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A New Histone Deacetylase Inhibitor, MHY219, Inhibits the Migration of Human Prostate Cancer Cells via HDAC1.

Umasankar DE ; Soma KUNDU ; Nabanita PATRA ; Mee Young AHN ; Ji Hae AHN ; Ji Yeon SON ; Jung Hyun YOON ; Hyung Ryoung MOON ; Byung Mu LEE ; Hyung Sik KIM

Biomolecules & Therapeutics.2015;23(5):434-441. doi:10.4062/biomolther.2015.026

Histone deacetylase (HDAC) inhibitors are considered novel agents for cancer chemotherapy. We previously investigated MHY219, a new HDAC inhibitor, and its potent anticancer activity in human prostate cancer cells. In the present study, we evaluated MHY219 molecular mechanisms involved in the regulation of prostate cancer cell migration. Similar to suberanilohydroxamic acid (SAHA), MHY219 inhibited HDAC1 enzyme activity in a dose-dependent manner. MHY219 cytotoxicity was higher in LNCaP (IC50=0.67 muM) than in DU145 cells (IC50=1.10 muM) and PC3 cells (IC50=5.60 muM) after 48 h of treatment. MHY219 significantly inhibited the HDAC1 protein levels in LNCaP and DU145 cells at high concentrations. However, inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type. MHY219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease-1 (MMP-1) and MMP-2 and induction of tissue inhibitor of metalloproteinases-1 (TIMP-1). These results suggest that MHY219 may potentially be used as an anticancer agent to block cancer cell migration through the repression of MMP-1 and MMP-2, which is related to the reduction of HDAC1.
Cell Movement ; Down-Regulation ; Drug Therapy ; Histone Deacetylase Inhibitors* ; Histone Deacetylases* ; Histones* ; Humans* ; Matrix Metalloproteinases ; Prostate* ; Prostatic Neoplasms* ; Repression, Psychology

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Acetylshikonin Inhibits Human Pancreatic PANC-1 Cancer Cell Proliferation by Suppressing the NF-kappaB Activity.

Seok Cheol CHO ; Bu Young CHOI

Biomolecules & Therapeutics.2015;23(5):428-433. doi:10.4062/biomolther.2015.102

Acetylshikonin, a natural naphthoquinone derivative compound, has been used for treatment of inflammation and cancer. In the present study, we have investigated whether acetylshikonin could regulate the NF-kappaB signaling pathway, thereby leading to suppression of tumorigenesis. We observed that acetylshikonin significantly reduced proliferation of several cancer cell lines, including human pancreatic PANC-1 cancer cells. In addition, acetylshikonin inhibited phorbol 12-myristate 13-acetate (PMA) or tumor necrosis-alpha (TNF-alpha)-induced NF-kappaB reporter activity. Proteome cytokine array and real-time RT-PCR results illustrated that acetylshikonin inhibition of PMA-induced production of cytokines was mediated at the transcriptional level and it was associated with suppression of NF-kappaB activity and matrix metalloprotenases. Finally, we observed that an exposure of acetylshikonin significantly inhibited the anchorage-independent growth of PANC-1 cells. Together, our results indicate that acetylshikonin could serve as a promising therapeutic agent for future treatment of pancreatic cancer.
Carcinogenesis ; Cell Line ; Cell Proliferation* ; Cytokines ; Humans* ; Inflammation ; NF-kappa B* ; Pancreatic Neoplasms ; Proteome

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Imperatorin Suppresses Degranulation and Eicosanoid Generation in Activated Bone Marrow-Derived Mast Cells.

Kyu Tae JEONG ; Eujin LEE ; Na Young PARK ; Sun Gun KIM ; Hyo Hyun PARK ; Jiean LEE ; Youn Ju LEE ; Eunkyung LEE

