• Archives of Pharmacal Research
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• v.29 no.1
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• pp.67-72
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• 2006

The abnormal proliferation of aortic vascular smooth muscle cells (VSMCs) plays a central role in the pathogenesis of atherosclerosis and restenosis after angioplasty and possibly also in the development of hypertension. The present study was designed to examine the inhibitory effects and the mechanism of luteolin 7-glucoside (L7G) on the platelet-derived growth factor (PDGF)-BB-induced proliferation of VSMCs. L7G significantly inhibited the PDGF-BB-induced proliferation and the DNA synthesis of the VSMCs in a concentration-dependent manner. Pre-incubation of the VSMCs with L7G significantly inhibited the PDGF-BB-induced extracellular signal-regulated kinase 1/2 (ERK1/2), Akt and the phospholipase C $(PLC)-{\gamma}1$ activation. However, L7G had almost no affect on the phosphorylation of $PDGF-{\beta}$ receptor tyrosine kinase, which was induced by PDGF-BB. These results suggest that L7G inhibits the PDGF-BB-induced proliferation of VSMCs via the blocking of $(PLC)-{\gamma}1$, Akt, and ERK1/2 phosphorylation.

• BMB Reports
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• v.46 no.7
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• pp.352-357
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• 2013

Atherosclerosis, which manifests as acute coronary syndrome, stroke, and peripheral arterial diseases, is a chronic inflammatory disease of the arterial wall. Prunella vulgaris, a perennial herb with a worldwide distribution, has been used as a traditional medicine in inflammatory disease. Here, we investigated the effects of P. vulgaris ethanol extract on TNF-${\alpha}$-induced inflammatory responses in human aortic smooth muscle cells (HASMCs). We found that P. vulgaris ethanol extract inhibited adhesion of monocyte/macrophage-like THP-1 cells to activated HASMCs. It also decreased expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin and ROS, No production in TNF-${\alpha}$-induced HASMCs and reduced NF-${\kappa}B$ activation. Furthermore, P. vulgaris extract suppressed TNF-${\alpha}$-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK). These results demonstrate that P. vulgaris possesses anti-inflammatory properties and can regulate TNF-${\alpha}$-induced expression of adhesion molecules by inhibiting the p38 MAPK/ERK signaling pathway.

• Development and Reproduction
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• v.23 no.2
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• pp.119-128
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• 2019

Melanoma is one of the most aggressive and treatment-resistant malignancies. Antidiabetic drug metformin has been reported to inhibit cell proliferation and metastasis in many cancers, including melanoma. Metformin suppresses the mammalian target of rapamycin (mTOR) and our previous study showed that it also inhibits the activity of extracellular signal-regulated kinase (ERK). Paclitaxel is currently prescribed for treatment of melanoma. However, paclitaxel induced the activation of ERK/mitogen-activated protein kinase (MAPK) pathway, a cell signaling pathway implicated in cell survival and proliferation. Therefore, we reasoned that combined treatment of paclitaxel with metformin could be more effective in the suppression of cell proliferation than treatment of paclitaxel alone. Here, we investigated the combinatory effect of paclitaxel and metformin on the cell survival in SK-MEL-28 melanoma cell line. Our study shows that the combination of paclitaxel and metformin has synergistic effect on cell survival and suppresses the expression of proteins involved in cancer metastasis. These findings suggest that the combination of paclitaxel and metformin can be a possible therapeutic option for treatment of melanoma.

• The Journal of Korean Obstetrics and Gynecology
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• v.36 no.1
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• pp.23-34
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• 2023

Objectives: This study was conducted to confirm the anticancer effect of Torilis Japonica (TJ) on cervical cancer and to determine whether the effect was apoptosis. Methods: In this study, the effect of TJ extract on toxicity, mitochondrial morphology, nuclear morphological changes, Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) pathway were investigated in HeLa cell, human cervical cancer cell. Results: The cytotoxicity, ratio of cells with nuclear changes to the total number of cells, and P38 phosphorylation increased in a concentration-dependent manner after administration of TJ extract. The length of mitochondria and ERK phosphorylation in HeLa cells decreased in a concentration-dependent manner after administration of TJ extract. Conclusions: TJ extract has an anticancer effect on cervical cancer cells, which is presumed to be due to apoptosis, and showed potential as a future cervical cancer treatment.

