Publications by authors named "Su Jung Hwang"

25 Publications

  • Page 1 of 1

Humulene Inhibits Acute Gastric Mucosal Injury by Enhancing Mucosal Integrity.

Antioxidants (Basel) 2021 May 11;10(5). Epub 2021 May 11.

Institute of Pharmaceutical Sciences and Research, College of Pharmacy and Inje, Inje University, 607 Obang-dong, Gimhae 621749, Korea.

This study was designed to determine whether α-humulene, a major constituent in many plants used in fragrances, has a protective role against gastric injury in vivo and in vitro. A rat model of hydrochloric acid (HCl)/ethanol-induced gastritis and human mast cells (HMC-1) were used to investigate the mucosal protective effect of α-humulene. α-Humulene significantly inhibited gastric lesions in HCl/ethanol-induced acute gastritis and decreased gastric acid secretion pyloric ligation-induced gastric ulcers in vivo. In addition, α-humulene reduced the amount of reactive oxygen species and malondialdehyde through upregulation of prostaglandin E2 (PGE2) and superoxide dismutase (SOD). In HMC-1 cells, α-humulene decreased intracellular calcium and increased intracellular cyclic adenosine monophosphate (cAMP) levels, resulting in low histamine levels. α-Humulene also reduced the expression levels of cytokine genes such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF) by downregulating nuclear factor-κB (NF-κB) nuclear translocation. Finally, α-humulene upregulated the expression levels of mucin 5AC (Muc5ac), Muc6, trefoil factor 1 (Tff1), trefoil factor 2 (Tff2), and polymeric immunoglobulin receptor (pigr). α-Humulene may attenuate HCl/ethanol-induced gastritis by inhibiting histamine release and NF-κB activation and stimulating antioxidants and mucosal protective factors, particularly Muc5ac and Muc6. Therefore, these data suggest that α-humulene is a potential drug candidate for the treatment of stress-induced or alcoholic gastritis.
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http://dx.doi.org/10.3390/antiox10050761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150829PMC
May 2021

Enhanced anti-angiogenic activity of novel melatonin-like agents.

J Pineal Res 2021 Aug 13;71(1):e12739. Epub 2021 May 13.

School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea.

Hypoxia-inducible factor-1 (HIF-1) plays an important role in cellular responses to hypoxia, including the transcriptional activation of several genes involved in tumor angiogenesis. Melatonin, also known as N-acetyl-5-methopxytryptamine, is produced naturally by the pineal gland and has anti-angiogenic effects in cancer through its ability to modulate HIF-1α activity. However, the use of melatonin as a therapeutic is limited by its low oral bioavailability and short half-life. Here, we synthesized melatonin-like molecules with enhanced HIF-1α targeting activity and less toxicity and investigated their effects on tumor growth and angiogenesis, as well as the underlying molecular mechanisms. Among melatonin derivatives, N-butyryl-5-methoxytryptamine (NB-5-MT) showed the most potent HIF-1α targeting activity. This molecule was able to (a) reduce the expression of HIF-1α at the protein level, (b) reduce the transcription of HIF-1α target genes, (c) reduce reactive oxygen species (ROS) generation, (d) decrease angiogenesis in vitro and in vivo, and (e) suppress tumor size and metastasis. In addition, NB-5-MT showed improved anti-angiogenic activity compared with melatonin due to its enhanced cellular uptake. NB-5-MT is thus a promising lead for the future development of anticancer compounds with HIF-1α targeting activity. Given that HIF-1α is overexpressed in the majority of human cancers, the melatonin derivative NB-5-MT could represent a novel potent therapeutic agent for cancer.
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http://dx.doi.org/10.1111/jpi.12739DOI Listing
August 2021

Phaseolin Attenuates Lipopolysaccharide-Induced Inflammation in RAW 264.7 Cells and Zebrafish.

Biomedicines 2021 Apr 13;9(4). Epub 2021 Apr 13.

School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Gyeonggi-do, Korea.

Kushen (Radix ) is used to treat ulcerative colitis, tumors, and pruritus. Recently, phaseolin, formononetin, matrine, luteolin, and quercetin, through a network pharmacology approach, were tentatively identified as five bioactive constituents responsible for the anti-inflammatory effects of . However, the role of phaseolin (one of the primary components of ) in the direct regulation of inflammation and inflammatory processes is not well known. In this study, the beneficial role of phaseolin against inflammation was explored in lipopolysaccharide (LPS)-induced inflammation models of RAW 264.7 macrophages and zebrafish larvae. Phaseolin inhibited LPS-mediated production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), without affecting cell viability. In addition, phaseolin suppressed pro-inflammatory mediators such as cyclooxygenase 2 (COX-2), interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in a dose-dependent manner. Furthermore, phaseolin reduced matrix metalloproteinase (MMP) activity as well as macrophage adhesion in vitro and the recruitment of leukocytes in vivo by downregulating Ninjurin 1 (Ninj1), an adhesion molecule. Finally, phaseolin inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB). In view of the above, our results suggest that phaseolin could be a potential therapeutic candidate for the management of inflammation.
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http://dx.doi.org/10.3390/biomedicines9040420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069760PMC
April 2021

RGS2-mediated translational control mediates cancer cell dormancy and tumor relapse.

J Clin Invest 2021 Jan;131(1)

Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy.

