• Biomolecules & Therapeutics
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• v.24 no.1
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• pp.62-66
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• 2016

Amygdalin, D-mandelonitrile-${\beta}$-D-glucoside-6-${\beta}$-glucoside, belongs to aromatic cyanogenic glycoside group derived from rosaceous plant seed. Mounting evidence has supported the anti-cancer effects of amygdalin. However, whether amygdalin indeed acts as an anti-tumor agent against breast cancer cells is not clear. The present study aimed to investigate the effect of amygdalin on the proliferation of human breast cancer cells. Here, we show that amygdalin exerted cytotoxic activities on estrogen receptors (ER)-positive MCF7 cells, and MDA-MB-231 and Hs578T triple-negative breast cancer (TNBC) cells. Amygdalin induced apoptosis of Hs578T TNBC cells. Amygdalin downregulated B-cell lymphoma 2 (Bcl-2), upregulated Bcl-2-associated X protein (Bax), activated of caspase-3 and cleaved poly ADP-ribose polymerase (PARP). Amygdalin activated a pro-apoptotic signaling molecule p38 mitogen-activated protein kinases (p38 MAPK) in Hs578T cells. Treatment of amygdalin significantly inhibited the adhesion of Hs578T cells, in which integrin ${\alpha}5$ may be involved. Taken together, this study demonstrates that amygdalin induces apoptosis and inhibits adhesion of breast cancer cells. The results suggest a potential application of amygdalin as a chemopreventive agent to prevent or alleviate progression of breast cancer, especially TNBC.

• International Journal of Molecular Medicine
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• v.46 no.5
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• pp.1923-1937
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• 2020

It has been suggested that oxidative stress involving reactive oxygen species (ROS) induces granulosa cell apoptosis, leading to follicular atresia, and that T-lymphokine-activated killer cell-originated protein kinase (TOPK) suppresses cancer cell apoptosis induced by several stimuli. However, it remains to be determined whether TOPK affects oxidative stress-induced granulosa cell apoptosis. The present study demonstrates that TOPK inhibition increases human granulosa COV434 cell apoptosis induced by hydrogen peroxide (H₂O₂). Co-treatment with the TOPK inhibitor, OTS514, in combination with H₂O₂ increased p53 acetylation and its expression, whereas it decreased Sirtuin 1 (SIRT1) expression, contributing to the promotion of apoptosis. In addition, the SIRT1 activator, resveratrol, or the SIRT1 inhibitor, Ex527, reduced or elevated H₂O₂-induced COV434 cell apoptosis, respectively. Furthermore, the p53 inhibitor, Pifithrin-μ, diminished the augmentation in poly(ADP-ribose) polymerase (PARP) cleavage induced by OTS514 plus H₂O₂, while the Mdm2 antagonist, Nutlin 3, increased PARP cleavage. Moreover, OTS514 further decreased the SIRT1 transcriptional activity decreased by H₂O₂, but promoted the H₂O₂-induced p53 or p21 transcriptional activity. Notably, the expression of exogenous p53 reduced SIRT1 transcriptional activity. Taken together, the findings of the present study demonstrate that TOPK inhibition promotes p53-mediated granulosa cell apoptosis through SIRT1 downregulation in response to H₂O₂. Therefore, it can be concluded that TOPK suppresses H₂O₂-induced apoptosis through the modulation of the p53/SIRT1 axis, suggesting a potential role of TOPK in the regulation of human granulosa cell apoptosis, leading to the promotion of abnormal follicular development.

• The Journal of Internal Korean Medicine
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• v.28 no.4
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• pp.902-910
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• 2007

Objective : Peroxisome proliferator-activated receptor (PPAR)-gamma, a transcription factor in adipocyte differentiation, has important effects on insulin sensitivity, atherosclerosis, endothelial cell function and inflammation. Through these effects, PPAR-gamma2 might be involved with type 2 diabetes and vascular disease, including diabetic complications. Recently, it has been reported that the C161T polymorphism in the exon 6 of PPAR-gamma is associated with type 2 diabetes interacting with uncoupling protein 2 (UCP2) gene, and is associated with acute myocardial infarction. We studied the association of this polymorphism with type 2 diabetes and its complications, such as retinopathy, ischemic stroke, nephropathy and neuropathy in Korean non-diabetic and type 2 diabetic populations. Methods : Three hundred and thirty eight type 2 diabetic patients (retinopathy: 64, ischemic stroke: 67, nephropathy: 39 and neuropathy: 76) and 152 healthy matched control subjects were evaluated. The PPAR-gamma C161T polymorphism was analyzed by PCR-RFLP. Results : PPAR-gamma C161T genotype and allele frequency did not show significant differences between type 2 diabetic patients and healthy controls (T allele: 17.0 vs. 14.5, OR= 1.21, P=0.3188). In the analysis for diabetic complications, T allele in diabetic nephropathy was significantly higher than controls (P=0.0358). T allele in the ischemic stroke patients was also higher than healthy controls, although it had no significance (P=0.1375). Conclusions : These results suggest that the C161T polymorphism of the PPAR-gamma gene might be associated with diabetic nephropathy in type 2 diabetes.

