• BMB Reports
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• v.54 no.1
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• pp.2-11
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• 2021

Antibody-based therapeutics targeting the inhibitory receptors PD-1, PD-L1, or CTLA-4 have shown remarkable clinical progress on several cancers. However, most patients do not benefit from these therapies. Thus, many efforts are being made to identify new immune checkpoint receptor-ligand pathways that are alternative targets for cancer immunotherapies. Nectin and nectin-like molecules are widely expressed on several types of tumor cells and play regulatory roles in T- and NK-cell functions. TIGIT, CD226, CD96 and CD112R on lymphoid cells are a group of immunoglobulin superfamily receptors that interact with Nectin and nectin-like molecules with different affinities. These receptors transmit activating or inhibitory signals upon binding their cognate ligands to the immune cells. The integrated signals formed by their complex interactions contribute to regulating immune-cell functions. Several clinical trials are currently evaluating the efficacy of anti-TIGIT and anti-CD112R blockades for treating patients with solid tumors. However, many questions still need to be answered in order to fully understand the dynamics and functions of these receptor networks. This review addresses the rationale behind targeting TIGIT, CD226, CD96, and CD112R to regulate T- and NK-cell functions and discusses their potential application in cancer immunotherapy.

• Journal of Applied Biological Chemistry
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• v.65 no.2
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• pp.93-99
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• 2022

Lysosome organelle extract (LOE) was derived from egg whites. The lysosome is an intracellular organelle that contains several hydrolysis enzymes. Previous studies have reported that LOE performs important functions, such as melanin de-colorization and anti-melanin production in B16F10 melanoma cells. However, its principal molecular and cellular mechanisms have not been elucidated till date. In non-cytotoxic conditions, LOE significantly inhibited α-MSH induced melanin synthesis of murine B16F10 cells. The anti-melanogenic activity of LOE was mediated by suppressing the mRNA expression of tyrosinase enzyme, tyrosinase related protein-1/2 (TRP-1/2), and microphthalmia-associated transcription factor (MITF) genes. By performing western blot analysis, we found that LOE significantly attenuated melanogenesis. In this case, LOE helped in increasing extracellular receptor kinase (ERK) phosphorylation in α-MSH induced B16F10 cells. Furthermore, MITF is found to be a key regulatory transcription factor in melanin synthesis; it was down-regulated by LOE through ERK phosphorylation. In this experiment, PD98059 (MEK inhibitor) was used to check whether LOE directly regulated the activity of ERK. Although LOE exerted inhibitory effect on melanin synthesis, we could not observe this effect in PD98059-treated α-MSH induced B16F10. These results strongly indicate that LOE is related to ERK activation and MITF degradation in anti-skin pigmentation. Hence, LOE should be utilized as a whitening agent of skin in the near future.

• Proceedings of the Ginseng society Conference
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• 1998.06a
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• pp.224-230
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• 1998

This study showed the anti-invasive activity of ginseng components, panaxadiol (PD) and panamatrlol (PT) on the highly metastatic HT1080 human flbrosarcoma cell line. PD and PT reduced tumor cell invasion through a reconstitute basement membrane in the transwell chamber. A significant down regulation of MMP-9 by PD and PT was detected by northern blot analysis. However, MMP-2 was constantly expressed. Quantitative gelatin based zymography confirmed a marked reduced expression of MMP-9 but not MMP-2 in the treatment of PD and PT. Since the chemical structures of PD and PT are very similar to that of dexamethasone, a synthetic glucocorticoid, it was investigated whether PD and PT act through GR. Western blot analysis and immunocytochemistry showed that PD and PT increased the GR fraction in the nucleus. These results suggest that ursolic acid may induce repression of MMP-9 by stimulating the nuclear translocation of GR and hence inhibiting the activity of AP-1 to TPA-responsible element of MMP-9 promoter region. In conclusion, we suggest that CR-induced down-regulation of MMP-9 by PD and PT contributes to reduce the invasive capacity of HT 1080 cells.

• Radiation Oncology Journal
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• v.34 no.4
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• pp.250-259
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• 2016

Immune checkpoint blockades including monoclonal antibodies (mAbs) of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) have been emerged as a promising anticancer therapy. Several immune checkpoint blockades have been approved by US Food and Drug Administration (FDA), and have shown notable success in clinical trials for patients with advanced melanoma and non-small cell lung cancer. Radiotherapy is a promising combination partner of immune checkpoint blockades due to its potent pro-immune effect. This review will cover the current issue and the future perspectives for combined with radiotherapy and immune checkpoint blockades based upon the available preclinical and clinical data.

