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REFERENCE LINKING PLATFORM OF KOREA S&T JOURNALS
> Journal Vol & Issue
Biomolecules & Therapeutics
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Journal DOI :
The Korean Society of Applied Pharmacology
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Volume & Issues
Volume 23, Issue 6 - Nov 2015
Volume 23, Issue 5 - Sep 2015
Volume 23, Issue 4 - Jul 2015
Volume 23, Issue 3 - May 2015
Volume 23, Issue 2 - Mar 2015
Volume 23, Issue 1 - Jan 2015
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Phosphorylation and Reorganization of Keratin Networks: Implications for Carcinogenesis and Epithelial Mesenchymal Transition
Kim, Hyun Ji ; Choi, Won Jun ; Lee, Chang Hoon ;
Biomolecules & Therapeutics, volume 23, issue 4, 2015, Pages 301~312
DOI : 10.4062/biomolther.2015.032
Metastasis is one of hallmarks of cancer and a major cause of cancer death. Combatting metastasis is highly challenging. To overcome these difficulties, researchers have focused on physical properties of metastatic cancer cells. Metastatic cancer cells from patients are softer than benign cancer or normal cells. Changes of viscoelasticity of cancer cells are related to the keratin network. Unexpectedly, keratin network is dynamic and regulation of keratin network is important to the metastasis of cancer. Keratin is composed of heteropolymer of type I and II. Keratin connects from the plasma membrane to nucleus. Several proteins including kinases, and protein phosphatases bind to keratin intermediate filaments. Several endogenous compounds or toxic compounds induce phosphorylation and reorganization of keratin network in cancer cells, leading to increased migration. Continuous phosphorylation of keratin results in loss of keratin, which is one of the features of epithelial mesenchymal transition (EMT). Therefore, several proteins involved in phosphorylation and reorganization of keratin also have a role in EMT. It is likely that compounds controlling phosphorylation and reorganization of keratin are potential candidates for combating EMT and metastasis.
An Aminopropyl Carbazole Derivative Induces Neurogenesis by Increasing Final Cell Division in Neural Stem Cells
Shin, Jae-Yeon ; Kong, Sun-Young ; Yoon, Hye Jin ; Ann, Jihyae ; Lee, Jeewoo ; Kim, Hyun-Jung ;
Biomolecules & Therapeutics, volume 23, issue 4, 2015, Pages 313~319
DOI : 10.4062/biomolther.2015.016
P7C3 and its derivatives, 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol (1) and N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)-4-methylbenzenesulfonamide (2), were previously reported to increase neurogenesis in rat neural stem cells (NSCs). Although P7C3 is known to increase neurogenesis by protecting newborn neurons, it is not known whether its derivatives also have protective effects to increase neurogenesis. In the current study, we examined how 1 induces neurogenesis. The treatment of 1 in NSCs increased numbers of cells in the absence of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2), while not affecting those in the presence of growth factors. Compound 1 did not induce astrocytogenesis during NSC differentiation. 5-Bromo-2`-deoxyuridine (BrdU) pulsing experiments showed that 1 significantly enhanced BrdU-positive neurons. Taken together, our data suggest that 1 promotes neurogenesis by the induction of final cell division during NSC differentiation.
