• Molecules and Cells
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• v.40 no.11
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• pp.837-846
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• 2017

As a component of the neurovascular unit, cerebral smooth muscle cells (CSMCs) are an important mediator in the development of cerebral vascular diseases such as stroke. Epoxyeicosatrienoic acids (EETs) are the products of arachidonic acid catalyzed by cytochrome P450 epoxygenase. EETs are shown to exert neuroprotective effects. In this article, the role of EET in the growth and apoptosis of CSMCs and the underlying mechanisms under oxygen glucose deprivation (OGD) conditions were addressed. The viability of CMSCs was decreased significantly in the OGD group, while different subtypes of EETs, especially 14,15-EET, could increase the viability of CSMCs under OGD conditions. RAPA (serine/threonine kinase Mammalian Target of Rapamycin), a specific mTOR inhibitor, could elevate the level of oxygen free radicals in CSMCs as well as the anti-apoptotic effects of 14,15-EET under OGD conditions. However, SP600125, a specific JNK (c-Jun N-terminal protein kinase) pathway inhibitor, could attenuate oxygen free radicals levels in CSMCs as well as the anti-apoptotic effects of 14,15-EET under OGD conditions. These results strongly suggest that EETs exert protective functions during the growth and apoptosis of CSMCs, via the JNK/c-Jun and mTOR signaling pathways in vitro. We are the first to disclose the beneficial roles and underlying mechanism of 14,15-EET in CSMC under OGD conditions.

• Biomolecules & Therapeutics
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• v.28 no.1
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• pp.104-109
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• 2020

Probenecid is a representative drug used in the treatment of gout. A recent study showed that probenecid effectively inhibits oxidative stress in neural cells. In the present study, we investigated whether probenecid can affect osteoclast formation through the inhibition of reactive oxygen species (ROS) formation in RAW264.7 cells. Lipopolysaccharide (LPS)-induced ROS levels were dose-dependently reduced by probenecid. Fluorescence microscopy analysis clearly showed that probenecid inhibits the generation of ROS. Western blot analysis indicated that probenecid affects two downstream signaling molecules of ROS, cyclooxygenase 2 (COX-2) and c-Jun N-terminal kinase (JNK). These results indicate that probenecid inhibits ROS generation and exerts antiosteoclastogenic activity by inhibiting the COX-2 and JNK pathways. These results suggest that probenecid could potentially be used as a therapeutic agent to prevent bone resorption.

• BMB Reports
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• v.50 no.9
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• pp.466-471
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• 2017

The results of this study show that c-Jun N-terminal kinase (JNK) activation was associated with the enhancement of docetaxel-induced cytotoxicity by simvastatin in DU145 human prostate cancer cells. To better understand the basic molecular mechanisms, we investigated simvastatin-regulated targets during simvastatin-induced cell death in DU145 cells using two-dimensional (2D) proteomic analysis. Thus, vimentin, Ras-related protein Rab-1B (RAB1B), cytoplasmic hydroxymethylglutaryl-CoA synthase (cHMGCS), thioredoxin domain-containing protein 5 (TXNDC5), heterogeneous nuclear ribonucleoprotein K (hnRNP K), N-myc downstream-regulated gene 1 (NDRG1), and isopentenyl-diphosphate Delta-isomerase 1 (IDI1) protein spots were identified as simvastatin-regulated targets involved in DU145 cell death signaling pathways. Moreover, the JNK inhibitor SP600125 significantly inhibited the upregulation of NDRG1 and IDI protein levels by combination treatment of docetaxel and simvastatin. These results suggest that NDRG1 and IDI could at least play an important role in DU145 cell death signaling as simvastatinregulated targets associated with JNK activation.

