[GnRH analogues in the management of uterine leiomyoma].
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Diphosphonates↗
Biomedical subjects
Takeshi Maruo
Publications and source records attributed to Takeshi Maruo.
Gene expression and immunolocalization of heparin-binding epidermal growth factor-like growth factor and human epidermal growth factor receptors in human corpus luteum.
BACKGROUND: The objective of this study was to elucidate gene expression and immunolocalization of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and human epidermal growth factor receptor (HER) family in the human ovary during luteal growth and regression. METHODS: Ovaries obtained from pre-menopausal women were used for immunohistochemistry and semiquantitative RT-PCR analysis. RESULTS: Immunoreactive HB-EGF was not detected in follicles or oocyte, while HB-EGF became apparent in granulosa luteal cells in the early luteal phase, and most abundant in the mid-luteal phase, but less abundant in the late luteal phase. Immunostaining for HER1 was very weak in granulosa luteal cells in the early and mid-luteal phases, and was not detected in the late luteal phase. Immunoreactive HER4 was abundant in the early luteal phase and became less abundant in the mid-luteal phase, whereas it was negative in the late luteal phase. Semiquantitative RT-PCR analysis revealed that HB-EGF and HER1 mRNA levels were high in the mid-luteal phase, whereas HER4 mRNA expression was high in the early luteal phase. CONCLUSIONS: HB-EGF may play a vital role in regulating luteal growth in a juxtacrine manner and through activating HER4 signalling.
Adult↗
Transfection of antisense chorionic gonadotropin beta gene into choriocarcinoma cells suppresses the cell proliferation and induces apoptosis.
CONTEXT: Choriocarcinoma cells not only synthesize human chorionic gonadotropin (hCG), but also express LH/CG receptors on the cell membrane. This suggests that the hCG and LH/CG receptors may play a role in regulating the biological function of choriocarcinoma cells in an autocrine/paracrine manner. OBJECTIVE AND METHODS: The objective of this study was to ascertain whether the inhibition of CGbeta gene expression in choriocarcinoma cells affects their proliferation and apoptosis. Expression vector bearing antisense CGbeta gene was transfected into the choriocarcinoma cell line, JAr. CGbeta protein synthesis was monitored by Western immunoblot, and CGbeta mRNA expression was determined by RT-PCR. Cell proliferation was assessed by 3-[4,5-dimethlthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay and nuclear incorporation of 5-bromo-2'-deoxyuridine, and the apoptosis-positive rate was assessed by terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling analysis and nuclear staining with Hoechst 32258. RESULTS: JAr cells transfected with antisense CGbeta gene (JAr-aCGbeta cells) showed a significant decrease in hCG production and cell proliferation compared with untransfected and mock-transfected cells. The apoptosis-positive rate of the JAr-aCGbeta cells significantly increased compared with that of the controls. LH/CG receptor expression in JAr-aCGbeta cells decreased compared with that in controls. By contrast, supplementation of exogenous hCG significantly increased the LH/CG receptor expression and viability of JAr-aCGbeta cells. CONCLUSIONS: These results suggest that hCG, through its binding to the LH/CG receptor, may augment proliferation and inhibit apoptosis in choriocarcinoma JAr cells, and that the introduction of an antisense gene may be a potential approach to the inhibition of choriocarcinoma cell growth.
Apoptosis↗
Comparative effects of heparin-binding epidermal growth factor-like growth factor on the growth of cultured human uterine leiomyoma cells and myometrial cells.
