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Yanggu, South Korea

Noh K.,Yeungnam University | Kim D.H.,Daewoo Pharm. Co. | Shin B.S.,Catholic University of Daegu | Yun H.-Y.,Chungnam National University | And 2 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2014

7- O-Succinyl macrolactin A (SMA) and its major metabolite macrolactin A (MA) are generated from Bacillus polyfermenticus KJS-2. Both substances show inhibitory effects on angiogenesis and cancer cell invasion. SMA in rat plasma is known to be relatively stable at room temperature, but MA was not detected due to its instability. Therefore, a stabilizer is required to accurately measure the substance in biological rat samples. In this study, NaF and eserine were examined to determine whether they could stabilize MA to allow for accurate measurement in rat plasma. We also developed a rapid and simple chromatographic method using tandem mass spectrometry (MS/MS) for the simultaneous determination of these compounds in rat plasma. After simple protein precipitation with acetonitrile including methaqualone (internal standard), the analytes were chromatographed on a Hilic column with a mobile phase of 10. mM formic acid aqueous solution, methanol, and acetonitrile (15:15:70, v/v). The accuracy and precision of the assay were in accordance with FDA regulations for the validation of bioanalytical methods. This analytical method was successfully applied to monitor plasma concentrations of both compounds over time following intravenous administration of a salt form of SMA in rats. © 2014 Elsevier B.V. Source

Kim D.,Daewoo Pharm. Co. | Suh Y.,Hanyang University | Lee H.,Dongseo University | Lee Y.,Dongseo University
International Journal of Molecular Medicine | Year: 2013

Aromatic turmerone (ar-turmerone) has been reported to have a cytotoxic effect on L-1210 and HL-60 cells. In the present study, we investigated the anticancer responses and immune activities in implanted tumor cells. Our study found that ar-turmerone inhibited the increase in the number of white blood cells, which normally increase by the injection of lymphoblast cells, or P388D1, and ar-turmerone increased lymphocyte percentage compared to the control. Tumor inhibi-tion rate in the ar-turmerone-treated group was 11.79%, and the apoptosis indexes of the control, ar-turmerone and Glivec groups were 4.22±1.02, 5.45±1.46 and 10.01±2.01, respectively, in which only the Glivec-treated group showed a significance. The positive rates of Bcl-2 and Bax proteins which were treated by ar-turmerone did not show marked differences compared to the control group, but the Bax protein in the Glivec-treated group increased compared to the control group. The density of caspase-1, -3, -6, -9, Bcl-2, Bax, p21 and p53 mRNA in the control, ar-turmerone and Glivec groups did not change consid-erably, but the Bax mRNA of the Glivec-treated group increased compared to the control group. The ar-turmerone-treated group increased T-lymphocyte and B-lymphocyte proliferation activi-ties compared to the control group, which was more significant in T-lymphocyte than in B-lymphocyte proliferation activity. The interleukin-2 (IL2) production activity of the ar-turmerone group increased compared to the control group. These findings suggest that ar-turmerone does not have a chemotherapeutic effect on tumor incidence, but it has a repressive effect on P388D1 lymphocytic leukemia. Furthermore, this protective effect of ar-turmerone from P388D1 lymphocytic leukemia resulted from the increased activity of tumor immunogenicity through increased T-lymphokine production and increased percentage of lymphocytes. Source

Kang Y.,Yeungnam University | Regmi S.C.,Yeungnam University | Kim M.Y.,Yeungnam University | Banskota S.,Yeungnam University | And 3 more authors.
Archives of Pharmacal Research | Year: 2015