• Journal of Ginseng Research
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• v.29 no.2
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• pp.94-99
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• 2005

In the previous study, we reported that the in viかo inhibitory effect of ginsenosides, active ingredient of Panax ginseng, on $5-HT_{3A}$ receptor channel activity is coupled to in vivo anti-vomiting and anti-nausea effect. In the present study, we further investigated that the inhibitory effect of ginsenosides, active ingredient of Panax ginseng, on 5-HT3A receptor channel activity is also coupled to attenuation of irritable bowel syndrome (IBS), which is induced by colorectal distention (CRD) and $0.6\%$ acetic acid treatment. The CRD-induced visceral pains induced by CRD and acetic acid treatment are measured by frequency of contractions of the external oblique muscle in conscious rats. Treatment of GTS significantly inhibited CRD-induced visceral pain with dose-dependent manner. The $EC_{50}$ was $5.5{\pm}4.7$ mg/kg ($95\%$ confidence intervals: 1.2-15.7) and the antinociceptive effect of GTS on visceral pain was persistent for 4 h. We also compared the effects of protopanaxadiol (PD) ginsenosides and protopanaxatriol (PT) ginsenosides with saline on acetic acid-and CRD-induced visceral pain, and found that protopanaxatriol (PT) ginsenosides was much more potent than PD ginsenosides in attenuating CRD-induced visceral pain. These results indicate that U ginsenosides of Panax ginseng are components far attenuation of experimentally CRD-induced visceral pains.

• Mycobiology
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• v.51 no.2
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• pp.94-108
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• 2023

Termitomyces sp. that grow in symbiosis with fungus-farming Termites have medicinal properties. However, they are rare in nature, and their artificial culture is challenging. The expression of AXL receptor tyrosine kinase and immune checkpoint molecules favor the growth of cancer cells. The study evaluated the optimal conditions for the artificial culture of Termitomyces and their inhibitory activity on AXL and immune checkpoint molecules in lung adenocarcinoma and melanoma cell lines. The culture of 45 strains of Termitomyces was compared. Five strains with marked growth rates were selected. Four of the selected strains form a single cluster by sequence analysis. The mycelium of 4 selected strains produces more fungal mass in potato dextrose broth than in a mixed media. The bark was the most appropriate solid substrate for Termitomyces mycelia culture. The mycelium of all five selected strains showed a higher growth rate under normal CO₂ conditions. The culture broth, methanol, and ethyl acetate of one selected strain (T-120) inhibited the mRNA relative expression of AXL receptor tyrosine kinase and immune checkpoint molecules in cancer cell lines. Overall, these results suggest the potential usefulness of Termitomyces extracts as a coadjuvant therapy in malignant diseases.

• The Korean Journal of Pharmacology
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• v.24 no.1
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• pp.31-42
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• 1988

The effect of Panaxadiol(PD), which is an active component of Korean Ginseng Saponins, on the secretion of catecholamines (CA) from the rabbit adrenal gland and its mode of action were investigated in the present study. $PD(400{\mu}g)$ increased significantly the secretion of CA from the isolated perfused rabbit adrenal gland. PD-induced secretion of CA was reduced markedly by treatment of atropine, CA secretion induced by Ach or PD was potentiated significantly by physostigmine-treatment. Chlorisondamine did inhibit CA secretion of PD or Ach. Perfusion of $PD(400{\mu}g)$ for 30 min enhanced the secretory activity of CA by Ach. Ouabain weakened the secretory response induced by PD but rather enhanced the response by Ach. Adenosine-treatment resulted in marked enhancement of CA secretion by PD or Ach, Pefusion with $Ca^{2+}-free$ Krebs containing EGTA (5 mM) for about 30 min totally blocked secretory effect induced by Ach and also weakened that by PD. From the above experimental results, it is suggested that PD causes secretion of catecholamines from the rabbit adrenal gland by a calcium-dependent exocytotic mechanism. The secretory effect of PD is due to the stimulation of cholinergic muscarinic and nicotinic receptors present in the adrenal gland and partly to a direct action on the chromaffin cell itself.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.3
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• pp.1321-1326
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• 2014