Biomolecules & Therapeutics.2015;23(5):421-427. doi:10.4062/biomolther.2015.023

Imperatorin has been known to exert many biological functions including anti-inflammatory activity. In this study, we investigated the inhibitory effects of imperatorin on the production of inflammatory mediators in mouse bone marrow-derived mast cells (BMMC). Imperatorin inhibited degranulation and the generation of eicosanoids (leukotriene C4 (LTC4) and prostaglandin D2 (PGD2)) in IgE/antigen (Ag)-stimulated BMMC. To elucidate the molecular mechanism involved in this process, we investigated the effect of imperatorin on intracellular signaling in BMMC. Biochemical analyses of the IgE/Ag-mediated signaling pathway demonstrated that imperatorin dramatically attenuated degranulation and the production of 5-lipoxygenase-dependent LTC4 and cyclooxygenase-2-dependent PGD2 through the inhibition of intracellular calcium influx/phospholipase Cgamma1, cytosolic phospholipase A2/mitogen-activated protein kinases and/or nuclear factor-kappaB pathways in BMMC. These results suggest that the effects of imperatorin on inhibition of degranulation and eicosanoid generation through the suppression of multiple steps of IgE/Ag-mediated signaling pathways would be beneficial for the prevention of allergic inflammation.
Animals ; Calcium ; Cytosol ; Eicosanoids ; Inflammation ; Leukotriene C4 ; Mast Cells* ; Mice ; Mitogen-Activated Protein Kinases ; Phospholipases ; Prostaglandin D2 ; Protein Kinases

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Fisetin Suppresses Macrophage-Mediated Inflammatory Responses by Blockade of Src and Syk.

Jun Ho KIM ; Mi Yeon KIM ; Jong Hoon KIM ; Jae Youl CHO

Biomolecules & Therapeutics.2015;23(5):414-420. doi:10.4062/biomolther.2015.036

Flavonoids, such as fisetin (3,7,3',4'-tetrahydroxyflavone), are plant secondary metabolites. It has been reported that fisetin is able to perform numerous pharmacological roles including anti-inflammatory, anti-microbial, and anti-cancer activities; however, the exact anti-inflammatory mechanism of fisetin is not understood. In this study, the pharmacological action modes of fisetin in lipopolysaccharide (LPS)-stimulated macrophage-like cells were elucidated by using immunoblotting analysis, kinase assays, and an overexpression strategy. Fisetin diminished the release of nitric oxide (NO) and reduced the mRNA levels of inducible NO synthase (iNOS), tumor necrosis factor (TNF)-alpha, and cyclooxygenase (COX)-2 in LPS-stimulated RAW264.7 cells without displaying cytotoxicity. This compound also blocked the nuclear translocation of p65/nuclear factor (NF)-kappaB. In agreement, the upstream phosphorylation events for NF-kappaB activation, composed of Src, Syk, and IkappaBalpha, were also reduced by fisetin. The phospho-Src level, triggered by overexpression of wild-type Src, was also inhibited by fisetin. Therefore, these results strongly suggest that fisetin can be considered a bioactive immunomodulatory compound with anti-inflammatory properties through suppression of Src and Syk activities.
Flavonoids ; Immunoblotting ; NF-kappa B ; Nitric Oxide ; Nitric Oxide Synthase ; Phosphorylation ; Phosphotransferases ; Plants ; Prostaglandin-Endoperoxide Synthases ; RNA, Messenger ; Tumor Necrosis Factor-alpha

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Paraquat Induces Apoptosis through a Mitochondria-Dependent Pathway in RAW264.7 Cells.

Yeo Jin JANG ; Jong Hoon WON ; Moon Jung BACK ; Zhicheng FU ; Ji Min JANG ; Hae Chan HA ; Seungbeom HONG ; Minsun CHANG ; Dae Kyong KIM

Biomolecules & Therapeutics.2015;23(5):407-413. doi:10.4062/biomolther.2015.075

Paraquat dichloride (N,N-dimethyl-4-4'-bipiridinium, PQ) is an extremely toxic chemical that is widely used in herbicides. PQ generates reactive oxygen species (ROS) and causes multiple organ failure. In particular, PQ has been reported to be an immunotoxic agrochemical compound. PQ was shown to decrease the number of macrophages in rats and suppress monocyte phagocytic activity in mice. However, the effect of PQ on macrophage cell viability remains unclear. In this study, we evaluated the cytotoxic effect of PQ on the mouse macrophage cell line, RAW264.7 and its possible mechanism of action. RAW264.7 cells were treated with PQ (0, 75, and 150 muM), and cellular apoptosis, mitochondrial membrane potential (MMP), and intracellular ROS levels were determined. Morphological changes to the cell nucleus and cellular apoptosis were also evaluated by DAPI and Annexin V staining, respectively. In this study, PQ induced apoptotic cell death by dose-dependently decreasing MMP. Additionally, PQ increased the cleaved form of caspase-3, an apoptotic marker. In conclusion, PQ induces apoptosis in RAW264.7 cells through a ROS-mediated mitochondrial pathway. Thus, our study improves our knowledge of PQ-induced toxicity, and may give us a greater understanding of how PQ affects the immune system.
Animals ; Annexin A5 ; Apoptosis* ; Caspase 3 ; Cell Death ; Cell Line ; Cell Nucleus ; Cell Survival ; Herbicides ; Immune System ; Macrophages ; Membrane Potential, Mitochondrial ; Mice ; Mitochondria ; Monocytes ; Multiple Organ Failure ; Paraquat* ; Rats ; Reactive Oxygen Species

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Role of miR-511 in the Regulation of OATP1B1 Expression by Free Fatty Acid.

