Publications by authors named "Jung-Hye Choi"

214 Publications

induces apoptotic cell death in ectopic endometrial 12Z cells through suppressing pyruvate dehydrogenase kinase 1 expression.

Exp Ther Med 2021 Apr 11;21(4):357. Epub 2021 Feb 11.

Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea.

Endometriosis is a common gynecological disease defined as the growth of endometrial tissues outside the uterus. Although the mechanism underlying the progression of endometriosis has not been fully elucidated, cancer-like aerobic glycolysis is considered to mediate the elevated growth and resistance to apoptosis of endometriotic cells. The heartwood of L. (family Leguminosae) is a herbal medicinal product used to treat gynecological symptoms, including algomenorrhea and amenorrhea. The results of the present study revealed that endometriotic 12Z cells exhibited more rapid growth than normal endometrial cells (THES). The expression levels of pyruvate dehydrogenase kinase (PDK)1 and 3 and lactate production were higher in 12Z cells than in THES cells. In addition, the 12Z cells were more sensitive to the cytotoxicity of the aqueous extract of heartwood (CS) than the THES cells. CS inhibited lactate production and phosphorylation of pyruvate dehydrogenase A by reducing the expression of PDK1. CS also increased mitochondrial reactive oxygen species (ROS) levels, decreased mitochondrial membrane potential and consequently stimulated the apoptosis of 12Z cells. CS-induced cell death was substantially inhibited by exogenous PDK1 expression. In conclusion, CS may be a novel drug candidate for treating endometriosis by inhibiting aerobic glycolysis and inducing ROS-mitochondria-mediated apoptotic cell death.
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http://dx.doi.org/10.3892/etm.2021.9788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903453PMC
April 2021

Agastache rugosa ethanol extract suppresses bone loss via induction of osteoblast differentiation with alteration of gut microbiota.

Phytomedicine 2021 Apr 14;84:153517. Epub 2021 Feb 14.

Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung, Gangwon-do 25451, Republic of Korea. Electronic address:

Purpose: Osteoporosis is a metabolic skeletal disease characterized by bone loss and an increased risk of fractures. This study aimed to investigate the therapeutic effect of Agastache rugosa on postmenopausal osteoporosis and elucidate its mechanisms in modulating the bone status.

Methods And Results: In the osteoblast differentiation process with MC3T3-E1 pre-osteoblasts, ethanol extract of Agastache rugosa (EEAR) and its compounds increased the expression of the proteins and genes of the osteoblast differentiation-related markers such as Runt-related transcription factor 2 (RUNX2) and β-catenin along with the elevation of calcium deposits. An ovariectomized mouse model was utilized to determine the impact of EEAR extract on postmenopausal osteoporosis. Twelve weeks of AR treatment suppressed the loss of bone strength, which was observed through micro-computed tomography. AR elevated osteogenic markers in the bone marrow cells, and collagen type 1 alpha 1 in the distal femoral bone. The results of the 16S rRNA gene sequencing analysis of cecal gut microbiomes demonstrated that AR reversed the ovariectomy-induced changes in the gut microbiomes.

Conclusion: Ethanol extract of Agastache rugosa has a therapeutic effect on postmenopausal osteoporosis via bone morphogenic protein, transforming growth factor β, and Wnt signaling pathway. It also increases the diversity of gut microbiota. Therefore, these data suggest that EEAR could be a potential candidate to treat postmenopausal osteoporosis.
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http://dx.doi.org/10.1016/j.phymed.2021.153517DOI Listing
April 2021

New Eudesmane-Type Sesquiterpene Glycosides from the Leaves of .

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

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

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

Iron-Storage Protein Ferritin Is Upregulated in Endometriosis and Iron Overload Contributes to a Migratory Phenotype.

Biomedicines 2020 Oct 27;8(11). Epub 2020 Oct 27.

College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

High levels of iron in the peritoneal cavity during menstruation have been implicated in the pathogenesis of endometriosis. However, whether iron directly affects the growth or migration of human endometriotic cells is poorly understood. This study demonstrated the presence of increased levels of the iron storage protein, ferritin, in the endometriotic tissues of patients with endometriosis. Furthermore, iron treatment stimulated the migration and epithelial-mesenchymal transition (EMT), but not growth, of 12Z human endometriotic cells. The expression of matrix metalloproteinase (MMP)-2/-9 was markedly increased through iron treatment in 12Z cells. Interestingly, intracellular reactive oxygen species (ROS) levels were significantly increased by iron in 12Z cells, and N-acetyl-L-cysteine significantly reduced iron-induced migration and MMP-2/-9 expression. Additionally, iron stimulated the activation of the NFκB pathway, and the activation was associated with iron-induced migration and MMP-2/-9 expression in 12Z cells. Moreover, iron markedly increased EMT and MMP-2/-9 expression in endometriotic lesions in an endometriosis mouse model. Taken together, these results suggest that iron may contribute to the migration abilities of human endometriotic cells via MMP expression through the ROS-NFκB pathway.
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http://dx.doi.org/10.3390/biomedicines8110454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694081PMC
October 2020

Short fully covered self-expandable metal stent for treatment of proximal anastomotic benign biliary stricture after living-donor liver transplantation.

Dig Endosc 2020 Oct 12. Epub 2020 Oct 12.