BACKGROUND: The objective of this study was to investigate the comparative effects of heparin-binding epidermal growth factor-like growth factor (HB-EGF) on the growth of cultured human leiomyoma cells and myometrial cells. METHODS: Isolated cells were subcultured in Phenol Red-free Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum for 120 h and then stepped down to serum-free conditions for an additional 24 and 48 h in the presence or absence of graded concentrations of HB-EGF (0.1, 1, 10 and 100 ng/ml). These cells were used for immunocytochemical analysis for Ki67, western blot analysis for proliferating cell nuclear antigen (PCNA) and human EGF receptor (HER1), and TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labelling (TUNEL) assay. RESULTS: Treatment with HB-EGF at concentrations >1 ng/ml significantly increased the Ki67-positive rate of cultured leiomyoma cells and myometrial cells. Treatment with HB-EGF also resulted in a dose-dependent increase in PCNA expression in both cells compared with untreated control cultures. A significant increase in PCNA expression in cultured myometrial cells was noted following treatment with HB-EGF at concentrations >1 ng/ml, whereas an increase in PCNA expression in cultured leiomyoma cells was noted following treatment with HB-EGF at concentrations >10 ng/ml. HER1 expression was significantly higher in untreated myometrial cells than in untreated leiomyoma cells. A significant increase in HER1 expression in myometrial cells was observed when treated with HB-EGF at concentrations >10 ng/ml, whereas a significant increase in HER1 expression in leiomyoma cells was noted only by the treatment with HB-EGF at concentrations >100 ng/ml. Treatment with HB-EGF decreased the TUNEL-positive rate of those cells with no significant differences between the two cell types. CONCLUSIONS: The results obtained suggest that HB-EGF plays a role in stimulating the proliferation of leiomyoma cells and myometrial cells and in inhibiting apoptosis of those cells through augmentation of HER1 expression. Since the proliferative potential of myometrial cells responded better to HB-EGF than that of leiomyoma cells, HB-EGF may play a more vital role in myometrial growth than leiomyoma growth.
Adult↗
Lack of association between endometriosis and N-acetyl transferase 1 (NAT1) and 2 (NAT2) polymorphisms in a Japanese population.
OBJECTIVE: We investigated the association between endometriosis and polymorphisms in the N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) genes in a Japanese population, having previously demonstrated a positive association with NAT2 polymorphisms in a UK population. METHODS: Genotyping for NAT1 alleles *3, *4, *10, and *11, and NAT2 alleles *4, *5A, *5B, *5C, *6A, and *7B was performed using polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) and allele-specific PCR (AS-PCR) analysis in 145 ethnically Japanese, endometriosis patients and 182 controls. The NAT1 and NAT2 allele and genotype frequencies were compared in cases and controls using the Fisher exact test. RESULTS: No significant differences between cases and controls were observed in the frequencies of the NAT1 and NAT2 alleles (P = .13; P = .91) and genotypes (P = .24; P = .79), and the NAT2 acetylation phenotypes (P = .46). Dividing the cases into a subgroup, consisting of women with severe disease only (n = 80), had no effect on the results. CONCLUSION: The distribution of NAT1 and NAT2 allele and genotype frequencies were not significantly different between Japanese cases and controls. Our findings suggest that polymorphisms in NAT1 and NAT2 are unlikely to be associated with an increased risk of endometriosis in the Japanese population.
Arylamine N-Acetyltransferase↗
Association study of endometriosis and intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms in a Japanese population.
OBJECTIVE: Endometriosis is an immune-related, chronic inflammatory disease with polygenic predisposition. Cell adhesion molecules are expressed in endometriotic lesions, and in cells and tissues that are involved in the development and progression of the disease. In this study, we investigated the possible association between endometriosis and the G241R and K469E polymorphisms in the intercellular adhesion molecule-1 (ICAM-1) gene in a Japanese population. METHODS: We compared the distribution of the G241R and K469E polymorphisms in the ICAM-1 gene in 126 endometriosis patients and 172 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in a Japanese population. RESULTS: There were no significant differences between the cases and controls in the allele frequencies or genotype distributions of either the G241R or K469E polymorphisms in the ICAM-1 gene. The endometriosis patients were divided into a subgroup of women with severe disease only. However, no significant differences were observed in the allele frequencies and genotype distributions of the ICAM-1 K469E polymorphisms between this subgroup and the controls. In contrast, only one in 169 controls was heterozygous (G/A genotype), and the A allele in the G241R polymorphism was not found in any of the 126 endometriosis patients. CONCLUSION: Our findings suggest that the G241R and K469E polymorphisms in the ICAM-1 gene are unlikely to be associated with an increased risk of endometriosis in the Japanese population.
