• Journal of Microbiology and Biotechnology
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• 제32권2호
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• pp.256-262
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• 2022

Panax ginseng C. A. Meyer is well known as traditional herbal medicine, and ginseng berries are known to exhibit potential immune-enhancing functions. However, little is known about the in vivo immunomodulatory activity of Korean ginseng berries. In this study, crude Korean ginseng berries polysaccharides (GBP) were isolated and their immunomodulatory activities were investigated using cyclophosphamide (CY)-induced immunosuppressive BALB/c mice. In CY-treated mice, oral administration of GBP (50-500 mg/kg BW) remarkably increased their spleen sizes and spleen indices and activated NK cell activities. GBP also resulted in the proliferation of splenic lymphocytes (coordinating with ConA: plant mitogen which is known to stimulate T-cell or LPS: endotoxin which binds receptor complex in B cells to promote the secretion of pro-inflammatory cytokines) in a dose-dependent manner. In addition, GBP significantly stimulated mRNA expression levels of immune-associated genes including interleukin-1β (IL-1β), IL-2, IL-4, IL-6, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), toll-like receptor 4 (TLR-4), and cyclooxygenase-2 (COX-2) in CY-treated mice. These results indicate that GBP is involved in immune effects against CY-induced immunosuppression. Thus, GBP could be developed as an immunomodulation agent for medicinal or functional food application.

• 동의생리병리학회지
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• 제36권1호
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• pp.1-6
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• 2022

The tuber of Pinellia ternata (Thunb.) Brei (TPT) used in traditional Oriental medicine for the treatment of cough, sputum, vomiting, and insomnia, possesses antioxidant, antibacterial, and anti-inflammatory effects. Although recent studies have reported the anticancer effects of TPT in several cancer cells, it is still unclear whether TPT regulates tumor-associated macrophage (TAM) characterized by the immunosuppressive M2 macrophage phenotype. Our results showed that the ethanol extract of TPT (ETPT) suppressed the migration of RAW264.7 mouse macrophage cells and THP-1 human monocytes differentiated into macrophages towards the conditioned media (CM) collected from lung cancer cells, suggesting that ETPT would attenuate the recruitment of macrophages into tumors. In addition, ETPT suppressed the interleukin (IL)-4 or IL-6-induced M2 macrophage polarization in RAW264.7 cells. ETPT treatment not only downregulated the mRNA expression of M2 macrophage markers including arginase-1, mannose receptor C type 1 (MRC-1), and IL-10, but also inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and STAT6, general regulators of M2 macrophage polarization. Finally, the transwell assay results showed that the CM from M2-polarized RAW264.7 cells increased the migration of mouse lewis lung carcinoma (LLC) cells, while those from RAW264.7 cells co-treated with ETPT and IL-6 significantly reduced the migration of LLC cells. Taken together, our observations clearly demonstrate that ETPT suppressed the cancer cell migration by regulating macrophage recruitment and M2 macrophage polarization.

• 동의생리병리학회지
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• 제36권5호
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• pp.175-180
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• 2022

The seeds of Trichosanthes kirilowii (STK) used in traditional Oriental medicine for the treatment of dry cough and constipation have diverse pharmacological activities, including hypolipidemic, antioxidant, immunosuppressive, and anticancer effects. However, the effect of STK on angiogenesis has not been studied yet. In this study, we investigated whether the ethanolic extract of STK (ESTK) can regulate the migration and tube formation of human umbilical vein endothelial cells (HUVECs) and explored the underlying mechanism. Results of transwell assay showed that ESTK treatment dose-dependently suppressed the migration of HUVECs. The conditioned medium collected from H1299 human lung cancer cells was used as a chemoattractant. Our observation suggests that ESTK would inhibit the recruitment of endothelial cells into tumors. In addition, ESTK treatment significantly reduced the tube formation of HUVECs. As a molecular mechanism, we found that vascular endothelial growth factor (VEGF)-induced phosphorylation of VEGF receptor 2 (VEGFR2) was completely blocked by ESTK treatment. The expression of angiogenic factors, including VEGFA, fibroblast growth factor 2 (FGF2), angiopoietin, placental growth factor (PGF), platelet derived growth factor (PDGF), angiogenin, and tumor necrosis factor (TNF)-α, was commonly decreased by ESTK treatment in H1299 cells, indicating that ESTK would reduce the production of angiogenic factors from cancer cells. Taken together, our results clearly demonstrated that ESTK exhibited anti-angiogenic effects in HUVECs, which provides another possible mechanism underlying the anticancer activities of STK.