Departments of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Objectives: Non-surgical methods have high success rates for treating benign biliary strictures (BBSs), but treatment of proximal strictures is difficult. Recent studies have reported that fully covered self-expandable metal stents (FCSEMSs) are useful for treating refractory BBSs. We investigated the efficacy of a short and removable FCSEMS with an anti-migration design for treatment of proximal BBSs.

Methods: Fully covered self-expandable metal stents were inserted endoscopically in patients with BBSs after living donor liver transplantation (LDLT). Each FCSEMS was initially maintained for 3 months and subsequently exchanged every 3 months until the stricture resolved. Adverse events and stricture recurrence after FCSEMS removal were assessed during follow-up.

Results: A total of 63 patients with a median age of 57 years were enrolled in this study; 50 were male. The most common underlying disease was hepatocellular carcinoma and the previous operation was LDLT. The mean duration from surgery to diagnosis of stricture was 8.5 months, and the mean stent indwelling time was 4.2 months. The technical success and stricture resolution rate were 100%. The recurrence rate was 23.8% and the adverse event rate was 12.7%. All stents were removable, and asymptomatic stent migration was observed in four patients (6.4%).

Conclusions: The newly designed FCSEMS is effective in the treatment of proximal BBSs after LDLT.
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http://dx.doi.org/10.1111/den.13871DOI Listing
October 2020

Reduced Levels of Intestinal Neuropeptides and Neurotrophins in Neurotoxin-Induced Parkinson Disease Mouse Models.

J Neuropathol Exp Neurol 2021 Jan;80(1):15-20

From the Neurobiota Research Center (NRC), Kyung Hee University, Seoul, South Korea.

Intestinal neuropeptides and neurotrophins as endocrine messengers play a key role in the bidirectional gut-brain interaction both in health and disease status. Their alterations in several neurological disorders have been reported, but whether a remarkable change occurs in Parkinson disease (PD) remains unexplored. In this study, we aimed to investigate the levels of 13 neuropeptides and 4 neurotrophins in the intestine of neurotoxin-induced PD mice. The PD mice were obtained by chronic injection of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) or MPTP/probenecid (MPTP/p). The levels of mRNA and protein expression in mouse intestines were measured by using real-time reverse transcription polymerase chain reaction and Western blotting, respectively. We found that the mRNA expression of 2 neuropeptides (cholecystokinin [CCK] and dynorphin A [Dyn A]) and 2 neurotrophins (brain-derived neurotrophic factor [BDNF] and neurotrophin-5) was significantly decreased in the colon of MPTP group compared to the vehicle-treated group. The protein levels of CCK, Dyn A, and BDNF were reduced in the colon of MPTP- or MPTP/p-treated mice compared to those of the vehicle-treated group. These data suggest that the intestinal expression of CCK, Dyn A, and BDNF was significantly reduced in PD animal models, and may play a role in the gut-brain axis in PD.
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http://dx.doi.org/10.1093/jnen/nlaa113DOI Listing
January 2021

Effect of stent placement on stone recurrence and post-procedural cholangitis after endoscopic removal of common bile duct stones.

Korean J Intern Med 2021 03 24;36(Suppl 1):S27-S34. Epub 2020 Aug 24.

Division of Gastroenterology, Department of Internal Medicine, Konkuk University Medical Center, Seoul, Korea.

Background/aims: After endoscopic treatment of common bile duct (CBD) stones, recurrence of choledocholithiasis due to small stone fragments and post-endoscopic retrograde cholangiopancreatography (post-ERCP) cholangitis can occur. We determined the effect of biliary stenting after removal of CBD stones on the recurrence of CBD stones and the incidence of post-ERCP cholangitis.

Methods: We performed a retrospective single-center study involving 483 patients who underwent ERCP for the removal of CBD stones. The patients were classified into two groups according to their biliary stenting status. The primary outcome was the rate of CBD stone recurrence and the secondary outcome was the incidence of post-ERCP cholangitis.

Results: Among the 483 patients, 219 and 264 did and did not receive a biliary stent after CBD stone removal, respectively. The incidence of stone recurrence was 15.5% and 7.6% in the non-stenting and stenting groups (p = 0.006), respectively, while the incidence of post-ERCP cholangitis was 4.6% and 2.7% (p = 0.256). In a multivariate analysis, biliary stenting significantly reduced the stone recurrence rate (odds ratio, 0.30; p = 0.004).

Conclusion: Biliary stenting after the removal of CBD stones reduces the stone recurrence rate and assisted recovery. For patients with large and multiple stones who undergo lithotripsy, preventive biliary stent insertion can reduce the rate of stone recurrence.
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http://dx.doi.org/10.3904/kjim.2020.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009149PMC
March 2021

TRPV1 Antagonist DWP05195 Induces ER Stress-Dependent Apoptosis through the ROS-p38-CHOP Pathway in Human Ovarian Cancer Cells.

Cancers (Basel) 2020 Jun 26;12(6). Epub 2020 Jun 26.