Slow-cycling/dormant cancer cells (SCCs) have pivotal roles in driving cancer relapse and drug resistance. A mechanistic explanation for cancer cell dormancy and therapeutic strategies targeting SCCs are necessary to improve patient prognosis, but are limited because of technical challenges to obtaining SCCs. Here, by applying proliferation-sensitive dyes and chemotherapeutics to non-small cell lung cancer (NSCLC) cell lines and patient-derived xenografts, we identified a distinct SCC subpopulation that resembled SCCs in patient tumors. These SCCs displayed major dormancy-like phenotypes and high survival capacity under hostile microenvironments through transcriptional upregulation of regulator of G protein signaling 2 (RGS2). Database analysis revealed RGS2 as a biomarker of retarded proliferation and poor prognosis in NSCLC. We showed that RGS2 caused prolonged translational arrest in SCCs through persistent eukaryotic initiation factor 2 (eIF2α) phosphorylation via proteasome-mediated degradation of activating transcription factor 4 (ATF4). Translational activation through RGS2 antagonism or the use of phosphodiesterase 5 inhibitors, including sildenafil (Viagra), promoted ER stress-induced apoptosis in SCCs in vitro and in vivo under stressed conditions, such as those induced by chemotherapy. Our results suggest that a low-dose chemotherapy and translation-instigating pharmacological intervention in combination is an effective strategy to prevent tumor progression in NSCLC patients after rigorous chemotherapy.
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http://dx.doi.org/10.1172/JCI136779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773398PMC
January 2021

Identification of differentially expressed genes in mouse embryonic stem cell under hypoxia.

Genes Genomics 2021 Apr 22;43(4):313-321. Epub 2020 Oct 22.

College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Inje-ro, Gimhae, Gyungnam, 50834, South Korea.

Background: Under hypoxia, mouse embryonic stem cells (mESCs) lose the ability to self-renew and begin to differentiate through down-regulation of LIFR-STAT3 pathway via hypoxia-inducible factor-1α (HIF-1α). However, it remains largely unknown what kinds of factors are involved in hypoxia-induced differentiation of mESCs.

Purpose: This study aims to identify the differentially expressed genes (DEGs) in early differentiation of mESCs under hypoxia.

Methods: Here we utilized a Genefishing technique to discover the new DEGs during hypoxia-induced early differentiation in CCE mESCs. Next, we investigated the role of DEGs using morphological observation, alkaline phosphatase (ALP) assay, STAT3 activation analysis, and biomarkers analysis for stemness.

Results: We detected 19 DEGs under hypoxia and performed cloning with sequencing in six genes. We confirmed the expression patterns of five DEGs including H2afz and GOT1 by realtime PCR assay. Among them, H2afz was significantly decreased under hypoxia, depending on HIF-1α. H2afz-overexpressing CCE mESCs maintained their ALP activity and stem cell markers (Nanog and Rex1), even in hypoxic condition. On the other hand, the early differentiation markers such as FGF5 and STAT5a, which had been increased in hypoxic conditions, were reduced by H2afz overexpression.

Conclusion: We discovered that H2afz could be a new target gene that functions in hypoxia-induced differentiation in mESCs and have revealed that it is involved in maintaining the pluripotency of mESCs in the early stages of differentiation. These findings will provide insights into mechanisms of hypoxia-mediated differentiation of mESCs during early development.
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http://dx.doi.org/10.1007/s13258-020-01009-4DOI Listing
April 2021

The ATF6-EGF Pathway Mediates the Awakening of Slow-Cycling Chemoresistant Cells and Tumor Recurrence by Stimulating Tumor Angiogenesis.

Cancers (Basel) 2020 Jul 2;12(7). Epub 2020 Jul 2.

Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul 08826, Korea.

Slow-cycling cancer cells (SCCs) with a quiescence-like phenotype are believed to perpetrate cancer relapse and progression. However, the mechanisms that mediate SCC-derived tumor recurrence are poorly understood. Here, we investigated the mechanisms underlying cancer recurrence after chemotherapy, focusing on the interplay between SCCs and the tumor microenvironment. We established a preclinical model of SCCs by exposing non-small-cell lung cancer (NSCLC) cells to either the proliferation-dependent dye carboxyfluorescein diacetate succinimidyl ester (CFSE) or chemotherapeutic drugs. An RNA sequencing analysis revealed that the established SCCs exhibited the upregulation of a group of genes, especially epidermal growth factor (EGF). Increases in the number of vascular endothelial growth factor receptor (VEGFR)-positive vascular endothelial cells and epidermal growth factor receptor (EGFR) activation were found in NSCLC cell line- and patient-derived xenograft tumors that progressed upon chemotherapy. EGFR tyrosine kinase inhibitors effectively suppressed the migration and tube formation of vascular endothelial cells. Furthermore, activating transcription factor 6 (ATF6) induced the upregulation of EGF, and its antagonism effectively suppressed these SCC-mediated events and inhibited tumor recurrence after chemotherapy. These results suggest that the ATF6-EGF signaling axis in SCCs functions to trigger the angiogenesis switch in residual tumors after chemotherapy and is thus a driving force for the switch from SCCs to actively cycling cancer cells, leading to tumor recurrence.
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http://dx.doi.org/10.3390/cancers12071772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407555PMC
July 2020

The Interplay between Slow-Cycling, Chemoresistant Cancer Cells and Fibroblasts Creates a Proinflammatory Niche for Tumor Progression.

