• Biomolecules & Therapeutics
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• v.23 no.1
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• pp.39-44
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• 2015

Tolfenamic acid (TA) is a traditional non-steroid anti-inflammatory drug (NSAID) and has been broadly used for the treatment of migraines. Nuclear factor kappa B (NF-${\kappa}B$) is a sequence-specific transcription factor and plays a key role in the development and progression of inflammation and cancer. We performed the current study to investigate the underlying mechanisms by which TA suppresses inflammation focusing on NF-${\kappa}B$ pathway in TNF-${\alpha}$ stimulated human normal and cancer cell lines and lipopolysaccharide (LPS)-stimulated mouse macrophages. Different types of human cells (HCT116, HT-29 and HEK293) and mouse macrophages (RAW264.7) were pre-treated with different concentrations of TA and then exposed to inflammatory stimuli such as TNF-${\alpha}$ and LPS. Transcriptional activity of NF-${\kappa}B$, $l{\kappa}B-{\alpha}$-degradation, p65 translocation and mitogen-activated protein kinase (MAPK) activations were measured using luciferase assay and Western blots. Pre-treatment of TA repressed TNF-${\alpha}$- or LPS-stimulated NF-${\kappa}B$ transactivation in a dose-dependent manner. TA treatment reduced degradation of $l{\kappa}B-{\alpha}$ and subsequent translocation of p65 into nucleus. TA significantly down-regulated the phosphorylation of c-Jun N-terminal kinase (JNK). However, TA had no effect on NF-${\kappa}B$ signaling and JNK phosphorylation in HT-29 human colorectal cancer cells. TA possesses anti-inflammatory activities through suppression of JNK/NF-${\kappa}B$ pathway in different types of cells.

• BMB Reports
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• v.51 no.6
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• pp.296-301
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• 2018

Mitochondrial DNA (mtDNA) mutations are often observed in various cancer types. Although the correlation between mitochondrial dysfunction and cancer malignancy has been demonstrated by several studies, further research is required to elucidate the molecular mechanisms underlying accelerated tumor development and progression due to mitochondrial mutations. We generated an mtDNA-depleted cell line, ${\rho}^0$, via long-term ethidium bromide treatment to define the molecular mechanisms of tumor malignancy induced by mitochondrial dysfunction. Mitochondrial dysfunction in ${\rho}^0$ cells reduced drug-induced cell death and decreased the expression of pro-apoptotic proteins including p53. The p53 expression was reduced by activation of nuclear $factor-{\kappa}B$ that depended on elevated levels of free calcium in $HCT116/{\rho}^0$ cells. Overall, these data provide a novel mechanism for tumor development and drug resistance due to mitochondrial dysfunction.

• Korean Journal of Fisheries and Aquatic Sciences
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• v.54 no.2
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• pp.152-161
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• 2021

Eisenia bicyclis is known to have secondary metabolites exhibiting various biological activities. In a preliminary study, the n-hexane fraction obtained from the ethanolic extract of E. bicyclis showed higher anti-inflammatory activity than the ethyl acetate and butyl alcohol fractions based on the inhibition of lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production in RAW 264.7 cells. Using this fraction (E. bicyclis hexane fraction, EHF), we investigated the molecular mechanisms underlying its anti-inflammatory effect in LPS-stimulated RAW 264.7 cells. Pretreatment of the cells with up to 50 ㎍/mL EHF significantly inhibited NO and prostaglandin E₂ production as well as their responsible enzyme proteins and mRNAs, in a dose-dependent manner (P<0.05). Similarly, EHF markedly reduced the production of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α as well as their mRNA levels. Nuclear translocation of nuclear factor-kappa B (NF-κB) was strongly suppressed by EHF treatment. EHF significantly reduced the phosphorylation of mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt in LPS-stimulated cells. Moreover, EHF reduced ear edema in phorbol myristate acetate (PMA)-induced mice. These results indicate that EHF contains potent anti-inflammatory compounds, which may be used as a dietary supplement for the prevention of inflammatory diseases.