Induction of Resistance to BRAF Inhibitor Is Associated with the Inability of Spry2 to Inhibit BRAF-V600E Activity in BRAF Mutant Cells
Ahn, Jun-Ho ; Han, Byeal-I ; Lee, Michael ;
Biomolecules & Therapeutics, volume 23, issue 4, 2015, Pages 320~326
DOI : 10.4062/biomolther.2015.007
The clinical benefits of oncogenic BRAF inhibitor therapies are limited by the emergence of drug resistance. In this study, we investigated the role of a negative regulator of the MAPK pathway, Spry2, in acquired resistance using BRAF inhibitor-resistant derivatives of the BRAF-V600E melanoma (A375P/Mdr). Real-time RT-PCR analysis indicated that the expression of Spry2 was higher in A375P cells harboring the BRAF V600E mutation compared with wild-type BRAF-bearing cells (SK-MEL-2) that are resistant to BRAF inhibitors. This result suggests the ability of BRAF V600E to evade feedback suppression in cell lines with BRAF V600E mutations despite high Spry2 expression. Most interestingly, Spry2 exhibited strongly reduced expression in A375P/Mdr cells with acquired resistance to BRAF inhibitors. Furthermore, the overexpression of Spry2 partially restored sensitivity to the BRAF inhibitor PLX4720 in two BRAF inhibitor-resistant cells, indicating a positive role for Spry2 in the growth inhibition induced by BRAF inhibitors. On the other hand, long-term treatment with PLX4720 induced pERK reactivation following BRAF inhibition in A375P cells, indicating that negative feedback including Spry2 may be bypassed in BRAF mutant melanoma cells. In addition, the siRNA-mediated knockdown of Raf-1 attenuated the rebound activation of ERK stimulated by PLX4720 in A375P cells, strongly suggesting the positive role of Raf-1 kinase in ERK activation in response to BRAF inhibition. Taken together, these data suggest that RAF signaling may be released from negative feedback inhibition through interacting with Spry2, leading to ERK rebound and, consequently, the induction of acquired resistance to BRAF inhibitors.
Autophagy Regulates Formation of Primary Cilia in Mefloquine-Treated Cells
Shin, Ji Hyun ; Bae, Dong-Jun ; Kim, Eun Sung ; Kim, Han Byeol ; Park, So Jung ; Jo, Yoon Kyung ; Jo, Doo Sin ; Jo, Dong-Gyu ; Kim, Sang-Yeob ; Cho, Dong-Hyung ;
Biomolecules & Therapeutics, volume 23, issue 4, 2015, Pages 327~332
DOI : 10.4062/biomolther.2015.025
Primary cilia have critical roles in coordinating multiple cellular signaling pathways. Dysregulation of primary cilia is implicated in various ciliopathies. To identify specific regulators of autophagy, we screened chemical libraries and identified mefloquine, an anti-malaria medicine, as a potent regulator of primary cilia in human retinal pigmented epithelial (RPE) cells. Not only ciliated cells but also primary cilium length was increased in mefloquine-treated RPE cells. Treatment with mefloquine strongly induced the elongation of primary cilia by blocking disassembly of primary cilium. In addition, we found that autophagy was increased in mefloquine-treated cells by enhancing autophagic flux. Both chemical and genetic inhibition of autophagy suppressed ciliogenesis in mefloquine-treated RPE cells. Taken together, these results suggest that autophagy induced by mefloquine positively regulates the elongation of primary cilia in RPE cells.
Chitin from Cuttlebone Activates Inflammatory Cells to Enhance the Cell Migration
Lim, Sung Cil ; Lee, Ki-Man ; Kang, Tae Jin ;
Biomolecules & Therapeutics, volume 23, issue 4, 2015, Pages 333~338
DOI : 10.4062/biomolther.2015.062
Our previous report showed that the extract from cuttlebone (CB) had wound healing effect in burned lesion of rat and the extract was identified as chitin by HPLS analysis. We herein investigated the morphology in CB extract using scanning electron microscope (SEM). Chitin was used as a control. There is no difference in morphology between CB extract and chitin. We also assessed the role of CB extract on the production of inflammatory mediators using murine macrophages and the migration of inflammatory cells. The extract induced the production of nitric oxide (NO) in macrophages. While the extract of CB itself stimulated macrophages to increase the expression of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-
, interleukin (IL)-
, and IL-6, CB extract suppressed the production of those cytokines by LPS. CB extract also induced the production of mouse IL-8 which is related to the cell migration, and treatment with CB enhanced fibroblast migration and invasion. Therefore, our results suggest that CB activates inflammatory cells to enhance the cell migration.
