• The Korean Journal of Pain
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• v.34 no.4
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• pp.405-416
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• 2021

Background: This study investigated the effect of intrathecal Sec-O-glucosylhamaudol (SOG) on the p38/c-Jun N-terminal kinase (JNK) signaling pathways, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-related inflammatory responses, and autophagy in a spinal nerve ligation (SNL)-induced neuropathic pain model. Methods: The continuous administration of intrathecal SOG via an osmotic pump was performed on male Sprague-Dawley rats (n = 50) with SNL-induced neuropathic pain. Rats were randomized into four groups after the 7th day following SNL and treated for 2 weeks as follows (each n = 10): Group S, sham-operated; Group D, 70% dimethylsulfoxide; Group SOG96, SOG at 96 ㎍/day; and Group SOG192, SOG at 192 ㎍/day. The paw withdrawal threshold (PWT) test was performed to assess neuropathic pain. Western blotting of the spinal cord (L5) was performed to measure changes in the expression of signaling pathway components, cytokines, and autophagy. Additional studies with naloxone challenge (n = 10) and cells were carried out to evaluate the potential mechanisms underlying the effects of SOG. Results: Continuous intrathecal SOG administration increased the PWT with p38/JNK mitogen-activated protein kinase (MAPK) pathway and NF-κB signaling pathway inhibition, which induced a reduction in proinflammatory cytokines with the concomitant downregulation of autophagy. Conclusions: SOG alleviates mechanical allodynia, and its mechanism is thought to be related to the regulation of p38/JNK MAPK and NF-κB signaling pathways, associated with autophagy during neuroinflammatory processes after SNL.

• International Journal of Oral Biology
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• v.30 no.3
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• pp.85-90
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• 2005

Homeostatic pH is very important for various cellular processes, including metabolism, survival, and death. An imbalanced-pH might induce cellular acidosis, which is involved in many abnormal events such as apoptosis and malignancy. One of several factors contributing to the onset of metabolic acidosis is the production of lactate and protons by lactate dehydrogenase (LDH) in anaerobic glycolysis. LDH is an important enzyme that catalyzes the reversible conversion of pyruvate to lactate. This study sought to examine whether decreases in extracellular pH induce apoptosis of CHO cells, and to elucidate the role of mitogen-activated protein kinases (MAPKs) in acidification-induced apoptosis. To test apoptotic signaling by acidification we used CHO dhfr cells that were sensitive to acidification, and CHO/anti-LDH cells that are resistant to acidification-induced apoptosis and have reduced LDH activity by stable LDH antisense mRNA expression. In the present study, cellular lactic acid-induced acidification and the role of MAPKs signaling in acidification-induced apoptosis were investigated. Acidification, which is caused by $HCO{_3}^-$-free conditions, induced apoptosis and MAPKs (ERK, JNK, and p38) activation. However, MAPKs were slightly activated in acidic conditions in the CHO/anti-LDH cells, indicating that lactic acid-induced acidification induces activation of MAPKs. Treatment with a p38 inhibitor, PD169316, increased acidification-induced apoptosis but apoptosis was not affected by inhibitors for ERK (U0126) or JNK (SP600125). Thus, these data support the hypothesis that activation of the p38 MAPK during acidification-induced apoptosis contributes to cell survival.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.3
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• pp.225-234
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• 2018

Adenosine is a naturally occurring breakdown product of adenosine triphosphate and plays an important role in different physiological and pathological conditions. Adenosine also serves as an important trigger in ischemic and remote preconditioning and its release may impart cardioprotection. Exogenous administration of adenosine in the form of adenosine preconditioning may also protect heart from ischemia-reperfusion injury. Endogenous release of adenosine during ischemic/remote preconditioning or exogenous adenosine during pharmacological preconditioning activates adenosine receptors to activate plethora of mechanisms, which either independently or in association with one another may confer cardioprotection during ischemia-reperfusion injury. These mechanisms include activation of $K_{ATP}$ channels, an increase in the levels of antioxidant enzymes, functional interaction with opioid receptors; increase in nitric oxide production; decrease in inflammation; activation of transient receptor potential vanilloid (TRPV) channels; activation of kinases such as protein kinase B (Akt), protein kinase C, tyrosine kinase, mitogen activated protein (MAP) kinases such as ERK 1/2, p38 MAP kinases and MAP kinase kinase (MEK 1) MMP. The present review discusses the role and mechanisms involved in adenosine preconditioning-induced cardioprotection.

