• 약학회지
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• 제41권1호
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• pp.81-85
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• 1997

Ceramide has been suggested as an important mediator of the effects of extracellular agonists on cell growth inhibition, differentiation, apoptosis. However the biochemical sign aling mechanism involved in transducing the effects of ceramide on leukemia cell differentiation is still unclear. In these respects, we examined the regulatory effects of ceramide on c-jun gene expression during differentiation. In U-937 cells. ceramide increased c-jun mRNA levels in a time-dependent manner. The half life, of c-jun mRNA was 30 min. In contrast, inhibition of protein synthesis with cycloheximide in the absence, of transcription with actinomycin D increased the half-life of c-jun mRNA in ceramide-treated U-937 cells to more than 90 min. In order to examine whether ceramide-inhibited c-jun gene expression is regulated through ceramide-activated protein phosphatase (CAPP), a direct target for the action of ceramide, okadaic acid were treated to the cells. Okadaic acid inhibited enhancement of c-jun mRNA induced by C2-ceramide in a dose-dependent manner. These results suggested that ceramide increases c-jun mRNA level during differentiation in U-937 cells and regulates the gene expression on posttranscriptional level. In addition, we provide the evidence that CAPP is involved in ceramide-induced c-jun gene expression in U-937 cells.

• 동의생리병리학회지
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• 제20권2호
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• pp.345-351
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• 2006

We have examined the induction of HL-60 cell differentiation by treatment of the water extract of Rhizoma Zingiberis Siccatum, which is a Korean traditional herbal medicine. It was observed that HL-60 cell proliferation was dose-dependently inhibited by treatment with various dose of Rhizoma Zingiberis Siccatum extract. The level of inhibition was identical to those of ATRA-treated cells. Rhizoma Zingiberis Siccatum extract treatment caused a significant change in NBT reduction (47%) and enhanced ATRA-induced NBT reduction. Treatment of Rhizoma Zingiberis Siccatum to HL-60 cells increased only CD11 b expression in the cells, and also increased markedly G0/G1 stage arrest. This can suggest that Rhizoma Zingiberis Siccatum induced the differentiation of HL-60 cell and enhanced ATRA-induced differentiation predominantly along the granulocytic lineage. The results present here show that Rhizoma Zingiberis Siccatum extract contains the potential effect of differentiation induction or acts as a agent enhancing the induction of differentiation.

• 고려인삼학회:학술대회논문집
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• 고려인삼학회 2006년도 춘계학술대회
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• pp.3-12
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• 2006

1 The present work was performed to investigate the effects of ginsenoside Rh2 on proliferation, cell cycle-regulation and differentiation of human leukemia HL-60 cells as well as the underlying mechanisms for these effects. 2 Ginsenoside Rh2 potently inhibited the proliferation of HL-60 cells in both a dose- and time-dependent manner with an $IC_{50}$, $20{\mu}M$. 3 DNA flow-cytometry indicated that ginsenoside Rh2 markedly induced a $G_1$ phase arrest of HL-60 cells. 4 Among the $G_1$ phase cell cycle-related proteins, the levels of cyclin-dependent kinase(CDK)4, 6 and cyclin D1, cyclin D2, cyclin D3 were reduced by ginsenoside Rh2, whereas the steadystate levels of CDK2 and cyclin E were unaffected. 5 The protein levels of a CDK inhibitor p16, $p21^{CIP1/WAF1}$ and $p27^{KIP1}$ were markedly increased by ginsenoside Rh2. 6 Ginsenoside Rh2 markedly enhanced the binding of $p21^{CIP1/WAF1}$ and $p27^{KIP1}$ with CDK2 and CDK6, resulting in the reduced activity of both kinases and the hypophosphorylation of Rb protein. 7 We furthermore suggest that ginsenoside Rh2 is a potent inducer of the differentiation of HL-60 cells, based on observations such as a reduction of the nitroblue tetrazolium level, an increase in the esterase activities and phagocytic activity, morphology changes, and the expression of CD11b, CD14, CD64 and CD66b surface antigens. 8 In conclusion, the onset of ginsenoside Rh2-induced the $G_0/G_1$ arrest of HL-60 cells prior to the differentiation is linked to a sharp up-regulation of the $p21^{CIP1/WAF1}$ level and a decrease in the CDK2, CDK4 and CDK6 activities. This is the first report demonstrating that ginsenoside Rh2 potently inhibits the proliferation of human promyelocytic HL-60 cells via the $G_1$ phase cell cycle arrest and differentiation induction.