• BMB Reports
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• v.40 no.4
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• pp.467-474
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• 2007

Autosomal recessive polycystic kidney disease (ARPKD) is one of the important genetic disorders in pediatric practice. Mutation of the polycystic kidney and hepatic disease gene 1 (PKHD1) was identified as the cause of ARPKD. The gene encodes a 67-exon transcript for a large protein of 4074 amino acids termed fibrocystin, but its function remains unknown. The neoplastic-like in cystic epithelial proliferation and the epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) axis overactivity are known as the most important characteristics of ARPKD. Since the misregulation of $Ca^{2+}$ signaling may lead to aberrant structure and function of the collecting ducts in kidney of rat with ARPKD, present study aimed to investigate the further mechanisms of abnormal proliferation of cystic cells by inhibition of PKHD1 expression. For this, a stable PKHD1-silenced HEK-293T cell line was established. Then cell proliferation rates, intracellular $Ca^{2+}$ concentration and extracellular signal-regulated kinase 1/2 (ERK1/2) activity were assessed after treatment with EGF, a calcium channel blocker and agonist, verapamil and Bay K8644. It was found that PKHD1-silenced HEK-293T cell lines were hyperproliferative to EGF stimulation. Also PKHD1-silencing lowered the intracellular $Ca^{2+}$ and caused EGF-induced ERK1/2 overactivation in the cells. An increase of intracellular $Ca^{2+}$ in PKHD1-silenced cells repressed the EGF-dependent ERK1/2 activation and the hyperproliferative response to EGF stimulation. Thus, inhibition of PKHD1 can cause EGF-induced excessive proliferation through decreasing intracellular $Ca^{2+}$ resulting in EGF-induced ERK1/2 activation. Our results suggest that the loss of fibrocystin may lead to abnormal proliferation in kidney epithelial cells and cyst formation in ARPKD by modulation of intracellular $Ca^{2+}$.

• Archives of Pharmacal Research
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• v.26 no.12
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• pp.1055-1060
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• 2003

Lysophosphatidic acid (LPA) is a well-known mitogen in various cell types. However, we found 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. However, the specific inhibition of the ERK or JNK pathways by PD98059 or D-JNKI1, respectively, did not restore the antiproliferative effect. We next examined changes in the expression of cell cycle related proteins. LPA decreased cyclin $D_1 and cyclin D_2$ levels but increased $p21^{WAF1/CIP1}$ (p21) and $p27^{KIP1}$ (p27) levels, which are known inhibitors of cyclin-dependent kinase. Flow cytometric analysis showed the inhibition of DNA synthesis by a reduction in the S phase and an increase in the $G_0/G_1$ phase of the cell cycle. Our results suggest that LPA induces cell cycle arrest by regulating the expressions of cell cycle related proteins.

• The Korean Journal of Physiology and Pharmacology
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• v.7 no.2
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• pp.97-101
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• 2003

The salivary glands produce 1.5L of fluid per day. As in other exocrine organs, the general mechanism in the salivary glands is that water movement occurs secondary to osmotic driving forces created by active salt transport. Therefore, high water permeability in the salivary glands is expected to have a variety of aquaporin (AQP), a water channel. Although some AQPs have been known to be present in the salivary glands, roles of parasympathetic nerve in AQP expression have not yet been examined. This study was designed to examine the changes of AQPs and extracellular signal-regulated kinase (ERK) in the submandibular glands after parasympathetic denervation. Right chorda-lingual nerve was cut, and each right (experiment) and left (control) submandibular gland was excised at 1, 3, 7, 14, 30 days after denervation. The denervated right submandibular glands were resulted in weight loss and morphologic changes, including cell loss and atrophy, as the time elapsed after parasympathetic denervation increased, whereas there were no histologic alteration in control side. AQP5 which is known to reside in apical membrane and secretory caraliculi of the submandibular acini were gradually underexpressed according, as the time after denervation increased. Expression of AQP4 in submandibular ductal epithelium was down-regulated after denervation. Besides, AQP3 and 8, which is known to be present in basolateral membrane of the glandular acini, were gradually underexpressed after denervation, similar to the pattern of other types. Expression of ERK, a mitogen-activated protein kinase, was downregulated after parasympathetic denervation in the submandibular gland. These results suggest that parasympathetic nervous system regulates the expression of AQPs in salivary glands, and is in part mediated by ERK pathway.