• The Journal of Internal Korean Medicine
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• v.30 no.4
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• pp.845-857
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• 2009

Background and Objectives : Korean mistletoe lectin (Viscum album coloratum agglutinin, VCA) and bee venom (BV) have been reported to induce apoptosis in various cancer cell lines in vitro and to show antitumor activity against a variety of tumors in animal models. However, the comparative effect of VCA and BV on the anti-cancer effect and mechanisms of action has not been determined. In this study, the effect in a human hepatocellular carcinoma cell line, Hep G2 cells, was examined. Methods : Cytotoxic effects of VCA and BV on Hep G2 cells were determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay in litro. The apoptotic cell death was then confirmed by propidium iodide staining and DNA fragmentation analysis. The mechanisms of action were examined by the expression of anti-apoptotic proteins and activation of mitogen-activated protein kinases. The involvement of kinase was examined in VCA or BV-induced apoptosis by using kinase inhibitors. Results : VCA and BV killed Hep G2 cells in a time and dose-dependent manner. Treatment of Hep G2 cells with VCA activated poly (ADP-ribose) polymerase-1 (PARP-1) known as a marker of apoptosis, and mitogen-activated protein kinases signaling pathways including MAPK/ERK, p38 MAPK and JNK. BV also activated PARP-1, MAPK/ERK. and p38 MAPK but not JNK. The expression level of anti-apoptotic molecule, Bcl-X, was decreased by VCA treatment but not by BV. Finally, the phosphorylation level of ERM proteins involved in the cytoskeleton homeostasis was decreased by both stimuli. VCA-induced apoptosis was partially inhibited by in the presence of JNK and p38 inhibitor, but BV only by p38 inhibitor. Conclusions : VCA-induced apoptosis is dependent on the activation of p38 and JNK. while BV-induced apoptosis is mediated by p38 activation in Hep G2 cells.

• Journal of Ginseng Research
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• v.42 no.1
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• pp.75-80
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• 2018

Background: The aim of the present study was to evaluate the potential protective effects of six ginsenosides (Rb1, Rb2, Rc, Rd, Rg1, and Rg3) isolated from Panax ginseng against tacrolimus (FK506)-induced apoptosis in renal proximal tubular LLC-PK1 cells. Methods: LLC-PK1 cells were treated with FK506 and ginsenosides, and cell viability was measured. Protein expressions of mitogen-activated protein kinases, caspase-3, and kidney injury molecule-1 (KIM-1) were evaluated by Western blotting analyses. The number of apoptotic cells was measured using an image-based cytometric assay. Results: Reduction in cell viability by $60{\mu}M$ FK506 was ameliorated significantly by cotreatment with ginsenosides Rg1 and Rb1. The phosphorylation of p38, extracellular signal-regulated kinases, and KIM-1, and cleavage of caspase-3, increased markedly in LLC-PK1 cells treated with FK506 and significantly decreased after cotreatment with ginsenoside Rb1. The number of apoptotic cells decreased by 6.0% after cotreatment with ginsenoside Rb1 ($10{\mu}M$ and $50{\mu}M$). Conclusion: The antiapoptotic effects of ginsenoside Rb1 on FK506-induced apoptosis were mediated by the inhibition of mitogen-activated protein kinases and caspase activation.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.96.1-96.1
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• 2003

Lysophosphatidic acid (LPA) is a well-known mitogen in various cell types. However, we were surprised to find that LPA inhibits melanocyte proliferation. Thus, we further investigated the possible signaling pathways involved in melanocyte growth inhibition. We first examined the regulation of the three major subfamilies of mitogen-activated protein (MAP) kinases and of the Akt pathway by LPA. The activations of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) were observed in concert with the inhibition of melanocyte proliferation by LPA, whereas p38 MAP kinase and Akt were not influenced by LPA. (omitted)

• Journal of Life Science
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• v.19 no.8
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• pp.1119-1124
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• 2009

Hyperlipidemia has been reported to be associated with the development of fatty liver. Palmitic acid, a major saturated fatty acid, is involved in the development of diverse diseases. The activation of mitogen activated protein kinases (MAPKs), such as Jun N-terminal kinase (INKs) and p38 MAPK is implicated in the apoptosis in diverse cells. Thus, this study was conducted to investigate the effects of palmitic acid on apoptosis and its relationship between JNK and p38 MAPK in cultured rat hepatocytes. In the present study, palmitic acid (>50 uM) decreased cell proliferation and increased lactate dehydrogenase activity in hepatocytes, which was blocked by the treatment of SP600125 (a JNK inhibitor) and SB203580 (a p38 MAPK inhibitor). Indeed, palmitic acid decreased Bcl-2 expression but increased Bax expression in rat hepatocytes, which was blocked by the treatment of SP600125 and SB203580. In addition, palmitic acid decreased glutathione (GSH) content and increased lipid peroxide formation, which was blocked by the treatment of SP600125 and SB203580. Western immunoblotting analysis also revealed that palmitic acid increased JNK and p38 MAPK. In conclusion, palmitic acid induced apoptosis through oxidative stress via JNK and p38 MAPK activation in rat hepatocytes.

