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MiR-204 acts as a potential therapeutic target in acute myeloid leukemia by increasing BIRC6-mediated apoptosis

  • Wang, Zhiguo;Luo, Hong;Fang, Zehui;Fan, Yanling;Liu, Xiaojuan;Zhang, Yujing;Rui, Shuping;Chen, Yafeng;Hong, Luojia;Gao, Jincheng;Zhang, Mei
    • BMB Reports
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    • v.51 no.9
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    • pp.444-449
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    • 2018
  • Acute myeloid leukemia (AML) is one of the most common hematological malignancies all around the world. MicroRNAs have been determined to contribute various cancers initiation and progression, including AML. Although microRNA-204 (miR-204) exerts anti-tumor effects in several kinds of cancers, its function in AML remains unknown. In the present study, we assessed miR-204 expression in AML blood samples and cell lines. We also investigated the effects of miR-204 on cellular function of AML cells and the underlying mechanisms of the action of miR-204. Our results showed that miR-204 expression was significantly downregulated in AML tissues and cell lines. In addition, overexpression of miR-204 induced growth inhibition and apoptosis in AML cells, including AML5, HL-60, Kasumi-1 and U937 cells. Cell cycle analysis further confirmed an augmentation in theapoptotic subG1 population by miR-204 overexpression. Mechanistically, baculoviral inhibition of apoptosis protein repeat containing 6 (BIRC6) was identified as a direct target of miR-204. Enforcing miR-204 expression increased the luciferase activity and expression of BIRC6, as well as p53 and Bax expression. Moreover, restoration of BIRC6 reversed the pro-apoptotic effects of miR-204 overexpression in AML cells. Taken together, this study demonstrates that miR-204 causes AML cell apoptosis by targeting BIRC6, suggesting miR-204 may play an anti-carcinogenic role in AML and function as a novel biomarker and therapeutic target for the treatment of this disease.

Effect of Euonymus alatus and Ulmus clavidiana var japonica on the immune system (화살나무 및 느릅나무 추출물이 면역계세포의 활성에 미치는 영향)

  • Kim, Jong-myeon;Choi, Min-soon;Cho, Jeong-gon;Jung, Young-mee;Park, Tae-wook
    • Korean Journal of Veterinary Research
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    • v.34 no.2
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    • pp.307-313
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    • 1994
  • We have previously shown that crude water extract of Euonymus alatus (EA) had strong prophylactic effect against chemically induced-and tumor cell implanted-cancer, and that the mechanisms responsible for its antitumor effects were due to nonspecific enhancement of the NK cell activities and the cell mediated immunity. However, it was unknown that any components of crude extract did work so, since it consisted of several components. In this paper, we fractionated the crude watar EA-extract into several fraction such as hexane-, ethylether-, ethyl acetate-, n-butanol- and water soluble-fraction, and screened the immune regulating activities of each fraction by the evaluation of lymphokine production and activated lymphocyte proliferation. As a result of the component fraction of EA-extract, it was found that n-butanol fraction was a potent immunostimulator, and the remained water soluble fraction also contained some stimulator, But, other fraction did not showed any remarkable effect. It is therefore suggested that EA-glycosides in n-butanol fraction may be new one of the potent biological response modifiers. The present study was also undertaken in an efforts to investigate the effects of elm-bark(EB, Ulmus clavidiana var japonica), which has been used for curing ulcer and inflammation as a folk medicine without any kind of experimental evidence to support this, on the cellular- and humoral-immune responses, lymphocyte function and NK cell activities in mice. Regardless of time and duration of EB-treatment, Arthus reaction and antibody response to SRBC were not modified by EB, but delayed hypersensitivity to SRBC was significantly enhanced only when EB was treated prior to SRBC-sensitization. EB slightly inhibited the proliferation responses of splenocytes to PHA-stimulation, but it significantly augmented the responses of these cells to S aureus Cowan 1 and Con A-activation, and these effects were manifested only when EB was added at culture initiation. EB did not influence Ig secretion of spleen cells but it significantly augmented the Con A-induced 1L 2 and MIF production of splenocytes. NK cell activities of splenocytes were markedly riled when effector cells were pretreated with EB and this augmentation was dine to the increase of binding affinity of effector cells to target cells and the target cell lytic activities of effector cells. These results led to the conclusion that EB triggers increase of cellular immune responses, such as delayed hypersensitivitiy, lymphokine production and NK cell activities. Also these results suggested that EB contains potent immune stimulants, which may provide the rational basis for their therapeutic use as one of the new biological response modifiers.