• 생명과학회지
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• 제18권1호
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• pp.75-83
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• 2008

인체 DNA topoisomerase는 DNA를 단일 또는 두 가닥을 일시적인 절단을 촉매하여 DNA의 topological 문제를 조절함으로써, DNA 복제, 전사, 재조합과 유사분열 과정 등에 관여한다. 이 효소는 많은 항생, 항암제의 표적효소로서 널리 알려져 있으며, 이들 유도체를 이용한 다양한 억제제의 개발과 임상적 응용에 관한 연구가 활발하게 진행되고 있다. 본 실험에서는 인체 백혈병 HL-60 세포에서 topoisomerase 억제제가 topoisomerase 기능 활성과 유전자 발현을 조절하는지를 규명하기 위하여 본 연구를 수행하였다. 연구 방법은 HL-60세포에 topoisomerase type I과 type II의 대표적 억제제인 10-hydroxycamptothecin (10-CPT)과 doxorubicin을 투여한 후 total RNA를 분리하였고, 10K-oligo-nucleotide microarray 방법으로 분석하여 유전자의 발현 양상을 조사하였다. 연구 결과에 의하면 10-CPT 또는 doxorubicin을 투여한 HL-60세포에서의 유전자 발현 양상은 주로 signal transduction, cell adhesion, cell cycle, cell growth, cell proliferation, cell differentiation, transcription 및 immune response 등과 관련이 있었다. Topoisomerase type I의 억제제인 10-CPT를 HL-60 세포주에 투여 하였을 때 type I으로 분류되는 topoisomerase III${\alpha}$, III${\beta}$ 및 I의 발현은 증가하였으나 type II인 topoisomerase II${\alpha}$와 II${\beta}$의 유전자의 발현은 감소되었다. 반대로 type II의 억제제인 doxorubicin을 투여하였을 때는 앞의 결과와 상반된 topoisomerase II${\alpha}$와 II${\beta}$의 유전자의 발현이 현저히 증가되었으며, topoisomerase III${\alpha}$와 III${\beta}$의 mRNA의 발현은 약간 감소하는 양상을 보였으나 의미 있는 차이는 없었다. 이 연구 결과는 앞으로 항암제의 기전을 밝히고 약물에 대한 치료 반응을 예측하고 새로운 약제 개발에 기초자료가 될 것으로 여겨진다.

• 대한임상검사과학회지
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• 제38권2호
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• pp.82-86
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• 2006

Leukemia arises in hematopoietic progenitor cells and is characterized by impaired or blocked differentiation, uncontrolled proliferation and resistance to apoptosis. Molecular mechanisms underlying cellular functions by $As_2O_3$, however, have been poorly investigated. The consensus of several reports is that $As_2O_3$ induces apoptosis in leukemia cells by activating genes for apoptosis. The present study aimed to investigate the effects of $As_2O_3$ on the cell cycle and its morphological change and a relationship between the caspase-3 and $As_2O_3$-induced apoptosis. Caspase-3 is involved in $As_2O_3$-induced apoptosis in K562 cells. In this study, to address whether $As_2O_3$-induced apoptosis is mediated by caspase-3 activity, the same samples were probed with a specific antibody. The pretreatment of $25{\mu}M$ Z-VAD-fmk, a specific inhibitor of caspase, decreased $As_2O_3$-induced cytotoxicity. And $As_2O_3$ significantly increased the percentages of the cells accumulated in the G2/M phase of the cell cycle in a time- and dose-dependent manner. Chromatin condensational changes were observed with Hoechst 33258 staining after treatment of $As_2O_3$. It was shown that $As_2O_3$-induced apoptosis is controlled through caspase-3 activation. These results may provide a useful rationale for CML treatment.

