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Biomedical subjects

E Attar

Publications and source records attributed to E Attar.

10 recordsLinked to original sources
PubMed2005

Aromatase and other steroidogenic genes in endometriosis: translational aspects.

Endometriosis is a common, chronic and estrogen-dependent gynaecological disorder associated with pelvic pain and infertility. In addition to, or perhaps as a consequence of, immune, environmental and genetic factors, endometriotic lesions show high estradiol (E(2)) biosynthesis and low E(2) inactivation compared with normal endometrium. Current medical therapies of pain, which aim to lower circulating E(2) concentrations, are not effective in at least half of these patients. We and others recently demonstrated the expression of a few steroidogenic genes in endometriosis. The most important genes in this group are steroidogenic acute regulatory protein (StAR) and aromatase. Both are essential for E(2) production. Prostaglandin E(2) (PGE(2)) is the most potent known stimulator of both StAR and aromatase. PGE(2) production in endometriosis is up-regulated by increased levels of the enzyme cyclo-oxygenase-2 (COX-2) in this tissue. COX-2 in turn is stimulated by E(2), interleukin-1beta (IL-1beta) and PGE(2) itself in endometrial and endometriotic cells. Thus, there is a positive feedback loop that favours continuous formation of E(2) and PGE(2) in endometriosis. These basic findings led to recent phase-II studies employing aromatase inhibitors in the treatment of endometriosis. Aromatase inhibitors treat both postmenopausal and premenopausal endometriosis at least as effectively as the existing medical treatments. In premenopausal women, we and others administered aromatase inhibitors in combination with an ovarian-suppressant treatment. In this review, we emphasize the most recent basic studies in detail and provide a short summary of recent clinical trials.

Aromatase↗
PubMed2005

Silencing p21(Waf1/Cip1/Sdi1) expression increases gene transduction efficiency in primitive human hematopoietic cells.

Adult hematopoietic and other tissue stem cells have highly constrained cell cycling that limits their susceptibility to standard gene therapy vectors, which depend upon chromosomal integration. Using cytokine cocktails to increase transduction efficiency often compromises subsequent stem cell function in vivo. We previously showed that p21(Waf1/Cip1/Sdi1) (p21) mediates stem cell quiescence in vivo and decreasing its expression ex vivo leads to an expansion of stem cell pool in vivo. Here, we report that application of p21 specific siRNA increased the gene transduction efficiency in hematopoietic stem cells while preserving cell multipotentiality. Both types of siRNA, synthesized siRNA and transcribed shRNA, reduced p21 expression in target cells by 85-98%. The effect of RNAi in these cells was transient and the level of p21 mRNA returned to base line 14-28 days after siRNA treatment. This brief interval of reduction, however, was sufficient to increase transduction efficiency to two- to four-fold in cell cultures, and followed by a seven- to eight-fold increase in mice. The RNAi treated, lentivector-transduced CD34+ cells retained multipotentiality as assessed in vitro by colony formation assay and in vivo by NOD/SCID mouse transplantation assay. Reduction of p21 resulted in an increased chromosomal integration of lentivector into target cellular DNA. Taken together, both synthesized and transcribed siRNA knocked down p21 expression in human CD34+ hematopoietic stem/progenitor cells. Silencing p21 expression increased gene transduction efficiency and vector integration while retaining stem cell multipotentiality. Thus, RNAi targeting of p21 is a useful strategy to increase stem cell gene transfer efficiency. Decreasing p21 expression transiently while increasing gene-transfer vector integration may ultimately facilitate clinical applications of gene therapy.

Adult↗
PubMed2002

Acetaminophen modulations of chemotherapy efficacy in MDAH 2774 human endometrioid ovarian cancer cells in vitro.

Epidemiological data have correlated consumption of nonsteroidal antinflammatory drugs with lowered risk for many types of cancer, and some recent studies indicate a reverse correlation with acetaminophen consumption and ovarian malignancy. In this study we examined effects of acetaminophen on plating, S-phase and colony growth of MDAH 2774 human endometrioid ovarian carcinoma, as well as sensitivity of this cell line to carboplatin in all three tests, and paclitaxel to clonogenic assay. Acetaminophen significantly enhanced S-phase in first 72 hours and enhanced cell population in 96 hours of plating monitorization, but decreased one week colony growth by approximately 80%, which was in the range of cytotoxic drugs. Interestingly with low dose carboplatin in first 72 hours acetaminophen enhanced cell proliferation more profoundly, but only thereafter decreased cell growth synergistically with carboplatin. It did not effect paclitaxel colony growth inhibiting acitivity. MDAH-2774 cell line lack p-53 and MSH-2, which are both 'gatekeeper' apoptosis inducing genes against genome damaging insult. Thus, presence of lower doses of oxidizing drugs may help the induction of proliferative signals, but only their sustained presence may overcome such signals and ultimately bring to cell demise.