• Journal of Radiation Protection and Research
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• 제48권1호
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• pp.1-8
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• 2023

Background: The purpose of this study is to evaluate the immunosuppressive and antioxidant effects of a novel radioprotective agent using the vitamin E derivative 2-(alpha-D-glucopyranosyl)methyl-2,5,7,8-tetramethylchroman-6-ol (TMG) and its effect on tumors, and to study its usefulness. Materials and Methods: In this study, C57BL/6NCrSlc mice were divided into four groups (control, TMG, radiation therapy [RT], and RT+TMG), using 10 mice in each group. In the TMG and 2 Gy+TMG groups, 500 mg/kg TMG was administered. Two groups (2 Gy and 2 Gy+TMG) among RT and RT+TMG groups were irradiated with 2 Gy in a single fraction, while the other two groups (6 Gy and 6 Gy+TMG) were irradiated locally with 6 Gy in three fractions. Results and Discussion: TMG positively affected CD4+ and CD8+ T lymphocytes. Tumor volumes and growth inhibition rates were compared. In order to evaluate how TMG administration affected tumor growth, Ehrlich cancer cells were injected into the thigh of mice, and the tumor volume and growth suppression rate were compared. Not only RT but also TMG alone inhibited tumor growth. If RT conducted to the mice with TMG, TMG could increase the number of leukocytes, primarily that of lymphocytes. TMG also inhibited tumor growth in addition to RT. Tumor growth was significantly inhibited in the 6 Gy+TMG group. Conclusion: In conclusion, TMG exerted an immunopotentiating effect mainly by increasing the white blood cell numbers including that of lymphocytes. In addition to RT, TMG also inhibited tumor growth. Therefore, TMG is considered to be a useful radioprotective agent in radiotherapy without tumor growth induction.

• Tuberculosis and Respiratory Diseases
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• 제86권4호
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• pp.304-318
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• 2023

Background: Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and significantly contribute to immune evasion. We investigated the effects of CAFs on the immune function of CD4+ and CD8+ T cells in non-small cell lung cancer (NSCLC). Methods: We isolated CAFs and normal fibroblasts (NFs) from tumors and normal lung tissues of NSCLC patients, respectively. CAFs were co-cultured with activated T cells to evaluate their immune regulatory function. We investigated the effect of CAF conditioned medium (CAF-CM) on the cytotoxicity of T cells. CAFs were also co-cultured with activated peripheral blood mononuclear cells and further incubated with cyclooxygenase-2 (COX2) inhibitors to investigate the potential role of COX2 in immune evasion. Results: CAFs and NFs were isolated from the lung tissues (n=8) and lymph nodes (n=3) of NSCLC patients. Immune suppressive markers, such as COX2 and programmed death-ligand 1 (PD-L1), were increased in CAFs after co-culture with activated T cells. Interestingly, CAFs promoted the expression of programmed death-1 in CD4+ and CD8+ T cells, and strongly inhibited T cell proliferation in allogenic and autologous pairs of CAFs and T cells. CAF-CM decreased the cytotoxicity of T cells. COX2 inhibitors partially restored the proliferation of CD4+ and CD8+ T cells, and downregulated the expression of COX2, prostaglandin E synthase, prostaglandin E2, and PD-L1 in CAFs. Conclusion: CAFs promote immune evasion by suppressing the function of CD4+ and CD8+ T cells via their effects on COX2 and PD-L1 in NSCLC. The immunosuppressive function of CAFs could be alleviated by COX2 inhibitors.

