• The Korean Journal of Physiology and Pharmacology
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• v.22 no.3
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• pp.331-341
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• 2018

The aim of the present study was to examine the effects of preemptive analgesia on the development of trigeminal neuropathic pain. For this purpose, mechanical allodynia was evaluated in male Sprague-Dawley rats using chronic constriction injury of the infraorbital nerve (CCI-ION) and perineural application of 2% QX-314 to the infraorbital nerve. CCI-ION produced severe mechanical allodynia, which was maintained until postoperative day (POD) 30. An immediate single application of 2% QX-314 to the infraorbital nerve following CCI-ION significantly reduced neuropathic mechanical allodynia. Immediate double application of QX-314 produced a greater attenuation of mechanical allodynia than a single application of QX-314. Immediate double application of 2% QX-314 reduced the CCI-ION-induced upregulation of GFAP and p-p38 expression in the trigeminal ganglion. The upregulated p-p38 expression was co-localized with NeuN, a neuronal cell marker. We also investigated the role of voltage-gated sodium channels (Navs) in the antinociception produced by preemptive application of QX-314 through analysis of the changes in Nav expression in the trigeminal ganglion following CCI-ION. Preemptive application of QX-314 significantly reduced the upregulation of Nav1.3, 1.7, and 1.9 produced by CCI-ION. These results suggest that long-lasting blockade of the transmission of pain signaling inhibits the development of neuropathic pain through the regulation of Nav isoform expression in the trigeminal ganglion. Importantly, these results provide a potential preemptive therapeutic strategy for the treatment of neuropathic pain after nerve injury.

• Biomolecules & Therapeutics
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• v.25 no.3
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• pp.249-258
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• 2017

To examine the effect of biflorin, a component of Syzygium aromaticum, on memory deficit, we introduced a scopolamine-induced cognitive deficit mouse model. A single administration of biflorin increased latency time in the passive avoidance task, ameliorated alternation behavior in the Y-maze, and increased exploration time in the Morris water maze task, indicating the improvement of cognitive behaviors against cholinergic dysfunction. The biflorin-induced reverse of latency in the scopolamine-treated group was attenuated by MK-801, an NMDA receptor antagonist. Biflorin also enhanced cognitive function in a naïve mouse model. To understand the mechanism of biflorin for memory amelioration, we performed Western blot. Biflorin increased the activation of protein kinase C-${\zeta}$ and its downstream signaling molecules in the hippocampus. These results suggest that biflorin ameliorates drug-induced memory impairment by modulation of protein kinase C-${\zeta}$ signaling in mice, implying that biflorin could function as a possible therapeutic agent for the treatment of cognitive problems.

• Nutrition Research and Practice
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• v.3 no.1
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• pp.3-8
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• 2009

The matrix metalloproteinases (MMP) play an important role in tumor invasion, angiogenesis and inflammatory tissue destruction. Increased expression of MMP was observed in benign tissue hyperplasia and in atherosclerotic lesions. Invasive cancer cells utilize MMP to degrade the extracellular matrix and vascular basement membrane during metastasis, where MMP-2 has been implicated in the development and dissemination of malignancies. The present study attempted to examine the antiangiogenic activity of the medicinal herbs of Aspergillus usamii var. shirousamii-transformed Angelicae Gigantis Radix and Zizyphus jujube (tAgR and tZj) with respect to MMP-2 production and endothelial motility in phorbol 12-myristate 13-acetate (PMA)- or VEGF-exposed human umbilical vein endothelial cells (HUVEC). Nontoxic tAgR and tZj substantially suppressed PMA-induced MMP-2 secretion. In addition, $25{\mu}g/mL$ tAgR and tZj prevented vascular endothelial growth factor-stimulated endothelial cell transmigration and tube formation. The results reveal that tAgR and tZj dampened endothelial MMP-2 production leading to endothelial transmigration and tube formation. tAgR and tZj-mediated inhibition of endothelial MMP may boost a therapeutic efficacy during vascular angiogenesis.

• Journal of Ginseng Research
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• v.43 no.3
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• pp.421-430
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• 2019