• 한국식품영양과학회지
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• 제23권3호
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• pp.443-452
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• 1994

This study describes the effects of novel1, 25-dihydroxyvitamin D$_3$ analong[1,25(OH)$_2$-16ene-23yne-26, 27-F6-D$_3$] on proliferation of the human histiocytic lymphoma cell line U937 in vitro. We also examined the expression of c-myc oncogene in U937 cells was apparently inhibited to 62% and 87% of the control level after 4 days in the presence of 10-8M and 10-7 M of this analog, respectively. This compound morpholgically and functionally differentiated U937 cells to nonocyte-macrophage phenotype showing the increase of adherence ability to surface and a decrease of N/C ratio in Giemsa staining . Especially, nonspecific esterase activity which is a marker of cell differentiation to monocyte-macrophage was positive, and production of the positive stained cells increased in a dose dependent fashion . The expression of c-myc oncogene by 1, 25(OH)$_2$D$_3$ analog(10-7 M) was reduced by 60% at the mRNA level as determined by Northern blotting. The effects of this novel analog on cell proliferation and cell differentiation may open op new therapeutic strategies for human disorders such as psoriassis and may provide a tool to understand the mechanism of action of vitamin D$_3$ seco-steroids in malignancy.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제31권6호
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• pp.535-540
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• 2009

Proliferation of abnormal hematopoietic cells with impaired differentiation, regulation and programmed cell death leads to leukemia. AML(acute myeloid leukemia) is a malignancy with malfunction of myeloid hematopoietic cells with acute behavior. The oral manifestations of the disease are posterior palate hemorrhage, gingival bleeding and gingival ulceration as a result of infection by normal oral flora and gingival infiltration by leukemic cells. A 49-year-old male patient was referred from local dental clinic. The patient was diagnosed with AML FAB M1 (acute myeloid leukemia French-American-British classification M1 myeloblastic leukemia without maturation). The oral infection focus was removed by a conservative treatment. 2 days after the dental treatment, the patient underwent chemotherapy. At 8-month follow-up, the overall outcome was excellent. Oral manifestations of AML are often the first indications of the malignancy. Therefore it is essential for dentists, especially oral and maxillofacial surgeons, to be aware of the diagnostic signs and complications associated with leukemia for better diagnosis and subsequent treatment and management.

• 혜화의학회지
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• 제10권2호
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• pp.83-89
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• 2002

In the literatual study of anti-tumor effects of chunghwangsan for leukemia, the results were as follows. 1. Chunghwangsan is composed of Indigo naturalis and Realgar. The composing rate is 9 : 1 and it is made into capsule or piece. The basic administration is 0.3g per day and could increase the quantity each day. 2. The effects of Chunghwangsan is expelling toxin and colling, colling blood to detumescence, drying wetness and anticancer are. So it can be used to treat AML, CML and lymphoma. 3. The anticancer component of Indigo naturalis is indirubin which has the effects of suppression the transplanted tumor, activating the phagocyte of macrophage, promoting the maturation of myeloblast to improve cure rate of CML. The anticancer component of Realgar is $As_2O_3$ which has the direct cellular toxicity for leukemia cell. 4. In viewpoints of oriental medicine, leukemia is malignant myeloid neoplasia in which pathogen invade to shaoyin(少陰). So Chunghwangsan which is expelling toxin and colling, colling blood to detumescence, drying wetness and anticancer is effective to leukemia. 5. In clinical reports, Chunghwangsan is often used in CML, and also used in AML, lymphoma and so on. 6. Chunghwangsan is cool-natured, so we must carefully pay attention to pregnant women and hematsdthenic patients. The main side effects are nausea, bone marrow pain, diarrhea, polydefecation, hematokezia and purpora. We sometimes take invigorating stomach medicine to prevent the side effects. 7. If we continuously develop Chunghwangsan and therapy for leukemia with syndrome differentiation. we can improve the response and cure rate for leukemia in the future.

