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ABSTRACT: This study examined the molecular mechanisms of apicidin in the modulation of human ovarian cancer SKOV-3 cells invasion and migration. Apicidin markedly decreased histone deacetylase 4 (HDAC4) expression and blocked cell migration and invasion. Cell migration was inhibited via down-regulation of matrix metalloproteinase-2 (MMP-2) and up-regulation of RECK in the HDAC4-blocked SKOV-3 cells. Apicidin significantly suppressed the binding of HDAC4 to Sp1 binding elements of the RECK promoter via repression of HDAC4. In an in vivo model, apicidin suppressed the growth of transplanted SKOV-3 cells by down-regulating HDAC4 and MMP-2. Apicidin may potentially be used as an anti-cancer agent for inhibition of cancer cell migration and invasion through the repression of MMP-2 which is related to the reduction of HDAC4.
Cancer letters 07/2012; 325(2):189-99. · 4.86 Impact Factor
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ABSTRACT: Chemokines have been implicated in the pathological process of endometriosis. We compared the effects of peritoneal fluid obtained from patients with endometriosis (ePF) and controls without endometriosis (cPF) on the release of monocyte-specific CC chemokines such as monocyte chemotactic protein-1 (MCP-1), regulated upon activation normal T cell expressed and secreted (RANTES), and macrophage inflammatory protein-1α (MIP-1α) by neutrophils, monocytes, and T cells. Moreover, we evaluated the correlation between the levels of chemokines in ePF and their release by these cells.
Cells were obtained from healthy young volunteers and cultured with ePF (n = 12) or cPF (n = 8). The chemokine levels in the ePF and the supernatants of cultured cells with ePF were then measured by ELISA.
There was a positive correlation between the levels of MCP-1 and MIP-1α in ePF. The addition of ePF to the cell cultures failed to increase the release of MCP-1, RANTES, and MIP-1α when compared to cPF, but the levels of RANTES in ePF were positively correlated with the release of RANTES by ePF-treated monocytes and T cells. Moreover, there was a positive correlation between the levels of RANTES and MIP-1α released by neutrophils and between the levels of MCP-1 and MIP-1α released by T cells. Finally, the levels of RANTES released by monocyte-derived macrophages and monocytes cultured with ePF were positively correlated.
These findings suggest that monocytes, neutrophils, and T cells release differential levels of MCP-1, RANTES, and MIP-1α in response to stimulation with ePF.
Archives of Gynecology 06/2011; 283(6):1333-41. · 0.91 Impact Factor
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ABSTRACT: Histone deacetylase (HDAC) inhibitors are a promising new class of anticancer agents that act by inhibiting cell proliferation and inducing apoptosis in a variety of cancer cells. Although apicidin acts as a potent HDAC inhibitor, the precise mechanism for its anti-tumor activity in human endometrial cancer cells is not completely understood. This study examined the anti-tumor effects of apicidin in Ishikawa cancer cells. The level of cell proliferation, the stage of the cell cycle, and apoptosis were measured after the apicidin treatment. Apicidin significantly inhibited the proliferation of Ishikawa cells in a dose-dependent manner. In addition, apicidin markedly up-regulated the p21(WAF1) and down-regulated the expression of cyclins (A, B1, D1, or E), and CDKs (2 or 4), which leading to cell cycle arrest. Cell cycle analysis showed that the apicidin treatment increased the proportion of cells in the G1 phase, and decreased the ratio of cells in the S phase in a dose-dependent manner. Apicidin significantly increased the sub-G1 population and the number of TUNEL positive apoptotic cells compared with the untreated control. These results were confirmed by poly-ADP ribose polymerase (PARP), an 85-kDa fragment resulting from PARP cleavage, where apicidin increased the level of PARP cleavage and caspase-3 activity in 1.0 microM apicidin-treated cells. Apicidin-induced apoptosis through caspase-3 activation was confirmed by the increase in the release of cytochrome c and the decrease in the Bax/Bcl-2 ratio. These results suggest that apicidin has anti-tumor properties on endometrial cancer cells by inducing selectively the genes related to cell cycle arrest and apoptosis.
Chemico-biological interactions 12/2008; 179(2-3):169-77. · 2.46 Impact Factor
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ABSTRACT: The aim of the present study was to investigate the number of early cleaving embryos as an effective predictor for multiple pregnancies in human in vitro fertilization (IVF).
The study analyzed early cleavage (EC) in 190 cycles of IVF. The EC of embryos to the two-cell stage was assessed at two time points, namely 25 and 27 h after insemination. Embryos that had cleaved at each time point were designated EC-1 and EC-2, respectively, whereas other embryos were designated as non-EC (NEC). The number of cycles with EC-1 embryos was not included in the results for the EC-2 group.