Acetaminophen↗
PubMed2002

Natural contraception using the Billings ovulation method.

OBJECTIVE: The Billings ovulation method (BOM) is a medical model of a natural procreation education method based on scientific observation of the changes in the cervical mucus. In this study we examined Turkish women's interest in accurate usage of cervical mucus changes in determining the ovulation time. METHOD: Fifteen regularly cycling women monitored their fertility patterns in 30 cycles using the BOM and urine luteinizing hormone (LH) kits. At the end ofeach cycle, the cervical mucus monitoring chart and LH kits were collected from the subjects and analyzed. RESULTS: The cervical mucus symptoms defined a potential fertile period of 10 days' average length, with the 'peak' mucus characteristic occurring at a mean of day 13.65 +/- 2.62 of the cycle. The duration ofthe LH surge, as observed in early morning urine samples, averaged 5 days, with the peak occurring at a mean of day 13.40 +/- 2.58 of the cycle. Data indicated that there was a strong correlation between LH in the urine and the peak in self-observed, cervical-vaginal mucus (p = 0.001). CONCLUSION: This study proved that women can distinguish patterns of ovulation and anovulation by self-detection of variations in cervical mucus characteristics, and that urinary LH levels strongly correlate with ovulation.

Adult↗
PubMed1997

GAS6 mediates adhesion of cells expressing the receptor tyrosine kinase Axl.

Axl is a receptor tyrosine kinase that contains both immunoglobulin and fibronectin III repeats in its extracellular domain reminiscent of cell adhesion molecules. Expression of the receptor tyrosine kinase Axl in the 32D myeloid cell line permits aggregation of cells in response to treatment with the native ligand GAS6; this aggregation was not observed in untreated 32D-Axl cells nor in treated parental cells. This aggregation can be blocked by the addition of excess Axl extracellular domain peptide and does not require intracellular Axl kinase activity. Cell surface binding activity of GAS6 was mapped to distinct plasma membrane interacting domains that are separate from the GAS6 motifs that engage the Axl receptor. This suggests that aggregation is mediated by a heterotypic intercellular mechanism whereby cell-bound GAS6 interacts with Axl receptor on an adjacent cell. This mechanism is supported by our observation that GAS6 binds to 32D parental cells which then permits their aggregation with untreated 32D-Axl cells. We have recently demonstrated that the GAS6-Axl interaction does not initiate mitogenesis in 32D cells. When considered with the adhesion results, these data suggest that an important biological function of the Axl-GAS6 interaction is to mediate cell-cell binding.

Animals↗
PubMed1997

Monocyte chemotactic protein-1 concentration in peritoneal fluid of women with endometriosis and its modulation of expression in mesothelial cells.

OBJECTIVE: To investigate monocyte chemotactic protein-1 concentrations in the peritoneal fluid (PF) of women with or without endometriosis, then assess peritoneal mesothelial cells as a potential source of monocyte chemotactic protein-1. DESIGN: Prospective study. SETTING: University medical center. PATIENT(S): Women with (n = 60) or without (n = 18) endometriosis. INTERVENTION(S): First monocyte chemotactic protein-1 levels in PF were measured, then mesothelial cells in culture were treated with cytokines. MAIN OUTCOME MEASURE(S): In PF and culture supernatants, monocyte chemotactic protein-1 was measured by ELISA. In vitro monocyte chemotactic protein-1 messenger RNA expression was evaluated by Northern analysis. RESULT(S): The median concentration of monocyte chemotactic protein-1 in PF of control women was 137 pg/mL (conversion factor to SI unit, 0.115; range, 12 to 418 pg/mL); that of women with moderate endometriosis was 205 pg/mL (range 65 to 6,000 pg/mL); and that of those with severe endometriosis was 1,165 pg/mL (0 to 2,602 pg/mL). Within the moderate to severe endometriosis group, monocyte chemotactic protein-1 levels were higher in women with untreated endometriosis (354 pg/mL range 0 to 6,000 pg/mL) than in women receiving GnRH agonist (128 pg/mL, range 0 to 216 pg/mL). In the control group, monocyte chemotactic protein-1 levels were higher in the proliferative phase than in the secretory phase. Mesothelial cells produced constitutively monocyte chemotactic protein-1; moreover, both interleukin-1 alpha and tumor necrosis factor-alpha induced higher levels of monocyte chemotactic protein-1. CONCLUSION(S): Levels of monocyte chemotactic protein-1 in PF were higher during the proliferative phase than secretory phase of control women and increased in moderate to severe endometriosis. The regulated expression of monocyte chemotactic protein-1 may recruit macrophages into PF and contribute to the pathogenesis of endometriosis.