Case-Control Studies↗
Effects of estriol on proliferative activity and expression of insulin-like growth factor-I (IGF-I) and IGF-I receptor mRNA in cultured human osteoblast-like osteosarcoma cells.
The present study was undertaken to elucidate whether estriol (E3) affects the proliferative activity and the expression of insulin-like growth factor-I (IGF-I) mRNA and IGF-I receptor (IGF-IR) mRNA in cultured human osteoblast-like osteosarcoma cells (HOS TE85). In this study, the effects of E3 on cultured HOS TE85 cells were compared with those of 17 beta-estradiol (E2). HOS TE85 cells were subcultured in phenol red-free Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum for 72 h and then stepped down to serum-free conditions for an additional 72 h in the absence or presence of E3 (3.52 x 10(-9), 3.52 x 10(-8), 3.52 x 10(-7) mol/l) or E2 (3.67 x 10(-8) mol/l). Treatment with either E3 (3.52 x 10(-8), 3.52 x 10(-7) mol/l) or E2 (3.67 x 10(-8) mol/l) resulted in an increase in the number of cultured HOS TE85 cells and their uptake of bromodeoxyuridine. Northern blot hybridization with a IGF-I cDNA probe revealed that RNA prepared from cultured HOS TE85 cells contained IGF-I mRNA transcripts of 1.8, 4.4 and 7.5 kb. Treatment with either E3 (3.52 x 10(-9), 3.52 x 10(-8), 3.52 x 10(-7) mol/l) or E2 (3.67 x 10(-8) mol/l) resulted in increased expression of the three mRNA transcripts relative tot hose in untreated control cultures. Semi-quantitative, reverse transcription polymerase chain reaction analysis showed that the 440-bp IGF-IR mRNA transcript was present in HOS TE85 cells and that treatment with either E3 or E2 did not affect the IGF-IRmRNA expression in these cells. These results demonstrate that E3 (3.52 x 10(-9), 3.52 x 10(-8), 3.52 x 10(-7) mol/l) exerts profound effects on the proliferative potential of cultured HOS TE85 cells, compatible with that of E2 (3.67 x 10(-8) mol/l), through the induction of IGF-I mRNA expression without affecting IGF-IR mRNA expression in these cells.
Bromodeoxyuridine↗
Lack of association between endometriosis and the CYP17 MspA1 polymorphism in UK and Japanese populations.
Endometriosis is a complex trait, which means that multiple susceptibility genes interact with one another and the environment to produce the phenotype. One of the genes previously implicated in the disease is CYP17; this encodes the enzyme P450c17alpha, which plays a vital role in steroid biosynthesis in the ovary. The presence of a single nucleotide polymorphism (T-->C) in the 5'-promoter region of the gene creates a new recognition site for the restriction enzyme MspA1 producing a mutant allele (A2), which affects circulating estrogen levels. In this study, we compared the frequency of the CYP17 MspA1 polymorphism in two different ethnic populations. DNA was obtained from (1) 94 women with revised American Fertility Society (rAFS) stage III-IV endometriosis and 97 male blood donors in the UK, and (2) 130 women with rAFS stage III-IV endometriosis and 179 female newborn infants in Japan. No significant differences in allele or genotype frequencies were seen in either population. The genotype distribution in the UK population was 33/94 [35.1%] (cases) and 39/97 [40.2%] (controls) for A1A1 (homozygous wild-type); 43/94 [45.7%] (cases) and 44/97 [45.4%] (controls) for A1A2; and 18/94 [19.1%] (cases) and 14/97 [14.4%] (controls) for A2A2. The genotype distribution in the Japanese population was 31/130 [23.9%] (cases) and 57/179 [31.8%] (controls) for A1A1; 73/130 [56.2%] (cases) and 89/179 [49.7%] (controls) for A1A2; and 26/130 [20.0%] (cases) and 33/179 [18.4%] (controls) for A2A2. The CYP17 MspA1 polymorphism is probably not associated with endometriosis in either the UK or the Japanese population.
