Publications by authors named "Jeong-Hyung Lee"

120 Publications

Structural characterization of prenylated compounds from Broussonetia kazinoki and their antiosteoclastogenic activity.

Phytochemistry 2021 May 31;188:112791. Epub 2021 May 31.

College of Pharmacy, Drug Research and Development Center, Daegu Catholic University, Gyeongbuk, 38430, Republic of Korea. Electronic address:

An undescribed 1,3-diphenylpropane derivative, kazinol V and six undescribed prenylated flavonoids, broussonols F-H and broussonols K-M were isolated from the roots of Broussonetia kazinoki Siebold, together with 12 known compounds. This is the first report of the isolation and structure determination of broussonol I from a natural source. The chemical structure of the undescribed compounds was determined using conventional NMR and HRMS data. Absolute configurations were assigned using time-dependent density functional theory calculations and Electronic Circular Dichroism (ECD) spectroscopy. The isolated compounds were screened for their effects on RANKL-induced osteoclast formation using RAW264.7 cells. Among them, broussonols F, G, and K showed a strong, dose-dependent antiosteoclastogenic activities. Broussonol K exhibited the most potent inhibitory activity and possessed bone resorption suppressive activity.
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http://dx.doi.org/10.1016/j.phytochem.2021.112791DOI Listing
May 2021

Phytochemicals Targeting JAK-STAT Pathways in Inflammatory Bowel Disease: Insights from Animal Models.

Molecules 2021 May 10;26(9). Epub 2021 May 10.

Division of Applied Life Science (BK21), PMBBRC and Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Korea.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that consists of Crohn's disease (CD) and ulcerative colitis (UC). Cytokines are thought to be key mediators of inflammation-mediated pathological processes of IBD. These cytokines play a crucial role through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathways. Several small molecules inhibiting JAK have been used in clinical trials, and one of them has been approved for IBD treatment. Many anti-inflammatory phytochemicals have been shown to have potential as new drugs for IBD treatment. This review describes the significance of the JAK-STAT pathway as a current therapeutic target for IBD and discusses the recent findings that phytochemicals can ameliorate disease symptoms by affecting the JAK-STAT pathway in vivo in IBD disease models. Thus, we suggest that phytochemicals modulating JAK-STAT pathways are potential candidates for developing new therapeutic drugs, alternative medicines, and nutraceutical agents for the treatment of IBD.
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http://dx.doi.org/10.3390/molecules26092824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126249PMC
May 2021

Epigenetic regulation of TGF-β-induced EMT by JMJD3/KDM6B histone H3K27 demethylase.

Oncogenesis 2021 Feb 26;10(2):17. Epub 2021 Feb 26.

Department of Biochemistry, Kangwon National University, Chuncheon, Gangwon-do, 24341, Republic of Korea.

Transforming growth factor-β (TGF-β) signaling pathways are well-recognized for their role in proliferation and epithelial-mesenchymal transition (EMT) of cancer cells, but much less is understood about their contribution to interactions with other signaling events. Recent studies have indicated that crosstalk between TGF-β and Ras signaling makes a contribution to TGF-β-mediated EMT. Here, we demonstrate that Jumonji domain containing-3 (JMJD3 also called KDM6B) promotes TGF-β-mediated Smad activation and EMT in Ras-activated lung cancer cells. JMJD3 in lung cancer patients was significantly increased and JMJD3 expression in lung tumor tissues was correlated with expression of K-Ras or H-Ras in particular, and its expression was regulated by Ras activity in lung cancer cells. JMJD3 promotes TGF-β-induced Smad activation and EMT in Ras-activated lung cancer cells through the induction of syntenin, a protein that regulates TGF-β receptor activation upon ligand binding. Tissue array and ChIP analysis revealed that JMJD3 epigenetically induces syntenin expression by directly regulating H3K27 methylation levels. Mechanical exploration identified a physical and functional association of JMJD3 with syntenin presiding over the TGF-β in Ras-activated lung cancer cells. Taken together, these findings provide new insight into the mechanisms by which JMJD3 promotes syntenin expression resulting in oncogenic Ras cooperation with TGF-β to promote EMT.
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http://dx.doi.org/10.1038/s41389-021-00307-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910473PMC
February 2021

Flavonoids from the peels of Citrus unshiu Markov. and their inhibitory effects on RANKL-induced osteoclastogenesis through the downregulation of c-Fos signaling in vitro.

Bioorg Chem 2021 Feb 5;107:104613. Epub 2021 Jan 5.

College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea; Vessel-Organ Interaction Research Center, VOICE (MRC), College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea. Electronic address:

Phytochemical investigation of Citrus unshiu peels led to the isolation of eight new flavonols (7-9, 11-15) and sixteen known compounds (1-6, 10, 16-24). Their structures were elucidated using spectroscopic analysis (1D, 2D NMR, and HR-MS). Besides, all isolated compounds (1-24) were evaluated for their inhibitory effects on receptor activator of RANKL-induced osteoclastogenesis in BMMs. Among them, dimethylmikanin (1), quercetogetin (2), 3,3',4',5,7,8-hexamethoxyflavone (3), 3-methoxynobiletin (4) showed a significant inhibitory effect on RANKL-induced osteoclast differentiation at a concentration of 10 μM. Moreover, 3-methoxynobiletin (4) suppressed RANKL-induced osteoclastogenesis by decreasing the number of osteoclasts and osteoclast actin-ring formation in a dose-dependent manner without causing any cytotoxic effects on BMMs. At the molecular level, 3-methoxynobiletin (4) inhibited RANKL-induced c-Fos expression and subsequently NFATc1 activation, as well as the expression of osteoclastogenesis-related marker genes c-Src and CtsK. These findings suggested that 3-methoxynobiletin (4) attenuated osteoclast differentiation by inhibiting RANKL-mediated c-Fos signaling and that it may have therapeutic potential for treating or preventing bone resorption-related diseases, such as osteoporosis.
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http://dx.doi.org/10.1016/j.bioorg.2020.104613DOI Listing
February 2021

PTP1B Inhibitory and Anti-inflammatory Properties of Constituents from Eclipta prostrata L.