Background: The ginsenoside Rg3, one of active components of red ginseng, has chemopreventive and anticancer potential. Cancer stem cells retain self-renewal properties which account for cancer recurrence and resistance to anticancer therapy. In our present study, we investigated whether the standardized Korean Red Ginseng extract (RGE) and Rg3 could modulate the manifestation of breast cancer stem cell-like features through regulation of self-renewal activity. Methods: The effects of RGE and Rg3 on the proportion of $CD44^{high}/CD24^{low}$ cells, as representative characteristics of stem-like breast cancer cells, were determined by flow cytometry. The mammosphere formation assay was performed to assess self-renewal capacities of breast cancer cells. Aldehyde dehydrogenase activity of MCF-7 mammospheres was measured by the ALDEFLUOR assay. The expression levels of Sox-2, Bmi-1, and P-Akt and the nuclear localization of hypoxia inducible $factor-1{\alpha}$ in MCF-7 mammospheres were verified by immunoblot analysis. Results: Both RGE and Rg3 decreased the viability of breast cancer cells and significantly reduced the populations of $CD44^{high}/CD24^{low}$ in MDA-MB-231 cells. RGE and Rg3 treatment attenuated the expression of Sox-2 and Bmi-1 by inhibiting the nuclear localization of hypoxia inducible $factor-1{\alpha}$ in MCF-7 mammospheres. Suppression of the manifestation of breast cancer stem cell-like properties by Rg3 was mediated through the blockade of Akt-mediated self-renewal signaling. Conclusion: This study suggests that Rg3 has a therapeutic potential targeting breast cancer stem cells.

• BMB Reports
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• v.54 no.3
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• pp.182-187
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• 2021

Leukotriene B4 (LTB4) is a lipid mediator of inflammation that is generated from arachidonic acid via the 5-lipoxygenase pathway. Previous studies have reported that the receptors of LTB4, BLT1, and BLT2 play mediatory roles in the allergic airway inflammation induced by ovalbumin (OVA). However, considering that house dust mites (HDMs) are the most prevalent allergen and well-known risk factor for asthmatic allergies, we are interested in elucidating the contributory roles of BLT1/2 in HDM-induced allergic airway inflammation. Our aim in this study was to investigate whether BLT1/2 play any roles in HDM-induced allergic airway inflammation. In this study, we observed that the levels of ligands for BLT1/2 [LTB4 and 12(S)-HETE (12(S)-hydroxyeicosatetraenoic acid)] were significantly increased in bronchoalveolar lavage fluid (BALF) after HDM challenge. Blockade of BLT1 or BLT2 as well as of 5-lipoxygenase (5-LO) or 12-lipoxygenase (12-LO) markedly suppressed the production of TH2 cytokines (IL-4, IL-5, and IL-13) and alleviated lung inflammation and mucus secretion in an HDM-induced eosinophilic airway-inflammation mouse model. Together, these results indicate that the 5-/12-LO-BLT1/2 cascade plays a role in HDM-induced airway inflammation by mediating the production of TH2 cytokines. Our findings suggest that BLT1/2 may be a potential therapeutic target for patients with HDM-induced allergic asthma.

• Molecules and Cells
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• v.44 no.12
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• pp.893-899
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• 2021

BLT2 is a low-affinity receptor for leukotriene B₄, a potent lipid mediator of inflammation generated from arachidonic acid via the 5-lipoxygenase pathway. The aim of this study was to investigate whether BLT2 plays any role in sepsis, a systemic inflammatory response syndrome caused by infection. A murine model of cecal ligation and puncture (CLP)-induced sepsis was used to evaluate the role of BLT2 in septic inflammation. In the present study, we observed that the levels of ligands for BLT2 (LTB₄ [leukotriene B₄] and 12(S)-HETE [12(S)-hydroxyeicosatetraenoic acid]) were significantly increased in the peritoneal lavage fluid and serum from mice with CLP-induced sepsis. We also observed that the levels of BLT2 as well as 5-lipoxygenase (5-LO) and 12-LO, which are synthesizing enzymes for LTB₄ and 12(S)-HETE, were significantly increased in lung and liver tissues in the CLP mouse model. Blockade of BLT2 markedly suppressed the production of sepsis-associated cytokines (IL-6 [interleukin-6], TNF-α [tumor necrosis factor alpha], and IL-1β [interleukin-β] as well as IL-17 [interleukin-17]) and alleviated lung inflammation in the CLP group. Taken together, our results suggest that BLT2 cascade contributes to lung inflammation in CLP-induced sepsis by mediating the production of inflammatory cytokines. These findings suggest that BLT2 may be a potential therapeutic target for sepsis patients.

• Journal of Microbiology and Biotechnology
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• v.32 no.4
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• pp.493-503
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• 2022

Forkhead transcription factor 3a (Foxo3a) is believed to be a tumor suppressor as its inactivation leads to cell transformation and tumor development. However, further investigation is required regarding the involvement of the activating transcription factor 3 (ATF3)-mediated Tat-interactive protein 60 (Tip60)/Foxo3a pathway in cancer cell apoptosis. This study demonstrated that Chelidonium majus upregulated the expression of ATF3 and Tip60 and promoted Foxo3a nuclear translocation, ultimately increasing the level of Bcl-2-associated X protein (Bax) protein. ATF3 overexpression stimulated Tip60 expression, while ATF3 inhibition by siRNA repressed Tip60 expression. Furthermore, siRNA-mediated Tip60 inhibition significantly promoted Foxo3a phosphorylation, leading to blockade of Foxo3a translocation into the nucleus. Thus, we were able to deduce that ATF3 mediates the regulation of Foxo3a by Tip60. Moreover, siRNA-mediated Foxo3a inhibition suppressed the expression of Bax and subsequent apoptosis. Taken together, our data demonstrate that Chelidonium majus induces SKOV-3 cell death by increasing ATF3 levels and its downstream proteins Tip60 and Foxo3a. This suggests a potential therapeutic role of Chelidonium majus against ovarian cancer.