• Tuberculosis and Respiratory Diseases
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• 제46권5호
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• pp.685-696
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• 1999

연구배경 : 특발성폐섬유화증은 만성적으로 간질 및 폐포에 염증반응과 섬유화가 진행되어 평균 생존기간이 5년 정도에 불과한 예후가 나쁜 질환이고 스테로이드나 면역억제제와 같이 부작용이 많은 약물치료로 효과를 보이는 환자는 일부에 불과하여 적극적 치료를 하기 힘든 실정이다. 이에 저자들은 특발성폐섬유화증에서 스테로이드 및 면역억제제 치료의 단기간 치료효과를 평가하면서 치료효과에 영향을 미치는 인자를 밝히고자 하였다. 방 법 : 1997년 1월부터 1998년 6월까지 삼성서울병원에서 수술적 폐생검을 통해 특발성 폐섬유화증으로 확진된 환자중 질환의 활동성이 있다고 판단되어 스테로이드나 면역억제제를 투여한 후 6개월이 경과한 18명 환자의 기록과 방사선 소견을 조사하였다. 치료전 기저검사로는 병력청취를 통한 임상적 특정과 폐기능검사, 기관지폐포세척술, 흉부HRCT를 시행하였고 치료 6개월째에 호흡곤란 정도의 변화, 폐기능검사의 변화와 흉부HRCT에서 병변 범위의 변화를 종합하여 치료효과를 판정하였다. 호전군은 1) 호흡곤란의 정도가 1단계이상 호전 2) FVC 또는 TLC가 10% 이상, 또는 DLco가 20% 이상 증가 3) 흉부HRCT소견상의 호전과 같은 3가지 항목중 2가지 이상 만족한 군으로 판정하였으며 나머지는 비호전군으로 정의하였다. 결 과 : 대상환자의 특성 대상환자 18명의 연령분포는 46세에서 69세로 연령의 중앙값은 54세였고, 남자가 6명, 여자가 12명이었다. 평균 흡연력은 8.6년이었고 치료전 호흡기증상의 기간이 평균 10개월이었다. 치료약제의 사용 전체 18명의 환자중 12명에서 prednisolone으로 치료를 시작하여 이중 2명은 치료중에도 임상적으로 악화를 보여 cyclophosphamide로 치료를 전환하였으나 질환의 악화가 진행하였으며 나머지 10명은 prednisolone만으로 끝까지 치료하여 7명이 호전군으로 판정되었다. Cyclophosphamide로 치료를 시작하였던 6명은 모두 약제변경없이 끝까지 투여하여 2명이 호전군으로, 4명은 비호전군으로 판정되었다. 치료효과 및 약제부작용 18명의 환자중 호전군이 9명이었고 비호전군이 9명이었다. 폐기능검사상 호전군에서 유일하게 FVC가 평균 15.7%가 증가하였고(p<0.05) 흉부HRCT 소견중 간유리음영의 면적이 유의한 감소를 보였으며($8.5{\pm}3.6%$ 감소, p<0.05) 비호전군에서는 불규칙 망상음영(2.7% 증가, p<0.05) 과 봉와양음영(7.0% 증가, p<0.05)의 범위가 증가하였다. 치료약제의 부작용으로는 스테로이드 유발성 정신병이 1명에서 발생하였는데 중도에 치료를 포기하여 최종 대상환자 18명에는 포함되지 않았고, 나머지 스테로이드 복용환자중 결핵성 늑막염 1명, 대상포진 2명, 백내장 1명, 당뇨병이 1명에서 발생하였고 cyclophosphamide 복용 환자군에서는 가벼운 위장장애 외에는 특별한 부작용이 없었다. 치료효과에 대한 예측인자 조직학적 분류상 NSIP(p<0.001), 여성(p<0.01), 호흡곤란의 정도가 3단계이상(p<0.05) 및 비흡연자(p<0.001), BAL 검사상 임파구 증가 소견(p<0.05)이 있었던 경우와 흉부HRCT상 불규칙 망상음영이나 봉와양음영의 면적이 적었던 경우(p<0.05)에 치료에 대한 반응이 좋았다. 결 론 : 특발성폐섬유화증 환자에서 내과적 약물치료는 적지 않은 부작용이 있었으나, 병리진단이 NSIP로 확인되거나 기관지폐포세척술 검사상 임파구 증가 소견이 있는 환자는 적극적인 스테로이드 및 면역억제제 치료를 통해 호전될 수 있을 것으로 생각된다. 향후 좀 더 많은 환자수에서 다변량분석을 통해 이러한 예측인자들의 독립적인 변수로서의 검정이 필요하리라 사료된다.