Anti-Proliferative Effect of Naringenin through p38-Dependent Downregulation of Cyclin D1 in Human Colorectal Cancer Cells
Song, Hun Min ; Park, Gwang Hun ; Eo, Hyun Ji ; Lee, Jin Wook ; Kim, Mi Kyoung ; Lee, Jeong Rak ; Lee, Man Hyo ; Koo, Jin Suk ; Jeong, Jin Boo ;
Biomolecules & Therapeutics, volume 23, issue 4, 2015, Pages 339~344
DOI : 10.4062/biomolther.2015.024
Naringenin (NAR) as one of the flavonoids observed in grapefruit has been reported to exhibit an anti-cancer activity. However, more detailed mechanism by which NAR exerts anti-cancer properties still remains unanswered. Thus, in this study, we have shown that NAR down-regulates the level of cyclin D1 in human colorectal cancer cell lines, HCT116 and SW480. NAR inhibited the cell proliferation in HCT116 and SW480 cells and decreased the level of cyclin D1 protein. Inhibition of proteasomal degradation by MG132 blocked NAR-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in the cells treated with NAR. In addition, NAR increased the phosphorylation of cyclin D1 at threonine-286 and a point mutation of threonine-286 to alanine blocked cyclin D1 downregulation by NAR. p38 inactivation attenuated cyclin D1 downregulation by NAR. From these results, we suggest that NAR-mediated cyclin D1 downregulation may result from proteasomal degradation through p38 activation. The current study provides new mechanistic link between NAR, cyclin D1 downregulation and cell growth in human colorectal cancer cells.
Anti-Influenza Activity of Betulinic Acid from Zizyphus jujuba on Influenza A/PR/8 Virus
Hong, Eun-Hye ; Song, Jae Hyoung ; Kang, Kyo Bin ; Sung, Sang Hyun ; Ko, Hyun-Jeong ; Yang, Heejung ;
Biomolecules & Therapeutics, volume 23, issue 4, 2015, Pages 345~349
DOI : 10.4062/biomolther.2015.019
Betulinic acid, a pentacyclic triterpene isolated from Jujube tree (Zizyphus jujuba Mill), has been known for a wide range of biological and medicinal properties such as antibacterial, antimalarial, anti-inflammatory, antihelmintic, antinociceptive, and anticancer activities. In the study, we investigated the antiviral activity on influenza A/PR/8 virus infected A549 human lung adenocarcinoma epithelial cell line and C57BL/6 mice. Betulinic acid showed the anti-influenza viral activity at a concentration of
without a significant cytotoxicity in influenza A/PR/8 virus infected A549 cells. Also, betulinic acid significantly attenuated pulmonary pathology including increased necrosis, numbers of inflammatory cells and pulmonary edema induced by influenza A/PR/8 virus infection compared with vehicle- or oseltamivir-treated mice in vivo model. The down-regulation of IFN-
level, which is critical for innate and adaptive immunity in viral infection, after treating of betulinic acid in mouse lung. Based on the obtained results, it is suggested that betulinic acid can be the potential therapeutic agent for virus infection via anti-inflammatory activity.
The Pharmacological Effects of Benachio-F
on Rat Gastrointestinal Functions
Poudel, Bijay Kumar ; Yu, Jae Young ; Kwon, Yong Sam ; Park, Hyoung Geun ; Son, Miwon ; Jun, Joon Ho ; Kim, Jeong Ah ; Kim, Jong Oh ;
Biomolecules & Therapeutics, volume 23, issue 4, 2015, Pages 350~356
DOI : 10.4062/biomolther.2015.035
Functional dyspepsia (FD) is a prevalent idiopathic upper gastrointestinal (GI) disorder characterized by diverse symptomatology including epigastric pain or discomfort, postprandial fullness, and early satiety. Although its pathophysiological mechanisms have not yet been fully established, the available studies suggest that the etiology of FD is invariably multifactorial. Benachio-F
(BF) is a proprietary liquid formulation of 7 herbal extracts that has been proposed to address this multifactorial etiology using multi-drug phytotherapy. The pharmacological effects of BF, in comparison with those of two other herbal products (Whalmyungsu
; WM and Iberogast
; IB) were evaluated in rats. In a laparotomy-induced rat model of delayed GI transit, BF significantly accelerated the delayed gastric emptying caused by morphine, apomorphine, and cisplatin, and also significantly increased mean gastric transit, as compared to the control animals. BF markedly increased gastric accommodation in rats and produced higher gastric volume values than did the control treatment. The effects of BF were generally comparable or superior to those of WM and IB in these models. Furthermore, BF significantly stimulated biliary flow, as compared to the control treatment. These results indicated that BF might have great potential as an effective phytotherapeutic agent capable of reducing GI symptoms and increasing quality of life in FD patients.