Biol Pharm Bull 2021 Mar 23;44(3):298-304. Epub 2020 Dec 23.

College of Pharmacy, Drug Research and Development Center, Daegu Catholic University.

The white-flowered leaves of Eclipta prostrata L. together with leaves of Scoparia dulcis and Cynodon dactylon are mixedly boiled in water and given to diabetic patients resulting in the significant improvement in the management of diabetes. However, the active constituents from this plant for antidiabetic and anti-obesity properties are remaining unclear. Thus, this study was to discover anti-diabetes and anti-obesity activities through protein tyrosine phosphatases (PTP)1B inhibitory effects. We found that the fatty acids (23, 24) showed potent PTP1B inhibition with IC values of 2.14 and 3.21 µM, respectively. Triterpenoid-glycosides (12-15) also exhibited strong to moderate PTP1B inhibitory effects, with IC values ranging from 10.88 to 53.35 µM. Additionally, active compounds were investigated for their PTP1B inhibitory mechanism and docking analysis. On the other hand, the anti-inflammatory activity from our study revealed that compounds (1-4, 7, 8, 10) displayed the significant inhibition nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Especially, compound 9 showed the potent inhibitory effects in LPS-induced NO production on RAW264.7 cell. Therefore, further Western blot analysis was performed to identify the inhibitory expression including heme oxygenase-1 (HO-1) and inhibitor of kappaB (IκB) phosphorylation.
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http://dx.doi.org/10.1248/bpb.b20-00994DOI Listing
March 2021

Human plasminogen-derived N-acetyl-Arg-Leu-Tyr-Glu antagonizes VEGFR-2 to prevent blood-retinal barrier breakdown in diabetic mice.

Biomed Pharmacother 2021 Feb 15;134:111110. Epub 2020 Dec 15.

Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 24341, Republic of Korea; Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon, Gangwon-Do, 24341, Republic of Korea. Electronic address:

Targeting the vascular endothelial growth factor (VEGF)/its receptor-2 (VEGFR-2) system has become a mainstay of treatment for many human diseases, including retinal diseases. We examined the therapeutic effect of recently developed N-acetylated Arg-Leu-Tyr-Glu (Ac-RLYE), a human plasminogen kringle-5 domain-derived VEGFR-2 antagonists, on the pathogenesis of diabetic retinopathy. Ac-RLYE inhibited VEGF-A-mediated VEGFR-2 activation and endothelial nitric oxide synthase (eNOS)-derived NO production in the retinas of diabetic mice. In addition, Ac-RLYE prevented the disruption of adherens and tight junctions and vascular leakage by inhibiting S-nitrosylation of β-catenin and tyrosine nitration of p190RhoGAP in the retinal vasculature of diabetic mice. Peptide treatment preserved the pericyte coverage of retinal capillaries by upregulating angiopoietin-2. These results suggest that Ac-RLYE potentially prevents blood-retinal barrier breakdown and vascular leakage by antagonizing VEGFR-2; Ac-RLYE can be used as a potential therapeutic drug for the treatment of diabetic retinopathy.
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http://dx.doi.org/10.1016/j.biopha.2020.111110DOI Listing
February 2021

Albanol B from Mulberries Exerts Anti-Cancer Effect through Mitochondria ROS Production in Lung Cancer Cells and Suppresses In Vivo Tumor Growth.

Int J Mol Sci 2020 Dec 14;21(24). Epub 2020 Dec 14.

Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 24414, Korea.

Albanol B (ABN-B), an arylbenzofuran derivative isolated from mulberries, has been shown to have anti-Alzheimer's disease, anti-bacterial and antioxidant activities. The aim of this study was to investigate the anti-cancer effect of this compound against lung cancer cells. The results show that ABN-B inhibited the proliferation of four human lung cancer cell lines (A549, BZR, H1975, and H226) and induced apoptosis, based on the cleavage of caspase-7 and PARP (poly (ADP-ribose) polymerase), as well as the downregulation of Bcl-2. ABN-B also induced cell cycle arrest at G/M by down-regulating the expression of CKD1 (cyclin-dependent kinase 1) and cyclin B1, but up-regulating p21 (cyclin-dependent kinase inhibitor 1) expression. Notably, ABN-B increased the production of mitochondrial reactive oxygen species (ROS); however, treatment with mito-TEMPO (a specific mitochondrial antioxidant) blocked ABN-B-induced cell cycle arrest at G/M and apoptosis, as well as the up-regulation of p21 and down-regulation of CDK1 and cyclin B1 induced by ABN-B. At the molecular level, ABN-B-induced mitochondrial ROS production increased the phosphorylation levels of AKT (protein kinase B) and ERK1/2 (extracellular signal-regulated kinase 1/2), while the inhibition of these kinases blocked the ABN-B-induced up-regulation of p21 and down-regulation of CDK1 and cyclin B1. Moreover, ABN-B significantly suppressed tumor growth in Ex-3LL (Lewis lung carcinoma) tumor-bearing mice. Taken together, these results suggest that ABN-B can exert an anti-cancer effect by inducing apoptosis and cell cycle arrest at G/M through mitochondrial ROS production in lung cancer cells.
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http://dx.doi.org/10.3390/ijms21249502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764986PMC
December 2020

Triterpenoids from Celastrus orbiculatus Thunb. inhibit RANKL-induced osteoclast formation and bone resorption via c-Fos signaling.

J Nat Med 2021 Jan 10;75(1):56-65. Epub 2020 Aug 10.