• The Korean journal of internal medicine
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• v.34 no.1
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• pp.146-155
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• 2019

Background/Aims: Indoxyl sulfate (IS) is a uremic toxin and an important causative factor in the progression of chronic kidney disease. Recently, paricalcitol (19-nor-1,25-dihydroxyvitamin D2) was shown to exhibit protective effects in kidney injury. Here, we investigated the effects of paricalcitol treatment on IS-induced renal tubular injury. Methods: The fluorescent dye 2',7'-dichlorofluorescein diacetate was used to measure intracellular reactive oxygen species (ROS) following IS administration in human renal proximal tubular epithelial (HK-2) cells. The effects of IS on cell viability were determined using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays and levels of apoptosis-related proteins (Bcl-2-associated protein X [Bax] and B-cell lymphoma 2 [Bcl-2]), nuclear $factor-{\kappa}B$ ($NF-{\kappa}B$) p65, and phosphorylation of mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) were determined by semiquantitative immunoblotting. The promoter activity of $NF-{\kappa}B$ was measured by luciferase assays and apoptosis was determined by f low cytometry of cells stained with f luorescein isothiocyanate-conjugated Annexin V protein. Results: IS treatment increased ROS production, decreased cell viability and induced apoptosis in HK-2 cells. IS treatment increased the expression of apoptosis-related protein Bax, decreased Bcl-2 expression, and activated phosphorylation of MAPK, $NF-{\kappa}B$ p65, and Akt. In contrast, paricalcitol treatment decreased Bax expression, increased Bcl-2 expression, and inhibited phosphorylation of MAPK, $NF-{\kappa}B$ p65, and Akt in HK-2 cells. $NF-{\kappa}B$ promoter activity was increased following IS, administration and was counteracted by pretreatment with paricalcitol. Additionally, flow cytometry analysis revealed that IS-induced apoptosis was attenuated by paricalcitol treatment, which resulted in decreased numbers of fluorescein isothiocyanate-conjugated Annexin V positive cells. Conclusions: Treatment with paricalcitol inhibited IS-induced apoptosis by regulating MAPK, $NF-{\kappa}B$, and Akt signaling pathway in HK-2 cells.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.7
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• pp.4441-4446
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• 2013

Cholangiocarcinoma (CCA) is a tumor of biliary ducts, which has a high mortality rate and dismal prognosis. Constitutively activation of the transcription factor nuclear factor kappa-B (NF-${\kappa}B$) has been previously demonstrated in CCA. It is therefore a potential target for CCA treatment. Effects of diethyldithiocarbamate (DDTC) on NF-${\kappa}B$-dependent apoptosis induction in cancer have been reported; however, anti-metastasis has never been addressed. Therefore, here the focus was on DDTC effects on CCA migration and adhesiond. Anti-proliferation, anti-migration and anti-adhesion activities were determined in CCA cell lines, along with p65 protein levels and function. NF-${\kappa}B$ target gene expression was determined by quantitative RT-PCR. DDTC inhibited CCA cell proliferation. Suppression of migration and adhesion were observed prior to anti-CCA proliferation. These effects were related to decreased p65, reduction in NF-${\kappa}B$ DNA binding, and impaired activity. Moreover, suppression of ICAM-1 expression supported NF-${\kappa}B$-dependent anti-metastatic effects of DDTC. Taken together, DDTC suppression of CCA migration and adhesion through inhibition of NF-${\kappa}B$ signaling pathway is suggested from the current study. This might be a promising treatment choice against CCA metastasis.

• International Journal of Oral Biology
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• v.45 no.2
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• pp.33-41
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• 2020

Neuroinflammation is known as the main mechanism implicated in the advancement of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The main feature of neuroinflammation is associated with the activation of microglia. The activated microglia increase proinflammatory cytokine production and induce progressive neuronal cell death. Citrus flavonoids show neuroprotective effects that are associated with the anti-inflammatory action of flavonoids in neurodegenerative diseases. Among these citrus flavonoids, kaempferol, naringin, and nobiletin show inhibitory effects on nuclear factor-κB and mitogen-activated protein kinase signaling pathways that can modulate inflammatory conditions in microglial cells. In the present review, we present the anti-inflammatory activities of citrus flavonoids and therapeutic potential of flavonoids as neuroprotective agents.

