• Asian Pacific Journal of Cancer Prevention
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• 제15권6호
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• pp.2439-2445
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• 2014

Cryptotanshinone (CPT), is a quinoid diterpene isolated from the root of the Asian medicinal plant, Salvia miotiorrhiza bunge. Numerous researchers have found that it could work as a potent antitumor agent to inhibit tumor growth in vitro, buith there has been much less emphasis on its in vivo role against breast tumors. Using a mouse tumor model of MCF7 cells, we showed that CPT strongly inhibited MCF7 cell growth in vivo with polarization of immune reactions toward Th1-type responses, stimulation of naive CD4+ T cell proliferation, and also increased IFN-${\gamma}$ and perforin production of CD4+ T cells in response to tumor-activated splenocytes. Furthermore, data revealed that the cytotoxic activity of CD4+ T cells induced by CPT was markedly abrogated by concanamycin A(CMA), a perforin inhibitor, but not IFN-${\gamma}$ Ab. On the other hand, after depletion of CD4+ T cells or blocked perforin with CMA in a tumor-bearing model, CPT could not effectively suppress tumor growth, but this phenomenon could be reversed by injecting naive CD4+ T cells. Thus, our results suggested that CPT mainly inhibited breast tumor growth through inducing cytotoxic CD4+ T cells to secrete perforin. We further found that CPT enhanced perforin production of CD4+ T cells by up-regulating JAK2 and STAT4 phosphorylation. These findings suggest a novel potential therapeutic role for CPT in tumor therapy, and demonstrate that CPT performs its antitumor functions through cytotoxic CD4+ T cells.

• IMMUNE NETWORK
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• 제13권4호
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• pp.116-122
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• 2013

This study was conducted to determine whether CD4 T cell responses to citrullinated fibrinogen occur in patients with rheumatoid arthritis (RA), especially in HLA-DR4-positive subjects. Whole peripheral blood mononuclear cells (PBMCs) of RA patients and control subjects were stimulated with citrullinated fibrinogen peptides, and T-cell production of proliferation and proinflammatory cytokines, such as interferon-${\gamma}$(IFN-${\gamma}$) and interleukin-17A (IL-17A), were measured. In addition, CD4 T cells from RA patients were stimulated with the citrullinated fibrinogen peptide, $Fib-{\alpha}$ R84Cit, identified as a DRB1*0401-restricted T cell epitope in HLA-DR4 transgenic mice, and the degree of T cell activation was examined similarly. No proliferative responses to the citrullinated fibrinogen peptides were observed in whole PBMCs or CD4 T cells from RA patients. Furthermore, no increased production of IFN-${\gamma}$ or IL-17A was found in whole PBMCs or CD4 T cells stimulated with the citrullinated fibrinogen peptides, although these cells responded to recall antigen, a mixture of tetanus toxoid, purified protein derivative (PPD) from Mycobacterium tuberculosis, and Candida albicans. The results of this study indicate that anti-citrulline immunity in RA patients may be mediated by fibrinogen because there is no evidence of CD4 T cell-mediated immune responses to citrullinated fibrinogen peptides.

• 융합정보논문지
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• 제11권4호
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• pp.111-121
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• 2021

감국의 유산균 발효를 통한 감국 배양물(CILL)의 비만억제 식품의 소재로서 가능성을 알아보기 위해 고지방식이로 유도된 C57BL/6 mice에서의 체중, body fat mass, T cell 등을 측정하였다. 체중 변화에서 CILL 군 (25.15±2.44 g)은 4주부터 체중 감소를 보였으며, 1주차부터 8주차까지 낮은 증체량을 유지했다(1.00±0.53 g). 8주 체중(30.38±4.17 g)은 HFD 군(60% high fat diet, 34.99±2.09 g) 대비 13.15%의 체중 감소를 보였다. Fat mass는 10.3022±2.8813 g로 감소했으며, 간 절대 중량에서 HFD 군에 비해 감소하였다. CD4+ T cell 4.84±1.33%, CD8+ T cell 7.02±2.26%, CD4+CD8+ T cell 1.46±0.81%로 HFD 군에 비해 높게 측정되었다. 결과적으로 CILL은 비만억제 효과가 있으며, CILL내의 비만억제 물질을 선별한다면 효과적인 비만억제 식품 소재로서의 가능성이 있을 것으로 사료된다.