Asian People↗
Acute onset of polymyalgia rheumatica in pregnancy.
BACKGROUND: Polymyalgia rheumatica is uncommon in young women and remains a diagnostic challenge for pregnant women. CASE: A 28-year-old pregnant woman developed polymyalgia rheumatica in the third trimester. Laboratory investigations revealed elevated erythrocyte sedimentation rate and C-reactive protein levels with normal muscle enzyme levels and seronegativity for rheumatoid factor. Although her symptoms deteriorated as pregnancy progressed, she drastically improved by treatment with prednisone. She underwent cesarean delivery at 39 weeks. She was relapse-free of polymyalgia rheumatica after discontinuation of prednisone on the 50th postoperative day. CONCLUSION: The diagnosis of polymyalgia rheumatica is important to properly manage pregnancy.
Acute Disease↗
Two cases of clinically suspected thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in the puerperium.
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Adult↗
[Human chorionic gonadotropin (hCG) and subunits].
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Abortion, Threatened↗
[Pregnancy specific beta1 glycoprotein (SP-1)].
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Abortion, Threatened↗
A novel RARbeta isoform directed by a distinct promoter P3 and mediated by retinoic acid in breast cancer cells.
Retinoids regulate gene transcription through activating retinoic acid receptors (RARs)/retinoic X receptors (RXRs). Of the three RAR receptors (alpha, beta, and gamma), RARbeta has been considered a tumor suppressor gene. Here, we identified a novel RARbeta isoform-RARbeta5 in breast epithelial cells, which could play a negative role in RARbeta signaling. Similar to RARbeta2, the first exon (59 bp) of RARbeta5 is RARbeta5 isoform specific, whereas the other exons are common to all of the RARbeta isoforms. The first exon of RARbeta5 does not contain any translation start codon, and therefore its protein translation begins at an internal methionine codon of RARbeta2, lacking the A, B, and part of C domain of RARbeta2. RARbeta5 protein was preferentially expressed in estrogen receptor-negative breast cancer cells and normal breast epithelial cells that are relatively resistant to retinoids, whereas estrogen receptor-positive cells that did not express detectable RARbeta5 protein were sensitive to retinoid treatment, suggesting that this isoform may affect the cellular response to retinoids. RARbeta5 isoform is unique among all of the RARs, because a corresponding isoform was not detectable for either RARalpha or RARgamma. RARbeta5 mRNA was variably expressed in normal and cancerous breast epithelial cells. Its transcription was under the control of a distinct promoter P3, which can be activated by all-trans-retinoic acid (atRA) and other RAR/RXR selective retinoids in MCF-7 and T47D breast cancer cells. We mapped the RARbeta5 promoter and found a region -302/-99 to be the target region of atRA. In conclusion, we identified and initially characterized RARbeta5 in normal, premalignant, and malignant breast epithelial cells. RARbeta5 may serve as a potential target of retinoids in prevention and therapy studies.
Amino Acid Sequence↗
Progesterone receptor modulator CDB-2914 down-regulates proliferative cell nuclear antigen and Bcl-2 protein expression and up-regulates caspase-3 and poly(adenosine 5'-diphosphate-ribose) polymerase expression in cultured human uterine leiomyoma cells.