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

Fourteen triterpenes, lup-20(29)-ene-3β,6β-diol (1), betulin (2), lupeol caffeate (3), 3β-caffeoyloxylup-20(29)-en-6α-ol (4), betulin-3β-yl-caffeate (5), 3β-trans-feruloylbetulin (6), betulinaldehyde 3-caffeate (7), 3-O-trans-caffeoylbetulinic acid (8), dammarenediol II 3-caffeate (9), 12-oleanene-3β,6α-diol (10), 11α-hydroxy-3β-amyrin (11), nivadiol (12), 29-hydroxyfriedelin (13), and celastrusin A (14) were isolated from Celastrus orbiculatus Thunb. and evaluated for their activity on receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs). Compounds betulin (2), betulin-3β-yl-caffeate (5), 3β-trans-feruloylbetulin (6), and 3-O-trans-caffeoylbetulinic acid (8) significantly inhibited osteoclast formation in a dose-dependent manner. Among these, betulin-3β-yl-caffeate (5) exhibited the most potent inhibitory activity. We demonstrated that betulin-3β-yl-caffeate (5) suppressed F-actin-ring formation and bone resorption activity. At the molecular level, betulin-3β-yl-caffeate (5) inhibited RANK-induced expression of c-Fos and the induction of nuclear factor of activated T cells 1 (NFATc1), a key transcription factor for osteoclast formation, and it also downregulated mRNA expression of osteogenesis-associated marker genes including tartrate-resistant acid phosphatase (TRAP), dendritic cell-specific transmembrane protein (DC-STAMP), and matrix metalloprotein (MMP). These results indicate that betulin-3β-yl-caffeate (5) may be a promising candidate for the treatment of osteoclast-related diseases such as osteoporosis.
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http://dx.doi.org/10.1007/s11418-020-01444-3DOI Listing
January 2021

3-Hydroxyolean-12-en-27-oic Acids Inhibit RANKL-Induced Osteoclastogenesis in Vitro and Inflammation-Induced Bone Loss in Vivo.

Int J Mol Sci 2020 Jul 23;21(15). Epub 2020 Jul 23.

Department of Biochemistry, Kangwon National University, Chuncheon, Gangwon-Do 24341, Korea.

Olean-12-en-27-oic acids possess a variety of pharmacological effects. However, their effects and underlying mechanisms on osteoclastogenesis remain unclear. This study aimed to investigate the anti-osteoclastogenic effects of five olean-12-en-27-oic acid derivatives including 3α,23-isopropylidenedioxyolean-12-en-27-oic acid (AR-1), 3-oxoolean-12-en-27-oic acid (AR-2), 3α-hydroxyolean-12-en-27-oic acid (AR-3), 23-hydroxy-3-oxoolean-12-en-27-oic acid (AR-4), and aceriphyllic acid A (AR-5). Among the five olean-12-en-27-oic acid derivatives, 3-hydroxyolean-12-en-27-oic acid derivatives, AR-3 and AR-5, significantly inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced mature osteoclast formation by reducing the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, F-actin ring formation, and mineral resorption activity. AR-3 and AR-5 decreased RANKL-induced expression levels of osteoclast-specific marker genes such as c-Src, TRAP, and cathepsin K (CtsK) as well as c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1). Mice treated with either AR-3 or AR-5 showed significant protection of the mice from lipopolysaccharide (LPS)-induced bone destruction and osteoclast formation. In particular, AR-5 suppressed RANKL-induced phosphorylation of JNK and ERK mitogen-activated protein kinases (MAPKs). The results suggest that AR-3 and AR-5 attenuate osteoclast formation in vitro and in vivo by suppressing RANKL-mediated MAPKs and NFATc1 signaling pathways and could potentially be lead compounds for the prevention or treatment of osteolytic bone diseases.
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http://dx.doi.org/10.3390/ijms21155240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432734PMC
July 2020

C5, A Cassaine Diterpenoid Amine, Induces Apoptosis via the Extrinsic Pathways in Human Lung Cancer Cells and Human Lymphoma Cells.

Int J Mol Sci 2020 Feb 14;21(4). Epub 2020 Feb 14.

Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea.

Apoptosis pathways in cells are classified into two pathways: the extrinsic pathway, mediated by binding of the ligand to a death receptor and the intrinsic pathway, mediated by mitochondria. Apoptosis is regulated by various proteins such as Bcl-2 (B-cell lymphoma 2) family and cellular FLICE (Fas-associated Death Domain Protein Interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which have been reported to inhibit caspase-8 activity. In this study, it was found that C5 (3β-Acetyl-nor-erythrophlamide), a compound of cassaine diterpene amine from Erythrophleum fordii, induced cell apoptosis in a variety of types of cancer cells. Induction of apoptosis in cancer cells by C5 was inversely related to the level of Bcl-2 expression. Overexpression of Bcl-2 into cancer cells significantly decreased C5-induced apoptosis. It was also found that treatment of cancer cells with a caspase-8 inhibitor significantly suppressed C5-induced apoptosis; however, treatment with caspase-9 inhibitors did not affect C5-induced apoptosis, suggesting that C5 may induce apoptosis via the extrinsic pathway by activating caspase-8. It was confirmed that treatment with C5 alone induced an association of FADD with procaspase-8; however, overexpression of c-FLIP decreased C5-induced caspase-8 activation. In conclusion, C5 could be utilized as a new useful lead compound for the development of an anti-cancer agent that has the goal of apoptosis.
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http://dx.doi.org/10.3390/ijms21041298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072863PMC
February 2020

6,7,4'-Trihydroxyflavone inhibits osteoclast formation and bone resorption in vitro and in vivo.

Phytother Res 2019 Nov 3;33(11):2948-2959. Epub 2019 Sep 3.

College of Pharmacy, Keimyung University, Daegu, Republic of Korea.

The balance between the osteoblasts and the osteoclasts is important for the maintenance of the skeleton of the human body. The osteoclasts absorb bone after differentiated into polymorphonuclear cells by the fusion of monocytes/macrophages. We have found that 6,7,4'-Trihydroxyflavone (THF), a compound from the heartwood of Dalbergia Odorifera inhibits receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation, actin ring formation, and bone resorption in RAW 264.7 cells and bone marrow macrophage. THF significantly inhibited the c-Jun-N-terminal kinase signaling pathway without affecting extracellular signal-regulated kinase, p38, and AKT signaling. Moreover, THF inhibited the expression of c-Fos, nuclear factor-activated T cells cytoplasm 1, cathepsin K, and c-src by RANKL. We used a lipopolysaccharide (LPS)-induced bone loss model in mice. Consequently, bone volume per tissue volume, trabecular number's reduction was recovered in THF-treated mice, and trabecular separation's augmentation was also attenuated by THF administration. In summary, THF inhibits RANKL-induced osteoclast differentiation by MAPK signaling pathway and inhibits bone resorption by destroying the actin ring in mature osteoclasts. THF also prevented LPS-induced bone loss in a mice model. Thus, THF may be useful in the treatment of bone diseases associated with excessive osteoclast differentiation and bone resorption.
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http://dx.doi.org/10.1002/ptr.6468DOI Listing
November 2019

The Effects of 2',4'-Dihydroxy-6'-methoxy-3',5'- dimethylchalcone from Buds on Human Pancreatic Cancer Cell Lines.