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

In addition to their analgesic activity, transient receptor potential vanilloid 1 (TRPV1) agonists and antagonists demonstrate profound anti-cancer activities in various human cancers. In the present study, we investigated the anti-cancer activity of a novel TRPV1 antagonist, DWP05195, and evaluated its molecular mechanism in human ovarian cancer cells. DWP05195 demonstrated potent growth inhibitory effects in all five ovarian cancer cell lines examined. DWP05195 induced apoptosis through the activation of caspase-3, -8, and -9. DWP05195 induced C/EBP homologous protein (CHOP) expression and endoplasmic reticulum (ER) stress. Sodium phenylbutyrate (4-PBA), an ER-stress inhibitor, and CHOP knockdown significantly suppressed DWP5195-induced cell death. DWP05195-enhanced CHOP expression stimulated intrinsic and extrinsic apoptotic pathways through the regulation of Bcl2-like11 (BIM), death receptor 4 (DR4), and DR5. DWP05195-induced cell death was associated with increased reactive oxygen species (ROS) levels and p38 pathway activation. Pre-treatment with the antioxidant N-acetyl-L-cysteine (NAC) significantly suppressed DWP05195-induced CHOP expression and p38 activation. Inhibition of NADPH oxidase (NOX) through p47phox knockdown abolished DWP05195-induced CHOP expression and cell death. Taken together, the findings indicate that DWP05195 induces ER stress-induced apoptosis via the ROS-p38-CHOP pathway in human ovarian cancer cells.
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http://dx.doi.org/10.3390/cancers12061702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352786PMC
June 2020

Lancemaside A Isolated from the Root of Inhibits Ovarian Cancer Cell Invasion via the Reactive Oxygen Species (ROS)-Mediated p38 Pathway.

Am J Chin Med 2020 29;48(4):1021-1034. Epub 2020 May 29.

Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, South Korea.

roots have been widely used in Korean cuisine and traditional medicine. This study aimed to investigate the antimetastatic effects of lancemaside A, a major triterpenoid saponin, isolated from the roots of , in human ovarian cancer cells. Lancemaside A significantly suppressed the migration and invasion and the expression of matrix metalloproteinases (MMPs)-2 and -9 in ovarian cancer A2780 and SKOV3 cells. Treatment with lancemaside A generated reactive oxygen species (ROS) in ovarian cancer cells. However, treatment with anti-oxidant N-acetyl-L-cysteine (NAC) significantly negated the anti-invasive activity of lancemaside A. Additionally, lancemaside A activated p38 MAP kinase, which is mediated by ROS generation. This is the first study, to our knowledge, to reveal that lancemaside A isolated from the roots of exerts antimetastatic activity through inhibition of MMP expression and cancer cell invasion via activation of the ROS-mediated p38 pathway.
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http://dx.doi.org/10.1142/S0192415X20500494DOI Listing
September 2020

Cancer incidence according to the National Health Information Database in Korean patients with end-stage renal disease receiving hemodialysis.

Korean J Intern Med 2020 09 20;35(5):1210-1219. Epub 2020 Feb 20.

Department of Occupational and Environmental Medicine, Hanyang University College of Medicine, Seoul, Korea.

Background/aims: The aim of this study was to investigate incidence, survival, and risk factors of cancer in end-stage renal disease (ESRD) patients with hemodialysis using information from the National Health Information Database (NHID).

Methods: Using the NHID, we identified ESRD patients who started maintenance hemodialysis between 2003 and 2005 in Korea. Patients were followed from initiation of hemodialysis to renal transplantation, death, or December 31, 2016, whichever came first. We calculated the incidence, survival, and risk factors of cancer.

Results: Of the total 14,382 ESRD patients, 1,124 (7.82%; men:women, 728:396) were diagnosed with cancer during follow-up. The mean duration from the start of hemodialysis to new cancer identification was 64.40 ± 41.81 months. Significant risk factors for the development of new cancer were old age, male sex, and liver disease. Conversely, patients with diabetes showed low risk for new cancer. The colorectum (17.31%) was the most common primary site of cancer in men, followed by the liver (15.8%), stomach (14.29%), lung (13.6%), and kidney (10.3%). In women, the colorectum (14.65%) was also the most common primary site of cancer, followed by the breast (12.88%), thyroid (12.63%), stomach (10.86%), and lung (8.08%). According to the primary site of cancer, breast cancer showed the longest median survival duration (130.93 months), followed by thyroid, kidney, colorectum, bladder, stomach, liver, and lung cancer. On multivariate analyses, overall survival was affected by age and diabetes.

Conclusion: The cancer incidence of chronic hemodialysis patients was relatively high. Thus, careful monitoring and a specific cancer screening program are needed for chronic hemodialysis patients.
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http://dx.doi.org/10.3904/kjim.2018.400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487292PMC
September 2020

Isoflavones Isolated from the Seeds of Induced Apoptotic Cell Death in Human Ovarian Cancer Cells.

Molecules 2020 Jan 3;25(1). Epub 2020 Jan 3.