Cancer Res 2020 06 19;80(11):2257-2272. Epub 2020 Mar 19.

Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.

Quiescent cancer cells are believed to cause cancer progression after chemotherapy through unknown mechanisms. We show here that human non-small cell lung cancer (NSCLC) cell line-derived, quiescent-like, slow-cycling cancer cells (SCC) and residual patient-derived xenograft (PDX) tumors after chemotherapy experience activating transcription factor 6 (ATF6)-mediated upregulation of various cytokines, which acts in a paracrine manner to recruit fibroblasts. Cancer-associated fibroblasts (CAF) underwent transcriptional upregulation of COX2 and type I collagen (Col-I), which subsequently triggered a slow-to-active cycling switch in SCC through prostaglandin E (PGE)- and integrin/Src-mediated signaling pathways, leading to cancer progression. Both antagonism of ATF6 and cotargeting of Src/COX2 effectively suppressed cytokine production and slow-to-active cell cycling transition in SCC, withholding cancer progression. Expression of COX2 and Col-I and activation of Src were observed in patients with NSCLC who progressed while receiving chemotherapy. Public data analysis revealed significant association between and expression and NSCLC relapse. Overall, these findings indicate that a proinflammatory niche created by the interplay between SCC and CAF triggers tumor progression. SIGNIFICANCE: Cotargeting COX2 and Src may be an effective strategy to prevent cancer progression after chemotherapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0631DOI Listing
June 2020

Synthesis of arbutin-gold nanoparticle complexes and their enhanced performance for whitening.

Arch Pharm Res 2019 Nov 29;42(11):977-989. Epub 2019 May 29.

College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Inje-ro, Gimhae, Gyungnam, 50834, South Korea.

Arbutin, a natural polyphenol, possesses numerous biological activities including whitening, anti-oxidant, anti-cancer, anti-inflammatory activities, as well as strong reducing power, making it an ideal bioactive ingredient for preparing gold nanoparticles (GNPs). Previously, we developed a novel green, mild synthetic method for GNPs using glycosides such as arbutin as reducing agents and stabilizers. Herein, we optimized the synthetic method for glycoside-GNPs using arbutin, methyl β-D-glucoside, and phenyl β-D-glucoside and validated their whitening efficacy in vitro and in vivo. The resulting glycoside-GNPs were predominantly mono-dispersed and spherical (10.30-17.13 nm diameter). Compared with arbutin itself, arbutin-GNP complexes (GNP-A1 and GNP-P2) displayed enhanced whitening capabilities. Furthermore, GNP-P2 exhibited enhanced anti-inflammatory activity and lacked the toxicity associated with arbutin. Bioactive glycoside-GNP complexes may open new directions for cosmeceuticals, and GNP-P2 may serve as a useful whitening ingredient in future cosmeceutical applications.
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http://dx.doi.org/10.1007/s12272-019-01164-7DOI Listing
November 2019

Protective Effects of Nargenicin A1 against Tacrolimus-Induced Oxidative Stress in Hirame Natural Embryo Cells.

Int J Environ Res Public Health 2019 03 22;16(6). Epub 2019 Mar 22.

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

Tacrolimus is widely used as an immunosuppressant to reduce the risk of rejection after organ transplantation, but its cytotoxicity is problematic. Nargenicin A1 is an antibiotic extracted from and is known to have antioxidant activity, though its mode of action is unknown. The present study was undertaken to evaluate the protective effects of nargenicin A1 on DNA damage and apoptosis induced by tacrolimus in hirame natural embryo (HINAE) cells. We found that reduced HINAE cell survival by tacrolimus was due to the induction of DNA damage and apoptosis, both of which were prevented by co-treating nargenicin A1 or N-acetyl-l-cysteine, a reactive oxygen species (ROS) scavenger, with tacrolimus. In addition, apoptosis induction by tacrolimus was accompanied by increases in ROS generation and decreases in adenosine triphosphate (ATP) levels caused by mitochondrial dysfunction, and these changes were significantly attenuated in the presence of nargenicin A1, which further indicated tacrolimus-induced apoptosis involved an oxidative stress-associated mechanism. Furthermore, nargenicin A1 suppressed tacrolimus-induced B-cell lymphoma-2 (Bcl-2) down-regulation, Bax up-regulation, and caspase-3 activation. Collectively, these results demonstrate that nargenicin A1 protects HINAE cells against tacrolimus-induced DNA damage and apoptosis, at least in part, by scavenging ROS and thus suppressing the mitochondrial-dependent apoptotic pathway.
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http://dx.doi.org/10.3390/ijerph16061044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466173PMC
March 2019

Upcycling of jellyfish (Nemopilema nomurai) sea wastes as highly valuable reducing agents for green synthesis of gold nanoparticles and their antitumor and anti-inflammatory activity.

Artif Cells Nanomed Biotechnol 2018 26;46(sup2):1127-1136. Epub 2018 Jul 26.

a College of Pharmacy , Inje University and Inje Institute of Pharmaceutical Sciences and Research , Gyeongnam , Republic of Korea.