Molecules 2019 Jul 11;24(14). Epub 2019 Jul 11.

Biomedical Sciences Department, Institute for Research & Executive Education (VNUK), The University of Danang, 158A Le Loi, Hai Chau District, Danang City 551000, Vietnam.

2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC), a principal natural chalcone of buds, suppresses the growth of many types of cancer cells. However, the effects of this compound on pancreatic cancer cells have not been evaluated. In our experiments, we explored the effects of this chalcone on two human pancreatic cancer cell lines. A cell proliferation assay revealed that DMC exhibited concentration-dependent cytotoxicity against PANC-1 and MIA PACA2 cells, with IC values of 10.5 ± 0.8 and 12.2 ± 0.9 µM, respectively. Treatment of DMC led to the apoptosis of PANC-1 by caspase-3 activation as revealed by annexin-V/propidium iodide double-staining. Western blotting indicated that DMC induced proteolytic activation of caspase-3 and -9, degradation of caspase-3 substrate proteins (including poly[ADP-ribose] polymerase [PARP]), augmented bak protein level, while attenuating the expression of bcl-2 in PANC-1 cells. Taken together, our results provide experimental evidence to support that DMC may serve as a useful chemotherapeutic agent for control of human pancreatic cancer cells.
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http://dx.doi.org/10.3390/molecules24142538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680674PMC
July 2019

Protective effects of extract of Cleistocalyx operculatus flower buds and its isolated major constituent against LPS-induced endotoxic shock by activating the Nrf2/HO-1 pathway.

Food Chem Toxicol 2019 Jul 25;129:125-137. Epub 2019 Apr 25.

Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, 24414, Republic of Korea. Electronic address:

The flower buds of Cleistocalyx operculatus are used as an important ingredient in herbal tea and herbal products in several tropical countries. However, their protective effects and underlying mechanisms on lipopolysaccharide (LPS)-induced endotoxic shock remain unclear. The aim of this study was to investigate the anti-inflammatory effects of ethanol extract of C. operculatus flower buds (ECO) and its major constituent 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) in macrophages and in an experimental LPS-induced sepsis mouse model. ECO inhibited the LPS-induced production and expression of pro-inflammatory mediators in macrophages. In an endotoxic shock mouse model, the oral administration of ECO rescued LPS-induced mortality, and attenuated LPS-induced increases in the serum levels of pro-inflammatory mediators, and damage of the lung and liver tissues. ECO increased the nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf2), as well as the expression of Nrf2 target genes, including heme oxygenase-1 (HO-1), in macrophages. Similar to the effects of ECO, DMC also inhibited the LPS-induced inflammatory response in macrophages and endotoxic shock in mice, and activated the Nrf2/HO-1 pathway. In conclusion, our findings suggested that ECO and its major constituent, DMC, attenuated LPS-induced endotoxic shock by activating the Nrf2/HO-1 pathway.
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http://dx.doi.org/10.1016/j.fct.2019.04.035DOI Listing
July 2019

Ethanol extract of Polyscias fruticosa leaves suppresses RANKL-mediated osteoclastogenesis in vitro and LPS-induced bone loss in vivo.

Phytomedicine 2019 Jun 2;59:152908. Epub 2019 Apr 2.

Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 24341, Republic of Korea. Electronic address:

Background: Many bone-related diseases such as osteoporosis and rheumatoid arthritis are commonly associated with the excessive activity of osteoclasts. Polyscias fruticosa has been used as traditional medicine for the treatment of ischemia and inflammation and also eaten as a salad. However, its effect on the bone related diseases has not been investigated yet.

Purpose: This study aimed to investigate the effect of ethanol extract of P. fruticosa on RANKL-induced osteoclastogenesis in vitro and LPS-induced bone loss in mouse, and evaluate anti-osteoclastogenic activities of its major constituents.

Methods: BMMs or RAW264.7 cells were treated with ethanol extract from P. fruticose leaves (EEPL), followed by an evaluation of cell viability, RANKL-induced osteoclast differentiation, actin-ring formation, and resorption pits activity. Effects of EEPL on RANKL-induced phosphorylation of MAPKs were evaluated by Western blotting. The expression levels of NFATc1 and c-Fos were evaluated by Western blotting or immunofluorescence assay. The expression levels of osteoclast-specific marker genes were evaluated by Western blotting and reverse transcription-qPCR analysis. A LPS-induced murine bone loss model was used to evaluate the protective effect of EEPL on inflammation-induced bone loss. HPLC analysis was performed to identify the major constituents of EEPL.

Results: EEPL significantly inhibited RANKL-induced osteoclast differentiation by decreasing the number of osteoclasts, osteoclast actin-ring formation, and bone resorption. EEPL suppressed RANKL-induced phosphorylation of p38 and JNK MAPKs, as well as the expression of c-Fos and NFATc1. EEPL decreased the expression levels of osteoclast marker genes, including MMP-9, TRAP and CtsK. Mice treated with EEPL significantly protected the mice from LPS-induced osteoclast formation and bone destruction as indicated by micro-CT and histological analysis of femurs. We also identified 3-O-[β-d-glucopyranosyl-(1→4)-β-d-glucuronopyranosyl] oleanolic acid 28-O-β-d-glucopyranosyl ester (1) and quercitrin (3) as the active constituents in EEPL for inhibiting RANKL-induced osteoclast differentiation.