Isorhamnetin Protects Human Keratinocytes against Ultraviolet B-Induced Cell Damage
Han, Xia ; Piao, Mei Jing ; Kim, Ki Cheon ; Hewage, Susara Ruwan Kumara Madduma ; Yoo, Eun Sook ; Koh, Young Sang ; Kang, Hee Kyoung ; Shin, Jennifer H ; Park, Yeunsoo ; Yoo, Suk Jae ; Chae, Sungwook ; Hyun, Jin Won ;
Biomolecules & Therapeutics, volume 23, issue 4, 2015, Pages 357~366
DOI : 10.4062/biomolther.2015.005
Isorhamnetin (3-methylquercetin) is a flavonoid derived from the fruits of certain medicinal plants. This study investigated the photoprotective properties of isorhamnetin against cell damage and apoptosis resulting from excessive ultraviolet (UV) B exposure in human HaCaT keratinocytes. Isorhamnetin eliminated UVB-induced intracellular reactive oxygen species (ROS) and attenuated the oxidative modification of DNA, lipids, and proteins in response to UVB radiation. Moreover, isorhamnetin repressed UVB-facilitated programmed cell death in the keratinocytes, as evidenced by a reduction in apoptotic body formation, and nuclear fragmentation. Additionally, isorhamnetin suppressed the ability of UVB light to trigger mitochondrial dysfunction. Taken together, these results indicate that isorhamnetin has the potential to protect human keratinocytes against UVB-induced cell damage and death.
Pro-Apoptotic Activity of 4-Isopropyl-2-(1-Phenylethyl) Aniline Isolated from Cordyceps bassiana
Kim, Mi Seon ; Lee, Yunmi ; Sung, Gi-Ho ; Kim, Ji Hye ; Park, Jae Gwang ; Kim, Han Gyung ; Baek, Kwang Soo ; Cho, Jae Han ; Han, Jaegu ; Lee, Kang-Hyo ; Hong, Sungyoul ; Kim, Jong-Hoon ; Cho, Jae Youl ;
Biomolecules & Therapeutics, volume 23, issue 4, 2015, Pages 367~373
DOI : 10.4062/biomolther.2015.021
Cordyceps species including Cordyceps bassiana are a notable anti-cancer dietary supplement. Previously, we identified several compounds with anti-cancer activity from the butanol fraction (Cb-BF) of Cordyceps bassiana. To expand the structural value of Cb-BF-derived anti-cancer drugs, we employed various chemical moieties to produce a novel Cb-BF-derived chemical derivative, KTH-13-amine-monophenyl [4-isopropyl-2-(1-phenylethyl) aniline (KTH-13-AMP)], which we tested for anti-cancer activity. KTH-13-AMP suppressed the proliferation of MDA-MB-231, HeLa, and C6 glioma cells. KTH-13-AMP also dose-dependently induced morphological changes in C6 glioma cells and time-dependently increased the level of early apoptotic cells stained with annexin V-FITC. Furthermore, the levels of the active full-length forms of caspase-3 and caspase-9 were increased. In contrast, the levels of total forms of caspases-3, caspase-8, caspase-9, and Bcl-2 were decreased in KTH-13-AMP treated-cells. We also confirmed that the phosphorylation of STAT3, Src, and PI3K/p85, which is linked to cell survival, was diminished by treatment with KTH-13-AMP. Therefore, these results strongly suggest that this compound can be used to guide the development of an anti-cancer drug or serve as a lead compound in forming another strong anti-proliferative agent.