• 한국임상수의학회지
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• 제28권6호
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• pp.549-554
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• 2011

FK506은 말기 간암환자의 간이식 후 널리 사용되는 면역억제제이다. Dexamethasone은 세포독성 암 치료에서 오심 방지, 정상세포의 보호와 기타 이유 등의로 빈번하게 병용처치된다. 본 연구의 목적은 간암세포주(Hep3B)에서 FK506의 항암효과와 FK506에 의한 항암효과에 대한 dexamethasone의 억제효과를 알아보기 위함이다. 세포의 손상은 세포 생존성 평가와 LDH 및 세포내 ROS 양의 측정으로 평가 하였다. 세포내 칼슘 농도([$Ca^{2+}$]i)와 JNK, Bax 단백질의 발현 정도도 평가하였다. FK506의 처치는 Hep3B의 세포사를 유도하였으며 세포생존성의 감소와 LDH, ROS 및 [$Ca^{2+}$]i 를 증가시켰다. FK506은 Bax와 JNK 의 활성을 증가시켰으며 Bcl-2의 활성을 억제하였다. Dexamethasone 처치 그 자체는 세포생존성, LDH와 ROS에 영향을 주지 않았다. 그러나 dexamethasone과 FK506의 병용처치는 FK506에 의한 LDH 방출, ROS 생성 및 JNK의 활성을 감소시켰다. 이 결과는 간암세포주에서 FK506은 항암효과를 가지지만 dexamethasone의 병용처치는 FK506에 의한 항암효과를 길항한다.

• Biomolecules & Therapeutics
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• 제29권2호
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• pp.166-174
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• 2021

Multiple myeloma is a malignant cancer of plasma cells. Despite recent progress with immunomodulatory drugs and proteasome inhibitors, it remains an incurable disease that requires other strategies to overcome its recurrence and non-response. Based on the high expression levels of programmed death-ligand 1 (PD-L1) in human multiple myeloma isolated from bone marrow and the murine myeloma cell lines, NS-1 and MOPC-315, we propose PD-L1 molecule as a target of anti-multiple myeloma therapy. We developed a novel anti-PD-L1 antibody containing a murine immunoglobulin G subclass 2a (IgG2a) fragment crystallizable (Fc) domain that can induce antibody-dependent cellular cytotoxicity. The newly developed anti-PD-L1 antibody showed significant antitumor effects against multiple myeloma in mice subcutaneously, intraperitoneally, or intravenously inoculated with NS-1 and MOPC-315 cells. The anti-PD-L1 effects on multiple myeloma may be related to a decrease in the immunosuppressive myeloid-derived suppressor cells (MDSCs), but there were no changes in the splenic MDSCs after combined treatment with lenalidomide and the anti-PD-L1 antibody. Interestingly, the newly developed anti-PD-L1 antibody can induce antibody-dependent cellular cytotoxicity in the myeloma cells, which differs from the existing anti-PD-L1 antibodies. Collectively, we have developed a new anti-PD-L1 antibody that binds to mouse and human PD-L1 and demonstrated the antitumor effects of the antibody in several syngeneic murine myeloma models. Thus, PD-L1 is a promising target to treat multiple myeloma, and the novel anti-PD-L1 antibody may be an effective anti-myeloma drug via antibody-dependent cellular cytotoxicity effects.