Clinical pregnancy rates were significantly higher in the EC-1 group compared with the EC-2 and NEC groups (58.2%, 31.8% and 22.9%, respectively; P < 0.05). The pregnancy outcome was positively related to the number of EC-1 embryos. Multiple pregnancy rates were significantly increased up to 41.4% when the number of EC-1 embryos was two or more.
The results confirm that 25 h after insemination is a more effective critical time point for the selection of EC embryos and that the number of EC embryos could be a useful parameter for the prediction of multiple pregnancies.
Journal of Obstetrics and Gynaecology Research 06/2008; 34(3):379-83. · 0.94 Impact Factor
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ABSTRACT: Thymic epithelial cells, which constitute a major component of the thymic microenvironment, provide a crucial signal for intrathymic T cell development and selection. Neuroimmune networks in the thymic microenvironment are thought to be involved in the regulation of T cell development. NGF is increasingly recognized as a potent immunomodulator, promoting "cross-talk" between various types of immune system cells. The present study clearly shows that NGF stimulates mouse thymic epithelial cell activities in vitro including cell proliferation, thymocyte adhesion to thymic epithelial cells, and the expression of cell adhesion molecules such as ICAM-1 and VCAM-1, and thymopoietic factors including IL-7, GM-CSF, SDF-1, TARC and TECK. Thus, our data are of considerable clinical importance showing that trophic NGF activity could be used to enhance the thymus regeneration and develop methods to improve host immunity when the immune function is depressed due to thymic involution.
Regulatory Peptides 05/2008; 147(1-3):72-81. · 2.11 Impact Factor
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ABSTRACT: In many clinical situations which cause thymic involution and thereby result in immune deficiency, T cells are the most often affected, leading to a prolonged deficiency of T cells. Since only the thymic-dependent T cell production pathway secures stable regeneration of fully mature T cells, seeking strategies to enhance thymic regeneration should be a key step in developing therapeutic methods for the treatment of these significant clinical problems. This study clearly shows that receptor activator of NF-kappaB ligand (RANKL) stimulates mouse thymic epithelial cell activities including cell proliferation, thymocyte adhesion to thymic epithelial cells, and the expression of cell death regulatory genes favoring cell survival, cell adhesion molecules such as ICAM-1 and VCAM-1, and thymopoietic factors including IL-7. Importantly, RANKL exhibited a significant capability to facilitate thymic regeneration in mice. In addition, this study demonstrates that RANKL acts directly on the thymus to activate thymus regeneration regardless of its potential influences on thymic regeneration through an indirect or systemic effect. In light of this, the present study provides a greater insight into the development of novel therapeutic strategies for effective thymus repopulation using RANKL in the design of therapies for many clinical conditions in which immune reconstitution is required.
Experimental and Molecular Medicine 03/2008; 40(1):59-70. · 2.48 Impact Factor
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ABSTRACT: Histone deacetylase (HDAC) inhibitors are promising new class of anticancer agents that act by inhibiting cell proliferation and inducing cell cycle arrest of various cancer cells. Psammaplin A (PsA) is a phenolic natural product that has been isolated from marine sponges, and has been suggested to be a promising novel HDAC inhibitor. However, the precise mechanism of PsA as a HDAC inhibitor is poorly understood. This study investigated the anti-tumor effect of PsA on endometrial human cancer cells.
The cell proliferation, cell cycle, and apoptosis were measured in Ishikawa endometrial cancer cells after PsA treatment.
PsA significantly inhibited the proliferation of Ishikawa cells in a dose-dependent manner. PsA markedly induced the expression of acetylated H3 and H4 histone proteins. In addition, PsA markedly up-regulated the expression of cyclin-dependent kinase inhibitor, p21(WAF1), and down-regulated the expression of pRb, cyclins, and CDKs, which lead to induce cell cycle arrest. Cell cycle analysis indicated that PsA treatment increased the proportion of cells in the G0/G1 and G2/M phases, and decreased the ratio of cells in the S phase.
The PsA treatment resulted in the significant induction of apoptosis, which was associated with p53 independent p21(WAF1) expression. These results suggest that PsA exhibits the antiproliferative effects on endometrial cancer cells through selective induction of genes related to cell cycle arrest and apoptosis.