Conclusion: The results showed that EEPL exerted anti-osteoclastogenic activity in vitro and in vivo by inhibiting RANKL-induced osteoclast differentiation and function, and suggested that EEPL could have beneficial applications for preventing or inhibiting osteoclast-mediated bone diseases.
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http://dx.doi.org/10.1016/j.phymed.2019.152908DOI Listing
June 2019

Diterpenoids isolated from the root of and their anti-inflammatory activity.

Nat Prod Res 2021 Mar 9;35(5):726-732. Epub 2019 Apr 9.

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

Four new diterpene-type compounds normiltirone () and isosalviamides F-H (-) together with twelve known compounds (, , -) were isolated from the roots of . Their structures were mainly elucidated from detailed spectroscopic data. All isolated compounds were evaluated for their ability to inhibit lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophages. Compound showed a strong inhibitory effect, with an IC value of 3.4 ± 1.2 μM.
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http://dx.doi.org/10.1080/14786419.2019.1596098DOI Listing
March 2021

Ganomycin I from Ganoderma lucidum attenuates RANKL-mediated osteoclastogenesis by inhibiting MAPKs and NFATc1.

Phytomedicine 2019 Mar 25;55:1-8. Epub 2018 Oct 25.

Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 24341, Republic of Korea. Electronic address:

Background: Many bone-related diseases such as osteoporosis and rheumatoid arthritis are commonly associated with excessive activity of the osteoclast. Ganomycin I (GMI), a meroterpenoid isolated from Vietnamese mushroom Ganoderma lucidum, possesses a variety of beneficial effects on human health. However, its impact and underlying mechanism on osteoclastogenesis remain unclear. In the present study, we investigated the effect of GMI on RANKL-induced osteoclast formation in mouse BMMs and RAW264.7 cells.

Methods: BMMs or RAW264.7 cells were treated with GMI followed by an evaluation of cell viability, RANKL-induced osteoclast differentiation, actin-ring formation, and resorption pits activity. Effects of GMI on RANKL-induced phosphorylation of MAPKs as well as the expression levels of NFATc1 and c-Fos were evaluated by Western blot analysis. Expression levels of osteoclast marker genes were evaluated by Western blot analysis and reverse transcription-qPCR.

Results: GMI significantly inhibited RANKL-induced osteoclast differentiation by decreasing the number of osteoclasts, osteoclast actin-ring formation, and bone resorption in a dose-dependent manner without affecting cell viability. At molecular level, GMI inhibited the RANKL-induced phosphorylation of ERK, JNK, and p38 MAPKs, as well as the expression levels of c-Fos and NFATc1, which are known to be crucial transcription factors for osteoclast formation. In addition, GMI decreased expression levels of osteoclastogenesis specific marker genes including c-Src, CtsK, TRAP, MMP-9, OSCAR, and DC-STAMP in RANKL-stimulated BMMs.

Conclusion: Our findings suggest that GMI can attenuate osteoclast formation by suppressing RANKL-mediated MAPKs and NFATc1 signaling pathways and the anti-osteoclastogenic activity of GMI may extend our understanding of molecular mechanisms underlying biological activities and pharmacological use of G. lucidum as a traditional anti-osteoporotic medicine.
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http://dx.doi.org/10.1016/j.phymed.2018.10.029DOI Listing
March 2019

Degalactotigonin, a Steroidal Glycoside from , Induces Apoptosis and Cell Cycle Arrest via Inhibiting the EGFR Signaling Pathways in Pancreatic Cancer Cells.

Biomed Res Int 2018 16;2018:3120972. Epub 2018 Dec 16.

Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 200-701, Republic of Korea.

Degalactotigonin () and three other steroidal compounds solasodine (), -acetyl solasodine (), and soladulcoside A () were isolated from the methanolic extract of , and their chemical structures were elucidated by spectroscopic analyses. The isolated compounds were evaluated for cytotoxic activity against human pancreatic cancer cell lines (PANC1 and MIA-PaCa2) and lung cancer cell lines (A549, NCI-H1975, and NCI-H1299). Only degalactotigonin () showed potent cytotoxicity against these cancer cell lines. Compound induced apoptosis in PANC1 and A549 cells. Further study on its mechanism of action in PANC1 cells demonstrated that significantly inhibited EGF-induced proliferation and migration in a concentration-dependent manner. Treatment of PANC1 cells with degalactotigonin induced cell cycle arrest at G0/G1 phase. Compound induced downregulation of cyclin D1 and upregulation of p21 in a time- and concentration-dependent manner and inhibited EGF-induced phosphorylation of EGFR, as well as activation of EGFR downstream signaling molecules such as Akt and ERK.
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http://dx.doi.org/10.1155/2018/3120972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311251PMC
April 2019

Lignans from Saururus chinensis exhibit anti-inflammatory activity by influencing the Nrf2/HO-1 activation pathway.

Arch Pharm Res 2019 Apr 4;42(4):332-343. Epub 2019 Jan 4.

College of Pharmacy, Drug Research and Development Center, Daegu Catholic University, Gyeongbuk, 712-702, Republic of Korea.

As part of our ongoing program to develop anti-inflammatory agents, an extract derived from Saururus chinensis collected in Korea was found to inhibit nitric oxide (NO) production in RAW264.7 cells. Bioassay-guided fractionation led to the isolation two new (1 and 2) and six known dineolignans (3-8). To the best of our knowledge, manassatin B (3) was isolated from S. chinensis for the first time. All structures were elucidated using extensive spectroscopic analysis. Of these compounds, 2 and 8 inhibited lipopolysaccharide (LPS)-induced production of NO and showed IC values of 5.80 and 1.52 µM, respectively. LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) was also significantly suppressed by the administration of 2 and 8. In addition, these lignans induced the expression of heme oxygenase-1 (HO-1) in a concentration-dependent manner. Nuclear translocation of nuclear-E2-related factor 2 (Nrf2), a key regulator of HO-1 protein expression, was also induced in RAW264.7 cells treated with 2 and 8. These findings suggested that these lignans exerted anti-inflammatory effects in RAW264.7 cells through modulation of the Nrf2/HO-1 pathway and that they were potential HO-1 inducers for preventing or treating inflammation.
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http://dx.doi.org/10.1007/s12272-018-1093-4DOI Listing
April 2019

Correction to: Anti-inflammatory activity of caffeic acid derivatives isolated from the roots of Salvia miltiorrhiza Bunge.

