• Journal of Physiology & Pathology in Korean Medicine
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• v.18 no.6
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• pp.1805-1809
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• 2004

In order to validate the use of Radix Curcumae Aromaticae as an anti-inflammatory drug in the traditional Korean medicine, I have investigated the effect of water-soluble extract of Radix Curcumae Aromaticae (ECA) on the expression of inducible heme oxygenase-1 (HO-1), which ha.s anti-inflammatory and cytoprotective effects stimulates, in human umbilical vein endothelial cells (HUVECs) stimulated with a high dose of pro-inflammatory tumor necrosis factor-alpha (TNF-α). The extract protected dose-dependently HUVECs against TNF-α-induced apoptosis, as measured qualitatively by a nuclear staining method using the fluoresoence DAPI and quantitatively by a flow cytometry using fluoresce-enhanced Annexin V antibody, and significantly Increased HO-1 expression, as determined by Western blotting analysis using anti-HO-1 antibody. Biockage of HO-1 activity by a pharmacological inhibitor reversed cytoprotection afforded by the extract, and treatment with carbon monoxide, one of HO-1 metabolites, resulted in cytoprotection comparable to the extract. These results suggest that ECA may have therapeutic potential in the control of endothelial disorders caused by inflammatory cytokines.

• Journal of Korean Neurosurgical Society
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• v.46 no.6
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• pp.552-557
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• 2009

Objective : Interferon-$\beta$, (IFN-$\beta$) has been used in the treatment of cancers. Inhibition of the enzyme cyclooxygenase (COX) with celecoxib had a significantly suppressive effect on tumor growth, angiogenesis, and metastasis in a variety of tumors. The aim of this study was to elucidate the antiglioma effect of combined treatment with IFN-$\beta$ and celecoxib in U87 glioma model. Methods : The in vitro effects of IFN-$\beta$ (50-1,000 IU/mL) and celecoxib ($50-250\;{\mu}M$) alone or combination of both on the proliferation and apoptosis of U87 cells were tested using MTT assay, FACS analysis and DNA condensation. To determine the in vivo effect, nude mice bearing intracerebral U87 xenograft inoculation were treated with IFN-$\beta$ intraperitoneally ($2{\times}10^5\;IU/day$ for 15 days), celecoxib orally (5, 10 mg/kg) or their combination. Results : IFN-$\beta$ or celecoxib showed an inhibitory effect on the proliferation of U87 cells. When U87 cells were treated with IFN-$\beta$ and celecoxib combination, it seemed that IFN-$\beta$ interrupted the antiproliferative and apoptotic activity of celecoxib. No additive effect was observed on the survival of the tumor bearing mice by the combination of IFN-$\beta$ and celecoxib. Conclusion : These results suggest that IFN-$\beta$ seems to inhibit the antiglioma effect of celecoxib, therefore combination of IFN-$\beta$ and celecoxib may be undesirable in the treatment of glioma.

• Biomolecules & Therapeutics
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• v.19 no.3
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• pp.282-287
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• 2011

Sirt1, a nicotinamide adenine dinucleotide ($NAD^+$)-dependent histone deacetylase, is known to deacetylate a number of proteins that are involved in various cellular pathways such as the stress response, apoptosis and cell growth. Modulation of the stress response by Sirtuin 1 (Sirt1) is achieved by the deacetylation of key proteins in a cellular pathway, and leads to a delay in the onset of cancer or aging. In particular, Sirt1 is known to play an important role in maintaining genomic stability, which may be strongly associated with a protective effect during tumorigenesis and during the onset of aging. In these studies, Sirt1 was generated in stably expressing cells and during the stimulation of DNA damage to examine whether it promotes survival. Sirt1 expressing cells facilitated the repair of DNA damage induced by either ionizing radiation (IR) or bleomycin (BLM) treatment. Fastened damaged DNA repair in Sirt1 expressing cells corresponded to prompt activation of Chk2 and ${\gamma}$-H2AX foci formation and promoted survival. Inhibition of Sirt1 enzymatic activity by a chemical inhibitor, nicotinamide (NIC), delayed DNA damage repair, indicating that promoted DNA damage repair by Sirt1 functions to induce survival when DNA damage occurs.

• Biomolecules & Therapeutics
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• v.25 no.5
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• pp.504-510
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• 2017