The present study was conducted to evaluate the effects of the progesterone receptor modulator CDB-2914 on proliferative activity and apoptosis in cultured human uterine leiomyoma cells. Isolated leiomyoma cells were subcultured in phenol red-free DMEM supplemented with 10% fetal bovine serum for 120 h and then stepped down to serum-free conditions for 12, 24, 48, and 96 h in the absence or presence of graded concentrations of CDB-2914 (10(-9), 10(-8), 10(-7), and 10(-6) M). The number of viable cultured leiomyoma cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazodium bromide assay. Proliferating cell nuclear antigen (PCNA) expression was evaluated by immunocytochemistry and Western blot analysis. Apoptosis was examined by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) assay. Caspase-3, cleaved poly(ADP-ribose) polymerase (PARP), and Bcl-2 expression were assessed by Western blot analysis. Compared with untreated control cultures, treatment with CDB-2914 decreased the number of viable cultured leiomyoma cells and the PCNA-positive rate in those cells and increased the TUNEL-positive rate in cultured leiomyoma cells in a dose-dependent manner. Western blot analysis revealed that treatment with CDB-2914 significantly decreased the expression of PCNA and Bcl-2 protein and increased the expression of cleaved caspase-3 and cleaved PARP in a dose-dependent manner compared with untreated control cultures. These results suggest that CDB-2914 inhibits the proliferation of cultured leiomyoma cells by down-regulating PCNA expression and induces apoptosis by up-regulating cleaved caspase-3 and PARP expression and down-regulating Bcl-2 protein expression in those cells.
Apoptosis↗
Effects of combined estriol/pravastatin therapy on intima-media thickness of common carotid artery in hyperlipidemic postmenopausal women.
BACKGROUND: Several studies show that 17beta-estradiol (E2) has protective effects on atherosclerosis in the arterial wall in postmenopausal women. Little information is, however, available regarding the effect of estriol (E3) on atherosclerosis. This study was conducted to investigate the effects of E3 alone and combined E3/pravastatin therapy on intima-media thickness (IMT) of common carotid artery in postmenopausal women. METHODS: Thirty-three postmenopausal women were allocated to four groups: daily treatment with E3 (2 mg) alone (E3 group, n = 10), pravastatin (10 mg) alone (pravastatin group, n = 6), combined treatment with E3 (2 mg) and pravastatin (10 mg; E3/pravastatin group, n = 7) and untreated control group (n = 10). All women attended the Kobe University Hospital once a year for routine gynecological and ultrasonographic examinations for the evaluation of atherosclerosis. RESULTS: A significant decrease in IMT was noted in the E3/pravastatin group compared with that in the untreated control group (p < 0.05), whereas there was no significant difference in the reduction rate of IMT in the pravastatin group, E3 group and untreated control group. CONCLUSIONS: The combined E3/pravastatin therapy appeared to retard the progression of atherosclerosis in postmenopausal women.
Arteriosclerosis↗
Gonadotropin-releasing hormone antagonist cetrorelix down-regulates proliferating cell nuclear antigen and epidermal growth factor expression and up-regulates apoptosis in association with enhanced poly(adenosine 5'-diphosphate-ribose) polymerase expression in cultured human leiomyoma cells.
The objective of this study was to elucidate the effects of GnRH antagonist Cetrorelix on proliferation and apoptosis in human leiomyoma cells cultured in vitro. Isolated leiomyoma cells were subcultured in phenol red-free DMEM supplemented with 10% fetal bovine serum for 120 h and then stepped down to serum-free conditions in the presence or absence of graded concentrations of Cetrorelix (10(-5) to 10(-8) mol/liter) for 6 d. Cultured leiomyoma cells were used for semiquantitative RT-PCR, immunocytochemistry, Western blot analysis, and terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling assay. RT-PCR analysis revealed the presence of mRNAs encoding for GnRH receptor and epidermal growth factor (EGF) in cultured leiomyoma cells. The number of viable cultured leiomyoma cells was significantly (P < 0.01) decreased by treatment with Cetrorelix compared with untreated control cultures. Immunocytochemical examination demonstrated that treatment with Cetrorelix attenuated the expression of proliferating cell nuclear antigen (PCNA) and EGF in cultured leiomyoma cells. Western blot analysis revealed that treatment with 10(-5) mol/liter Cetrorelix significantly (P < 0.01) decreased PCNA expression. In addition, treatment with 10(-5) mol/liter Cetrorelix remarkably increased the terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling-positive rate and poly(ADP-ribose) polymerase expression at 24 h of treatment compared with untreated control cultures (P < 0.01). Furthermore, treatment with 10(-5) mol/liter Cetrorelix decreased immunoreactive EGF protein and EGF mRNA expression in cultured leiomyoma cells at 4 d of treatment. GnRH antagonist Cetrorelix may directly inhibit leiomyoma cell growth by down-regulating proliferation in association with a decrease in EGF mRNA expression and by up-regulating apoptosis in those cells.