• BMB Reports
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• v.48 no.9
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• pp.519-524
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• 2015

Vascular inflammatory process has been suggested to play a key role in initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Thus, in this study, we attempted to determine whether three structurally related polyphenols found in the Chinese herb Huang Qui, namely baicalin, baicalein, and wogonin, can suppress vascular inflammatory processes induced by high glucose (HG) in human umbilical vein endothelial cells (HUVECs) and mice. Data showed that HG induced markedly increased vascular permeability, monocyte adhesion, expressions of cell adhesion molecules (CAMs), formation of reactive oxygen species (ROS) and activation of nuclear factor (NF)-κB. Remarkably, all of the above mentioned vascular inflammatory effects of HG were attenuated by pretreatment with baicalin, baicalein, and wogonin. Vascular inflammatory responses induced by HG are critical events underlying development of various diabetic complications, therefore, our results suggest that baicalin, baicalein, and wogonin may have significant therapeutic benefits against diabetic complications and atherosclerosis. [BMB Reports 2015; 48(9): 519-524]

• International Journal of Oral Biology
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• v.46 no.1
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• pp.7-14
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• 2021

Vinpocetine induces anti-inflammatory effects in various inflammatory diseases via the inhibition of phosphodiesterase type-1-independent nuclear factor-κB signaling pathway and the release of inflammatory cytokines. In this study, we investigated the effect of vinpocetine on the proliferation of colon cancer cells and its underlying molecular mechanisms. Our data showed that vinpocetine inhibits the viability and proliferation of colon cancer cells. Vinpocetine treatment induced cell death in HCT116 cells, which the percentages of sub-G1 phase were significantly increased, and the apoptosis-related genes were regulated after HCT116 cells were treated with vinpocetine. In sum, our findings indicated that vinpocetine could be a therapeutically useful candidate in the treatment of colon cancer.

• Journal of Life Science
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• v.25 no.9
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• pp.993-999
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• 2015

The beetle Popillia flavosellata has been no reported its functional effects. In this study, we investigated the anti-inflammatory effect of P. flavosellata ethanol extract (PFE) on RAW 264.7 mouse macrophage cells treated with lipopolysaccharide (LPS) for the induction of inflammation. First, we examined the cytotoxicity of PFE in the RAW 264.7 cells at a concentration of 2,000 μg/ml or less. To evaluate the anti-inflammatory effects of PFE, we investigated the expression levels of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, and proinflammatory enzymes, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-induced RAW 264.7 cells. In addition, we examined whether PFE inhibited the translocation of nuclear factor kappa B (NF-κB) p65 into the nucleus in the LPS-induced RAW 264.7 cells. We found that the protein levels of TNF-α and IL-6 were decreased in the LPS-induced RAW 264.7 cells after the treatment with PFE in a dose-dependent manner. In addition, we confirmed that PFE inhibited the translocation of NF-κB p65 into the nucleus, as well as the protein expression levels of iNOS and COX-2. Accordingly, we propose that PFE exerts an anti-inflammatory effect through the down-regulation of NF-κB p65, TNF-α, IL-6, iNOS, and COX-2 via the toll like receptor (TLR)-4 inflammatory signaling pathway.

• Journal of Veterinary Science
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• v.24 no.1
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• pp.2.1-2.14
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• 2023

Background: Hypothermia is a crucial environmental factor that elevates the risk of cardiovascular disease, but the underlying effect is unclear. Objectives: This study examined the role of cold stress (CS) in cardiac injury and its underlying mechanisms. Methods: In this study, a chronic CS-induced myocardial injury model was used; mice were subjected to chronic CS (4℃) for three hours per day for three weeks. Results: CS could result in myocardial injury by inducing the levels of heat shock proteins 70 (HSP70), enhancing the generation of creatine phosphokinase-isoenzyme (CKMB) and malondialdehyde (MDA), increasing the contents of tumor necrosis factor-α (TNF-α), high mobility group box 1 (HMGB1) interleukin1b (IL-1β), IL-18, IL-6, and triggering the depletion of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). Multiple signaling pathways were activated by cold exposure, including pyroptosis-associated NOD-like receptor 3 (NLRP3)-regulated caspase-1-dependent/Gasdermin D (GSDMD), inflammation-related toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)-mediated nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK), as well as oxidative stressinvolved thioredoxin-1/thioredoxin-interacting protein (Txnip) signaling pathways, which play a pivotal role in myocardial injury resulting from hypothermia. Conclusions: These findings provide new insights into the increased risk of cardiovascular disease at extremely low temperatures.