• Tuberculosis and Respiratory Diseases
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• v.78 no.3
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• pp.218-226
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• 2015

Background: Eph receptors and ephrin ligands have several functions including angiogenesis, cell migration, axon guidance, fluid homeostasis, oncogenesis, inflammation and injury repair. The EphA2 receptor potentially mediates the regulation of vascular permeability and inflammation in response to lung injury. Methods: Mice were divided into 3 experimental groups to study the role of EphA2 signaling in the lipopolysaccharide (LPS)-induced lung injury model i.e., IgG+phosphate-buffered saline (PBS) group (IgG instillation before PBS exposure), IgG+LPS group (IgG instillation before LPS exposure) and EphA2 monoclonal antibody (mAb)+LPS group (EphA2 mAb pretreatment before LPS exposure). Results: EphA2 and ephrinA1 were upregulated in LPS-induced lung injury. The lung injury score of the EphA2 mAb+LPS group was lower than that of the IgG+LPS group ($4.30{\pm}2.93$ vs. $11.45{\pm}1.20$, respectively; p=0.004). Cell counts (EphA2 mAb+LPS: $11.33{\times}10^4{\pm}8.84{\times}10^4$ vs. IgG+LPS: $208.0{\times}10^4{\pm}122.6{\times}10^4$; p=0.018) and total protein concentrations (EphA2 mAb+LPS: $0.52{\pm}0.41mg/mL$ vs. IgG+LPS: $1.38{\pm}1.08mg/mL$; p=0.192) were decreased in EphA2 mAb+LPS group, as compared to the IgG+LPS group. In addition, EphA2 antagonism reduced the expression of phospho-p85, phosphoinositide 3-kinase $110{\gamma}$, phospho-Akt, nuclear factor ${\kappa}B$, and proinflammatory cytokines. Conclusion: This results of the study indicated a role for EphA2-ephrinA1 signaling in the pathogenesis of LPS-induced lung injury. Furthermore, EphA2 antagonism inhibits the phosphoinositide 3-kinase-Akt pathway and attenuates inflammation.

• Journal of Life Science
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• v.30 no.6
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• pp.532-541
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• 2020

In this study, we describe the inhibition of adipocyte differentiation by the lactic acid bacteria (LAB) fermentation product of Chrysanthemum indicum L. (CI) extract to control obesity. Preparation of LAB-fermented products was performed to overcome the cytotoxicity of CI extract. During fermentation and 3T3-L1 cell line experiment, cytotoxicity was not induced in the CI fermentation products over 1 day in culture. Fermented materials from highly proliferative cultures were selected for treatment of 3T3-L1 cells and for comparison with unfermented control groups. Cell survival and undifferentiated cell populations were decreased differentiation population in all experimental groups compared with controls, as measured using fluorescence-activated cell sorting analysis. Akt pathway activity increased upon treatment with these fermented extracts in 3T3-L1 cells. Gli2 depleted at the protein level in association with adipocyte differentiation. LAB KCTC 3115- and 3109-fermented extract treatment caused controlled Gli2 protein accumulation. Moreover, KCTC 3115 and 3109 were found to reduce C/EBPα and FAS was depleted, whereas pACC was increased at the protein level upon treatment with the fermentation products of each of the four LAB used in this study. With Lactococcus lactis subsp. lactis KCTC 3115 fermentation, the regulation of adipose differentiation and hedgehog signaling were also suppressed, thereby inhibiting the differentiation of progenitor cells. The basis for the activation of hedgehog signaling may provide insights into the treatment of obesity and the inhibition of adipocyte differentiation.

• CELLMED
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• v.8 no.3
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• pp.13.1-13.8
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• 2018