• Oncology Reports
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• v.43 no.2
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• pp.711-717
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• 2020

The aim of the present study was to investigate the metabolic and anticancer effects of troglitazone (TGZ) with a focus on the potential role of mitochondrial pyruvate utilization. 2-Deoxyglucose (2-DG) was more cytotoxic in CT26 cancer cells compared with T47D cells, despite a smaller suppression of glucose uptake. On the other hand, TGZ caused a more prominent shift to glycolytic metabolism and was more cytotoxic in T47D cells. Both effects of TGZ on T47D cells were dose-dependently reversed by addition of methyl pyruvate (mPyr), indicating suppression of mitochondrial pyruvate availability. Furthermore, UK5099, a specific mitochondrial pyruvate carrier inhibitor, closely simulated the metabolic and antitumor effects of TGZ and their reversal by mPyr. This was accompanied by a substantial reduction of activated p70S6K. In CT26 cells, UK5099 did not reduce activated p70S6K and only modestly decreased cell proliferation. In these cells, combining glutamine restriction with UK5099 further increased glucose uptake and completely suppressed cell proliferation. Thus, TGZ-mediated inhibition of mitochondrial pyruvate utilization is an effective treatment for cancer cells that are more dependent on mitochondrial glucose metabolism. By contrast, cancer cells that are more glycolysis-dependent may require suppression of glutamine utilization in addition to blocking mitochondrial pyruvate availability for a full antitumor effect.

• Journal of Korean Neurosurgical Society
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• v.66 no.4
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• pp.356-381
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• 2023

Although immunotherapy has been broadly successful in the treatment of hematologic malignancies and a subset of solid tumors, its clinical outcomes for glioblastoma are still inadequate. The results could be due to neuroanatomical structures such as the blood-brain-barrier, antigenic heterogeneity, and the highly immunosuppressive microenvironment of glioblastomas. The antitumor efficacy of endogenously activated effector cells induced by peptide or dendritic cell vaccines in particular has been insufficient to control tumors. Effector cells, such as T cells and natural killer (NK) cells can be expanded rapidly ex vivo and transferred to patients. The identification of neoantigens derived from tumor-specific mutations is expanding the list of tumor-specific antigens for glioblastoma. Moreover, recent advances in gene-editing technologies enable the effector cells to not only have multiple biological functionalities, such as cytokine production, multiple antigen recognition, and increased cell trafficking, but also relieve the immunosuppressive nature of the glioblastoma microenvironment by blocking immune inhibitory molecules, which together improve their cytotoxicity, persistence, and safety. Allogeneic chimeric antigen receptor (CAR) T cells edited to reduce graft-versus-host disease and allorejection, or induced pluripotent stem cell-derived NK cells expressing CARs that use NK-specific signaling domain can be a good candidate for off-the-shelf products of glioblastoma immunotherapy. We here discuss current progress and future directions for T cell and NK cell therapy in glioblastoma.

• Journal of Microbiology and Biotechnology
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• v.27 no.10
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• pp.1820-1826
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• 2017

Lipoteichoic acid (LTA), a cell wall component of gram-positive bacteria, is recognized by Toll-like receptor 2, expressed on certain mammalian cell surfaces, initiating signaling cascades that include nuclear factor kappa-light-chain-enhancer of activated B cells (NF-${\kappa}B$) and mitogen-activated protein kinase. There are many structural and functional varieties of LTA, which vary according to the different species of gram-positive bacteria that produce them. In this study, we examined whether LTA isolated from Staphylococcus aureus (aLTA) affects the expression of junction proteins in keratinocytes. In HaCaT cells, tight junction-related gene expression was not affected by aLTA, whereas adherens junction-related gene expression was modified. High doses of aLTA induced the phosphorylation of extracellular signal-regulated protein kinases 1 and 2, which in turn induced the epithelial-mesenchymal transition (EMT) of HaCaT cells. When cells were given a low dose of aLTA, however, NF-${\kappa}B$ was activated and the total cell population increased. Taken together, our study suggests that LTA from S. aureus infections in the skin may contribute both to the outbreak of EMT-mediated carcinogenesis and to the genesis of wound healing in a dose-dependent manner.