In the current study, macrolactin compounds, macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA), were investigated for their anti-angiogenic activities and action mechanism. MA and SMA inhibited in vitro and in vivo angiogenesis induced by three different classes of pro-angiogenic factors, VEGF, IL-8, and TNF-α. SMA exhibited stronger anti-angiogenic activity than MA, and such anti-angiogenic activity of SMA was consistently observed in MDA-MB-231 human breast cancer cell-inoculated CAM assay showing dose-dependent suppression of tumor growth and tumor-induced angiogenesis. In an in vitro PI3K competitive activity assay, SMA induced concentration-dependent inhibition of class I PI3K isoforms, p110α, p110β, p110δ, and p110γ. In addition, non-receptor tyrosine kinase c-Src, which is involved in the activation of PI3K heterodimer, was suppressed by MA and SMA. Correspondingly, MA and SMA significantly inhibited the stimulus-induced phosphorylation of Akt, mTOR, p70S6K, and ribosomal S6 in human umbilical vein endothelial cells (HUVECs). At the same time, the stimulus-induced production of reactive oxygen species (ROS) and activation of NF-κB were significantly suppressed by MA and SMA. Moreover, the macrolactins suppressed NF-κB-regulated HSP90 protein expression, which stabilizes phosphorylated Akt and NADPH oxidase. Suppression of NF-κB in macrolactin-treated HUVECs with concurrent inhibition of rS6 indicates that MAs effectively block angiogenesis through down-regulation of genes related to angiogenesis at both transcriptional and translational levels. Taken together, the results demonstrate that anti-angiogenic effect of MA and SMA is mediated through inhibition of PI3K/Akt and NADPH oxidase-derived ROS/NF-κB signaling pathways. These results further indicate that MA and SMA may be applicable for treatment of various diseases associated with angiogenesis. © 2014 The Pharmaceutical Society of Korea. Source

Park S.,Yeungnam University | Regmi S.C.,Yeungnam University | Park S.-Y.,Yeungnam University | Lee E.K.,Yeungnam University | And 4 more authors.
European Journal of Pharmacology | Year: 2014

Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, are pivotal for the development of inflammatory bowel disease (IBD), and down-regulation of the cytokines and cytokine-induced inflammatory responses therefore constitute pharmacological targets for the development of therapeutic strategies in IBD. In the current study, we found that 7-O-succinyl macrolactin A (SMA), a macrolide, potently inhibited TNF-α-induced adhesion of monocytes to colonic epithelial cells in a concentration-dependent manner, similar to rapamycin, a mTOR inhibitor. In addition, oral administration of SMA resulted in a significant suppression of clinical signs of TNBS-induced rat colitis, including weight loss, colon tissue edema, and myeloperoxidase activity, a marker for inflammatory cell infiltration, as well as microscopic damage score in a histomorphological examination of HE-stained colon tissue. More importantly, SMA was more efficacious in inhibition of intestinal inflammation than 5-aminosalicylic acid (5-ASA), an active metabolite of sulfasalazine, the most commonly prescribed agent for the treatment of IBD. Such anti-inflammatory activity showed correlation with significant suppression of adhesion molecules (ICAM-1 and VCAM-1), T-helper 1-type cytokines (TNF-α, IL-6), and chemokines (MCP-1, IL-8). In addition to inhibition of NF-κB nuclear translocation, SMA also caused significant suppression of TNF-α-induced phosphorylation of PI3K, Akt, mTOR and p70S6 kinase, similar to the effect of rapamycin, an immunosuppressant macrolide. Taken together, the current results suggest that managing both mTOR and NF-κB activation pathways using SMA may be a good therapeutic intervention for the treatment of IBD. © 2014 Elsevier B.V. Source

Jung J.W.,Catholic University of Korea | Kim J.M.,Catholic University of Korea | Kwon M.H.,Catholic University of Korea | Kim D.H.,Daewoo Pharm. Co. | Kang H.E.,Catholic University of Korea
Xenobiotica | Year: 2014

As promising anti-macular degeneration and/or anti-tumour agents, a better understanding of the pharmacokinetics of macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA) is essential. Thus, we evaluated the pharmacokinetics of MA and SMA after intravenous, oral, or intraperitoneal administration of each drug to mice.Both hepatic and extra-hepatic extractions of MA were expected based on the rapid total body clearance (CL) of MA. MA also showed a large steady-state volume of distribution (Vss) in mice. A relatively slower CL (by 54.1%) and smaller Vss (by 85.8%) were observed for SMA than for MA. In accordance with the larger Vss values of MA than of SMA, the mouse tissues studied had good affinity to MA but less affinity to SMA.Both MA and SMA had an extremely low oral extent of absolute bioavailability (F). This could have been a result of the instability of MA and SMA in the gastrointestinal tract, supported by their unstable property in acidic buffer. Gastrointestinal and/or hepatic first-pass extraction of MA and SMA may be other reasons.The pharmacokinetic profiles of both MA and SMA were much improved (greater AUC and F values) following intraperitoneal administration than following oral administration due to avoidance of acidic degradation and/or gastrointestinal first-pass extraction. © 2014 Informa UK Ltd. Source

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