• The Korean Journal of Physiology and Pharmacology
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• v.20 no.3
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• pp.297-304
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• 2016

Klotho functions as a tumor suppressor predominantly expressed in renal tubular cells, the origin of clear cell renal cell carcinoma (ccRCC). Altered expression and/or activity of growth factor receptor have been implicated in ccRCC development. Although Klotho suppresses a tumor progression through growth factor receptor signaling including insulin-like growth factor-1 receptor (IGF-1R), the role of Klotho acting on IGF-1R in ccRCC and its clinical relevance remains obscure. Here, we show that Klotho is favorable prognostic factor for ccRCC and exerts tumor suppressive role for ccRCC through inhibiting IGF-1R signaling. Our data shows the following key findings. First, in tumor tissues, the level of Klotho and IGF-1R expression are low or high, respectively, compared to that of adjacent non-neoplastic parenchyma. Second, the Klotho expression is clearly low in higher grade of ccRCC and is closely associated with clinical outcomes in tumor progression. Third, Klotho suppresses IGF-1-stimulated cell proliferation and migration by inhibiting PI3K/Akt pathway. These results provide compelling evidence supporting that Klotho acting on IGF-1R signaling functions as tumor suppressor in ccRCC and suggest that Klotho is a potential carcinostatis substance for ccRCC.

• The Korean Journal of Physiology and Pharmacology
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• v.20 no.6
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• pp.581-593
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• 2016

The advantages of monounsaturated fatty acids (MUFAs) on insulin resistance and type 2 diabetes mellitus (T2DM) have been well established. However, the molecular mechanisms of the anti-diabetic action of MUFAs remain unclear. This study examined the anti-hyperglycemic effect and explored the molecular mechanisms involved in the actions of fish oil- rich in MUFAs that had been acquired from hybrid catfish (Pangasius larnaudii${\times}$Pangasianodon hypophthalmus) among experimental type 2 diabetic rats. Diabetic rats that were fed with fish oil (500 and 1,000 mg/kg BW) for 12 weeks significantly reduced the fasting plasma glucose levels without increasing the plasma insulin levels. The diminishing levels of plasma lipids and the muscle triglyceride accumulation as well as the plasma leptin levels were identified in T2DM rats, which had been administrated with fish oil. Notably, the plasma adiponectin levels increased among these rats. The fish oil supplementation also improved glucose tolerance, insulin sensitivity and pancreatic histological changes. Moreover, the supplementation of fish oil improved insulin signaling ($p-Akt^{Ser473}$ and p-PKC-${\zeta}/{\lambda}^{Thr410/403}$), $p-AMPK^{Thr172}$ and membrane GLUT4 protein expressions, whereas the protein expressions of pro-inflammatory cytokines (TNF-${\alpha}$ and nuclear NF-${\kappa}B$) as well as p-PKC-${\theta}^{Thr538}$ were down regulated in the skeletal muscle. These data indicate that the effects of fish oil-rich in MUFAs in these T2DM rats were partly due to the attenuation of insulin resistance and an improvement in the adipokine imbalance. The mechanisms of the anti-hyperglycemic effect are involved in the improvement of insulin signaling, AMPK activation, GLUT4 translocation and suppression of pro-inflammatory cytokine protein expressions.

• Journal of Microbiology and Biotechnology
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• v.18 no.2
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• pp.355-364
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• 2008

Mushrooms are regarded as one of the well-known foods and biopharmaceutical materials with a great deal of interest. ${\beta}$-Glucan is the major component of mushrooms that displays various biological activities such as antidiabetic, anticancer, and antihyperlipidemic effects. In this study, we explored the molecular mechanism of its immunostimulatory potency in immune responses of macrophages, using exopolysaccharides prepared from liquid culture of Lentinus edodes. We found that fraction II (F-II), with large molecular weight protein polysaccharides, is able to strongly upregulate the phenotypic functions of macrophages such as phagocytic uptake, ROS/NO production, cytokine expression, and morphological changes. F-II triggered the nuclear translocation of NF-${\kappa}B$ and activated its upstream signaling cascades such as PI3K/Akt and MAPK pathways, as assessed by their phosphorylation levels. The function-blocking antibodies to dectin-1 and TLR-2, but not CR3, markedly suppressed F-II-mediated NO production. Therefore, our data suggest that mushroom-derived ${\beta}$-glucan may exert its immunostimulating potency via activation of multiple signaling pathways.