• Journal of Acupuncture Research
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• 제22권2호
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• pp.71-81
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• 2005

Objective : Dear antler (Cervus korean TEMMINCK var. mantchuricus Swinhoe) used for traditional immunosuppressive and immuno-activating action. The effect of deer antler herbal-acupuncture(DAH) solution, prepared by water extract method, on cathepsin activities in bone tissues (cartilage and synovial) cells from mouse rheumatoid arthritis (RA) model was studied. The cysteine endoprotease cathepsin mediates degradation of the MHC class II invariant chain (Ii) in human and mouse antigen-presenting cells. The studies described here examine the functional significance of cathepsin inhibition on autoantigen presentation and organ-specific autoimmune diseases in a murine model for RA. Methods : An animal model for RA in BALB/c mice thymectomized 3 days after birth (3d-Tx) was constructed All 3d-Tx BALB/c mice developed autoimmune lesions in the bone tissue cells, starting at 3 weeks of age, and the disease mediated by CD4+ T cells was chronic and progressive. Significant inhibitory effects of DAH solution on cathepsin S and L were observed in each organ in a dose-dependent manner. Moreover, we confirmed that cathepsin S and L activity in each organ were clearly inhibited by DAB solution. When we examined the inhibitory effects of DAH solution against autoantigen-specific T cell responses in vitro, in regional lymph node cells, but not in spleens, from model mice, a significant inhibitory effect of DAB solution was observed in a dose-dependent manner. DAH solution do not block T cell proliferation to Con A, indicated that the dose of DAB solution 10 to $20\;{\mu}g/m{\ell}$ was sufficient to inactivate the autoantigen-specific T cell responses in vitro. In vivo therapeutic effects of DAB solution were examined in a murine model for RA, autoantigen-specific (C-II-specific) T cell response were significantly inhibited in LNCs from DAH solution-treated mice. Results : Iinhibition of cathepsin S and L in vivo alters autoantigen presentation and development of organ-specific autoimmunity in RA model. Conclusion : These data identify selective inhibition of cysteine protease cathepsin S and L as a potential therapeutic strategy for autoimmune disease process such RA. Thus, DAH solution will served as a potent anti-inflammatory and anti-arthritic agents for treatment of human RA.

• IMMUNE NETWORK
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• 제7권1호
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• pp.31-38
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• 2007

Background: Mizoribine (MZR) is an imidazole nucleoside isolated from Eupenicillium brefeldianum. MZR is currendy in clinical use for patients who have undergone renal transplantation. Therapeutic efficacy of MZR has also been demonstrated in rheumatoid arthritis and lupus nephritis. MZR has been shown to inhibit the proliferation or lymphocytes by interfering with inosine monophosphate dehydrogenase. Since the exact mechanism by which MZR benefits rheumatoid arthritis (RA) is not clear, we investigated the ability of MZR to direct its immunosuppressive influences on other antigen presenting cells, such as macrophages. Methods: Mouse macrophage RAW264.7 cells were stimulated with lipopolysaccharide in the presence of MZR. To elucidate the mechanism of the therapeutic efficacy in chronic inflammatory diseases, we examined the effects of MZR on the production of pro-inflammatory cytokines, nitric oxide (NO) and prostaglandin $E_2\;(PGE_2)$ in macrophages. Results: MZR dose-dependendy decreased the production of nitric oxide and pro- inflammatory cytokines such as tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$), interleukins $1{\beta}$ (IL-${\beta}$ and IL-6 $PGE_2$. Examination of gene expression levels showed that the anti-inflammatory effect correlated with the down-regulation of inducible nitiric oxide synthase expression, cycloxygenase-2 expression and TNF-${\alpha}$ gene expression. Conclusion: In this work, we resulted whether MZR $(1.25{\sim}10{\mu}g/ml)$ inhibited macrophage activation by inhibiting secretion of pro-inflammatory cytokines, NO and $PGE_2$. These findings provide an explanation for the therapeutic efficacy of MZR in chronic inflammation-associated diseases.