Due to its tentacle poison and huge body, giant jellyfish (Nemopilema nomurai) poses challenging issues to the environment and ecosystems. Here we developed, upcycling a giant jellyfish extract as a reducing agent, a green synthetic method of gold nanoparticles (JF-AuNPs) which possess biological activities. The colloidal solutions of JF-AuNPs were blue, violet, purple and pink depending on the extract concentration. UV-visible spectra exhibited two surface plasmon resonance bands at 5 4 0 ∼ 550 nm and 810 nm. Spherical shapes with an average size of 35.2 ± 8.7 nm and triangular nanoplates with an average height of 70.5 ± 30.3 nm were observed. A face-centered cubic structure was confirmed by high-resolution X-ray diffraction. JF-AuNPs exhibited significant cytotoxic effect against HeLa cancer cells but not against normal cells such as NIH-3T3 and Raw 264.7 cells. In HeLa cells, JF-AuNPs decreased the phosphorylation of AKT and ERK, which are crucial for cell proliferation. Also, JF-AuNPs decreased NO secretion and iNOS expression levels, resulting in anti-inflammatory effects in LPS-inflamed macrophages. Collectively, we established a green synthesis of anti-tumorigenic and anti-inflammatory JF-AuNPs using the extract of jellyfish sea wastes. Thus, beneficial effects of JF-AgNPs must be weighed in further studies in vivo and it can be potent nanomedicine for future applications.
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http://dx.doi.org/10.1080/21691401.2018.1480490DOI Listing
June 2019

The aqueous extract from Artemisia capillaris inhibits acute gastric mucosal injury by inhibition of ROS and NF-kB.

Biomed Pharmacother 2018 Mar 20;99:681-687. Epub 2018 Feb 20.

College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 607 Obang-Dong, Gimhae, Gyungnam, 621-749, South Korea; u-Healthcare & Anti-Aging Rearch Center (u-HARC), Inje University, Gyeongnam, South Korea. Electronic address:

Artemisia capillaris, also called "InJin" in Korean, has been used as traditional oriental medicine in Korea because of its various pharmacological activities. These include hepatoprotective, analgesic, and antipyretic activities. The present study was designed to validate the beneficial effects of the aqueous extract of A. capillaris (AEAC) against acute gastric mucosal injury and investigate the underlying molecular mechanisms. The pharmacological efficacy of AEAC was evaluated using the gastric ulcer index and histological examination. AEAC decreased gastric mucosal lesions mediated by HCl/ethanol in vivo in a dose-dependent manner. Interestingly, the mucosal damage was almost prevented by pretreatment with 200 or 400?mg/kg AEAC. However, AEAC did not have acid-neutralizing activity in vitro and did not prevent histamine secretion in HMC-1 mast cells. In the gastric mucosa, AEAC also significantly inhibited lipid peroxide formation through superoxide dismutase (SOD) activation. Moreover, AEAC strongly reduced the generation of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and interleukin-1? (IL-1?), through nuclear factor kappa B (NF-?B) downregulation. Taken together, our findings suggest that AEAC inhibits inflammation and maintains oxidant/antioxidant homeostasis, resulting in a gastro-protective effect against HCl/ethanol-induced gastric damage. Therefore, AEAC might be a promising drug or useful neutraceutical for treatment of gastritis and gastric ulcer.
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http://dx.doi.org/10.1016/j.biopha.2018.01.118DOI Listing
March 2018

An aqueous extract of Nomura's jellyfish ameliorates inflammatory responses in lipopolysaccharide-stimulated RAW264.7 cells and a zebrafish model of inflammation.

Biomed Pharmacother 2018 Apr 28;100:583-589. Epub 2018 Feb 28.

College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 607 Obang-dong, Gimhae, Gyungnam, 621-749, South Korea. Electronic address:

The recent mass emergence of Nomura's jellyfish (Nemopilema nomurai) has caused much economic and environmental damage. However, there is no innovative strategy to dispose of or utilize these jellyfish. Some reports suggest that the jellyfish may be bioactive resources and a source of important compounds with antibacterial activity. Here, we examined the effect of an aqueous extract of Nomura's jellyfish (AENJ) on lipopolysaccharide (LPS)-stimulated Raw 264.7 macrophages and a zebrafish model of inflammation and analyzed the underlying molecular mechanisms. AENJ downregulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA levels in LPS-stimulated Raw 264.7 macrophages, with no apparent cytotoxic effects. However, AENJ had no effect on expression of other inflammation-related genes such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and MCP-1. Furthermore, AENJ reduced expression of nerve injury-induced protein 1 (Ninj1), which is an important adhesion molecule, thereby reducing cell adhesion to the extracellular matrix (ECM) in vitro. The inhibitory effect of AENJ on leukocytes was confirmed in LPS-microinjected zebrafish larvae; AENJ reduced the number of the infiltrate accumulating at the site of inflammation. In addition, AENJ suppressed the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 in LPS-stimulated Raw 264.7 cells. Finally, AENJ blocked nuclear translocation of nuclear factor kappa B (NF-κB), a key transcription factor for inflammatory responses, in Raw 264.7 cells in a dose-dependent manner. Collectively, the data suggest that AENJ inhibits expression of COX and iNOS by blocking NF-κB signaling pathways and suppresses the activity of macrophages by downregulating Ninj1 and MMPs. Therefore, AENJ may be a useful preventive neutraceutical, or therapeutic agent against inflammatory disorders.
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http://dx.doi.org/10.1016/j.biopha.2018.01.116DOI Listing
April 2018

A synthetic Nitraria alkaloid, isonitramine protects pancreatic β-cell and attenuates postprandial hyperglycemia.