Gynecologic Oncology 02/2008; 108(1):27-33. · 3.89 Impact Factor
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ABSTRACT: Immunological abnormalities of cell-mediated and humoral immunity might be associated with the pathogenesis of endometriosis. This study has examined the effects of peritoneal fluid obtained from patients with endometriosis (ePF) on the phenotypic characteristics of macrophages and dendritic cells (DCs) derived from monocytes. Monocytes were obtained from healthy young volunteers and cultured with ePF (n=12) or a control PF (cPF) (n=5) in the presence or absence of macrophage-colony stimulating factor (M-CSF) or IL-4 plus granulocyte macrophage-colony stimulating factor (GM-CSF). The ePF was demonstrated to increase expression levels of CD14 and CD64 on isolated monocytes in the presence or absence of M-CSF. Compared with cPF, addition of 10% ePF to GM-CSF plus IL-4-treated monocytes significantly down-regulated CD1a expression and up-regulated CD64 expression, but did not enhance expression levels of class II MHC. ePF had no effect, however, on tumor necrosis factor-alpha-induced maturation of DC. Levels of IL-6, IL-10 and M-CSF production were higher in ePF-treated than cPF-treated monocytes for both cell culture conditions with GM-CSF plus IL-4 and M-CSF. A neutralizing IL-6 antibody, but not an IL-10 antibody, abrogated the ePF-induced down-regulation of CD1a, up-regulation of CD64 and secretion of M-CSF. These results suggest that ePF favorably induces monocyte differentiation toward macrophages rather than DCs, and that this effect is mediated by IL-6. A reciprocal mode of cell differentiation between macrophages and DCs in response to ePF may be related to the pathogenesis of endometriosis.
Journal of Reproductive Immunology 02/2008; 77(1):63-74. · 2.97 Impact Factor
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Jun Sik Lee,
Sang Gap Kim,
Hyung Keun Kim,
Tae-Hyung Lee,
Young-Il Jeong,
Chang-Min Lee,
Man-Soo Yoon, Yong Jin Na,
Dong-Soo Suh,
Nam Cheol Park,
In-Hak Choi,
Gi-Young Kim,
Yung Hyun Choi,
Hae Young Chung,
Yeong-Min Park
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ABSTRACT: Silibinin is the primary active compound in silymarin. It has been demonstrated to exert anti-carcinogenic effects and hepato-protective effects. However, the effects of silibinin on the maturation and immunostimulatory activities exhibited by dendritic cells (DCs) remain, for the most part, unknown. In this study, we have attempted to determine whether silibinin can influence surface molecule expression, dextran uptake, cytokine production, capacity to induce T-cell differentiation, and the signaling pathways underlying these phenomena in murine bone marrow-derived DCs. Silibinin was shown to significantly suppress the expression of CD80, CD86, MHC class I, and MHC class II in the DCs, and was also associated with impairments of LPS-induced IL-12 expression in the DCs. Silibinin-treated DCs proved highly efficient with regard to Ag capture via mannose receptor-mediated endocytosis. Silibinin also inhibited the LPS-induced activation of MAPKs and the nuclear translocation of the NF-kappaB p65 subunit. Additionally, silibinin-treated DCs evidenced an impaired induction of Th1 response, and a normal cell-mediated immune response. These findings provide new insight into the immunopharmacological functions of silibinin, especially with regard to their impact on the DCs. These findings expand our current understanding of the immunopharmacological functions of silibinin, and may prove useful in the development of therapeutic adjuvants for acute and chronic DC-associated diseases.
Journal of Cellular Physiology 03/2007; 210(2):385-97. · 3.87 Impact Factor
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ABSTRACT: An increase in the level of the vascular endothelial growth factor (VEGF) production has been reported in the peritoneal fluid (PF) of endometriosis patients. This suggests that changes in the vascular permeability and angiogenesis play an important role in the pathophysiology of this disease. This study examined the effects of the PF obtained from endometriosis patients on the release of VEGF by neutrophils and monocytes.
Neutrophils and monocytes were obtained from young healthy volunteers and cultured with the PF obtained from either endometriosis patients (EPF) (n=18) or a control group (CPF) (n=4). A human monocyte/macrophage cell line, THP-1, was cultured with either 10% EPF or 10% CPF. The PF and culture supernatants were assayed for VEGF using ELISA. Real-time PCR and Western blotting were used to measure the VEGF mRNA and protein expression level, respectively.
The VEGF levels were higher in the EPF than in the CPF (591+/-75 versus 185+/-31 pg/ml, P<0.05). However, the level of VEGF released by THP-1 cells in CPF and EPF was similar. The EPF induced the release of VEGF by neutrophils, but no VEGF was released by monocytes. The VEGF mRNA expression levels in the neutrophils were higher in the EPF, which was abrogated by cycloheximide, suggesting that the EPF induces the production of VEGF in neutrophils. Neutralizing antibodies against IL-8 and TNF-alpha did not completely prevent the EPF-induced release of VEGF by the neutrophils, even though these growth factors stimulated the release of VEGF by neutrophils. There was a positive correlation between the VEGF and IL-10 concentrations in the EPF (correlation coefficient=0.549, P=0.012, n=18), but the neutralizing antibody of IL-10 did not affect the release of VEGF by the EPF-treated neutrophils.
The EPF induced the production and release of VEGF by neutrophils, suggesting that neutrophils may be a source of peritoneal VEGF. In addition, neutrophil-derived VEGF might be a marker for diagnosing endometriosis.