• Journal of Korean Medicine for Obesity Research
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• v.19 no.2
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• pp.89-96
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• 2019

Objectives: We investigated whether membrane free stem cell extract from adipose tissue (MFSCE) has anti-diabetic effect. Methods: To determine glucose uptake effect of MFSCE, we carried out glucose uptake assay in 3T3-L1 adipocytes. The regulatory mechanisms of MFSCE on glucose uptake were examined by Western blot analysis. Results: When MFSCE was treated to adipocytes at the concentration of 0.5, 1, 2.5, and 5 ㎍/mL, 2-deoxyglucose-6-phosphate uptake was elevated approximately 1.8-fold compared to cells not treated with MFSCE. It indicated that MFSCE enhances glucose uptake in 3T3-L1 adipocytes. In addition, MFSCE reduced phosphorylation of insulin receptor substrate-1 at serine 307 and induced Akt and glucose transporter 4 protein expressions that were related to insulin signaling. Furthermore, MFSCE regulated adenosine monophosphate-activated protein kinase (AMPK) pathway by increases of increase phosphorylation of AMPK and acetyl-CoA carboxylase that were related to AMPK pathway. Conclusions: These results indicated that MFSCE promotes glucose uptake via modulation of insulin signaling and AMPK pathway. Therefore, MFSCE could be a promising agent for treatment of diabetes mellitus.

• Biomedical Science Letters
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• v.2 no.2
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• pp.175-185
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• 1996

The mitogen-activated protein(MAP) kinase signal transduction pathway represents an important mechanism by which mitogen, such as serum and PMA, regulate cell proliferation and differentiation. Target substrates of the MAP kinase are located within several compartments containing plasma membranes and nucleus. We now report that serum addition induces proliferation of the P388 murine leukemia cell, but PMA does not, while both serum and PMA treatment cause translocation of the MAP kinase, mainly p42$^{mapk}$ isoform, from cytosol into the nucleus, which was monitored by immunoblot analysis using polyclonal anti-ERK1 antibodies. We investigated whether the MAP kinase was capable of phosphorylating c-Jun protein and GST-fusion proteins, the P562$^{kk}$N-terminal peptides (1-77 or 1-123 domain) of the T cell tyrosine kinase, using the partially purified MAP kinase by SP-sephadex C-50, phenyl superose and Mono Q column chromatography. We found that the partially purified MAP kinase was able to phosphorylate c-Jun protein and the GST-fusion protein expressed using E.coli DH5$\alpha$ which is transformed with pGEX-3Xb plasmid vector carrying of p562$^{kk}$N-terminal peptide-encoding DNA. These results imply that tyrosine kinase receptor/Ras/Raf/MAP kinase pathway is a major mechanism for mitogen-induced cell proliferation in P388 murine leukemia cell and that the various MAP kinase isoforms may have their own target substrates located in distinct subcellular compartments.

• IMMUNE NETWORK
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• v.7 no.4
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• pp.167-172
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• 2007

Various cell types that express regulatory function may influence the pathogenesis of most and perhaps all infections. Some regulatory cells are present at the time of infection whereas others are induced or activated in response to infection. The actual mechanisms by which different types of infections signal regulatory cell responses remain poorly understood. However a most likely mechanism is the creation of a microenvironment that permits the conversion of conventional T cells into cells with the same antigen specificity that have regulatory function. Some possible means by which this can occur are discussed. The relationship between regulatory cells and infections is complex especially with chronic situations. The outcome can either be of benefit to the host or damage the disease control process or in rare instances appears to be a component of a finely balanced relationship between the host and the infecting agent. Manipulating the regulatory cell responses to achieve a favorable outcome of infection remains an unfulfilled objective of therapeutic immunology.

• Food Science and Biotechnology
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• v.18 no.4
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• pp.928-931
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• 2009

Effects of perilla leaf extracts (PLE) on adipocytes differentiation of 3T3-L1 cells were examined. Ethanol extract of PLE treatment significantly decreased lipid accumulation, a marker of adipogenesis, in a dose-dependent manner. Moreover, gene expression levels of peroxisome proliferator-activated receptor ${\gamma}$ ($PPAR{\gamma}$), the key adipogenic transcription factor, were markedly decreased by PLE. PLE also suppressed adipocyte fatty acid binding protein (aP2) and glycerol-3-phosphate dehydrogenase (GPDH), which are adipogenic marker proteins. These results suggest that PLE treatment suppressed differentiation of 3T3-L1 adipocytes, in part by down-regulating expression of adipogenic transcription factor and other specific target genes.