Metabolism 2017 05 10;70:107-115. Epub 2017 Feb 10.

College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 607 Obang-dong, Gimhae, Gyungnam, 621-749, South Korea; u-Healthcare & Anti-aging Research Center (u-HARC), Inje University, Gyeongnam, South Korea. Electronic address:

Objective: The extracts of Nitraria genus are composed of Nitraria alkaloids and have been used traditionally as a hypoglycemic medicine. However, the efficacy and precise mechanism of Nitraria alkaloids remain largely unknown.

Methods: Previously, we reported the total synthesis of (+)-isonitramine, one of Nitraria alkaloids. In this study, we investigated the anti-diabetic potential of isonitramine in diabetes mellitus and its underlying molecular mechanism in carbohydrate catabolism in vitro and in vivo.

Results: Isonitramine exerted significant inhibitory effect on α-glucosidases but not α-amylase in vitro. In zebrafish, isonitramine alleviated the streptozotocin (STZ)-induced postprandial hyperglycemia and protected the pancreatic damages against alloxan-induced oxidative stress in vivo. Also, isonitramine induced insulin without any toxicities and downregulated phosphoenolpyruvate carboxykinase (PEPCK), which catalyzes the first committed step in gluconeogenesis.

Conclusion: Taken together, isonitramine inhibited α-glucosidase activity and PEPCK expression, while increased insulin expression, resulting in attenuating the postprandial hyperglycemia. Also, isonitramine protected the pancreas from ROS-mediated toxicities. Therefore, isonitramine may be a new drug candidate for the treatment of diabetes mellitus.
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http://dx.doi.org/10.1016/j.metabol.2017.02.002DOI Listing
May 2017

Spermidine Protects against Oxidative Stress in Inflammation Models Using Macrophages and Zebrafish.

Biomol Ther (Seoul) 2018 Mar;26(2):146-156

Anti-Aging Research Center and Department of Biochemistry, Dongeui University College of Korean Medicine, Busan 47227, Republic of Korea.

Spermidine is a naturally occurring polyamine compound that has recently emerged with anti-aging properties and suppresses inflammation and oxidation. However, its mechanisms of action on anti-inflammatory and antioxidant effects have not been fully elucidated. In this study, the potential of spermidine for reducing pro-inflammatory and oxidative effects in lipopolysaccharide (LPS)-stimulated macrophages and zebrafish was explored. Our data indicate that spermidine significantly inhibited the production of pro-inflammatory mediators such as nitric oxide (NO) and prostaglandin E (PGE), and cytokines including tumor necrosis factor-α and interleukin-1β in RAW 264.7 macrophages without any significant cytotoxicity. The protective effects of spermidine accompanied by a marked suppression in their regulatory gene expression at the transcription levels. Spermidine also attenuated the nuclear translocation of NF-κB p65 subunit and reduced LPS-induced intracellular accumulation of reactive oxygen species (ROS) in RAW 264.7 macrophages. Moreover, spermidine prevented the LPS-induced NO production and ROS accumulation in zebrafish larvae and was found to be associated with a diminished recruitment of neutrophils and macrophages. Although more work is needed to fully understand the critical role of spermidine on the inhibition of inflammation-associated migration of immune cells, our findings clearly demonstrate that spermidine may be a potential therapeutic intervention for the treatment of inflammatory and oxidative disorders.
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http://dx.doi.org/10.4062/biomolther.2016.272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839493PMC
March 2018

Physicochemical properties and sensory evaluation of mandarin () beverage powder spray-dried at different inlet air temperatures with different amounts of a mixture of maltodextrin and corn syrup.

Food Sci Biotechnol 2016 31;25(5):1345-1351. Epub 2016 Oct 31.

Faculty of Herbal Food Cuisine and Nutrition, Daegu Hanny University, Gyeongsan, Gyeongbuk, 38578 Korea.

This study aimed to investigate the effects of varying mixtures of maltodextrin and corn syrup on the physicochemical characteristics and sensory evaluation results of mandarin beverage powder under different spay drying conditions including inlet air temperature and concentration of carrier agents. Higher inlet air temperatures increase in the a* value, pH, and WSI while decreasing the moisture content, L* value, b* value, vitamin C content, and bulk density. Increasing carrier agent concentration caused increases in the L* value and pH along with decreases in the moisture content, a* value, b* value, WSI, vitamin C content and bulk density. Water activity and WAI showed no significant differences among samples. Drying yield was maximized when the inlet air temperature reached 135°C and the carrier agent concentration was 35%. In sensory evaluation, as the concentration of the carrier agents increased, the taste received a higher preference rating, while the color was less preferred.
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http://dx.doi.org/10.1007/s10068-016-0211-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049278PMC
October 2016

An α-quaternary chiral latam derivative, YH-304 as a novel broad-spectrum anticancer agent.

Int J Oncol 2016 Dec 11;49(6):2480-2486. Epub 2016 Oct 11.

College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam 621-749, Republic of Korea.