Inhibitor of nuclear factor kappa-B kinase beta ($IKK{\beta}$) plays a critical role in cell proliferation and inflammation in various cells by activating $NF-{\kappa}B$ signaling. However, the interrelationship between peroxisome proliferator-activated receptor ${\alpha}$ ($PPAR{\alpha}$) and $IKK{\beta}$ in cell proliferation is not clear. In this study, we investigated the possible role of $PPAR{\alpha}$ in the hepatic cell death in the absence of $IKK{\beta}$ gene using liver-specific Ikkb-null ($Ikkb^{F/F-AlbCre}$) mice. To examine the function of $PPAR{\alpha}$ activation in hepatic cell death, wild-type ($Ikkb^{F/F}$) and $Ikkb^{F/F-AlbCre}$ mice were treated with $PPAR{\alpha}$ agonist Wy-14,643 (0.1% w/w chow diet) for two weeks. As a result of Wy-14,643 treatment, apoptotic markers including caspase-3 cleavage, poly (ADP-ribose) polymerase (PARP) cleavage and TUNEL-positive staining were significantly decreased in the $Ikkb^{F/F-AlbCre}$ mice. Surprisingly, Wy-14,643 increased the phosphorylation of p65 and STAT3 in both Ikkb and $Ikkb^{F/F-AlbCre}$ mice. Furthermore, BrdU-positive cells were significantly increased in both groups after treatment with Wy-14,643. Our results suggested that $IKK{\beta}-derived$ hepatic apoptosis could be altered by $PPAR{\alpha}$ activation in conjunction with activation of $NF-{\kappa}B$ and STAT3 signaling.

• The Journal of Internal Korean Medicine
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• v.38 no.6
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• pp.1021-1034
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• 2017

Objectives: The aim of this study was to investigate the effects of Gaejigayonggolmoryo-tang (GYT) on ulcerative colitis induced by dextran sodium sulfate (DSS) in mice. Methods: Colitis was induced by free drinking of 5% DSS in six-week-old male ICR mice. The experimental groups were the sample group, the control group, and the normal group. The sample group was treated with GYT for three days after being was given 5% DSS for five days. The control group was given water, instead of GYT, for three days after the five days of 5% DSS. The normal group was untreated (not given 5% DSS), for comparison purposes. Results: Cellular experiments showed that GYT inhibits the expression of the inflammatory enzymes COX-2 and iNOS, and the production of NO. Based on the primary cellular experiments, the effects of GYT on ulcerative colitis induced by DSS of mouse tissues were investigated. GYT reduced tissue damage and apoptosis by inhibiting the expression of the inflammatory enzymes $NF-{\kappa}B$ p65, COX-2, and iNOS. In the cellular experiment, GYT was more effective in inhibiting the expression of COX-2 than in inhibiting the expression of iNOS. GYT was evidently effective in tissues in inhibiting the expression of COX-2. Conclusions: Based on the results here, GYT may have therapeutic effects on ulcerative colitis induced by DSS. GYT is worthy of research and development as a COX-2 inhibitor and a potential drug for inflammatory bowel diseases from natural products. Further investigations for exact mechanisms will be needed.

• The Korean Journal of Physiology and Pharmacology
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• v.9 no.5
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• pp.283-289
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• 2005

Endothelium, particularly pulmonary endothelium, is predisposed to injury by reactive oxygen species (ROS) and their derivatives. Heme oxygenase (HO) has been demonstrated to provide cytoprotective effects in models of oxidant-induced cellular and tissue injuries. In the present study, we investigated the effects of YS 49 against oxidant [tert-butylhydroperoxide (TBH)]-induced injury using cultured sheep pulmonary artery endothelial cells (SPAECs). The viability of SPAECs was determined by quantifying reduction of a fluorogenic indicator Alamar blue. We found that TBH decreased cell viability in a timeand concentration-dependent manner. YS 49 concentration- and time-dependently increased HO-1 induction on SPAECs. As expected, YS 49 significantly decreased the TBH-induced cellular injury. In the presence of zinc protophorphyrin, HO-1 inhibitor, effect of YS 49 was significantly inhibited, indicating that HO-1 plays a protective role for YS 49. Furthermore, YS 49 showed free radical scavenging activity as evidenced by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and inhibition of lipid peroxidation. However, YS 49 did not inhibit apoptosis induced by lipopolysaccharide (LPS) in SPAECs. Taken together, HO-1 induction along with strong antioxidant action of YS 49 may be responsible for inhibition of TBH-induced injury in SPAECs.

• The Korean Journal of Physiology and Pharmacology
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• v.24 no.3
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• pp.267-276
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• 2020

T In the present study, we investigated the effect of oncogenic H-Ras on rat mdr1b expression in NIH3T3 cells. The constitutive expression of H-Ras^V12 was found to downregulate the mdr1b promoter activity and mdr1b mRNA expression. The doxorubicin-induced mdr1b promoter activity of the H-Ras^V12 expressing NIH3T3 cells was markedly lower than that of control NIH3T3 cells. Additionally, there is a positive correlation between the level of H-Ras^V12 expression and a sensitivity to doxorubicin toxicity. To examine the detailed mechanism of H-Ras^V12-mediated down-regulation of mdr1b expression, antioxidant N-acetylcysteine (NAC) and NADPH oxidase inhibitor diphenylene iodonium (DPI) were used. Pretreating cells with either NAC or DPI significantly enhanced the oncogenic H-Ras-mediated down-regulation of mdr1b expression and markedly prevented doxorubicin-induced cell death. Moreover, NAC and DPI treatment led to a decrease in ERK activity, and the ERK inhibitors PD98059 or U0126 enhanced the mdr1b-Luc activity of H-Ras^V12-NIH3T3 and reduced doxorubicin-induced apoptosis. These data suggest that Ras^V12 expression could downregulate mdr1b expression through intracellular reactive oxygen species (ROS) production, and ERK activation induced by ROS, is at least in part, contributed to the downregulation of mdr1b expression.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.2
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• pp.535-538
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• 2016