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

The seeds of are used in fishing, pesticides, and folk medicine in Ethiopia. Here, the anti-cancer effects of isoflavones isolated from were evaluated in human ovarian cancer cells. We found that isoflavone ferrugone and 6,7-dimethoxy-3',4'-methylenedioxy-8-(3,3-dimethylallyl)isoflavone (DMI) had potent cytotoxic effects on human ovarian cancer cell A2780 and SKOV3. Ferrugone and DMI treatment increased the sub-G1 cell population in a dose-dependent manner in A2780 cells. The cytotoxic activity of ferrugone and DMI was associated with the induction of apoptosis, as shown by an increase in annexin V-positive cells. Z-VAD-fmk, a broad-spectrum caspase inhibitor, and z-DEVD-fmk, a caspase-3 inhibitor, significantly reversed both the ferrugone and DMI-induced apoptosis, suggesting that cell death stimulated by the isoflavones is mediated by caspase-3-dependent apoptosis. Additionally, ferrugone-induced apoptosis was found to be caspase-8-dependent, while DMI-induced apoptosis was caspase-9-dependent. Notably, DMI, but not ferrugone, increased the intracellular levels of reactive oxygen species (ROS), and antioxidant N-acetyl-L-cysteine (NAC) attenuated the pro-apoptotic activity of DMI. These data suggest that DMI induced apoptotic cell death through the intrinsic pathway via ROS production, while ferrugone stimulated the extrinsic pathway in human ovarian cancer cells.
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http://dx.doi.org/10.3390/molecules25010207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983189PMC
January 2020

Characterization of Nivalenol-Producing That Causes Cereal Head Blight in Korea.

Plant Pathol J 2019 Dec 12;35(6):543-552. Epub 2019 Dec 12.

Microbial Safety Team, National Institute of Agricultural Sciences, Wanju 55365, Korea.

of the species complex causes head blight in small-grain cereals. The nivalenol (NIV) chemotypes of is more common than the deoxynivalenol (DON) chemotypes of or in Korea. To understand the prevalence of NIV in Korean cereals, we characterized the biological traits of 80 cereal isolates of producing NIV or 3-acetyl-deoxynivalenol (3-ADON), and 54 with 3-ADON or 15-acetyl-deoxynivalenol (15-ADON). There was no significant difference in mycelial growth between the chemotypes, but isolates grew approximately 30% faster than isolates on potato dextrose agar. Sexual and asexual reproduction capacities differed markedly between the two species. Both chemotypes of (3-ADON and 15-ADON) produced significantly higher numbers of perithecia and conidia than NIV. The highest level of mycotoxins (sum of trichothecenes and zearalenone) was produced by 3-ADON on rice medium, followed by 15-ADON, 3-ADON, and NIV. Zearalenone levels were correlated with DON levels in some chemotypes, but not with NIV levels. Disease assessment on barley, maize, rice, and wheat revealed that both and isolates were virulent toward all crops tested. However, there is a tendency that virulence levels of NIV isolates on rice were higher than those of isolates. Taken together, the phenotypic traits found among the Korean NIV isolates suggest an association with their host adaptation to certain environments in Korea.
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http://dx.doi.org/10.5423/PPJ.OA.06.2019.0168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901258PMC
December 2019

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

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

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

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

Chemical Constituents of the Leaves of Butterbur () and Their Anti-Inflammatory Effects.

Biomolecules 2019 11 29;9(12). Epub 2019 Nov 29.

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

Two new aryltetralin lactone lignans, petasitesins A and B were isolated from the hot water extract of the leaves of butterbur () along with six known compounds. The chemical structures of lignans and were elucidated on the basis of 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data, electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra. Petasitesin A and cimicifugic acid D showed significant inhibitory effects on the production of both prostaglandin E2 (PGE) and NO in RAW264.7 macrophages. The expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were inhibited by compound in RAW264.7 cells. Furthermore, compounds and exhibited strong affinities with both iNOS and COX-2 enzymes in molecular docking studies.
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http://dx.doi.org/10.3390/biom9120806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995602PMC
November 2019

β-Caryophyllene in the Essential Oil from Induces G Phase Cell Cycle Arrest in Human Lung Cancer Cells.

Molecules 2019 Oct 18;24(20). Epub 2019 Oct 18.

College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

is a plant widespread in East Asia, used in folk medicine to treat various disorders, such as pneumonia, colitis, stomatitis, and carbuncle. Whether the essential oil from (ECB) and its active constituents have anti-proliferative activities in lung cancer is unknown. Therefore, we investigated the cytotoxic effects of ECB in A549 and NCI-H358 human lung cancer cells. Culture of A549 and NCI-H358 cells with ECB induced apoptotic cell death, as revealed by an increase in annexin V staining. ECB treatment reduced mitochondrial membrane potential (MMP), disrupted the balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins, and activated caspase-8, -9, and -3, as assessed by western blot analysis. Interestingly, pretreatment with a broad-spectrum caspase inhibitor (z-VAD-fmk) significantly attenuated ECB-induced apoptosis. Furthermore, gas chromatography-mass spectrometry (GC/MS) analysis of ECB identified six compounds. Among them, β-caryophyllene exhibited a potent anti-proliferative effect, and thus was identified as the major active compound. β- Caryophyllene induced G cell cycle arrest by downregulating cyclin D1, cyclin E, cyclin-dependent protein kinase (CDK) -2, -4, and -6, and RB phosphorylation, and by upregulating p21 and p27. These results indicate that β-caryophyllene exerts cytotoxic activity in lung cancer cells through induction of cell cycle arrest.
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http://dx.doi.org/10.3390/molecules24203754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832734PMC
October 2019

Effect of Dehydrocostus Lactone Isolated from the Roots of on the Apoptosis of Endometriotic Cells and the Alternative Activation of Endometriosis-Associated Macrophages.

Am J Chin Med 2019 5;47(6):1289-1305. Epub 2019 Sep 5.

Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyunghee-Daero, Dongdaemoon-Gu, Seoul 02447, South Korea.

The roots of have been used in traditional medicine in Asia to treat inflammation and diseases associated with pain, including endometriosis. The aim of this study was to investigate the anti-endometriotic effect of dehydrocostus lactone, an active compound in roots, using human endometriotic cells and macrophages stimulated by these cells. Dehydrocostus lactone induced apoptotic cell death in 12Z human endometriotic cells. Dehydrocostus lactone stimulated the activation of caspase-3, -8, and -9, while caspase inhibitors significantly reversed the dehydrocostus lactone-induced cell death in 12Z cells. In addition, dehydrocostus lactone decreased the production of PGE and neurotrophins (BDNF, NGF, NT3, and NT4/5), which are regarded as endometriosis-associated pain factors in human endometriotic cells. Moreover, dehydrocostus lactone inhibited the expression of M2 markers (CD206, and Trem-2), IL-10, VEGF, and MMP-2/-9 in endometriosis-associated macrophages (EAMs). Furthermore, dehydrocostus lactone inhibited the Akt and NFB pathways in both endometriotic cells and EAMs. Taken together, our findings suggest that dehydrocostus lactone, an active compound of , has anti-endometriotic activities via induction of apoptosis and downregulation of pain factors in endometriotic cells and inhibition of the alternative activation of EAMs.
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http://dx.doi.org/10.1142/S0192415X19500666DOI Listing
February 2020

Effect of Stem Cell Source and Dose on Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Idiopathic Aplastic Anemia: Data from the Korean Aplastic Anemia Trials.

Acta Haematol 2020 7;143(3):232-243. Epub 2019 Aug 7.

Division of Hematology and Cellular Therapy, Ulsan University Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Objective: We aimed to evaluate the effect of stem cell source and dose on the survival of various donor subgroups, such as matched sibling donor (MSDs) and alternative donors (ADs), upon bone marrow (BM) or peripheral blood stem cell (PBSC) infusion in aplastic anemia (AA).

Methods: We retrospectively investigated the effects of stem cell source and dose on allogeneic hematopoietic stem cell transplantation (alloHSCT) in AA.

Results: A total of 267 patients were included in this analysis. The BM-treated group showed an association with low incidence of any-grade acute graft versus host disease (GvHD) (p < 0.001). A higher stem cell dose was related with a low incidence of extensive chronic GvHD in MSDs (p = 0.025). Multivariate analysis for overall survival (OS) revealed that only age at alloHSCT <31 years (p = 0.010) and prior platelet transfusion <86 U (p = 0.046) in MSDs and higher stem cell dose (hazard ratio = 2.596, p = 0.045) in ADs were favorable prognostic factors.

Conclusion: PBSCs could be preferred in AD because high stem cell dose may be easily achieved to improve the OS at the expense of acute GvHD. However, BM stem cells are preferred in MSDs.
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http://dx.doi.org/10.1159/000501496DOI Listing
August 2020

Hepatocyte nuclear factor-1 beta protects endometriotic cells against apoptotic cell death by up-regulating the expression of antiapoptotic genes†.

Biol Reprod 2019 10;101(4):686-694

College of Pharmacy, Kyung Hee University, Seoul, South Korea.

The overexpression of hepatocyte nuclear factor-1 beta (HNF1β) in endometriotic lesion has been demonstrated. However, the role of HNF1β in endometriosis remains largely unknown. Human endometriotic 12Z cells showed higher level of HNF1β when compared with normal endometrial HES cells. In human endometriotic 12Z cells, HNF1β knockdown increased susceptibility to apoptotic cell death by oxidative stress, while HNF1β overexpression suppressed apoptosis. In addition, HNF1β knockdown and overexpression significantly decreased and increased, respectively, the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent antiapoptotic genes. Knockdown of the antiapoptotic genes significantly reduced the HNF1β-induced resistance against oxidative stress in 12Z cells. Furthermore, HNF1β regulated the transcriptional activity of NF-κB, and an NF-κB inhibitor suppressed the HNF1β-enhanced NF-κB-dependent antiapoptotic gene expression and the resistance of the 12Z cells against cell death. Taken together, these data suggest that HNF1β overexpression may protect endometriotic cells against oxidative damage by augmenting antiapoptotic gene expression.
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http://dx.doi.org/10.1093/biolre/ioz127DOI Listing
October 2019

Complications Following Colonoscopy in a Nationwide Standard Cohort: A Retrospective Case-control Study.

Korean J Gastroenterol 2019 03;73(3):152-158

Center of Biomedical Data Science, Yonsei University Wonju College of Medicine, Wonju, Korea

Background/aims: Despite the many reports of colonoscopy complications worldwide, few studies have been performed at the population level in Korea. In this study, a population-based study was performed to evaluate the incidence of post-colonoscopy perforations compared to a control group.

Methods: Between January 2011 and December 2011, data for all cases (age over 45) who underwent a colonoscopy were collected from National Health Insurance Service using a random sampling method. The clinical characteristics and perforation incidence (within 30 days after the colonoscopy) of cases were identified, and cases were then compared with controls who had not undergone a colonoscopy.