Effects of Resveratrol Supplementation on Oxidative Damage and Lipid Peroxidation Induced by Strenuous Exercise in Rats
Xiao, Ning-Ning ;
Biomolecules & Therapeutics, volume 23, issue 4, 2015, Pages 374~378
DOI : 10.4062/biomolther.2015.015
The purpose of the present study was to investigate the effects of resveratrol supplementation on oxidative damage and lipid peroxidation induced by strenuous exercise in rats. The rats were randomly divided into five groups: a sedentary control group, an exercise control group, and three treatment exercise groups administered increasing doses of resveratrol (25, 50, and 100 mg/kg body weight). Resveratrol was administered by oral gavage once daily for four weeks. At the end of the four-week period, the rats performed a strenuous exercise on the treadmill, and the levels of lactate dehydrogenase (LDH), creatine kinase (CK), malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE), and 8-hydroxy-2`-deoxyguanosine (8-OHdG) were measured. The results showed that resveratrol supplementation had protective effects against strenuous exercise-induced oxidative damage and lipid peroxidation by lowering the levels of LDH, CK, MDA, 4-HNE, and 8-OHdG in the serum or muscle of rats. These beneficial effects are probably owing to the inherent antioxidant activities of resveratrol.
Evaluation of Eye Irritation Potential of Solid Substance with New 3D Reconstructed Human Cornea Model, MCTT HCE
Jang, Won-hee ; Jung, Kyoung-mi ; Yang, Hye-ri ; Lee, Miri ; Jung, Haeng-Sun ; Lee, Su-Hyon ; Park, Miyoung ; Lim, Kyung-Min ;
Biomolecules & Therapeutics, volume 23, issue 4, 2015, Pages 379~385
DOI : 10.4062/biomolther.2015.004
The eye irritation potential of drug candidates or pharmaceutical ingredients should be evaluated if there is a possibility of ocular exposure. Traditionally, the ocular irritation has been evaluated by the rabbit Draize test. However, rabbit eyes are more sensitive to irritants than human eyes, therefore substantial level of false positives are unavoidable. To resolve this species difference, several three-dimensional human corneal epithelial (HCE) models have been developed as alternative eye irritation test methods. Recently, we introduced a new HCE model, MCTT HCE
which is reconstructed with non-transformed human corneal cells from limbal tissues. Here, we examined if MCTT HCE
can be employed to evaluate eye irritation potential of solid substances. Through optimization of washing method and exposure time, treatment time was established as 10 min and washing procedure was set up as 4 times of washing with 10 mL of PBS and shaking in 30 mL of PBS in a beaker. With the established eye irritation test protocol, 11 solid substances (5 non-irritants, 6 irritants) were evaluated which demonstrated an excellent predictive capacity (100% accuracy, 100% specificity and 100% sensitivity). We also compared the performance of our test method with rabbit Draize test results and in vitro cytotoxicity test with 2D human corneal epithelial cell lines.
Cardiovascular Safety Pharmacology of Sibutramine
Yun, Jaesuk ; Chung, Eunyong ; Choi, Ki Hwan ; Cho, Dae Hyun ; Song, Yun Jeong ; Han, Kyoung Moon ; Cha, Hey Jin ; Shin, Ji Soon ; Seong, Won-Keun ; Kim, Young-Hoon ; Kim, Hyung Soo ;
Biomolecules & Therapeutics, volume 23, issue 4, 2015, Pages 386~389
DOI : 10.4062/biomolther.2015.033
Sibutramine is an anorectic that has been banned since 2010 due to cardiovascular safety issues. However, counterfeit drugs or slimming products that include sibutramine are still available in the market. It has been reported that illegal sibutramine-contained pharmaceutical products induce cardiovascular crisis. However, the mechanism underlying sibutramine-induced cardiovascular adverse effect has not been fully evaluated yet. In this study, we performed cardiovascular safety pharmacology studies of sibutramine systemically using by hERG channel inhibition, action potential duration, and telemetry assays. Sibutramine inhibited hERG channel current of HEK293 cells with an
in patch clamp assay and increased the heart rate and blood pressure (
in heart rate and
in blood pressure) in beagle dogs at a dose of 30 mg/kg (per oral), while it shortened action potential duration (at
, resulted in 15% and 29% decreases in
, and 9% and 17% decreases in
, respectively) in the Purkinje fibers of rabbits and had no effects on the QTc interval in beagle dogs. These results suggest that sibutramine has a considerable adverse effect on the cardiovascular system and may contribute to accurate drug safety regulation.