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Dietary Supplementation with Acanthopanax senticosus Extract Modulates Cellular and Humoral Immunity in Weaned Piglets

  • Kong, Xiangfeng;Yin, Yulong;Wu, Guoyao;Liu, Hejun;Yin, Fugui;Li, Tiejun;Huang, Ruilin;Ruan, Zheng;Xiong, Hua;Deng, Zeyuan;Xie, Mingyong;Liao, Yiping;Kim, Sungwoo
    • Asian-Australasian Journal of Animal Sciences
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    • v.20 no.9
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    • pp.1453-1461
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    • 2007
  • This study was conducted to test the hypothesis that dietary supplementation with an herbal extract of Acanthopanax senticosus (AS) enhances the immune response in weaned piglets. Sixty piglets weaned at 21 days of age were randomly assigned to 3 treatment groups representing the addition of 0 or 1 g/kg of the AS extract or 0.2 g/kg of colistin (an antibiotic) to maize- and soybean meal-based diets (n = 20 per group). On days 7, 14 and 28 after initiation of the addition, total and differential counts of leucocytes, proliferating activity of peripheral lymphocytes, serum levels of immunoglobulins (Ig) and cytokines and the spleen index were determined. The AS extract decreased (p<0.05) the number of neutrophils on days 7 and 28 in comparison with the control group and reduced (p<0.05) serum interleukin-$1{\beta}$ level on day 28 compared with the other 2 groups. Dietary supplementation with the AS extract increased (p<0.05) the lymphocyte/leukocyte ratio on day 28 compared with the control group and increased the proliferating activity of lymphocytes on days 14 and 28 compared with the other 2 groups. The AS extract increased (p<0.05) the serum content of IgG on day 7 and of IgG and IgM on day 28 compared with the other 2 groups, as well as increasing the serum content of tumor necrosis factor on day 7 and spleen index on days 7 and 28 compared with the control group. Collectively, these findings suggest that the AS extract as a dietary additive enhances the cellular and humoral immune responses of weaned piglets by modulating the production of immunocytes, cytokines and antibodies.

Overview of Transforming Growth Factor β Superfamily Involvement in Glioblastoma Initiation and Progression

  • Nana, Andre Wendindonde;Yang, Pei-Ming;Lin, Hung-Yun
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.16
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    • pp.6813-6823
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    • 2015
  • Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive of human brain tumors and has a stunning progression with a mean survival of one year from the date of diagnosis. High cell proliferation, angiogenesis and/or necrosis are histopathological features of this cancer, which has no efficient curative therapy. This aggressiveness is associated with particular heterogeneity of the tumor featuring multiple genetic and epigenetic alterations, but also with implications of aberrant signaling driven by growth factors. The transforming growth factor ${\beta}$ ($TGF{\beta}$) superfamily is a large group of structurally related proteins including $TGF{\beta}$ subfamily members Nodal, Activin, Lefty, bone morphogenetic proteins (BMPs) and growth and differentiation factor (GDF). It is involved in important biological functions including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. This superfamily is also considered to impact on cancer biology including that of GBM, with various effects depending on the member. The $TGF{\beta}$ subfamily, in particular, is overexpressed in some GBM types which exhibit aggressive phenotypes. This subfamily impairs anti-cancer immune responses in several ways, including immune cells inhibition and major histocompatibility (MHC) class I and II abolishment. It promotes GBM angiogenesis by inducing angiogenic factors such as vascular endothelial growth factor (VEGF), plasminogen activator inhibitor (PAI-I) and insulinlike growth factor-binding protein 7 (IGFBP7), contributes to GBM progression by inducing metalloproteinases (MMPs), "pro-neoplastic" integrins (${\alpha}v{\beta}3$, ${\alpha}5{\beta}1$) and GBM initiating cells (GICs) as well as inducing a GBM mesenchymal phenotype. Equally, Nodal promotes GICs, induces cancer metabolic switch and supports GBM cell proliferation, but is negatively regulated by Lefty. Activin promotes GBM cell proliferation while GDF yields immune-escape function. On the other hand, BMPs target GICS and induce differentiation and sensitivity to chemotherapy. This multifaceted involvement of this superfamily in GBM necessitates different strategies in anti-cancer therapy. While suppressing the $TGF{\beta}$ subfamily yields advantageous results, enhancing BMPs production is also beneficial.