• International Journal of Oral Biology
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• v.39 no.1
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• pp.49-56
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• 2014

We investigated the role of central P2X receptors in inflammatory pain transmission in the orofacial area in rats. Experiments were carried out using male Sprague-Dawley rats weighing 230-280g. Complete Freund's adjuvant (CFA, $40{\mu}L$) was applied subcutaneously to the vibrissa pad to produce inflammatory pain. The intracisternal administration of iso-PPADS tetrasodium salt, a non-selective P2X receptor antagonist, A317491 sodium salt hydrate, a $P2X_{2/3}$ receptor antagonist, 5-BDBD, a $P2X_4$ receptor antagonist, or A438079 hydrochloride, a $P2X_7$ receptor antagonist, was performed 5 days after CFA injection. Subcutaneous injections of CFA produced increases in thermal hypersensitivity. Intracisternal injections of iso-PPADS ($25{\mu}g$) or A438079 (25 or $50{\mu}g$) produced significant anti-hyperalgesic effects against thermal stimuli compared to the vehicle group. A317491 or 5-BDBD did not affect the head withdrawal latency times in rats showing an inflammatory response. Subcutaneous injections of CFA resulted in the up-regulation of OX-42, a microglia marker, and GFAP, an astrocyte marker, in the medullary dorsal horn. The intracisternal administration of A438079 reduced the numbers of activated microglia and astrocytes in the medullary dorsal horn. These results suggest that a blockade of the central $P2X_7$ receptor produces antinociceptive effects, mediated by inhibition of glial cell function in the medullary dorsal horn. These data also indicate that central $P2X_7$ receptors are potential targets for future therapeutic approaches to inflammatory pain in the orofacial area.

• Journal of Life Science
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• v.28 no.1
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• pp.116-129
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• 2018

Living creatures possess long-conserved mechanisms to maintain homeostasis in response to various stresses. However, chronic and continuous exposure to stress can result in the excessive production of stress hormones, including catecholamines, which have harmful effects on health. Studies on the relationship between the sympathetic nervous system (SNS) and cancer have been conducted based on the traditional hypothesis that stress can promote cancer progression. Many preclinical and epidemiological studies have suggested that the regulation of ${\beta}$-adrenergic signaling, which mediates SNS activity, can suppress the progression of solid tumors. SNS activation has highly pleiotropic effects on tumor biology, as it stimulates oncogenes, survival pathways, the epithelial - mesenchymal transition, and invasion. Moreover, it inhibits DNA repair and programmed cell death and regulates the tumor microenvironment, including immune cells, endothelial cells, the extracellular matrix, mesenchymal cells, and adipocytes. Although targeted therapies on the molecular basis of tumor proliferation are currently receiving increased attention, they have clinical limitations, such as the compensatory activation of other signaling pathways, emergence of drug resistance, and various side effects, which raise the need for pleiotropic cancer regulation. This review summarizes the effects of the SNS on the development and progression of cancer and discusses the clinical perspectives of ${\beta}$-blockade as a novel therapeutic strategy for this disease.

• Archives of Plastic Surgery
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• v.33 no.1
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• pp.39-45
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• 2006

This study is to examine the relationship between TGF-b1 expression and CTGF expression, and to evaluate the effect of Sp1 blockade on the expression of TGF-b1, CTGF and extracellular genes, clones of fibroblasts stably transfected with Sp1 decoy ODN. R-Sp1 decoy ODN was highly resistant to degradation by nucleases or serum, compared to the linear or phosphorothioated-Sp1 decoy ODN. Skin wounds were created on the back of 36 anesthetized rats. They were divided into four groups-the rats with normal skin, with wounded skin without decoy, with wounded skin injected with R-Sp1 decoy, and with wounded skin injected with mismatched R-Sp1 decoy, respectively. Skins were collected at 3rd, 5th, 7th, 14th day after wounding. Cellular RNA was extracted by RT-PCR analysis. TGF-${\beta}1$ and CTGF were deeply related with skin fibrosis during scar formation and it appeared that TGF-${\beta}1$ may cause the induction of CTGF expression. R-Sp1 decoy ODN inhibited TGF-${\beta}1$ and CTGF expression both in cultured fibroblasts and in the skin of rats. These results indicate that targeting Sp1 with R-type decoy efficiently blocks extracellular matrix gene expression, and suggest an important new therapeutic approach to control the scarring in normal wound healing and fibrotic disorders.