Results: Among 1,380,000 subjects, 31,177 cases and 62,354 controls were identified. Perforation occurred in 14 patients (0.04%) in the case group and one patient (<0.01%) in the control group (RR, 28.0; 95% CI 3.7-212.9, p<0.001). Subgroup analysis was followed according to the endoscopic procedure, gender and age. In subgroup analysis, colonoscopy-associated perforations occurred more in the therapeutic procedure (RR, 26; 95% CI 1.46-461.46), male (RR, 50; 95% CI 2.96-844.41), and age of 45-60 years (RR, 30; 95% CI 1.71-525.23).

Conclusions: A colonoscopy procedure is related to an increased risk of perforation at the population level. In addition, the therapeutic procedure, male, and age of 45-60 years appeared to be associated with an increased risk of perforation.
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http://dx.doi.org/10.4166/kjg.2019.73.3.152DOI Listing
March 2019

Anticancer Activity of Gukulenin A Isolated from the Marine Sponge In Vitro and In Vivo.

Mar Drugs 2019 Feb 21;17(2). Epub 2019 Feb 21.

College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

Gukulenin A is a bis-tropolone tetraterpenoid isolated from the marine sponge . In this study, we examined the anticancer activities of gukulenin A in ovarian cancer cell lines (A2780, SKOV3, OVCAR-3, and TOV-21G) and in an ovarian cancer mouse model generated by injecting A2780 cells. We found that gukulenin A suppressed tumor growth in A2780-bearing mice. Gukulenin A markedly inhibited cell viability in four ovarian cancer cell lines, including the A2780 cell line. Gukulenin A treatment increased the fraction of cells accumulated at the sub G1 phase in a dose-dependent manner and the population of annexin V-positive cells, suggesting that gukulenin A induces apoptotic cell death in ovarian cancer cells. In addition, gukulenin A triggered the activation of caspase-3, -8, and -9, and caspase inhibitors attenuated gukulenin A-induced A2780 cell death. The results suggest that gukulenin A may be a potential therapeutic agent for ovarian cancer.
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http://dx.doi.org/10.3390/md17020126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410303PMC
February 2019

Author Correction: nc886 is induced by TGF-β and suppresses the microRNA pathway in ovarian cancer.

Nat Commun 2018 12 19;9(1):5458. Epub 2018 Dec 19.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, 77555-1072, USA.

In the original version of the Supplementary Information file associated with this Article, Supplementary Fig. 18 panel b was inadvertently replaced with a duplicate of panel a. The error has now been fixed and the corrected version of the Supplementary Information PDF is available to download from the HTML version of the Article.
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http://dx.doi.org/10.1038/s41467-018-07818-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300664PMC
December 2018

23-Hydroxyursolic Acid Isolated from the Stem Bark of Induces Apoptosis through Fas/Caspase-8-Dependent Pathway in HL-60 Human Promyelocytic Leukemia Cells.

Molecules 2018 Dec 13;23(12). Epub 2018 Dec 13.

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

The natural product 23-hydroxyursolic acid (23-HUA) is a derivative of ursolic acid, which is known to induce cancer cell apoptosis. However, apoptotic effects and mechanisms of 23-HUA have not been well characterized yet. Herein, we investigated the molecular mechanisms of 23-HUA-induced apoptosis in HL-60 human promyelocytic leukemia cells. 23-HUA-treated HL-60 cells showed apoptotic features including internucleosomal DNA condensation and fragmentation as well as externalization of phosphatidylserine residues. 23-HUA induced a series of mitochondrial events including disruption of mitochondrial membrane potential (), cytochrome and Smac/DIABLO release and loss of balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins in HL-60 cells. In addition, 23-HUA activated caspase-8, caspase-9 and caspase-3. Pretreatment with a broad caspase inhibitor (z-VAD-fmk), a caspase-3 inhibitor (z-DEVD-fmk), and a caspase-8 inhibitor (z-IETD-fmk) significantly attenuated 23-HUA-induced DNA fragmentation. After 23-HUA-induced apoptosis, proteins expression levels of FasL, Fas and FADD constituting the death-inducing signaling complex (DISC) were upregulated in HL-60 cells. Moreover, transfection with Fas or FADD siRNA significantly blocked 23-HUA-induced DNA fragmentation and caspases activation. Taken together, these findings indicate that 23-HUA induces apoptosis in HL-60 human promyelocytic leukemia cells through formation of DISC and caspase-8 activation leading to loss of and caspase-3 activation.
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http://dx.doi.org/10.3390/molecules23123306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321063PMC
December 2018

Increased α2-6 sialylation of endometrial cells contributes to the development of endometriosis.

Exp Mol Med 2018 12 12;50(12):1-12. Epub 2018 Dec 12.

Department of Korean Medical Science, School of Korean Medicine, Seoul, Republic of Korea.