• Natural Product Sciences
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• v.15 no.1
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• pp.32-36
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• 2009

Glutamate causes neurotoxicity through formation of reactive oxygen species and activation of mitogen-activated protein kinase (MAPK) pathways. MAPK phosphatase-1 (MKP-1) is one of the phosphatases responsible for dephosphorylation/deactivation of three MAPK families: the extracellular signal-regulated kinase-1/2 (ERK-1/2), the c-Jun N-terminal kinase-1/2 (JNK-1/2), and the p38 MAPK. In this report, the potential involvement of MKP-1 in neuroprotective effects of curcumin, the active ingredient of turmeric (Curcuma longa), was examined using HT22 cells. Glutamate caused cell death and activation of ERK-1/2 but not p38 MAPK or JNK-1/2. Blockage of ERK-1/2 by its inhibitor protected HT22 cells against glutamate-induced toxicity. Curcumin attenuated glutamate-induced cell death and ERK-1/2 activation. Interestingly, curcumin induced MKP-1 activation. In HT22 cells transiently transfected with small interfering RNA against MKP-1, curcumin failed to inhibit glutamate-induced ERK-1/2 activation and to protect HT22 cells from glutamate-induced toxicity. These results suggest that curcumin can attenuate glutamate-induced neurotoxicity by activating MKP-1 which acts as the negative regulator of ERK-1/2. This novel pathway may contribute to and explain at least one of the neuroprotective actions of curcumin.

• Journal of Physiology & Pathology in Korean Medicine
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• v.19 no.2
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• pp.501-507
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• 2005

Shikonin is a chemically characterized component of traditional herbal medicine, the root of Lithospermum erythrorhizon and has been shown to possess antitumor activities. Here we investigated anticancer potential of shikonin and its possible mechanism of action in LLC cells. Shikonin inhibited the proliferation of LLC cells in a concentration-dependent manner. It was also demonstrated that shikonin induced apoptosis in LLC cells by Annexin V staining and TUNEL staining analysis. Shikonin treatment was caused that decrease of Bcl-2, activation of caspases and cleavage of PARP. And shikonin also induced that the activation of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38. Interestingly, the cell proliferation inhibition induced by shikonin was recovered by specific inhibitors of JNK and p38 but the inhibitor of MEK, the upstream kinase of ERK, did not recover. Additionally, shikonin administration at doses of 5 mg/kg in C57BL/6 mice strongly inhibited the primary tumor growth of LLC. Taken together, these results suggest that shikonin may suppress LLC cell proliferation by inducing an apoptotic process via activation of caspases and MAPKs

• Food Science of Animal Resources
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• v.41 no.5
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• pp.749-762
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• 2021

Colostrum, which contains various immune and growth factors, aids wound healing by promoting keratinocyte proliferation. Aquaporins (AQPs) are small, hydrophobic membrane proteins that regulate cellular water retention. However, few studies have examined the effect of processed colostrum whey on AQP-3 expression in human skin cells. Here, we investigated the effect of milk, colostrum, fermented milk, and fermented colostrum whey on AQP-3 expression in keratinocyte HaCaT cells. Concentrations of 100-400 ㎍/mL of fermented colostrum whey were found to induce HaCaT cell proliferation. AQP-3 was found to be expressed exclusively in HaCaT cells. AQP-3 expression was significantly increased in 100 ㎍/mL fermented colostrum whey-treated cells compared with that in controls. Moreover, fermented colostrum increased p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation, but not ERK1/2 phosphorylation. Thus, our results suggest that fermented colostrum whey increased AQP-3 expression in, and the proliferation of, keratinocytes via JNK and p38 MAPK activation.

• Bulletin of the Korean Chemical Society
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• v.35 no.11
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• pp.3169-3174
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• 2014

Numerous studies have examined the role of flavonoids in modulating inflammatory responses in vitro. In this study, we found a novel flavonoid, 3,6,3'-trihydroxyflavone (1), with anti-inflammatory effects. Anti-inflammatory activity and mechanism of action were examined in mouse macrophages stimulated with lipopolysaccharide (LPS). Our results showed that the anti-inflammatory effects of 1 are mediated via p38 mitogen-activated protein kinase (p38 MAPK), Jun-N terminal kinase (JNK), and the extracellular-signal-regulated kinase (ERK) pathway in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Binding studies revealed that 1 had a high binding affinity to JNK1 ($1.568{\times}10^8M^{-1}$) and that the 3- and 6-hydroxyl groups of the C-ring and A-ring of 1 participated in hydrogen bonding interactions with the side chains of Asn114 and Lys55, respectively. The oxygen at the 3' position of the B-ring formed a hydrogen bond with side chain of Met111. Therefore, 1 could be a potential inhibitor of JNKs, with potent anti-inflammatory activity.