• Korean Journal of Food Science and Technology
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• v.52 no.6
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• pp.622-626
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• 2020

Recent studies have suggested that Canavalia gladiate, a dietary food and traditional folk medicine, has promising pharmaceutical potential, but the effects have mostly been demonstrated using its organo-soluble extract. To date, its immunomodulatory effect depending on the extraction method is unclear. Here, the immune responses of macrophages to C. gladiate and the underlying mechanisms were studied. C. gladiate hot water extract (CGW) induced cytokine production in bone marrow-derived macrophages (BMDMs) in a dose-dependent manner, whereas its ethanolic extract (CGE) did not. Immunoblotting analysis also showed that CGW activated nuclear factor (NF)-κB and mitogen-activated protein kinases (MAPKs). Moreover, an inhibitor assay revealed the involvement of NF-κB, p38, and JNK, but not ERK, in CGW-induced cytokine production. CGE inhibited lipopolysaccharide-stimulated production of pro-inflammatory cytokines and activation of NF-κB and MAPKs in BMDMs. The results suggest that C. gladiate regulates the immune responses of macrophages differently depending on the extraction method.

• Journal of Photoscience
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• v.9 no.2
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• pp.229-232
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• 2002

There are two distinct UV-responsive signaling pathways in UV-irradiated mammalian cells, i.e., the DNA damage-dependent and -independent pathways. The former occurs in nucleus and results in growth arrest and apoptosis via post-translational modification of p53. The latter is initiated by oxidative stress and/or by damages in cell membrane or cytoplasm, which activate signaling cascade through intracellular molecules including mitogen activated protein kinases (MAPK). In normal human fibroblastic cells, all of MAPK family members, extracellular signal-related kinases (ERK), c-Jun N-terminal kinases (JNK) and p38, were rapidly phosphorylated following UV-irradiation. ERK phosphorylation was suppressed by an inhibitor of receptor tyrosine kinases (RTK). As ERK usually responds to mitogenic stimuli from RTK ligands, UV-induced ERK phosphorylation may be linked to the proliferation of survived cells. In contrast, phosphorylation of JNK and p38, as well as apoptosis, were modulated by the level of UV-generated oxidative stress Therefore, JNK and p38 may take part in oxidative stress-mediated apoptosis. Phosphorylation of p53 at Ser and Thr residues are essential for stabilization and activation of p53. Among several sites reported, we confirmed phosphorylation at Ser-15 and Ser-392 after UV-irradiation. Both of these were inhibited by a phosphoinositide 3-kinase inhibitor, presumably due to the shutdown of signals from DNA damage to p53. Phosphorylation at Ser-392 was also sensitive to an antioxidant and a p38 inhibitor, suggesting that Ser-392 of p53 is one of the possible points where DNA damage-dependent and -independent apoptic signals merge. Thus, MAPK pathway links UV-induced intracellular signals to the nuclear responses and modifies DNA damage-dependent cellular outcome, resulting in the determination of cell death.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.6
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• pp.451-456
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• 2001

In rat hippocampus, kainic acid (KA; 10 mg/kg; i.p.) increased the phosphorylated forms of ERK1/2 (p-ERK1/2) and Jun kinase1 (p-JNK1), but not p-JNK2 and p38 (p-p38). The preadministration with cycloheximide (CHX; 5 mg/kg; i.p.) inhibited KA-induced increase of p-JNK1, but not p-ERK1/2. Surprisingly, the phosphorylated upstream MAP kinase kinases (p-MKKs) were not correlated with their downstream MAP kinases. The basal p-MKK1/2 levels were completely abolished by KA, which were reversed by CHX. In addition, p-MKK4 and p-MKK3/6 levels were enhanced by CHX alone, but were attenuated by KA. Thus, our results showed that KA increased the p-ERK and p-JNK levels in rat hippocampus, which were not parallel with their classical upstreamal kinases.