• 약학회지
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• 제46권3호
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• pp.213-218
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• 2002

In the previous report, we described the in vivo antitumor activity of PJ-4, a protein-polysaccharide fraction prepared from the culture filtrate of an insect-born fungus, Paecilomyces tenuipes DGUM 32001. In the present study, we elucidated the immunomodulating activity of PJ-4 on the BALB/c mouse splenic lymphocytes using flow cytometrical techniques. As a result, PJ-4 was found to stimulate the lymphocytes not only to form lymphoblasts but also to express CD25 (IL-2 receptor $\alpha$ chain) molecule, which is well known as a T cell activation marker. More interestingly, its T cell stimulatory activity was more strongly exerted on CD8$^{+}$ T cells than on CD4$^{+}$ T cells. All these data suggest that PJ-4 exerts its antitumor activity at least partly through stimulation of T cells which play major roles in the cell-mediated immune system.tem.

• Natural Product Sciences
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• 제23권4호
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• pp.239-246
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• 2017

27-Hydroxycholesterol (27OHChol) has been reported to induce differentiation of monocytic cells into a mature dendritic cell phenotype. We examined the effect of methanol extract of Nardostachys chinensis (Nard) on 27OHChol-induced differentiation using THP-1, a human monocytic cell line. Treatment of monocytic cells with methanol extract of Nard resulted in decreased transcription and surface expression of CD80, CD83, and CD88 elevated by 27OHChol in a dose-dependent manner. Surface levels of MHC class I and II molecules elevated by 27OHChol were also reduced to basal levels by treatment with the Nard extract. Decreased endocytosis activity caused by 27OHChol was recovered by treatment with the Nard extract. CD197 expression and cell attachment were attenuated by the Nard extract. In addition, levels of transcription and surface expression of CD molecules involved in atherosclerosis, such as CD105, CD137, and CD166 upregulated by 27OHChol were significantly decreased by treatment with methanol extract of Nard. These results indicate that methanol extract of Nard down-regulates 27OHChol-induced differentiation of monocytic cells into a mature dendritic cell phenotype and expression of CD molecules associated with atherosclerosis. The current study suggests that biological activity of oxygenated cholesterol derivatives can be inhibited by herbal medication.

• 대한한방종양학회지
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• 제4권1호
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• pp.89-110
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• 1998

Yookmijihwangtang has been widely used oriental herb prescriptions, which is healing some discuss that come from insufficiency of innate essence and deficiency of kidney Ki. The meaning of healing discusses tonification of insufficient innate essence and insufficient kidney Ki can be regarded as reinforcement of wholely power of keeping homeostasis, that is correlated with immuno-responsibility which protects subject from outer antigen to keep normal vital condition. This study was aimed to investigate correlative effects of Yookmijihwangtang water abstract on the RBC, WBC, blood CD4+ T helper cell count, blood testosterone, blood cAMP and blood cortisol. 40 Sprague-Dawley male rats were divided into 5 groups(Normal, Control, Sample I, Sample II, Sample III), 6 animals in every group. Normal group was not treated anything, control group was administrated normal saline in the same dosage of Sample I. 3 Sample groups were received some of Yookmijihwangtang water abstract at one time per 24 hours during 5 days in different dosage. Sample I(1/310pack/ml), Sample II(1/62pack/ml), Sample III(1/2.4pack/ml). After finishing treatment, all experimental subjects were killed for blood sample on RBC, WBC, blood CD4+ T helper cell count, spleen CD4+ T helper cell count, axillary lymph node CD4+ T helper cell count. blood cAMP, blood testosterone and blood cortisol. The results were as follows; RBC and WBC were increased in all sample groups. Blood CD4+ T helper cell count(CD4+ T cell count in the blood/whole lymphocyte count in the blood ${\times}100%$) was Normal $46.17{\pm}5.88$, Control $44.50{\pm}4.37$, Sample I $53.00{\pm}2.28$, Sample II $53.83{\pm}3.87$, Sample III $52.17{\pm}2.93$. By the 95% Duncan ANOVA all experimental groups(sample I, Sample II, Sample III) showed slight significant difference from Normal and Control. Blood cAMP(nmol/l) were Normal $1.12{\pm}0.17$, Control $1.16{\pm}0.32$, Sample I $0.46{\pm}0.07$, Sample II $0.44{\pm}0.04$, Sample III $0.54{\pm}0.04$. All experimental groups were singificantly different from both Normal and Control groups(p<0.05). Blood cortisol(nl/ml) were Normal $100.00{\pm}2.00$ Control $90.00{\pm}4.00$, Sample I $440.00{\pm}5.00$, Sample II $520.00{\pm}40.00$, Sample III $470.00{\pm}7.00$. Blood cortisol of all experimental groups were significantly increased(p<0.05). The results suggest that Yookmijihwangtang water abstract could be administrated to patients who have some diseases insufficient essence.