Arch Pharm Res 2019 04;42(4):378

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

The author would like to include conflict of interest statement of the online published article. The correct conflict of interest statement should read as: Conflict of interest The authors declare no conflict of interest.
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http://dx.doi.org/10.1007/s12272-018-1090-7DOI Listing
April 2019

Trichosanhemiketal A and B: Two 13,14-seco-13,14-epoxyporiferastanes from the root of Trichosanthes kirilowii Maxim.

Bioorg Chem 2019 03 13;83:105-110. Epub 2018 Oct 13.

College of Pharmacy, Drug Research and Development Center, Daegu Catholic University, Gyeongbuk 38430, Republic of Korea. Electronic address:

Of the 32 Trichosanthes species in China, T. kirilowii Maxim. is the most renowned species used in traditional Chinese medicine and has diverse pharmacological properties. However, most of the phytochemical studies of T. kirilowii have focused on the fruits and seeds. In our investigation of the chemical constituents of T. kirilowii roots, two previously undescribed sterols [trichosanhemiketal A and B (1 and 2)], together with 13 known compounds, were isolated and their structures were elucidated. To the best of our knowledge, this represents the first isolation of compounds with a 13,14-seco-13,14-epoxyporiferastane (1-2) skeleton from the Cucurbitaceae family. The anti-inflammatory activity of the isolated compounds was determined through an analysis of their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage RAW264.7 cells. Of the compounds, 4, 5, 6, and 8 showed significant inhibitory activities, with IC values of 8.5, 15.1, 25.4, and 28.5 µM, respectively. In addition, compound 4 inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expression in a concentration-dependent manner.
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http://dx.doi.org/10.1016/j.bioorg.2018.10.019DOI Listing
March 2019

Triterpenoids from Ziziphus jujuba induce apoptotic cell death in human cancer cells through mitochondrial reactive oxygen species production.

Food Funct 2018 Jul;9(7):3895-3905

Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 24414, Republic of Korea.

Ziziphus jujuba var. inermis Rehder is an edible fruit-producing species of the Rhamnaceae family. In the present study, we isolated eight triterpenoids (1-8) from the fruits of Z. jujuba var. inermis and evaluated their apoptotic cell-death-inducing activities in human cancer cell lines (A549, PC-3, and MDA-MB-231). The structures of compounds 1-8 were determined by spectroscopic methods. Among these, four isomers of coumaroyl alphitolic acid showed potent cytotoxic activities on these cancer cells: 3-O-cis-p-coumaroyl alphitolic acid (3), 3-O-trans-p-coumaroyl alphitolic acid (4), 2-O-trans-p-coumaroyl alphitolic acid (5), and 2-O-cis-p-coumaroyl alphitolic acid (6). Moreover, compounds 3-6 induced apoptotic cell death in a concentration-dependent manner. We further investigated the apoptosis-inducing effects of compound 4 in PC-3 cells which triggered the cleavage of procaspase-3, procaspase-7, procaspase-8, bid, and PARP. Compound 4 increased both the mitochondrial reactive oxygen species (ROS) production and the phosphorylation of p38 MAPK (mitogen-activated protein kinase), but decreased the mitochondrial membrane potential. Pretreatment with Mito-TEMPO (a specific mitochondrial-targeted antioxidant) or a specific p38 inhibitor (SB203580) attenuated apoptotic cell death triggered by compound 4 which suggests that compound 4 may induce apoptotic cell death in these cancer cells by increasing the mitochondrial ROS production as well as the subsequent p38 MAPK activation. The study findings provide a rational base to use Ziziphus extracts for cancer treatments in traditional oriental medicine.
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http://dx.doi.org/10.1039/c8fo00526eDOI Listing
July 2018

Lactones from the pericarps of Litsea japonica and their anti-inflammatory activities.

Bioorg Med Chem Lett 2018 06 22;28(11):2109-2115. Epub 2018 Apr 22.

College of Pharmacy, Drug Research and Development Center, Daegu Catholic University, Gyeongbuk 38430, Republic of Korea. Electronic address:

Five new lactones, litsenolide F (1), lisealactone H (10), lisealactone H (11), akolactone D (13), and akolactone E (14), along with thirteen known compounds were isolated from the pericarps of Litsea japonica (Thunb.) Jussieu. Their chemical structures were elucidated by extensive spectroscopic analyses, including 1D and 2D NMR, HRMS, and chemical methods. The isolated compounds were evaluated for their inhibitory effects on NO production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Among them, 2-alkylidene-3-hydroxy-4-methylbutanolide derivatives (compounds 1-9) exhibited the most potent activity, with IC values in the range of 2.9-12.8 μM. In additon, compounds 1, 3, 4, and 6 showed inhibition of iNOS and COX-2 expression in concentration-dependent manner. Compound 3 suppresses mRNA expression of iNOS, COX-2, IL-6, and TNF-α in LPS-stimulated RAW264.7 cells. Based on these evidence, the isolated lactones from L. japonica could be promissing candidates for the development of new anti-inflammatory agents.
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http://dx.doi.org/10.1016/j.bmcl.2018.04.023DOI Listing
June 2018

Desoxyrhapontigenin inhibits RANKL‑induced osteoclast formation and prevents inflammation‑mediated bone loss.

Int J Mol Med 2018 Jul 17;42(1):569-578. Epub 2018 Apr 17.

Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon‑Do 24341, Republic of Korea.