In the field of osteoporosis, there has been growing interest in anabolic agents that enhance bone formation. The purpose of this study was to examine the effects of NNMBS 246 osteoblastic differentiation with associated signaling pathways. NNMBS 246 markedly increased alkaline phosphatase (ALP) activity and calcium nodule formation. Stimulation with NNMBS 246 not only increased the differentiation markers (ALP, OPN, OCN) level and transcription markers (RUNX2, Osterix) mRNA expression but also upregulated the ECM molecules and OPG mRNA expression. Treatments of NNMBS 246 downregulated MMPs (MMP-1, MMP-2, MMP-9), but RANKL mRNA expression. Furthermore, NNMBS 246 activated osteoblastic differentiation markers and formed calcium nodules in human periodontal ligament cells (hPDLCs) and cementoblast cells. NNMBS 246 induced phosphorylation of MAPKs, Akt, nuclear p65 and IkB-${\alpha}$. BMP-2/Smad and ${\beta}$-catenin signaling pathways were activated by NNMBS 246. Sirtinol (SIRT1 inhibitor) inhibited NNMBS 246-induced osteoblastic differentiation markers mRNA expression. These results suggested that NNMBS 246 has the potential to enhance osteoblastogenesis probably through the activation of BMP/Smad and ${\beta}$-catenin signal pathways, and SIRT1 plays as critical mediator in bone anabolic effect of NNMBS 246.

• Biomolecules & Therapeutics
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• v.25 no.4
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• pp.354-361
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• 2017

Transcriptional co-activator with a PDZ-binding motif (TAZ) is an important factor in lysophosphatidic acid (LPA)-induced promotion of migration and proliferation of human mesenchymal stem cells (MSCs). The expression of TAZ significantly increased at 6 h after LPA treatment, and TAZ knockdown inhibited the LPA-induced migration and proliferation of MSCs. In addition, embryonic fibroblasts from TAZ knockout mice exhibited the reduction in LPA-induced migration and proliferation. The LPA1 receptor inhibitor Ki16425 blocked LPA responses in MSCs. Although TAZ knockdown or knockout did not reduce LPA-induced phosphorylation of ERK and AKT, the MEK inhibitor U0126 or the ROCK inhibitor Y27632 blocked LPA-induced TAZ expression along with the reduction in the proliferation and migration of MSCs. Our data suggest that TAZ is an important mediator of LPA signaling in MSCs in the downstream of MEK and ROCK signaling.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.27 no.2
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• pp.110-122
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• 2005

Adenoid cystic carcinoma (ACC) of salivary glands has a protracted clinical course with perineural invasion, delayed onset of hematogenous metastasis, and poor responses to classical cytotoxic chemotherapic agents. Most deaths from salivary ACC are caused by lung metastases that are resistant to conventional therapy. Therefore, knowledge of cellular properties and tumor-host interactions that influence the dissemination of metastatic cells is important for the design of more effective therapy of salivary cancer. I determined in vitro expression of epidermal growth factor receptor (EGFR) and its downstream effectors and vascular endothelial growth factor receptor (VEGFR)-2 on a human salivary ACC cell line (ACC2). I also evaluated the expression of EGF and VEGF signaling molecules and metastasis-related proteins on human salivary ACC cells orthotopically growing in nude mice. In Western blot and immunohistochemical analyses, EGFR and VEGFR-2 were presented and phosphorylated in ACC2 cells. In human parotid cancer xenografts in nude mice, EGF and VEGF signaling molecules, IL-8, and MMP-9 were expressed at markedly higher levels than in normal parotid tissues. Moreover, tumor-associated endothelial cells of this orthotopic parotid tumor expressed phosphorylated VEGFR-2 and phosphorylated Akt, which is a cell-survival protein. These data show that those biomarkers can be molecular targets for therapy of salivary ACC, which has a propensity for delayed lung metastasis.

• BMB Reports
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• v.47 no.12
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• pp.685-690
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• 2014

The Ras/Raf/MEK/Erk signaling pathway is important for regulation of cell growth, proliferation, differentiation, survival, and apoptosis in response to a variety of extracellular stimuli. Lack of Erk MAPK activation is observed in several cancer cells despite active activation of Ras. However, little is known about the modulation of Erk1/2 activity by active Ras. Here, we show that overexpression of active H-Ras (H-RasG12R) in NIH3T3 fibroblasts impaired FGF2-induced Erk1/2 phosphorylation, as compared to wild-type cells. Northern blot analysis revealed that prolonged expression of active Ras increased MAP kinase phosphatase 3 (MKP3) mRNA expression, a negative regulator of Erk MAPK. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway abrogated active Ras-induced up-regulation of MKP3 expression, leading to the rescue of Erk1/2 phosphorylation. Our results demonstrated that the Ras/Raf/MEK/Erk signaling cascade is negatively regulated by the PI3K/Aktdependent transcriptional activation of the MKP3 gene.