Background/Aim: Toll-like receptor 4 (TLR4) and B7-H1, both normally expressed restricted to immune cells, are found to be aberrantly expressed in a majority of human tumors and may play important roles in regulation of tumor immunity. It has been shown that urothelial bladder cancer (UBC) patients can manifest tumoral immune escape which may be a potential critical factor in tumor pathogenesis and progression. However, so far, the mechanisms of UBC-related immune escape have not been clarified. The aim of this study was to investigate the effect of TLR4 and B7-H1 on immune escape of UBC. Methods: Bladder cancer T24 cells were pre-incubated with LPS and co-cultured with tumor specific CTLs. CTL cytotoxicity and apoptosis rates were measured by MTT assay and flow cytometry, respectively. The effects of an ERK inhibitor on B7-H1 expression and CTL cytotoxicity against T24 cells were also evaluated. In addition, TLR4, B7-H1 and PD-1 protein expression was analyzed by immunohistochemistry in 60 UBC specimens and 10 normal urothelia. Results: TLR4 activation protected T24 cells from CTL killing via B7-H1 overexpression. However PD98059, an inhibitor of ERK, enhanced CTL killing of T24 cells by reducing B7-H1 expression. TLR4 expression was generally decreased in UBC specimens, while B7-H1 and PD-1 were greatly overexpressed. Moreover, expression of both B7-H1 and PD-1 was significantly associated with UICC stage and WHO grade classification. Conclusions: TLR4 and B7-H1 may contribute to immune escape of UBC. Targeting B7-H1 or the ERK pathway may offer new immunotherapy strategies for bladder cancer.

• Tuberculosis and Respiratory Diseases
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• v.82 no.3
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• pp.227-233
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• 2019

Background: Programmed death-ligand 1 (PD-L1), a transmembrane protein, binds to the programmed death-1 (PD-1) receptor, and anti-PD-1 therapy enables immune responses against tumors. This study aimed to assess clinical characteristics of PD-L1 expression using immunohistochemistry among Korean patients with lung cancer. Methods: We retrospectively reviewed the data of patients with pathologically proven lung cancer from a single institution. PD-L1 expression determined by Tumor Proportion Score (TPS) was detected using 22C3 pharmDx (Agilent Technologies) and SP263 (Ventana Medical Systems) assays. Results: From July 2016 to July 2017, 267 patients were enrolled. The main histologic type was adenocarcinoma (69.3%). Most participants were smokers (67.4%) and had clinical stage IV disease (60.7%). In total, 116 (42%) and 58 (21%) patients had TPS ${\geq}1%$ and ${\geq}50%$, respectively. The patients were significantly older in TPS ${\geq}1%$ group than in TPS <1% group ($64.83{\pm}9.38years$ vs. $61.73{\pm}10.78years$, p=0.014), not in TPS ${\geq}50%$ cutoff value ($64.69{\pm}9.39$ vs. $62.36{\pm}10.51$, p=0.178). Regarding histologic grade, higher proportions of poorly differentiated tumor were observed in the TPS ${\geq}1%$ (40.8% vs. 25.8%, p=0.020) and TPS ${\geq}50%$ groups (53.2% vs. 27.2%, p=0.004). Among 34 patients examined with 22C3 and SP263 assays, 27 had positive results in both assays, with a cutoff of TPS ${\geq}1%$ (r=0.826; 95% confidence interval, 0.736-0.916). Conclusion: PD-L1 expression, defined as TPS ${\geq}1%$, was related to older age and poorly differentiated histology. There was a similar distribution of PD-L1 expression in both 22C3 and SP263 results.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.6
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• pp.499-506
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• 2015

Angiotensin II (Ang II), a key mediator of hypertensive, causes structural changes in the arteries (vascular remodeling), which involve alterations in cell growth, vascular smooth muscle cell (VSMC) hypertrophy. Ang II promotes fibrotic factor like IGFBP5, which mediates the profibrotic effects of Ang II in the heart and kidneys, lung and so on. The purpose of this study was to identify the signaling pathway of IGFBP5 on cell proliferation and migration of Ang II-stimulated VSMC. We have been interested in Ang II-induced IGFBP5 and were curious to determine whether a Pitavastatin would ameliorate the effects. Herein, we investigated the question of whether Ang II induced the levels of IGFBP5 protein followed by proliferation and migration in VSMC. Pretreatment with the specific Angiotensin receptor type 1 (AT1) inhibitor (Losartan), Angiotensin receptor type 2 (AT2) inhibitor (PD123319), MAPK inhibitor (U0126), ERK1/2 inhibitor (PD98059), P38 inhibitor (SB600125) and PI3K inhibitor (LY294002) resulted in significantly inhibited IGFBP5 production, proliferation, and migration in Ang II-stimulated VSMC. In addition, IGFBP5 knockdown resulted in modulation of Ang II induced proliferation and migration via IGFBP5 induction. In addition, Pitavastatin modulated Ang II induced proliferation and migration in VSMC. Taken together, our results indicated that Ang II induces IGFBP5 through AT1, ERK1/2, P38, and PI3K signaling pathways, which were inhibited by Pitavastatin. These findings may suggest that Pitavastatin has an effect on vascular disease including hypertension.