• Journal of Physiology & Pathology in Korean Medicine
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• v.26 no.4
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• pp.469-474
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• 2012

Fagopyrum esculentum(FE) is an important food crop and medicinal plant that is used to improve diabetes, obesity, hypertension, hypercholesterolemia and constipation in Korea, but the underlying mechanisms involved in its anti-allergic activity are not fully understood. We investigated the effects on the release of inflammatory mediator and proximal signal events in $Fc{\varepsilon}RI$-mediated RBL-2H3 cell activation. FE reduced antigen (DNP-HSA)-induced release of histamine, prostaglandin D2 (PGD2) and cysteinyl Leukotriene (cysLT) in IgE-sensitized RBL-2H3 cells. In addition, it inhibited antigen-induced HDC2 and COX-2 and 5-LO mRNA expression in IgE-sensitized RBL-2H3 cells. FE also suppressed antigen-induced $Fc{\varepsilon}RI{\beta}$ and $Fc{\varepsilon}RI{\gamma}$ subunit mRNA expression in these cells. To identify the mechanisms underpinning the inhibition of release of inflammatory mediators such as histamine and PGD2 and cysLT by FE, we examined the proximal signal events of intracellular FceRI signaling molecules. FE suppressed antigen-induced phosphorylation of Lyn, Syk, LAT, $PLC{\gamma}1$, PI3K, Akt and cPLA2. Collectively, the anti-allergic effects of FE in vitro suggest its possible therapeutic application to inflammatory allergic diseases, in which its inhibition of inflammatory mediator and FceRI-dependent signaling events in mast cells may be hugely beneficial.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.7
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• pp.3219-3226
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• 2014

Chemotherapy continues to be a mainstay of cancer treatment, although drug resistance is a major obstacle. Lipid metabolism plays a critical role in cancer pathology, with elevated ether lipid levels. Recently, alkylglyceronephosphate synthase (AGPS), an enzyme that catalyzes the critical step in ether lipid synthesis, was shown to be up-regulated in multiple types of cancer cells and primary tumors. Here, we demonstrated that silencing of AGPS in chemotherapy resistance glioma U87MG/DDP and hepatic carcinoma HepG2/ADM cell lines resulted in reduced cell proliferation, increased drug sensitivity, cell cycle arrest and cell apoptosis through reducing the intracellular concentration of lysophosphatidic acid (LPA), lysophosphatidic acid-ether (LPAe) and prostaglandin E2 (PGE2), resulting in reduction of LPA receptor and EP receptors mediated PI3K/AKT signaling pathways and the expression of several multi-drug resistance genes, like MDR1, MRP1 and ABCG2. ${\beta}$-catenin, caspase-3/8, Bcl-2 and survivin were also found to be involved. In summary, our studies indicate that AGPS plays a role in cancer chemotherapy resistance by mediating signaling lipid metabolism in cancer cells.

• Molecules and Cells
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• v.41 no.10
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• pp.909-916
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• 2018

In pancreatic ${\beta}$ cells, glucose stimulates the biosynthesis of insulin at transcriptional and post-transcriptional levels. The RNA-binding protein, polypyrimidine tract-binding protein 1 (PTBP1), also named hnRNP I, acts as a critical mediator of insulin biosynthesis through binding to the pyrimidine-rich region in the 3'-untranslated region (UTR) of insulin mRNA. However, the underlying mechanism that regulates its expression in ${\beta}$ cells is unclear. Here, we report that glucose induces the expression of PTBP1 via the insulin receptor (IR) signaling pathway in ${\beta}$ cells. PTBP1 is present in ${\beta}$ cells of both mouse and monkey, where its levels are increased by glucose and insulin, but not by insulin-like growth factor 1. PTBP1 levels in immortalized ${\beta}$ cells established from wild-type (${\beta}IRWT$) mice are higher than levels in ${\beta}$ cells established from IR-null (${\beta}IRKO$) mice, and ectopic re-expression of IR-WT in ${\beta}IRKO$ cells restored PTBP1 levels. However, PTBP1 levels were not altered in ${\beta}IRKO$ cells transfected with IR-3YA, in which the Tyr1158/1162/1163 residues are substituted with Ala. Consistently, treatment with glucose or insulin elevated PTBP1 levels in ${\beta}IRWT$ cells, but not in ${\beta}IRKO$ cells. In addition, silencing Akt significantly lowered PTBP1 levels. Thus, our results identify insulin as a pivotal mediator of glucose-induced PTBP1 expression in pancreatic ${\beta}$ cells.