COH-IVF Outcomes for Infertile Patients With Borderline Ovarian Tumor After Conservative Treatment (경계성 난소 종양의 보존적 수술 후 불임 환자에서 체외수정시술의 유용성)

  • Lee, Hyun-Joo;Ahn, Ka-Yougng;Hahn, Ho-Suap;Park, Chan-Woo;Yang, Kwang-Moon;Lee, In-Ho;Kim, Tae-Jin;Lim, Kyung-Taek;Lee, Ki-Heon;Kang, Inn-Soo
    • Clinical and Experimental Reproductive Medicine
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    • v.34 no.2
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    • pp.87-94
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    • 2007
  • Objective: To examine determinants of successful pregnancy and evaluate COH-IVF outcomes of infertile patients after conservative surgical treatment of borderline ovarian tumor (BOT). Methods: In women of BOT (n=93), from January 1995 to December 1999, 44 of 93 women underwent conservative surgical treatment. From theses 44 women, patients characteristics, surgical and histological parameters were compared between 14 women who conceived and 30 women who failed to conceive. For 5 infertile women of 30 women who failed to conceive, 10 attempt IVF cycles were analysed; clinical pregnancy rate (CPR), implantation rate (IR) and live birth rate (LBR). Results: Women who conceived tend to be younger (25.9 vs 27.0 years) and lower serum CA-125 level (59.7 vs 72.9) compared to women who failed to conceive without significant difference. For 8 cycles out of 10 attempt IVF cycles, except for 2 cancellation cycles, the mean number of oocytes retrieved was 5.6 (range 2$\sim$16) with a mean fertilization rate of 74.4%. The CPR, IR and LBR per embryo transfer were 50.0% (4/8 cycles), 31.6% (6/19) and 50.0% (4/8 cycles) respectively. During the mean follow-up period after COH-IVF initiation, 29.6 (range 14$\sim$61) months, no recurrence was found. Conclusion: No determinant of successful pregnancy was found after conservative treatment for BOT. COH-IVF may be considered for infertile patients after conservative treatment of BOT. However, larger clinical studies with longer follow-up are necessary to evaluate the safety and efficacy of COH-IVF. All patients should be informed of the potential risks associated with ovarian hyperstimulation and close follow-up is necessary after COH-IVF.

Concurrent Chemoradiotherapy in Elderly Patients with Locally Advanced Esophageal Carcinoma (고령의 국소 진행된 식도암환자에서 동시 항암화학방사선치료)