Desoxyrhapontigenin (DRG), a stilbene compound from Rheum undulatum, has been found to exhibit various pharmacological activities, however, its impact on osteoclast formation has not been investigated. The present study investigated the effect of DRG on receptor activator of nuclear factor‑κB ligand (RANKL)‑induced osteoclast differentiation in mouse bone marrow macrophages (BMMs) and inflammation‑induced bone loss in vivo. BMMs or RAW264.7 cells were treated with DRG, followed by an evaluation of cell viability, RANKL‑induced osteoclast differentiation, actin‑ring formation and resorption pits activity. The effects of DRG on the RANKL‑induced phosphorylation of MAPK and the expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and c‑Fos were evaluated using western blot analysis once the BMMs were exposed to RANKL and DRG. The expression levels of osteoclast marker genes were also evaluated using western blot analysis and reverse transcription‑quantitative polymerase chain reaction A lipopolysaccharide (LPS)‑induced murine bone loss model was used to evaluate the protective effect of DRG on inflammation‑induced bone‑loss. The results demonstrated that DRG suppressed the RANKL‑induced differentiation of BMMs into osteoclasts, osteoclast actin‑ring formation and bone resorption activity in a dose‑dependent manner. Furthermore, DRG significantly inhibited LPS‑induced bone loss in a mouse model. At the molecular level, DRG inhibited the RANKL‑induced activation of extracellular signal‑regulated kinase, the expression of c‑Fos, and the induction of NFATc1, a crucial transcription factor for osteoclast formation. DRG decreased the expression levels of osteoclast marker genes, including matrix metalloproteinase‑9, tartrate‑resistant acid phosphatase and cathepsin K. In conclusion, these findings suggested that DRG inhibited the differentiation of BMMs into mature osteoclasts by suppressing the RANKL‑induced activator protein‑1 and NFATc1 signaling pathways, and may be a potential candidate for treating and/or preventing osteoclast‑associated diseases, including osteoporosis.
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http://dx.doi.org/10.3892/ijmm.2018.3627DOI Listing
July 2018

A prenylated flavonoid, 10-oxomornigrol F, exhibits anti-inflammatory effects by activating the Nrf2/heme oxygenase-1 pathway in macrophage cells.

Int Immunopharmacol 2018 Feb 22;55:165-173. Epub 2017 Dec 22.

Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 24414, Republic of Korea. Electronic address:

Prenylated flavonoids are a unique class of naturally occurring flavonoids that have various pharmacological activities. In the present study, we investigated the anti-inflammatory effect in murine macrophages of a prenylated flavonoid, 10-oxomornigrol F (OMF), which was isolated from the twigs of Morus alba (Moraceae). OMF inhibited the lipopolysaccharide (LPS)-induced production of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 in RAW264.7 cells, as well as in mouse bone marrow-derived macrophages (BMMs). OMF also rescued LPS-induced septic mortality in ICR mice. LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α and IL-6 was also significantly suppressed by OMF treatment in RAW264.7 cells. Treatment of RAW264.7 cells with OMF induced heme oxygenase (HO)-1 mRNA and protein expression and increased the nuclear translocation of the nuclear factor-E2-related factor 2 (Nrf2) as well as the expression of Nrf2 target genes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1). Treatment of RAW264.7 cells with OMF increased the intracellular level of reactive oxygen species (ROS) and the phosphorylation levels of p38 mitogen-activated protein kinase (MAPK); co-treatment with the antioxidant N-acetyl-cysteine (NAC) blocked this OMF-induced p38 MAPK phosphorylation. Moreover, NAC, or SB203580 (a p38 MAPK inhibitor), blocked the OMF-induced nuclear translocation of Nrf2 and HO-1 expression, suggesting that OMF induces HO-1 expression by activating Nrf2 through the p38 MAPK pathway. Consistent with the notion that the Nrf2/HO-1 pathway has anti-inflammatory properties, inhibiting HO-1 significantly abrogated the anti-inflammatory effects of OMF in LPS-stimulated RAW264.7 cells. Taken together, these findings suggest that OMF exerts its anti-inflammatory effect by activating the Nrf2/HO-1 pathway, and may be a potential Nrf2 activator to prevent or treat inflammatory diseases.
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http://dx.doi.org/10.1016/j.intimp.2017.12.015DOI Listing
February 2018

A cassaine diterpene alkaloid, 3β-acetyl-nor-erythrophlamide, suppresses VEGF-induced angiogenesis and tumor growth via inhibiting eNOS activation.

Oncotarget 2017 Nov 28;8(54):92346-92358. Epub 2017 Sep 28.

Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Republic of Korea.

Angiogenesis is one of the hallmarks of cancer, playing an essential role in tumor growth, invasion, and metastasis. 3β-Acetyl-nor-erythrophlamide (3-ANE), a cassaine diterpene alkaloid compound from , exerts various pharmacological effects, including antitumor activity. However, the effects of 3-ANE on tumor angiogenesis and its potential molecular mechanism are still unknown. Here, we demonstrated that 3-ANE inhibited the vascular endothelial growth factor (VEGF)-mediated proliferation, migration, invasion, and capillary-like tube formation of human umbilical vascular endothelial cells (HUVECs), without inducing apoptosis. We also found that 3-ANE blocked angiogenesis , and suppressed tumor angiogenesis and human lung adenocarcinoma growth in the xenograft tumor model. Furthermore, we showed that 3-ANE blocked VEGF-mediated endothelial nitric oxide synthase (eNOS) phosphorylation, vascular permeability and NO production in HUVECs, via disrupting the VEGF-induced association of eNOS and heat-shock protein 90 (HSP90). Our studies therefore provide the first evidence that 3-ANE inhibits tumor angiogenesis by inhibiting the VEGF-mediated eNOS activation and NO production, and 3-ANE could be a potential candidate in angiogenesis-related disease therapy.
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http://dx.doi.org/10.18632/oncotarget.21307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696186PMC
November 2017

Anti-inflammatory activity of caffeic acid derivatives isolated from the roots of Salvia miltiorrhiza Bunge.

Arch Pharm Res 2018 Jan 9;41(1):64-70. Epub 2017 Nov 9.