Adult↗
The tumor necrosis factor-alpha promoter -1031C polymorphism is associated with decreased risk of endometriosis in a Japanese population.
BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional proinflammatory cytokine, associated with various inflammatory and autoimmune diseases. Elevated TNF-alpha levels in peritoneal fluid have been reported in women with endometriosis, suggesting that TNF-alpha may be involved in the development of endometriosis. In this study, we investigated the possible association between endometriosis and the TNF-alpha gene promoter polymorphisms -238G/A, -308G/A, -857C/T, -863C/A and -1031T/C in a Japanese population. METHODS: We compared the distribution of the -238G/A, -308G/A, -857C/T, -863C/A and -1031T/C polymorphisms in the promoter region of TNF-alpha in 130 endometriosis cases and 185 controls using PCR-RFLP analysis. RESULTS: The allele frequencies of -238A, -308A, -857T, -863A and -1031C in controls were 2.0%, 1.3%, 19.4%, 17.0% and 18.6%, and in the cases 1.1%, 0.3%, 19.6%, 18.6% and 13.6%, respectively. No significant differences in frequencies were found between the crude endometriosis cases and controls. However, when the endometriosis group was divided into a subgroup of women with stage IV disease only, the frequency of the -1031C allele was significantly lower in this subgroup than controls. CONCLUSIONS: The variability of the -1031T/C polymorphism of the TNF-alpha gene may be associated with susceptibility to (AUTHOR: as meant?) endometriosis.
Asian People↗
Progesterone down-regulates insulin-like growth factor-I expression in cultured human uterine leiomyoma cells.
BACKGROUND: Insulin-like growth factor-I (IGF-I) plays crucial roles in uterine leiomyoma cell growth through stimulating proliferation and inhibiting apoptosis. The present study was conducted to elucidate whether progesterone affects IGF-I and its receptor expression in cultured leiomyoma cells. METHODS: Isolated leiomyoma cells were subcultured in Phenol Red-free Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum for 120 h and then stepped down to serum-free conditions for an additional 48 h in the presence or absence of 17beta-estradiol (E(2)) (10 ng/ml) or progesterone (100 ng/ml). IGF-I and its receptor mRNA and immunoreactive IGF-I in the cultured cells were assessed by quantitative RT-PCR with Southern blot analysis and by radioimmunoassay with Seppak C18 chromatography, respectively. The presence of estrogen receptor (ER) and progesterone receptor (PR) in cultured leiomyoma cells was immunocytochemically examined. RESULTS: Both treatment with progesterone alone and treatment with E(2) and progesterone combined significantly decreased IGF-I mRNA and protein expression in cultured leiomyoma cells compared with that in untreated cultures, but treatment with E(2) alone did not. IGF-I receptor mRNA expression in those cells was not affected by treatment with either E(2) or progesterone. Immunocytochemical analysis revealed that PR protein expression in cultured leiomyoma cells maintained in a serum-free condition for 48 h whereas ER protein expression in the cells remarkably decreased after 24 h culture under the serum-free condition. CONCLUSIONS: The present study provided evidence for the first time that progesterone down-regulates IGF-I mRNA and protein expression in cultured leiomyoma cells without affecting IGF-I receptor mRNA expression.
Adult↗