Human Reproduction 07/2006; 21(7):1846-55. · 4.47 Impact Factor
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ABSTRACT: Test of human papillomavirus (HPV) is a useful adjunctive tool of Pap smear to screen cervical cancer. We have developed a novel HPV genotyping DNA chip arrayed by multiple oligonucleotide probes of both L1 and E6/E7 gene sequence of 42 types of anogenital HPV.
Consensus PCR products of L1 and E6/E7 gene sequences of HPV are hybridized to arrayed probes on the HPV chip and HPV genotypes are identified by fluorescence scanner. We have comparatively analyzed the value of HPV DNA chip and DNA sequencing in 100 cervical cancer tissues.
Overall, 98 cervical cancer tissues were found to harbor DNA sequences of high-risk type HPVs, of which 88 (89.8%) were detected by PCR-sequencing of L1 alone, 98 (100%) by PCR-sequencing of both L1 and E6/E7, and 98 (100%) by HPV DNA chip, respectively. All of the genotypes of HPV detected on sequencing analysis were also found on DNA chip analysis. HPV DNA chip was superior to direct DNA sequencing in detection of mixed infection.
These results suggest that HPV DNA chip analysis in the present study is highly accurate for detection and genotyping of HPV and may have potential value as a robust, high-throughput screening test of uterine cervix cancer.
Gynecologic Oncology 02/2006; 100(1):38-43. · 3.89 Impact Factor
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ABSTRACT: The increased production of pro-inflammatory chemoattractant cytokines for neutrophils in endometriosis suggests that changes in the immune system play an important role in the pathophysiology of endometriosis. The effects of plasma and peritoneal fluid from patients with advanced endometriosis on the apoptosis of neutrophils were investigated.
Apoptotic changes of neutrophils were evaluated by morphological changes using Giemsa staining. Apoptosis was confirmed by DNA electrophoretic analysis.
Compared with the plasma (n = 20) and peritoneal fluid (n = 5) of healthy controls, the addition of 10% plasma (n = 20) and peritoneal fluid (n = 10) from patients with endometriosis to an in-vitro culture of neutrophils from healthy subjects reduced the percentage of apoptotic cells from 65.3 +/- 6.6 to 27.2 +/- 4.6% (P < 0.001) and from 45.3 +/- 4.8 to 10.5 +/- 4.3% (P < 0.001) respectively. Neutralizing interleukin-8 antibody abrogated the delay of neutrophil apoptosis induced by peritoneal fluid, but not in the plasma of endometriosis patients.
These findings show that interleukin-8 is one of the neutrophil survival factors in the peritoneal fluid of endometriosis patients and that an unidentified survival factor is also present in the plasma of patients with endometriosis.
Human Reproduction 04/2002; 17(3):595-600. · 4.47 Impact Factor
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ABSTRACT: Purpose: Our objective was to explain a relationshipbetween concentrations of tumor necrosis factor- (TNF-)and nitric oxide (NO) in follicular fluid, oocyte quality, andoutcomes of in vitro fertilization=nembryo transfer (IVF-ET).
Methods: The concentrations of TNF- and NO weremeasured in 115 follicular fluid samples collected from 43patients undergoing IVF-ET program, due to tubalobstruction, some with endometriosis (8 patients) or hydrosalpinx(5 patients). A correlation of these factors concentrationsand the oocyte quality, the oocyte maturity, andinfertility-associated diseases was analyzed.
Results: No correlation was found between concentrationsof NO and TNF- in follicular fluid. NO concentrations infollicular fluids were significantly higher in patients withendometriosis (P < 0.001)="" or="" hydrosalpinx="" (p="">< 0.01)compared="" to="" the="" patients="" with="" just="" tubal="" obstruction.="" follicularno="" concentration="" differences="" according="" to="" oocyte="" maturityand="" oocyte="" quality="" were="" not="" found.="" in="" contrast,="">concentrations in follicular fluids were significantly higher inpoor quality oocytes (P < 0.05)="" but="" were="" not="" associatedwith="" infertility-associated="" diseases,="" such="" as="" hydrosalphinxor="" endometriosis,="" and="" the="" oocyte="" maturity.="" no="" significantdifferences="" in="" follicular="" levels="" of="" no="" and=""> as well asIVF-ET parameters of pregnant and nonpregnant groupswere revealed.
Conclusions: There is no significant correlation betweenthe concentrations of NO and TNF- in follicular fluid. NOlevels in follicular fluid are altered in infertility-associateddiseases. However, TNF- levels but not NO levels influenceoocyte quality. These results suggest that the production ofNO and TNF- in follicular fluid may be regulated viadifferent pathways and can be tempered withinfertility-associated diseases, thereby influencing oocyte qualitylocally.
Journal of Assisted Reproduction and Genetics 03/2000; 17(4):222-228. · 1.84 Impact Factor
