after 12 weeks. Compared with the placebo, three parameters of skin elasticity, including overall elasticity (R2), net elasticity (R5), and ratio of elastic recovery to total deformation (R7), improved after 12 weeks of oral WHS (600 mg) administration. Changes in skin texture and roughness were significantly reduced in both WHS groups. No WHS-related adverse reactions were reported. Hence, WHS could be used as a health supplement for skin anti-aging.
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http://dx.doi.org/10.3390/nu12061588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352416PMC
May 2020

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

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

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

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

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

Inhibitory effect of moschamine isolated from Carthamus tinctorius on LPS-induced inflammatory mediators via AP-1 and STAT1/3 inactivation in RAW 264.7 macrophages.

Bioorg Med Chem Lett 2017 12 18;27(23):5245-5251. Epub 2017 Oct 18.

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

Seeds of Carthamus tinctorius L. (Compositae) have been used in Korean traditional medicines for the treatment of cardiovascular and bone diseases. In this study, we investigated the anti-inflammatory effects of known serotonin derivatives (1-9) isolated from the ethyl acetate (EtOAc) soluble fraction from the seeds of C. tinctorius. Compound 2, identified as moschamine, most potently inhibited lipopolysaccharide (LPS)-induced production of prostaglandin E (PGE) and nitric oxide (NO) in RAW 264.7 macrophages. Moschamine concentration-dependently inhibited LPS-induced PGE and NO production in RAW 264.7 macrophages. Consistent with these findings, moschamine suppressed the protein and mRNA levels of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase (mPGES)-1, and inducible NO synthase (iNOS), interleukin (IL)-6, and IL-1β. In addition, pretreatment of moschamine significantly inhibited LPS-stimulated the transcriptional activity of activator protein-1 (AP-1) and the phosphorylation of signal transducer and activator of transcription (STAT)1/3 in RAW 264.7 macrophages. Moreover, moschamine inhibited LPS-induced the phosphorylation of p38 mitogen-activated protein kinase (p38) and extracellular signal-regulated kinase (ERK), but it had no effect on c-Jun N-terminal kinase (JNK). These results suggest that the mechanism of anti-inflammatory activity of moschamine is associated with the downregulation of COX-2, mPGES-1, iNOS, IL-6, and IL-1β expression through the suppression of AP-1 and STAT1/3 activation in LPS-induced RAW 264.7 macrophages.
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http://dx.doi.org/10.1016/j.bmcl.2017.10.035DOI Listing
December 2017

Pharmacological Profiles of a Highly Potent and Long-Acting Angiotensin II Receptor Antagonist, Fimasartan, in Rats and Dogs after Oral Administration.

Biol Pharm Bull 2017 ;40(7):992-1001

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

The pharmacological profile of fimasartan, [2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-one, a new non-peptide angiotensin type 1 (AT)-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, fimasartan showed slow dissociation and irreversible binding to AT subtype receptors in membrane fractions of HEK-293 cells with a K of 0.03 nM and a T of 63.7 min. The inhibitory effect of fimasartan on angiotensin II (Ang II)-induced contraction persisted longer after washout than that of losartan or candesartan. In conscious rats, a single dose of fimasartan (0.3, 1, or 3 mg/kg; per os (p.o.)) dose-dependently antagonized Ang II-induced pressor responses. Both orally administrated fimasartan and losartan dose-dependently decreased mean arterial pressure in furosemide-treated rats and dogs, and fimasartan administered orally at 1, 3, or 10 mg/kg reduced blood pressure in conscious spontaneously hypertensive rats. Taken together, these findings indicate that fimasartan has potent and sustained binding affinity at the AT receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in various conscious rats and dogs models after its oral administration.
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http://dx.doi.org/10.1248/bpb.b16-00987DOI Listing
May 2018
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