Jin Fu PENG ; Li LIU ; Cheng Xian GUO ; Shi Kun LIU ; Xiao Ping CHEN ; Li Hua HUANG ; Hong XIANG ; Zhi Jun HUANG ; Hong YUAN ; Guo Ping YANG

Biomolecules & Therapeutics.2015;23(5):400-406. doi:10.4062/biomolther.2015.010

MicroRNAs (miRNAs) are a family of non-coding RNA that are able to adjust the expression of many proteins, including ATP-binding cassette transporter and organic cation transporter. We sought to evaluate the effect of miR-511 on the regulation of OATP1B1 expression by free fatty acids. When using free fatty acids to stimulate Chang liver cells, we found that the expression of miR-511 increased significantly while the expression of OATP1B1 decreased. We also proved that SLCO1B1 is the target gene of miR-511 with a bioinformatics analysis and using the dual luciferase reporter assay. Furthermore, the expressions of SLCO1B1 and OATP1B1 decreased if transfecting Chang liver cells with miR-511, but did not increase when transfecting the inhibitors of miR-511 into steatosis cells. Our study indicates that miR-511 may play an important role in the regulation of OATP1B1 expression by free fatty acids.
Computational Biology ; Fatty Acids, Nonesterified ; Humans ; Liver ; Luciferases ; MicroRNAs ; RNA, Untranslated

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Immortalization of Primary Keratinocytes and Its Application to Skin Research.

Moonju CHOI ; Choongho LEE

Biomolecules & Therapeutics.2015;23(5):391-399. doi:10.4062/biomolther.2015.038

As a major component of the epidermal tissue, a primary keratinocyte has served as an essential tool not only for the study of pathogenesis of skin-related diseases but also for the assessment of potential toxicities of various chemicals used in cosmetics. However, its short lifespan in ex vivo setting has been a great hurdle for many practical applications. Therefore, a number of immortalization attempts have been made with success to overcome this limitation. In order to understand the immortalization process of a primary keratinocyte, several key biological phenomena governing its lifespan will be reviewed first. Then, various immortalization methods for the establishment of stable keratinocyte cell lines will be explained. Finally, its application to a three-dimensional skin culture system will be described.
Aging ; Biological Phenomena ; Cell Line ; Keratinocytes* ; Skin*

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Histopathological Evaluation of Heart Toxicity of a Novel Selective PPAR-gamma Agonists CKD-501 in db/db Mice.

Hyun Il YANG ; Woo Sik KIM ; Dal Hyun KIM ; Jin Seok KANG

Biomolecules & Therapeutics.2013;21(1):84-88.

High risk of cardiovascular diseases caused by existing PPAR-gamma agonists such as rosiglitazone and pioglitazone has been recently reported. CKD-501 is a novel selective PPAR-gamma agonist as a potential target to reduce cardiovascular risk in non-insulin dependent diabetes mellitus (NIDDM). In this study, We investigated potential cardiotoxicity of CKD-501 and compared its toxicity with that of rosiglitazone or pioglitazone using db/db mice. After 12-week repeated administration of CKD-501 at doses of 3, 10 and 30 mg/kg/day or rosiglitazone at doses of 10 and 30 mg/kg/day or pioglitazone at doses of 200 and 540 mg/kg/day, animals were sacrificed for investigation of potential toxicities. Diameters of left ventricles and areas of cardiomyocytes were measured. And lipid accumulation and apoptosis in heart muscle were examined by oil red O staining and TUNEL staining, respectively. Diameters of left ventricles were significantly increased in high dose treatment group of pioglitazone compared to control (p<0.05), while other groups showed a tendency for an increase. All test articles induced significantly the increase of area of cardiomyocytes in heart compared to control (p<0.01), in regular order as pioglitazone > CKD-501 > or = rosiglitazone. However, lipid accumulation and apoptotic changes in heart were not observed in all dosing groups. Taken together, the myocardial cell hypertrophy of CKD-501 are relatively lower than that of pioglitazone and similar to rosiglitazone. And it is suggested that the myocardial cell hypertrophy of CKD-501 are less adverse in clinical use for the management of the NIDDM.
Animals ; Apoptosis ; Cardiovascular Diseases ; Diabetes Mellitus ; Diabetes Mellitus, Type 2 ; Heart Ventricles ; Heart* ; Hypertrophy ; In Situ Nick-End Labeling ; Mice* ; Myocardium ; Myocytes, Cardiac