• 한국식품영양과학회지
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• 제27권1호
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• pp.141-148
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• 1998

This study describes the effects of 1,25-dihydroxyvitamin D3[1,25(OH)2D3, calcitriol] analog, 1,25(OH)2-16ene-23yne-D3 on proliferatin and differentiatin of the human histiocytic lymphoma cell line U937. This paper also describes the effects of 1,25(OH)2-16ene-23yne-D3 on ${\gamma}$-interferon(IFN-${\gamma}$) synthesis by phytohemagglutinin-activated peripheral blood lymphocytes(PBLs). In the present investigation, 1,25(OH2)-16ene-23yne-D3 was compared to the natural metablite of vitamin D3, 1,25(OH)2D3. 1,25(OH)2-16ene-23yne-D3 was more potent than 1,25(OH)2D3 for inhibition of proliferation and induction of differentiation of U937 cells, Its effects on inhibition of proliferation was about 30-fold more potent than 1,25(OH)2D3. On induction of differentiation as measured by nonspecific esterase (NSE) activity and morphologic change, this analog morphologically and functionally differentiated U937 cells to monocyte-macrophage phenotype showing a decrease of N/C ration in Giemsa staining and the increase of adherence ability of surface. After 3 days in culture, a more significant supression of IFN-${\gamma}$ synthesis analog on supression of IFN-${\gamma}$ synthesis was a dose-dependent manner, with peak activity at 10-7M. The strong direct effects of 1,25(OH)2-16ene-23yne-D3 on cell proliferation and cell differentiation, make this compound an interesting candidate for clinical studies for several types of malignancies, and the effects on supression of IFN-${\gamma}$ synthesis provide the further evidence for a role of 1,25(OH)2-16ene-23yne-D3 in immunoregulation.

• Molecules and Cells
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• 제38권11호
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• pp.966-974
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• 2015

Despite the presence of toll like receptor (TLR) expression in conventional $TCR{\alpha}{\beta}$ T cells, the direct role of TLR signaling via myeloid differentiation factor 88 (MyD88) within T lymphocytes on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT) remains unknown. In the allo-SCT model of C57BL/6 ($H-2^b$) ${\rightarrow}$ B6D2F1 ($H-2^{b/d}$), recipients received transplants of wild type (WT) T-cell-depleted (TCD) bone marrow (BM) and splenic T cells from either WT or MyD88 deficient (MyD88KO) donors. Host-type ($H-2^d$) P815 mastocytoma or L1210 leukemia cells were injected either subcutaneously or intravenously to generate a GVHD/GVL model. Allogeneic recipients of MyD88KO T cells demonstrated a greater tumor growth without attenuation of GVHD severity. Moreover, GVHD-induced GVL effect, caused by increasing the conditioning intensity was also not observed in the recipients of MyD88KO T cells. In vitro, the absence of MyD88 in T cells resulted in defective cytolytic activity to tumor targets with reduced ability to produce IFN-${\gamma}$ or granzyme B, which are known to critical for the GVL effect. However, donor T cell expansion with effector and memory T-cell differentiation were more enhanced in GVHD hosts of MyD88KO T cells. Recipients of MyD88KO T cells experienced greater expansion of Foxp3- and IL4-expressing T cells with reduced INF-${\gamma}$ producing T cells in the spleen and tumor-draining lymph nodes early after transplantation. Taken together, these results highlight a differential role for MyD88 deficiency on donor T-cells, with decreased GVL effect without attenuation of the GVHD severity after experimental allo-SCT.