• BMB Reports
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• v.55 no.9
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• pp.447-452
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• 2022

Neurogenic differentiation 1 (NeuroD1) is an essential transcription factor for neuronal differentiation, maturation, and survival, and is associated with inflammation in lipopolysaccharide (LPS)-induced glial cells; however, the concrete mechanisms are still ambiguous. Therefore, we investigated whether NeuroD1-targeting miRNAs affect inflammation and neuronal apoptosis, as well as the underlying mechanism. First, we confirmed that miR-30a-5p and miR-153-3p, which target NeuroD1, reduced NeuroD1 expression in microglia and astrocytes. In LPS-induced microglia, miR-30a-5p and miR-153-3p suppressed pro-inflammatory cytokines, reactive oxygen species, the phosphorylation of c-Jun N-terminal kinase, extracellular-signal-regulated kinase (ERK), and p38, and the expression of cyclooxygenase and inducible nitric oxide synthase (iNOS) via the NF-κB pathway. Moreover, miR-30a-5p and miR-153-3p inhibited the expression of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasomes, NLRP3, cleaved caspase-1, and IL-1β, which are involved in the innate immune response. In LPS-induced astrocytes, miR-30a-5p and miR-153-3p reduced ERK phosphorylation and iNOS expression via the STAT-3 pathway. Notably, miR-30a-5p exerted greater anti-inflammatory effects than miR-153-3p. Together, these results indicate that miR-30a-5p and miR-153-3p inhibit MAPK/NF-κB pathway in microglia as well as ERK/STAT-3 pathway in astrocytes to reduce LPS-induced neuronal apoptosis. This study highlights the importance of NeuroD1 in microglia and astrocytes neuroinflammation and suggests that it can be regulated by miR-30a-5p and miR-153-3p.

• BMB Reports
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• v.51 no.11
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• pp.596-601
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• 2018

Colon cancer is one of the most lethal and common malignancies worldwide. STK899704, a novel synthetic agent, has been reported to exhibit anticancer effects towards numerous cancer cells. However, the effect of STK899704 on the biological properties of colon cancer, including cancer cell migration and cancer stem cells (CSCs), remains unknown. Here, we examined the inhibitory effect of STK899704 on cell migration and CSC stemness. In the wound healing assay, STK899704 significantly inhibited the motility of colon cancer cells. Furthermore, STK899704 downregulated the mRNA expression levels of the cell migration mediator focal adhesion kinase (FAK). STK899704 also suppressed mitogen-activated protein kinase kinase and extracellular signal-regulated kinase, which are downstream signaling molecules of FAK. Additionally, STK899704 inhibited stemness gene expression and sphere formation in colon cancer stem cells. These results suggest that STK899704 can be used to treat human colon cancer.

• Journal of Ginseng Research
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• v.32 no.1
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• pp.1-7
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• 2008

Ginseng saponin has been shown to inhibit the development of dependence on morphine, cocaine, methamphetamine, but the antinarcotics effects of ginseng on nalbuphine remains still largely unknown. Ginseng administration attenuated the naloxone-induced jumping behavior on nalbuphine dependent mice. The development of morphine dependence was mediated through ${\mu}-opioid$ receptor, however, development of nalbuphine dependence was mediated through ${\kappa}-opioid$ receptor. However, it was found that the efficacy of analgesic antagonism of GTS was mediated through the serotonergic mechanism, not mediated through the opioid receptor. In addition, ginseng administration modulated cellular signal transduction in the brain. The increased NMDA receptor subunit (NR1, pNR1), phosphate extracellular signal regulated protein kinase (pERK), phosphate cAMP response element binding protein (pCREB) expression by nalbuphine was decreased by the administration of ginseng powder in cortex, hippocampus, striatum of rat brain. These results suggest that ginseng could be one of the targets of antinarcotic therapies to reduce the development of tolerance and dependence on nalbuphine as well as morphine.