Previously, we reported that α-quaternary chiral lactam derivatives have broad spectrum anticancer activity. However, the underlying molecular mechanisms and its relevance are largely unknown. In the present study, we report progress on α-quaternary chiral lactam analogues that address this, focusing on the novel analogue YH-304 as a candidate to broadly target human cancer cells. The effect of YH-304 on cell transformation was assessed by clonogenic assay in non-small cell lung cancer cells (NSCLCs) A549 and 226B. Proapoptotic activity of YH-304 was determined by TUNEL assay and cleaved PARP, cleaved caspase-9, and Bax as markers for apoptosis. The p53-dependency and therapeutic spectrum of YH-304 was assessed by western blot analysis, real-time PCR, and cell viability assays in cells expressing endogenous wild or mutant p53. The effect of YH-304 on angiogenesis in vivo was examined by bFGF-mediated angiogenesis assay in zebrafish. Finally, the effect of YH-304 on AKT and ERK activation (phosphorylation) as a putative mechanism underlying the effect of YH-304 on bFGF-mediated angiogenesis was assessed using western blotting. We found that YH-304 significantly decreases the colony-forming activities of both A549 and 226B cells, inducing cellular apoptosis. Unlike nutlin-3 (p53 pathway activator), YH-304 did not affect the expression levels of p53 and its target gene such as p21 and thus showed p53-independent anticancer activity with broad spectrum. In addition, YH-304 inhibited bFGF-induced angiogenesis in vivo through mediating AKT and ERK signaling pathway, which plays an important role in bFGF activation and angiogenesis. Taken together, our data indicate that YH-304 may represent a novel therapeutic option for the treatment of cancer in a p53-independent manner.
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http://dx.doi.org/10.3892/ijo.2016.3726DOI Listing
December 2016

Smoking-associated lung cancer prevention by blockade of the beta-adrenergic receptor-mediated insulin-like growth factor receptor activation.

Oncotarget 2016 Oct;7(43):70936-70947

Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

Activation of receptor tyrosine kinases (RTKs) is associated with carcinogenesis, but its contribution to smoking-associated lung carcinogenesis is poorly understood. Here we show that a tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced insulin-like growth factor 1 receptor (IGF-1R) activation via β-adrenergic receptor (β-AR) is crucial for smoking-associated lung carcinogenesis. Treatment with NNK stimulated the IGF-1R signaling pathway in a time- and dose-dependent manner, which was suppressed by pharmacological or genomic blockade of β-AR and the downstream signaling including a Gβγ subunit of β-AR and phospholipase C (PLC). Consistently, β-AR agonists led to increased IGF-1R phosphorylation. The increase in IGF2 transcription via β-AR, signal transducer and activator of transcription 3 (STAT3), and nuclear factor-kappa B (NF-κB) was associated with NNK-induced IGF-1R activation. Finally, treatment with β-AR antagonists suppressed the acquisition of transformed phenotypes in lung epithelial cells and lung tumor formation in mice. These results suggest that blocking β-AR-mediated IGF-1R activation can be an effective strategy for lung cancer prevention in smokers.
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http://dx.doi.org/10.18632/oncotarget.12342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342599PMC
October 2016

STAT3-mediated IGF-2 secretion in the tumour microenvironment elicits innate resistance to anti-IGF-1R antibody.

Nat Commun 2015 Oct 14;6:8499. Epub 2015 Oct 14.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea.

Drug resistance is a major impediment in medical oncology. Recent studies have emphasized the importance of the tumour microenvironment (TME) to innate resistance, to molecularly targeted therapies. In this study, we investigate the role of TME in resistance to cixutumumab, an anti-IGF-1R monoclonal antibody that has shown limited clinical efficacy. We show that treatment with cixutumumab accelerates tumour infiltration of stromal cells and metastatic tumour growth, and decreases overall survival of mice. Cixutumumab treatment stimulates STAT3-dependent transcriptional upregulation of IGF-2 in cancer cells and recruitment of macrophages and fibroblasts via paracrine IGF-2/IGF-2R activation, resulting in the stroma-derived CXCL8 production, and thus angiogenic and metastatic environment. Silencing IGF-2 or STAT3 expression in cancer cells or IGF-2R or CXCL8 expression in stromal cells significantly inhibits the cancer-stroma communication and vascular endothelial cells' angiogenic activities. These findings suggest that blocking the STAT3/IGF-2/IGF-2R intercellular signalling loop may overcome the adverse consequences of anti-IGF-1R monoclonal antibody-based therapies.
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http://dx.doi.org/10.1038/ncomms9499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608384PMC
October 2015

Green synthesis of gold nanoparticles using chlorogenic acid and their enhanced performance for inflammation.

Nanomedicine 2015 Oct 21;11(7):1677-88. Epub 2015 May 21.

College of Pharmacy, Inje University, Gyeongnam, Republic of Korea; u-Healthcare & Anti-aging Reearch Center (u-HARC), Inje University, Gyeongnam, Republic of Korea; Biohealth Products Research Center (BPRC), Inje University, Gyeongnam, Republic of Korea; National Creative Research Initiatives (NCRI) Center for Isogeometric Optimal Design, Seoul National University, Seoul, Republic of Korea. Electronic address:

Unlabelled: Here we developed a novel green synthesis method for gold nanoparticles (CGA-AuNPs) using chlorogenic acid (CGA) as reductants without the use of other chemicals and validated the anti-inflammatory efficacy of CGA-AuNPs in vitro and in vivo. The resulting CGA-AuNPs appeared predominantly spherical in shape with an average diameter of 22.25±4.78nm. The crystalline nature of the CGA-AuNPs was confirmed by high-resolution X-ray diffraction and by selected-area electron diffraction analyses. High-resolution liquid chromatography/electrospray ionization mass spectrometry revealed that the caffeic acid moiety of CGA forms quinone structure through a two-electron oxidation causing the reduction of Au(3+) to Au(0). When compared to CGA, CGA-AuNPs exhibited enhanced anti-inflammatory effects on NF-κB-mediated inflammatory network, as well as cell adhesion. Collectively, green synthesis of CGA-AuNPs using bioactive reductants and mechanistic studies based on mass spectrometry may open up new directions in nanomedicine and CGA-AuNPs can be an anti-inflammatory nanomedicine for future applications.