  • Jung, Bae-Kwon;Kang, Ki-Mun;Lee, Gyeong-Won;Kang, Jung-Hoon;Kim, Hoon-Gu;Lee, Won-Seob;Chai, Gyu-Young
    • Radiation Oncology Journal
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    • v.27 no.2
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    • pp.84-90
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    • 2009
  • Purpose: The effect of concurrent chemoradiotherapy was analyzed in elderly patients when used in the treatment of locally advanced esophageal cancer. Materials and Methods: The retrospective analysis included 28 elderly patients aged 65 or older, with histopathologically confirmed squamous cell carcinoma of the esophagus, underwent concurrent chemoradiotherapy from January 2001 to July 2007. The squamous cell carcinoma disease stages included 8 patients (28.8%) in stage IIa, 10 patients (35.7%) in stage IIb, and 10 patients (35.7%) in stage III. Fractionated radiotherapy was performed with a 6 MV or 10 MV X-ray for 45~63 Gy (median: 59.4 Gy). Chemotherapy was applied concurrently with the initiation of radiotherapy. A 75 mg/$m^2$ dose of Cisplatin was intravenously administered on day 1. Further, 5-FU 1,000 mg/$m^2$ was continuously administered intravenously from days 1 to 4. This regimen was performed twice at 3-week intervals during radiotherapy. Two cycles of consolidation chemotherapy was performed after radiotherapy. Results: The follow-up period was 3~72 months (median: 19 months). The treatment responses after concurrent chemoradiotherapy included a complete response in 11 patients (39.3%), a partial response in 14 patients (50.0%), and no response in 3 patients (10.7%). The overall response rate was 89.3% (25 patients). The overall 1-, 2- and 3-year survival rates were 55.9%, 34.6% and 24.2%, respectively. The median survival time was 15 months. Two-year survival rates of patients with a complete response, partial response, and no response were 46.2%, 33.0%, and 0%, respectively. The stage and tumor response after concurrent chemoradiotherapy were statistically significant prognostic factors related with survival. No treatment-related deaths occurred in this study. Conclusion: Concurrent chemoradiotherapy is a relatively effective treatment without serious complications in elderly patients with locally-advanced esophageal cancer.

The Extract from Artemisia annua Linné. Induces p53-independent Apoptosis through Mitochondrial Signaling Pathway in A549 Lung Cancer Cells (A549 폐암세포에서 미토콘드리아 경로를 통한 개똥쑥 추출물의 apoptosis 유도 효과)

  • Kim, Bo-Min;Kim, Guen-Tae;Kim, Eun-Ji;Lim, Eun-Gyeong;Kim, Sang-Yong;Kim, Young-Min
    • Journal of Life Science
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    • v.26 no.8
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    • pp.887-894
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    • 2016
  • The extract from Artemisia annuain L.(AAE) is known as a medicinal herb that is effective against cancer. Apoptosis is the process of programmed cell death, and mitochondria are known to play a central role in cell death control. In this study, we evaluated the p53-independent apoptosis of extract of AAE through downregulation of Bcl-2 and the mitochondrial pathway in A549 (lung cancer cells). AAE may exert cancer cell apoptosis through regulating p-Akt, Cox-2, p53 and mitochondria-mediated apoptotic proteins. p-Akt/cox-2 is known to play an important role in cell proliferation and cell survival. The Bcl-2 pro-apoptotic proteins (such as Bax, Bak and Bim) mediate the permeabilization of the mitochondrial outer membrane. Treatment of AAE reduces p-Akt, p-Mdm2, cox-2 and anti-apoptotic proteins (such as Bcl-2), while tumor suppressor p53 and pro-apoptotic proteins. Activation of Bax/Bak releases cytochrome c from mitochondria to the cytosol to activate a caspase. Caspase-3 is the major effector caspase associated with apoptotic pathways. Caspase-3 generally exists in cytoplasm in the form of a pro-enzyme. In the initiation stage of apoptosis, caspase-3 is activated by proteolytic cleavage and activated caspase-3 cleaves poly (ADP-ribose) polymerase (PARP). We treated Pifithrin-α (p53 inhibitor) and Celecoxib (Cox-2 inhibitor) to learn the relationship between the signal transduction of proteins associated with apoptosis. These results suggest that AAE induces apoptosis through a p53-independent pathway in A549.