Endometriosis is a disease characterized by implants of endometrial tissue outside the uterine cavity and is strongly associated with infertility. Focal adhesion of endometrial tissue to the peritoneum is an indication of incipient endometriosis. In this study, we examined the effect of various cytokines that are known to be involved in the pathology of endometriosis on endometrial cell adhesion. Among the investigated cytokines, transforming growth factor-β1 (TGF-β1) increased adhesion of endometrial cells to the mesothelium through induction of α2-6 sialylation. The expression levels of β-galactoside α2-6 sialyltransferase (ST6Gal) 1 and ST6Gal2 were increased through activation of TGF-βRI/SMAD2/3 signaling in endometrial cells. In addition, we discovered that terminal sialic acid glycan epitopes of endometrial cells engage with sialic acid-binding immunoglobulin-like lectin-9 expressed on mesothelial cell surfaces. Interestingly, in an in vivo mouse endometriosis model, inhibition of endogenous sialic acid binding by a NeuAcα2-6Galβ1-4GlcNAc injection diminished TGF-β1-induced formation of endometriosis lesions. Based on these results, we suggest that increased sialylation of endometrial cells by TGF-β1 promotes the attachment of endometrium to the peritoneum, encouraging endometriosis outbreaks.
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http://dx.doi.org/10.1038/s12276-018-0167-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290765PMC
December 2018

Resveratrol analog, N-(4-methoxyphenyl)-3,5-dimethoxybenzamide induces G/M phase cell cycle arrest and apoptosis in HeLa human cervical cancer cells.

Food Chem Toxicol 2019 Feb 30;124:101-111. Epub 2018 Nov 30.

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

In this study, several resveratrol analogs were synthesized and evaluated in search of a more effective anti-proliferative resveratrol analog. Among the evaluated resveratrol analogs, we have identified N-(4-methoxyphenyl)-3,5-dimethoxybenamide (MPDB) as a potent anti-proliferative compound. Treatment with MPDB resulted in G/M phase cell cycle arrest, which was accompanied by alteration of G/M-related protein expression and phosphorylation. MPDB-induced G/M arrest was blocked by transfection of ATM/ATR siRNAs, indicating the critical role of ATM/ATR in G/M phase arrest. In addition, treatment with MPDB displayed the activation of caspase and decreased Bcl-xl protein expression after 20 h in HeLa cells. Moreover, MPDB increased cytosolic cytochrome c release and Fas and Fas-L protein expression, indicating intrinsic and extrinsic apoptosis pathway, respectively. These results suggest that MPDB is a new and potent compound that induces ATM/ATR-dependent G/M phase cell cycle arrest and apoptosis, implicating it as a putative candidate in the investment of cervical cancer therapy.
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http://dx.doi.org/10.1016/j.fct.2018.11.062DOI Listing
February 2019

Novel Rhodanine Derivative, 5-[4-(4-Fluorophenoxy) phenyl]methylene-3-{4-[3-(4-methylpiperazin-1-yl) propoxy]phenyl}-2-thioxo-4-thiazolidinone dihydrochloride, Induces Apoptosis via Mitochondria Dysfunction and Endoplasmic Reticulum Stress in Human Colon Cancer Cells.

Molecules 2018 Nov 6;23(11). Epub 2018 Nov 6.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea.

We previously reported that 5-[4-(4-fluorophenoxy) phenyl] methylene-3-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}-2-thioxo-4-thiazolidinone dihydrochloride (KSK05104) has potent, selective and metabolically stable IKKβ inhibitory activities. However, the apoptosis-inducing of KSK05104 and its underlying mechanism have not yet been elucidated in human colon cancer cells. We show that KSK05104 triggered apoptosis, as indicated by externalization of Annexin V-targeted phosphatidylserine residues in HT-29 and HCT-116 cells. KSK05104 induced the activation of caspase-8, -9, and -3, and the cleavage of poly (ADP ribose) polymerase-1 (PARP-1). KSK05104-induced apoptosis was significantly suppressed by pretreatment with z-VAD-fmk (a broad caspase inhibitor). KSK05104 also induced release of cytochrome (Cyt ), apoptosis inducing factor (AIF), and endonuclease G (Endo G) by damaging mitochondria, resulting in caspase-dependent and -independent apoptotic cell death. KSK05104 triggered endoplasmic reticulum (ER) stress and changed the intracellular calcium level ([Ca]). Interestingly, treatment with KSK05104 activated not only ER stress marker proteins including inositol-requiring enzyme 1-alpha (IRE-1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), but also μ-calpain, and caspase-12 in a time-dependent manner. KSK05104-induced apoptosis substantially decreased in the presence of BAPTA/AM (an intracellular calcium chelator). Taken together, these results suggest that mitochondrial dysfunction and ER stress contribute to KSK05104-induced apoptosis in human colon cancer cells.
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http://dx.doi.org/10.3390/molecules23112895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278386PMC
November 2018

Maintenance of the fistulous tract after recanalization via magnetic compression anastomosis in completely obstructed benign biliary stricture.

Scand J Gastroenterol 2018 Oct - Nov;53(10-11):1393-1398. Epub 2018 Oct 23.

a Department of Internal Medicine , Severance Hospital, Yonsei University College of Medicine , Seoul , Korea.

Objective: This study compared the efficacy of a percutaneous transhepatic cholangioscopy (PTCS) catheter and a fully covered self-expandable metal stent (FCSEMS) for maintaining biliary tract patency after magnetic compression anastomosis (MCA).

Methods: This study included patients with completely obstructed benign biliary stricture (BBS), which was resolved by MCA and subsequent insertion of a PTCS catheter or FCSEMS. We compared the restenosis-free time after removal of the PTCS catheter or FCSEMS, and the rate of complications.