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Antidepressant-Like Effects of Lycii Radicis Cortex and Betaine in the Forced Swimming Test in Rats.

Soo Jeong KIM ; Mi Sook LEE ; Ji Hyun KIM ; Tae Hee LEE ; Insop SHIM

Biomolecules & Therapeutics.2013;21(1):79-83.

The purpose of the present study was to examine the effect of Lycii Radicis Cortex (LRC) and betaine (BT) on immobility and neurochemical change in the forced swimming test (FST) in the rat. LRC, BT or fluoxentine was administered intraperitoneally to Sprague-Dawley rats three times (1, 5 and 23.5 h) before the FST. To investigate antidepressant-like effect, serotonin (5-HT) and norepinephrine (NE) were examined in the hippocampus and hypothalamus of rats. LRC (100 mg/kg) and BT (30, 100 mg/kg) significantly decreased the immobility time in the FST. LRC (100 mg/kg) significantly increased both 5-HT and NE levels in the hypothalamus of rats exposed to FST. BT (100 mg/kg) significantly increased 5-HT levels in the hypothalamus and hippocampus of rats. Taken together, these results demonstrated that improvement in the behavioral changes after LRC and BT administration may be mediated by elevation of 5-HT level in the hypothalamus and hippocampus, indicating a possible antidepressant-like activity. The present results suggest that the efficacy of LRC and BT in an animal model of depression may provide anti-depressant effects in human, which remains to be determined.
Animals ; Betaine* ; Depression ; Hippocampus ; Humans ; Hypothalamus ; Models, Animal ; Norepinephrine ; Physical Exertion* ; Rats* ; Rats, Sprague-Dawley ; Serotonin ; Serotonin Agents

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Anti-Inflammatory, Antioxidant, Anti-Angiogenic and Skin Whitening Activities of Phryma leptostachya var. asiatica Hara Extract.

Hyun Joo JUNG ; Young Wook CHO ; Hye Won LIM ; Hojin CHOI ; Dam Jung JI ; Chang Jin LIM

Biomolecules & Therapeutics.2013;21(1):72-78.

This work aimed to assess some pharmacological activities of P. leptostachya var. asiatica Hara. The dried roots of P. leptostachya var. asiatica Hara were extracted with 70% ethanol to generate the powdered extract, named PLE. Anti-angiogenic activity was detected using chick chorioallantoic membrane (CAM) assay. In vitro anti-inflammatory activity was evaluated via analyzing nitric oxide (NO) content, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Antioxidant activity was determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay and reactive oxygen species (ROS) level in the stimulated macrophage cells. Matrix metalloproteinase-9 (MMP-9) and -2 (MMP-2) activities in the culture media were detected using zymography. PLE exhibits an anti-angiogenic activity in the CAM assay, and displays an inhibitory action on the generation of NO in the LPS-stimulated macrophage cells. In the stimulated macrophage cells, it is able to diminish the enhanced ROS level. It can potently scavenge the stable DPPH free radical. It suppresses the induction of iNOS and COX-2 and the enhanced MMP-9 activity in the stimulated macrophage cells. Both monooxygenase and oxidase activities of tyrosinase were strongly inhibited by PLE. Taken together, the dried roots of P. leptostachya var. asiatica Hara possess anti-angiogenic, anti-inflammatory, antioxidant and skin whitening activities, which might partly provide its therapeutic efficacy in traditional medicine.
Chorioallantoic Membrane ; Culture Media ; Cyclooxygenase 2 ; Ethanol ; Macrophages ; Matrix Metalloproteinase 9 ; Medicine, Traditional ; Monophenol Monooxygenase ; Nitric Oxide ; Nitric Oxide Synthase Type II ; Oxidoreductases ; Reactive Oxygen Species ; Skin*

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