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

Ten caffeic acid derivatives (1-10) were isolated from the roots of Salvia miltiorrhiza by using various chromatographic methods and their chemical structures were spectroscopically elucidated. The absolute configurations of chiral centers were determined by comparison with reported coupling constants, optical rotation values, and CD techniques. Anti-inflammatory activities were evaluated using nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 inhibition assays, and by determining the expression of heme oxygenase (HO)-1. Two new caffeic acid derivatives, 8-epiblechnic acid 9-methyl ester (4) and 8-epiblechnic acid 9'-methyl ester (5), and eight known derivatives, caffeic acid methyl ester (1), shimobashiric acid B (2), rosmarinic acid methyl ester (3), salvianolic acid C (6), methyl salvianolate C (7), lithospermic acid monomethyl ester (8), lithospermic acid dimethyl ester (9), and dimethyl lithospermate B (10), were isolated from the ethyl acetate fraction of S. miltiorrhiza. All caffeic acid derivatives were evaluated for their inhibitory effect on NO production. Compounds 2 and 3 inhibited NO production with IC values of 1.4 and 0.6 μM, respectively. These compounds also strongly inhibited the production of iNOS and COX-2. In addition, compound 3 induced the expression HO-1 in a concentration-dependent manner at 0.1, 0.3, and 1.0 μM.
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http://dx.doi.org/10.1007/s12272-017-0983-1DOI Listing
January 2018

Eupatolide inhibits the TGF-β1-induced migration of breast cancer cells via downregulation of SMAD3 phosphorylation and transcriptional repression of ALK5.

Oncol Lett 2017 Nov 15;14(5):6031-6039. Epub 2017 Sep 15.

Department of Biological Science, Sookmyung Women's University, Seoul 04310, Republic of Korea.

The epithelial-mesenchymal transition (EMT) is a hallmark of cancer metastasis, and the associated molecular signaling pathways are regarded as therapeutic targets for cancer treatment. Thus, suppressing EMT with a natural chemical compound may be of therapeutic benefit. Eupatolide is a natural chemical compound extracted from the medicinal plant , which is used in Eastern Asia to treat bronchitis, disorders of the digestive system and inflammation. Besides the anti-inflammatory function of eupatolide, the present study found that eupatolide suppressed the migration and invasion of breast cancer cells, which was associated with the downregulation of vimentin in MDA-MB-231 cells and the upregulation of E-cadherin in MCF-7 cells. Treatment with eupatolide also significantly inhibited the migration and invasion of breast cancer cells that had been stimulated with transforming growth factor-β1 (TGF-β1). Eupatolide also suppressed TGF-β1-induced EMT via downregulation of mothers against decapentaplegic homolog 3 (SMAD3) phosphorylation and transcriptional repression of TGF-β receptor 1 (ALK5). In addition to this canonical pathway, the non-canonical protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways were also inhibited by eupatolide treatment. In summary, the results suggest that eupatolide suppresses the migration and invasion of breast cancer cells by blocking the canonical ALK5-SMAD3 signaling pathway and the non-canonical ERK and AKT signaling pathways.
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http://dx.doi.org/10.3892/ol.2017.6957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661662PMC
November 2017

Sappanone A inhibits RANKL-induced osteoclastogenesis in BMMs and prevents inflammation-mediated bone loss.

Int Immunopharmacol 2017 Nov 23;52:230-237. Epub 2017 Sep 23.

Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 24341, Republic of Korea. Electronic address:

Receptor activator of nuclear factor-kB ligand (RANKL) is a key factor in the differentiation and activation of osteoclasts. Suppressing osteoclastogenesis is considered an effective therapeutic approach for bone-destructive diseases, such as osteoporosis and rheumatoid arthritis. Sappanone A (SPNA), a homoisoflavanone compound isolated from the heartwood of Caesalpinia sappan, has been reported to exert anti-inflammatory effects; however, the effects of SPNA on osteoclastogenesis have not been investigated. In the present study, we describe for the first time that SPNA inhibits RANKL-induced osteoclastogenesis in mouse bone marrow macrophages (BMMs) and suppresses inflammation-induced bone loss in a mouse model. SPNA inhibited the formation of osteoclasts from BMMs, osteoclast actin-ring formation, and bone resorption in a concentration-dependent manner. At the molecular level, SPNA significantly inhibited RANKL-induced activation of the AKT/glycogen synthase kinase-3β (GSK-3β) signaling pathway without affecting its activation of the mitogen-activated protein kinases (MAPKs) JNK, p38, and ERK. In addition, SPNA suppressed the induction of nuclear factor of activated T cells cytoplasmic 1 (NFATc1), which is a crucial transcription factor in osteoclast differentiation. As a result, SPNA decreased osteoclastogenesis-related marker gene expression, including CtsK, TRAP, dendritic cell-specific transmembrane protein (DC-STAMP), MMP-9 and osteoclast-associated receptor (OSCAR). In a mouse inflammatory bone loss model, SPNA significantly inhibited lipopolysaccharide (LPS)-induced bone loss by suppressing the number of osteoclasts. Taken together, these findings suggest that SPNA inhibits osteoclastogenesis and bone resorption by inhibiting the AKT/GSK-3β signaling pathway and may be a potential candidate compound for the prevention and/or treatment of inflammatory bone loss.
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http://dx.doi.org/10.1016/j.intimp.2017.09.018DOI Listing
November 2017

Anti-inflammatory activities of compounds from twigs of Morus alba.

Fitoterapia 2017 Jul 18;120:17-24. Epub 2017 May 18.

College of Pharmacy, Catholic University of Daegu, Gyeongbuk 38430, Republic of Korea. Electronic address:

Five new compounds, 10-oxomornigrol F (1), (7″R)-(-)-6-(7″-hydroxy-3″,8″-dimethyl-2″,8″-octadien-1″-yl)apigenin (2), ramumorin A (3), ramumorin B (4), and (4S,7S,8R)-trihydroxyoctadeca-5Z-enoic acid (5), together with 31 known compounds (6-36), were isolated from the twigs of Morus alba (Moraceae). The chemical structures of these compounds were established using spectroscopic analyses, 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and Mosher's methods. The anti-inflammatory activities of the compounds were evaluated by investigating their ability to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage RAW 264.7 cells. Compounds 1, 2, 13, 17, 19, 25-28, and 32 showed inhibitory effects with IC values ranging from 2.2 to 5.3μg/mL. Compounds 1, 2, 17, 25, and 32 reduced LPS-induced inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner. In addition, pretreating the cells with compound 1, 17, and 32 significantly suppressed LPS-induced expression of cyclooxygenase-2 (COX-2) protein.
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http://dx.doi.org/10.1016/j.fitote.2017.05.004DOI Listing
July 2017