From The Clinical Editor: Gold nanoparticles (Au NPs) have been shown to be very useful in many applications due to their easy functionalization capability. In this article, the authors demonstrated a novel method for the synthesis of gold nanoparticles using chlorogenic acid (CGA) as reductants. In-vitro experiments also confirmed biological activity of the resultant gold nanoparticles. Further in-vivo studies are awaited.
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http://dx.doi.org/10.1016/j.nano.2015.05.002DOI Listing
October 2015

Insulin-like growth factor binding protein-3 inhibits cell adhesion via suppression of integrin β4 expression.

Oncotarget 2015 Jun;6(17):15150-63

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.

We previously reported that IGF binding protein-3 (IGFBP-3), a major IGF-binding protein in human serum, regulates angiogenic activities of human head and neck squamous cell carcinoma (HNSCC) cells and human umbilical vein endothelial cells (HUVECs) through IGF-dependent and IGF-independent mechanisms. However, the role of IGFBP-3 in cell adhesion is largely unknown. We demonstrate here that IGFBP-3 inhibits the adhesion of HNSCC cells and HUVECs to the extracellular matrix (ECM). IGFBP-3 reduced transcription of a variety of integrins, especially integrin β4, and suppressed phosphorylation of focal adhesion kinase (FAK) and Src in these cells through both IGF-dependent and IGF-independent pathways. IGFBP-3 was found to suppress the transcription of c-fos and c-jun and the activity of AP1 transcription factor. The regulatory effect of IGFBP-3 on integrin β4 transcription was attenuated by blocking c-jun and c-fos gene expression via siRNA transfection. Taken together, our data show that IGFBP-3 has IGF-dependent and -independent inhibitory effects on intracellular adhesion signaling in HNSCC and HUVECs through its ability to block c-jun and c-fos transcription and thus AP-1-mediated integrin β4 transcription. Collectively, our data suggest that IGFPB-3 may be an effective cancer therapeutic agent by blocking integrin-mediated adhesive activity of tumor and vascular endothelial cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558142PMC
http://dx.doi.org/10.18632/oncotarget.3825DOI Listing
June 2015

Chlorogenic acid inhibits hypoxia-induced angiogenesis via down-regulation of the HIF-1α/AKT pathway.

Cell Oncol (Dordr) 2015 Apr 6;38(2):111-8. Epub 2015 Jan 6.

College of Pharmacy, Inje University, 197 Inje-ro, Gimhae, Gyeongnam, 621-749, Republic of Korea.

Background: The hypoxia-inducible factor-1 (HIF-1) is known to play an important role in cellular responses to hypoxia, including the transcriptional activation of a number of genes involved in tumor angiogenesis. Chlorogenic acid (CGA), one of the most abundant polyphenols in the human diet, has been reported to inhibit cancer cell growth. The effect of CGA on tumor angiogenesis and its underlying mechanisms are, as yet, unknown.

Methods: The effect of CGA on HIF-1α expression was assessed by Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR) assays in A549 lung cancer cells. The transcriptional activity of the HIF-1 complex was confirmed using a luciferase assay. To assess whether angiogenic factors are increased under hypoxic conditions in these cells, vascular endothelial growth factor (VEGF) expression levels were measured by RT-PCR and Western blotting. The direct effect of CGA on human vascular endothelial cells (HUVEC) under hypoxic conditions was analyzed using in vitro assays, including tube-formation, wound healing and Transwell invasion assays. To investigate the effect of CGA on angiogenesis in vivo, we performed a Matrigel plug assay in a mouse model. Finally, the effect of CGA on AKT and ERK activation (phosphorylation) as a putative mechanism underlying the effect of CGA on VEGF-mediated angiogenesis inhibition was assessed using Western blotting.

Results: We found that CGA significantly decreases the hypoxia-induced HIF-1α protein level in A549 cells, without changing its mRNA level. CGA was, however, found to suppress the transcriptional activity of HIF-1α under hypoxic conditions, leading to a decrease in the expression of its downstream target VEGF. We also found that CGA can block hypoxia-stimulated angiogenesis in vitro and VEGF-stimulated angiogenesis in vivo using HUVEC cells. In addition, we found that CGA can inhibit the HIF-1α/AKT signaling pathway, which plays an important role in VEGF activation and angiogenesis.

Conclusions: Our data indicate that CGA plays a role in the suppression of angiogenesis via inhibition of the HIF-1α/AKT pathway. CGA may represent a novel therapeutic option for the treatment of (lung) cancer.
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http://dx.doi.org/10.1007/s13402-014-0216-2DOI Listing
April 2015

Phenyl-β-D-Glucopyranoside Exhibits Anti-inflammatory Activity in Lipopolysaccharide-Activated RAW 264.7 Cells.

Inflammation 2015 ;38(3):1071-9

College of Pharmacy, Inje University, Gimhae, Korea.