• YAKHAK HOEJI
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• v.51 no.6
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• pp.482-489
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• 2007

Kaempferitrin, isolated from Kenaf (Hibiscus cannabinus), was examined to evaluate its modulatory effects on antigen-presenting cell functions of macrophages/monocytes such as phagocytosis of foreign materials, up-regulation of costimulatory molecules (CD40, CD80 and CD86), adhesion molecule activation, and antigen processing and presentation. Kaempferitrin strongly blocked up-regulation of CD40, CD80 and CD86, but not pattern recognition receptor (PRR) (e.g., TLR2). It also suppressed functional activation of CD29 (${\beta}1$-integrins), as assessed by cell-cell adhesion assay, required for T cell-antigen-presenting cell (APC) interaction. Furthermore, this compound did not block a simple activation of CD29, as assessed by cell-fibronectin adhesion assay. However, the compound did not diminish phagocytic uptake, an initial step for antigen processing, and ROS generation in RAW264.7 cells. In particular, to understand molecular mechanism of kaempferitrin-mediated inhibition, the regulatory role of LPS-induced signaling events was examined using immunoblotting analysis. Interestingly, this compound dose dependently suppressed the phosphorylation of $I{\kappa}B{\alpha}$, Src, Akt and Syk, demonstrating that it can negatively modulate the activation of these signaling enzymes. Therefore, our data suggested that kaempferitrin may be involved in regulating APC function-relevant immune responses of macrophages and monocytes by regulating intracellular signaling.

• Journal of Microbiology and Biotechnology
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• v.29 no.7
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• pp.1155-1164
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• 2019

Lichens contain diverse bioactive secondary metabolites with various chemical and biological properties, which have been widely studied. However, details of the inhibitory mechanisms of their secondary metabolites against influenza A virus (IAV) have not been documented. Here, we investigated the antiviral effect of lichen extracts, obtained from South Korea, against IAV in MDCK cells. Of the lichens tested, Nipponoparmelia laevior (LC24) exhibited the most potent inhibitory effect against IAV infection. LC24 extract significantly increased cell viability, and reduced apoptosis in IAV-infected cells. The LC24 extract also markedly reduced (~ 3.2 log-fold) IAV mRNA expression after 48 h of infection. To understand the antiviral mechanism of LC24 against IAV, proteomic (UPLC-$HDMS^E$) analysis was performed to compare proteome modulation in IAV-infected (V) vs. mock (M) and LC24+IAV (LCV) vs. V cells. Based on Ingenuity Pathway Analysis (IPA), LC24 inhibited IAV infection by modulating several antiviral-related genes and proteins (HSPA4, HSPA5, HSPA8, ANXA1, ANXA2, $HIF-1{\alpha}$, AKT1, MX1, HNRNPH1, HNRNPDL, PDIA3, and VCP) via different signaling pathways, including $HIF-1{\alpha}$ signaling, unfolded protein response, and interferon signaling. These molecules were identified as the specific biomarkers for controlling IAV in vitro and further confirmation of their potential against IAV in vivo is required. Our findings provide a platform for further studies on the application of lichen extracts against IAV.

• Biomolecules & Therapeutics
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• v.30 no.4
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• pp.360-367
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• 2022

Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor. Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion. KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. Furthermore, KRC-108 exhibited antitumor activity in vivo in a KM12C cell xenograft model. These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers.

• Animal Bioscience
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• v.37 no.1
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• pp.61-73
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• 2024

Objective: The main objective of this study was to define molecular mechanisms associated with thermal stress responses of chickens from commercial broilers (BR, Ross 308), Thai native chickens (NT) and crossbreeds between BR×NT (H75). Methods: Twenty days before reaching specific market age, chickens from each breed were divided into control and thermal-stressed groups. The stressed groups were exposed to a cyclic thermal challenge (35℃±1℃ for 6 h, followed by 26℃±1℃ for 18 h) for 20 days. Control group was raised under a constant temperature of 26℃±1℃. Pectoralis major (n = 4) from each group was collected for transcriptome analysis using HiSeq Illumina and analysis of glycogen and lactate. Gene expression patterns between control and thermal-stressed groups were compared within the same breeds. Results: Differentially expressed transcripts of 65, 59, and 246 transcripts for BR, NT, and H75, respectively, were revealed by RNA-Seq and recognized by Kyoto encyclopedia of genes and genomes database. Pathway analysis underlined altered glucose homeostasis and protein metabolisms in all breeds. The signals centered around phosphatidylinositol 3-kinase (PI3K)/Akt signaling, focal adhesion, and MAPK signaling in all breeds with slight differences in molecular signal transduction patterns among the breeds. An extensive apoptosis was underlined for BR. Roles of AMPK, MAPK signaling and regulation of actin cytoskeleton in adaptive response were suggested for H75 and NT chickens. Lower glycogen content was observed in the breast muscles of BR and NT (p<0.01) compared to their control counterparts. Only BR muscle exhibited increased lactate (p<0.01) upon exposure to the stress. Conclusion: The results provided a better comprehension regarding the associated biological pathways in response to the cyclic thermal stress in each breed and in chickens with different growth rates.