• IMMUNE NETWORK
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• 제6권2호
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• pp.93-101
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• 2006

Background: Memory T lymphocytes of the immune system provide long-term protection in response to bacterial or viral infections/immunization. Ag concentration has also been postulated to be important in determining whether T cell differentiation favors effector versus memory cell development. In the present study we hypothesized that naive Ag-specific $CD4^+$ T cells briefly stimulated with different Ag doses at the primary exposure could affect establishment of memory cell pool after secondary immunization. Methods: To assess this hypothesis, the response kinetics of DO11.10 TCR $CD4^+$ T cells primed with different Ag doses in vitro was measured after adoptive transfer to naive BALB/c mice. Results: Maximum expansion was shown in cells primarily stimulated with high doses of ovalbumin peptide $(OVA_{323-339})$, whereas cells in vitro stimulated with low dose were expanded slightly after in vivo secondary exposure. However, the cells primed with low $OVA_{323-339}$ peptide dose showed least contraction and established higher number of memory cells than other treated groups. When the cell division was analyzed after adoptive transfer, the high dose Ag-stimulated donor cells have undergone seven rounds of cell division at 3 days post-adoptive transfer. However, there was very few division in naive and low dose of peptide-treated group. Conclusion: These results suggest that primary stimulation with a low dose of Ag leads to better memory $CD4^+$ T cell generation after secondary immunization. Therefore, these facts imply that optimally primed $CD4^+$ T cells is necessary to support effective memory pool following administration of booster dose in prime-boost vaccination.

• 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.

• 약학회지
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• 제49권1호
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• pp.60-67
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• 2005

Nonclassical aminobenz[cd]indole antifolates 4, 5 and 6, in which the glutamic acid moiety of the classical antifolates is substituted by 2-phenylglycinamide or 3-aminobenzamide, were synthesized and their in vitro antitumor activity was evaluated. The purpose of this substitution is that the lipophilicity is enhanced due to the aromatic ring of the target compounds for the passive transport through lipid membrane of cells while the hydrogen bonding of the amide is retained in the active site of the enzyme, thymidylate synthase, where the glutamate is originally present. The target compounds were highly cytotoxic against tumor cell lines of murine and human origin with micromolar to nanomolar $IC_{50}$ values. Most effective was compound 4 ($N^6-methyl-N^6$-[4-[(${\alpha}$(S)-aminocarbonylbenzyl) aminocarbonyl]benzyl]-2,6-diaminobenz[cd]indole)with $IC_{50}$ of 2 nM against SW480, human colon adenocarcinoma cell line, which is 650-fold more potent than the reference compound 3.

• 대한한방소아과학회지
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• 제12권1호
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• pp.257-276
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• 1998

Introduction The effects of Samchulkunbitang on the immunosuppression induced by methotrexate in rats were investigated in this experument. The multiple parameters of immunity assessed in each rats includes the rate of body weight loss, weight changes in thymus, spleen and axillary lymphnode. The number of lymphocytes and CD4+ T cell count in the blood, thymus, spleen and axillary lymphnode were also measured. Methodology Male Sprague-Dawley rats were chosen as an experiment object and were divided into 4 groups by a random selection. Each group consisted of 6 rats. The normal group didn't receive any treatment. The control group was administered with methotrexate for 5 days. The sample Ⅰ group was administered with Samchulkunbitang for 5 days. The sample Ⅱ group was administered with both Samchulkunbitang and methotrexate for 5 days. The dosage of medication was 2cc/day, 1cc given at 10 AM and another 1cc given at 5 PM. Results The rate of body weight loss was significantly increased in the Sample Ⅰ and Sample Ⅱ group. The weight of thymus and spleen were significantly increased in Sample Ⅰ and Sample Ⅱ groups While the weight of axillary lymphnode did not show much increase. No significant differences were measured among the experimental groups. Blood lymphocyte count, blood CD4+ T cell count, spleen lymphocyte count, axillary lymphnode lymphocyte and CD4+ T cell count were significantly increased in Sample Ⅰ and Sample Ⅱ groups while spleen CD4+ T cell count did not show much increase. No significant differences were measured among the experimental groups. Conclusion As one can witness from the above results, administration of Samchulkunbitang played potent role in increasing immune system among the rats treated with methotrexate which induces immunosuppression. Overall increase of lymphocyte count and CD4+ T cell count in the sample groups with Samchulkunbitang effectively proves its ability to boost the immune system.