Phenyl-β-D-glucopyranoside is a component of Phellodendron amurense with anti-cancer and anti-inflammatory activities. In the present study, we investigated the role of phenyl-β-D-glucopyranoside in inflammation using lipopolysaccharide (LPS)-stimulated murine Raw 264.7 macrophages. Phenyl-β-D-glucopyranoside not only inhibited nitric oxide (NO) production but also significantly inhibited the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) without inducing cytotoxicity. Phenyl-β-D-glucopyranoside also attenuated proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and other inflammation-related genes, such as IL-6 in a concentration-dependent manner. Furthermore, phenyl-β-D-glucopyranoside abolished increased adhesion, ninjurin 1 (Ninj1) expression, and matrix metalloproteinase (MMP) activity induced by endotoxin treatment. Finally, phenyl-β-D-glucopyranoside inhibited the nuclear translocation of nuclear factor-κB (NF-κB), which is one of the most important transcription factors involved in the inflammatory process. Taken together, phenyl-β-D-glucopyranoside may be beneficial for the prevention and treatment of anti-inflammatory diseases.
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http://dx.doi.org/10.1007/s10753-014-0072-2DOI Listing
February 2016

Transcriptional and posttranslational regulation of insulin-like growth factor binding protein-3 by Akt3.

Carcinogenesis 2014 Oct 18;35(10):2232-43. Epub 2014 Jun 18.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea,

Insulin-like growth factor (IGF)-dependent and -independent antitumor activities of insulin-like growth factor binding protein-3 (IGFBP-3) have been proposed in human non-small cell lung cancer (NSCLC) cells. However, the mechanism underlying regulation of IGFBP-3 expression in NSCLC cells is not well understood. In this study, we show that activation of Akt, especially Akt3, plays a major role in the mRNA expression and protein stability of IGFBP-3 and thus antitumor activities of IGFBP-3 in NSCLC cells. When Akt was activated by genomic or pharmacologic approaches, IGFBP-3 transcription and protein stability were decreased. Conversely, suppression of Akt increased IGFBP-3 mRNA levels and protein stability in NSCLC cell lines. Characterization of the effects of constitutively active form of each Akt subtype (HA-Akt-DD) on IGFBP-3 expression in NSCLC cells and a xenograft model indicated that Akt3 plays a major role in the Akt-mediated regulation of IGFBP-3 expression and thus suppression of Akt effectively enhances the antitumor activities of IGFBP-3 in NSCLC cells with Akt3 overactivation. Collectively, these data suggest a novel function of Akt3 as a negative regulator of IGFBP-3, indicating the possible benefit of a combined inhibition of IGFBP-3 and Akt3 for the treatment of patients with NSCLC.
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http://dx.doi.org/10.1093/carcin/bgu129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178467PMC
October 2014

Asymmetric synthesis and evaluation of α-quaternary chiral lactam derivatives as novel anticancer agents.

Arch Pharm Res 2014 Oct 2;37(10):1264-70. Epub 2013 Nov 2.

College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, 621-749, Gyeongnam, Korea.

Asymmetric synthesis of α-quaternary chiral lactam derivatives as novel anticancer agents and evaluation of their cytotoxic potentials and spectrums are reported. Among the developed lactam derivatives, the most active new compounds (S)-4m and (S)-4n synthesized via asymmetric phase-transfer catalytic alkylation in very high optical yields (98 % ee) show promising in vitro anticancer activities with low micromolar IC50 values against colon, uterus, lung, and breast human cancer cells.
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http://dx.doi.org/10.1007/s12272-013-0274-4DOI Listing
October 2014

Anti-inflammatory effects of chlorogenic acid in lipopolysaccharide-stimulated RAW 264.7 cells.

Inflamm Res 2014 Jan 15;63(1):81-90. Epub 2013 Oct 15.

College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyungnam, 621-749, Republic of Korea.

Objectives And Design: Chlorogenic acid, which belongs to the polyphenols, is an anti-oxidant and anti-obesity agent. In this study, we investigated the role of chlorogenic acid in inflammation.

Materials And Methods: Anti-inflammatory effects of chlorogenic acid were examined in lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages and BV2 microglial cells. We observed the level of various inflammation markers such as nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and chemokine (C-X-C motif) ligand 1 (CXCL1) under LPS treatment with or without chlorogenic acid. To clarify the specific effect of chlorogenic acid, we evaluated the adhesion activity of macrophages and ninjurin1 (Ninj1) expression level in macrophages. Finally, we confirmed the activation of the nuclear factor-κB (NF-κB) signaling pathway, which is one of the most important transcription factors in the inflammatory process.

Results: Chlorogenic acid significantly inhibited not only NO production but also the expression of COX-2 and iNOS, without any cytotoxicity. Chlorogenic acid also attenuated pro-inflammatory cytokines (including IL-1β and TNF-α) and other inflammation-related markers such as IL-6 in a dose-dependent manner. Additionally, endotoxin-induced adhesion of macrophages and the expression level of ninjurin1 (Ninj1) were decreased by chlorogenic acid. Finally, chlorogenic acid inhibited the nuclear translocation of NF-κB.

Conclusions: Chlorogenic acid may be beneficial for the prevention and treatment of anti-inflammatory diseases.
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http://dx.doi.org/10.1007/s00011-013-0674-4DOI Listing
January 2014
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