Results: A total of 49 patients were analyzed. The mean ages of the patients in these groups were 50.1 and 49.6 years, respectively. The predisposing conditions causing complete BBS were liver transplantation (n = 38), abdominal surgery (n = 10) and trauma (n = 1). The mean indwelling durations were 176 and 128 days in the PTCS catheter and FCSEMS groups, respectively. The mean follow-up duration after removal of the PTCS catheter and FCSEMS were 2259 and 680.5 days, respectively. Three patients in the PTCS group and three patients in the FCSEMS group experienced stricture relapse. The mean duration between recurrence and stent removal were 924 and 265 days, respectively, and the numbers of stricture-free days did not differ significantly between the two groups. The adverse event rate did not differ significantly between the PTCS and FCSEMS groups (50% vs. 24.2%, respectively).

Conclusions: FCSEMSs have an efficacy and safety similar to those of PTCS catheters for maintaining biliary tract patency after MCA, but are more convenient for patients.
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http://dx.doi.org/10.1080/00365521.2018.1526968DOI Listing
April 2019

Chemical constituents of the roots of Codonopsis lanceolata.

Arch Pharm Res 2018 Nov 27;41(11):1082-1091. Epub 2018 Sep 27.

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

A new phenylpropanoid (1), a new alkaloid (11), and a new natural polyacetylene (17), together with nine phenolic compounds (2-10), five alkaloids (12-16), three polyacetylenes (18-20), three triterpenoidal saponins (21-23), one phenylethanoid glycoside (24), and three hexyl glycosides (25-27) with previous known structures, were isolated from the roots of Codonopsis lanceolata. All of the isolates 1-27 were evaluated for their inhibitory effects on LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages and cell viability in A2780 human ovarian cancer cells. Among the isolates, lancemasides A and B have a significant inhibitory effect on the production of NO in RAW264.7 cells (IC values < 50 μM). In A2780 cells, lancemaside A exhibited the most potent inhibitory effect on cell viability. This is the first report on the pharmacological activities of lancemaside B (22).
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http://dx.doi.org/10.1007/s12272-018-1080-9DOI Listing
November 2018

(-)-Asarinin from the Roots of Induces Apoptotic Cell Death via Caspase Activation in Human Ovarian Cancer Cells.

Molecules 2018 Jul 25;23(8). Epub 2018 Jul 25.

College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

Two tetrahydrofurofurano lignans ( and ), four phenylpropanoids (⁻), and two alkamides ( and ) were isolated from the EtOAc-soluble fraction of the roots of . The chemical structures of the isolates were identified by analysis of spectroscopic data measurements, and by a comparison of their data with published values. The isolates (, , ⁻) were evaluated for their cytotoxicity against human ovarian cancer cells (A2780 and SKOV3) and immortalized ovarian surface epithelial cells (IOSE80PC) using a MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assay. Of the isolates, (-)-asarinin () exhibited the most potent cytotoxicity to both A2780 and SKOV3 cells. A propidium iodide/annexin V-fluorescein isothiocyanate (V-FITC) double staining assay showed that (-)-asarinin () induces apoptotic cell death in ovarian cancer cells. In addition, (-)-asarinin () increased the activation of caspase-3, caspase-8, and caspase-9 in ovarian cancer cells. Pretreatment with caspase inhibitors attenuated the cell death induced by (-)-asarinin (). In conclusion, our findings show that (-)-asarinin () from the roots of may induce caspase-dependent apoptotic cell death in human cancer cells.
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http://dx.doi.org/10.3390/molecules23081849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222791PMC
July 2018

Author Correction: Mutant p53 stimulates cell invasion through an interaction with Rad21 in human ovarian cancer cells.

Sci Rep 2018 Jul 18;8(1):11032. Epub 2018 Jul 18.

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

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-29327-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052072PMC
July 2018

Chemical Constituents of Apios americana Tubers and Their Inhibitory Activities on Nitric Oxide Production in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages.

J Nat Prod 2018 07 22;81(7):1598-1603. Epub 2018 Jun 22.

Herbal Medicine Research Division , Korea Institute of Oriental Medicine , Daejeon 34054 , Republic of Korea.

Apios americana is an important food crop producing edible tubers with high nutritional and medicinal values and is widely cultivated in many countries. Despite its usefulness, research on its secondary metabolites and biological activities has been limited. In the present study, a new coumaronochromone, (2 R,3 S)-3,7,4'-trihydroxy-5-methoxycoumaronochromone (1), and two new isoflavone glucosides, 7,2',4'-trihydroxy-5-methoxyisoflavone-4'- O-β-d-glucopyranoside (3) and 5,7,4'-trihydroxyisoflavone-7- O-β-d-gentiotrioside (5), were isolated from the tubers of A. americana via chromatographic separation. Seventeen known compounds (2, 4, and 6-20) were also obtained from this plant part. The chemical structures of 1, 3, and 5 were determined by the interpretation of spectroscopic data. The absolute structure of the new compound 1 was established from experimental and calculated electronic circular dichroism spectra. This is the first study to determine the absolute configuration of a 3-hydroxycoumaronochromone derivative. The potential anti-inflammatory activity of the 20 isolates obtained was evaluated by measuring their inhibitory effects on nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 macrophages. Among the isolates, seven compounds (1, 3, 6-8, 15, and 20) showed substantial inhibition of nitric oxide production in RAW 264.7 cells, with the most active being compound 1 (IC value of 0.38 ± 0.04 μM).
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http://dx.doi.org/10.1021/acs.jnatprod.8b00182DOI Listing
July 2018