• Clinical and Experimental Reproductive Medicine
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• v.46 no.2
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• pp.43-49
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• 2019

Primordial follicle activation is a process in which individual primordial follicles leave their dormant state and enter a growth phase. While existing hormone stimulation strategies targeted the growing follicles, the remaining dormant primordial follicles were ruled out from clinical use. Recently, in vitro activation (IVA), which is a method for controlling primordial follicle activation, has provided an innovative technology for primary ovarian insufficiency (POI) patients. IVA was developed based on Hippo signaling and phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/forkhead box O3 (FOXO3) signaling modulation. With this method, dormant primordial follicles are activated to enter growth phase and developed into competent oocytes. IVA has been successfully applied in POI patients who only have a few remaining remnant primordial follicles in the ovary, and healthy pregnancies and deliveries have been reported. IVA may also provide a promising option for fertility preservation in cancer patients and prepubertal girls whose fertility preservation choices are limited to tissue cryopreservation. Here, we review the basic mechanisms, translational studies, and current clinical results for IVA. Limitations and further study requirements that could potentially optimize IVA for future use will also be discussed.

• Korean Journal of Pharmacognosy
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• v.51 no.4
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• pp.317-324
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• 2020

Mast cells play a key role in IgE-mediated allergic response. We investigated whether Swertia pseudochinensis Hara extract (SPE) inhibits IgE-mediated allergic response in mast cells and an allergic animal model. Additionally, we explored SPE's mechanism of action in mast cells. Our results showed that SPE inhibited both antigen-stimulated degranulation and the production of TNF-α and IL-4 in bone marrow-derived mast cells (BMMCs) and rat basophilic leukemia (RBL)-2H3 cells. SPE also suppressed allergic response in IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. As for the mechanism of action of SPE in mast cells, it inhibited the activation of Syk kinase, a critical signaling protein in the FcεRI-mediated signaling pathway, and also the activation of LAT, a downstream adaptor protein of Syk. We further observed the reduced activation of mitogen-activated protein (MAP) kinases (P38, ERK1/2, and JNK) and Akt in mast cells. Our results described for the first time that SPE has an anti-allergic effect by suppressing mast cells through the inhibition of Syk kinase. Therefore, SPE may be useful for the treatment of type I allergic diseases.

• Korean Journal of Exercise Nutrition
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• v.24 no.3
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• pp.32-38
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• 2020

[Purpose] Sarcopenia is considered one of the major causes of disability in the elderly population and is highly associated with aging. Exercise is an essential strategy for improving muscle health while aging and involves multiple metabolic and transcriptional adaptations. Although the beneficial effects of exercise modalities on skeletal muscle structure and function in aging are well recognized, the exact cellular and molecular mechanisms underlying the influence of exercise have not been fully elucidated. [Methods] We summarize the biochemical pathways involved in the progression and pathogenesis of sarcopenia and describe the beneficial effects of exercise training on the relevant signaling pathways associated with sarcopenia. [Results] This study briefly introduces current knowledge on the signaling pathways involved in the development of sarcopenia, effects of aerobic exercise on mitochondria-related parameters and mitochondrial function, and role of resistance exercise in the regulation of muscle protein synthesis against sarcopenia. [Conclusion] This review suggested that the beneficial effects of exercise are still under-explored, and accelerated research will help develop better modalities for the prevention, management, and treatment of sarcopenia.

• BMB Reports
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• v.56 no.3
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• pp.160-165
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• 2023

Vascular calcification is common in cardiovascular diseases including atherosclerosis, and is associated with an increased risk of pathological events and mortality. Some semaphorin family members play an important role in atherosclerosis. In the present study, we show that Semaphorin 4D/Sema4D and its Plexin-B1 receptor were significantly upregulated in calcified aorta of a rat chronic kidney disease model. Significantly higher Sema4D and Plexin-B1 expression was also observed during inorganic phosphate-induced calcification of vascular smooth muscle cells. Knockdown of Sema4D or Plexin-B1 genes attenuated both the phosphate-induced osteogenic phenotype of vascular smooth muscle cells, through regulation of SMAD1/5 signaling, as well as apoptosis of vascular smooth muscle cells, through modulation of the Gas6/Axl/Akt survival pathway. Taken together, our results offer new insights on the role of Sema4D and Plexin-B1 as potential therapeutic targets against vascular calcification.