Background: Cyclooxygenase 2 (COX-2) is important as an enzyme in the pathway leading to the production of prostaglandin E2 (PGE2) and arachidonic acid. This pathway is known to play a role in inflammation, tumor growth, invasiveness and metastasis, inhibition of apoptosis and angiogenesis. Inhibition of COX-2 has been shown to be a promising antitumor and antiangiogenic strategy in several tumor types, including renal cell carcinoma (RCC). Therefore, we decided to evaluate the immunohistochemical expression of this marker and its association with several clinicopathological characteristics in a series of cases. Materials and Methods: COX-2 expression was examined immunohistochemically in tumor tissues obtained from 96 patients who underwent radical (94 cases) or partial (2 cases) nephrectomy. Correlations between COX-2 expression and clinicopathologic findings including pathologic stage, nuclear grade and other indicator of prognosis were examined. Results: Of 96 tumors, 20.9% were positive for COX-2 expression. A correlation was found between COX-2 expression and tumor histological subtype (P=0.03).The papillary subtype showed maximum expression of this marker (43.8%) and the clear subtype minimum (14.7%). There were also possible links between COX-2 expression and pathologic stage, nuclear grade and nodal involvement but the results were not statistically significant (P=0.8, P= 0.14 and P=0.06, respectively). No correlation was found between COX2 expression and patient age, gender, tumor size, metastasis or survival. Conclusions: In our study, COX-2 expression was correlated with the histological subtype of RCC. Additional research is required to determine the link between COX-2 expression and prognosis and also evaluation of probable effectiveness of COX-2 inhibitor drugs in treatment of RCC patients.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.6
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• pp.2569-2574
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• 2015

Necroptosis, also known as "programmed necrosis", has emerged as a critical factor in a variety of pathological and physiological processes and is considered a cell type-specific tightly regulated process with mechanisms that may vary rather greatly due to the change of cell line. Here we used HT-29, a human colon cancer cell line, to establish a necroptosis model and elucidate associated mechanisms. We discovered that cobalt chloride, a reagent that could induce hypoxia-inducible $factor-1{\alpha}(HIF1{\alpha})$ expression and therefore mimic the hypoxic microenvironment of tumor tissue in some aspects induces necroptosis in HT-29 cells when caspase activity is compromised. On the other hand, apoptosis appears to be the predominant death form when caspases are functioning normally. HT-29 cells demonstrated significantly increased RIPK1, RIPK3 and MLKL expression in response to cobalt chloride plus z-VAD treatment, which was accompanied by drastically increased $IL1{\alpha}$ and IL6 expression, substantiating the notion that necrosis can induce profound immune reactions. The RIPK1 kinase inhibitor necrostatin-1 and the ROS scavenger NAC each could prevent necrosis in HT-29 cells and the efficiency was enhanced by combined treatment. Thus by building up a necroptosis model in human colon cancer cells, we uncovered that mechanically RIP kinases collaborate with ROS during necrosis promoted by cobalt chloride plus z-VAD, which leads to inflammation. Necroptosis may present a new target for therapeutic intervention in cancer cells that are resistant to apoptotic cell death.

• Journal of Microbiology and Biotechnology
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• v.27 no.6
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• pp.1090-1097
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• 2017

Rhus verniciflua Stokes (RVS), an herbal medicine found in East Asia, was extracted and further fractionated to investigate its antioxidant capacity and neuroprotective effects. The RVS ethyl acetate (EtOAc) fraction had the highest level of total phenolics and antioxidant capacity among all solvent fractions tested. Pretreatment of PC-12 cells with the EtOAc fraction effectively attenuated $H_2O_2$-induced oxidative damage. Furthermore, the EtOAc fraction significantly attenuated caspase-3 activity, resulting in inhibition of $H_2O_2$-induced apoptosis. We identified and quantified fustin, sulfuretin, and butein in the EtOAc fraction using accurate mass quadrupole time-of-flight mass spectrometry and reversed-phase high-performance liquid chromatography. The intracellular antioxidant capacity and superoxide dismutase (SOD) activity were significantly increased in PC-12 cells treated with the EtOAc fraction and with individual flavonoids. When cells were pretreated with the EtOAc fraction or individual flavonoids and then co-incubated with diethyldithiocarbamic acid (an inhibitor of SOD activity), cell viability against $H_2O_2$-induced oxidative stress was attenuated. These results suggest that the RVS EtOAc fraction and its flavonoid constituents protect PC-12 cells against $H_2O_2$-induced neurotoxicity through their antioxidant properties.