• The Korean Journal of Physiology and Pharmacology
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• v.11 no.5
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• pp.163-169
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• 2007

The neurotoxicity of amyloid $\beta(A\beta)$ is associated with an increased production of reactive oxygen species and apoptosis, and it has been implicated in the development of Alzheimer's disease. While(-)-epigallocatechin-3-gallate(EGCG) suppresses $A\beta$-induced apoptosis, the mechanisms underlying this process have yet to be completely clarified. This study was designed to investigate whether EGCG plays a neuroprotective role by activating cell survival system such as protein kinase C(PKC), extracellular-signal-related kinase(ERK), c-Jun N-terminal kinase(JNK), and anti-apoptotic and pro-apoptotic genes in SH-SY5Y human neuroblastoma cells. One ${\mu}M\;A{\beta}_{1-42}$ decreased cell viability, which was correlated with increased DNA fragmentation evidenced by DAPI staining. Pre-treatment of SH-SY5Y neuroblastoma cells with EGCG($1{\mu}M$) significantly attenuated $A{\beta}_{1-42}$-induced cytotoxicity. Potential cell signaling candidates involved in this neuroprotective effects were further examined. EGCG restored the reduced PKC, ERK, and JNK activities caused by $A{\beta}_{1-42}$ toxicity. In addition, gene expression analysis revealed that EGCG prevented both the $A{\beta}_{1-42}$-induced expression of a pro-apoptotic gene mRNA, Bad and Bax, and the decrease of an anti-apoptotic gene mRNA, Bcl-2 and Bcl-xl. These results suggest that the neuroprotective mechanism of EGCG against $A{\beta}_{1-42}$-induced apoptotic cell death includes stimulation of PKC, ERK, and JNK, and modulation of cell survival and death genes.

• Journal of Life Science
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• v.33 no.2
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• pp.176-182
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• 2023

The stems of Dendrobium moniliforme are used in traditional Oriental medicine as a Yin tonic to nourish the stomach, promote the production of body fluid, and reduce fever. This study investigated the effects of the aqueous extract of D. moniliforme stems (DME) on mast cell degranulation and the expression of tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), and histamine-synthesizing enzyme histidine decarboxylase (HDC). We used rat mast cell line RBL-2H3 cells and stimulated them with PMA plus calcium ionophore (PMACI). Pretreatment with DME significantly inhibited PMACI-induced β-hexosaminidase release and the expression of TNF-α, IL-4, and HDC. Furthermore, DME suppressed PMACI-induced nuclear translocation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1). In addition, HDC expression was inhibited by SP600125 (JNK inhibitor), PD98059 (ERK inhibitor), and SB203580 (p38 kinase inhibitor). Finally, the phosphorylation of p38 kinase, extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK) was inhibited by pretreatment with DME. These results suggest that DME has inhibitory effects against degranulation, cytokine (TNF-α and IL-4) and HDC expression, and that HDC expression is mediated by MAPK signaling. These findings suggest that DME may have therapeutic potential in the treatment of hypersensitive and inflammatory diseases.

• Journal of Ginseng Research
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• v.41 no.2
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• pp.227-231
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• 2017

Background: Ginsenosides are active components of Panax ginseng that exert various health benefits including kidney protection effect. The medicinal activity of ginsenosides can be enhanced by modulating their stereospecificity by heat processing. Ginsenosides Rk2 and Rh3 represent positional isomers of the double bond at C-20(21) or C-20(22). Methods: The present study investigated the kidney-protective effects of ginsenosides Rk2 and Rh3 against cisplatin, a platinum based anticancer drug, induced apoptotic damage in renal proximal LLC-PK1 cells. Results: As a result, ginsenoside Rh3 shows a stronger protective effect than that shown by Rk2. Cisplatin-induced elevated protein levels of phosphorylated c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), p38, and cleaved caspase-3 decreased after cotreatment with ginsenoside Rh3. The increase in the percentage of apoptotic LLC-PK1 cells induced by cisplatin treatment also significantly reduced after cotreatment with ginsenoside Rh3. Conclusion: These results demonstrate that inhibition of the JNK and ERK mitogen-activated protein kinase signaling cascade plays a critical role in mediating the renoprotective effect of ginsenoside Rh3.