Antineoplastic Agents, Hormonal↗
PubMed1996

Modulation of leukemia inhibitory factor gene expression and protein biosynthesis in the human fallopian tube.

OBJECTIVE: The fallopian tube is the site of fertilization and early embryonic growth and a common site of ectopic implantation. Although the factors responsible for early embryogenesis and implantation are incompletely understood, leukemia inhibitory factor may have an important role in early embryonic development and implantation. We set out to evaluate the production and modulation of leukemia inhibitory factor in the fallopian tube. STUDY DESIGN: We first investigated leukemia inhibitory factor messenger ribonucleic acid levels in fallopian tubes. We then investigated leukemia inhibitory factor messenger ribonucleic acid and protein production in tubal epithelial and stromal cell cultures. RESULTS: Leukemia inhibitory factor messenger ribonucleic acid is expressed in the fallopian tube with only slight variation during the menstrual cycle; however, it is markedly elevated in association with ectopic pregnancy. The level is higher in the tubal mucosa than in the remaining layers and is higher in the more distal segments of the fallopian tube. Estradiol and progesterone did not modulate leukemia inhibitory factor expression in epithelial or stromal cell cultures. Interleukin-1 alpha, tumor necrosis factor-alpha, and transforming growth factor-beta enhanced leukemia inhibitory factor expression in epithelial and stromal cells, with transforming growth factor-beta 1 enhancing expression by fourfold in stromal cells. Epithelial cells secreted high levels of leukemia inhibitory factor compared with stromal cells (332 +/- 89 vs 25 +/- 42 pg/mg total protein). Yet stromal cells treated with transforming growth factor-beta alone or in combination with epidermal growth factor and platelet-derived growth factor, as well as TNF-alpha alone or in combination with interleukin-1 alpha enhanced secretion of leukemia inhibitory factor at or above the levels found with epithelial cells. CONCLUSIONS: We speculate that the high constitutive levels of leukemia inhibitory factor expressed in the ampullary portion of the fallopian tube may play a role in early embryonic development. Additionally, elevated expression with ectopic implantation and the marked induction of secretion in the tubal stroma by growth factors and cytokines suggest a link between inflammation, leukemia inhibitory factor, and tubal ectopic pregnancies.

Adult↗
PubMed1996

Interleukin-8 concentration in peritoneal fluid of patients with endometriosis and modulation of interleukin-8 expression in human mesothelial cells.

Interleukin-8 (IL-8) is a chemoattractant and activating factor for human neutrophlls and a potent angiogenic agent. The peritoneal fluid of women with endometriosis has been shown to have increased neutrophil chemotactic activity. We postulate that IL-8 may be an important modulator in the pathogenesis of endometriosis and adhesion formation. We first investigated IL-8 concentrations in the peritoneal fluid of women with or without endometriosis, then assessed peritoneal mesothelial cells as a potential source of peritoneal fluid IL-8. Northern blot analysis and enzyme-linked immunosorbent assay (ELISA) were used to investigate IL-8 mRNA and protein modulation. The mean concentration of IL-8 in samples obtained from control patients (n = 28) was 4.8 +/- 0.5 pg/ml; from patients with minimal-mild endometriosis (n = 24) was 27.5 +/- 2.6 pg/ml; and from patients with moderate-severe endometriosis (n = 21) was 530.2 +/- 65.1 pg/ml. Confluent mesothelial cells were incubated with human recombinant IL-1 alpha (0.01-100 IU/ml) or tumour necrosis factor (TNF)-alpha (0.01 to 100 ng/ml) for 2-24 h. IL-8 mRNA was detectable in non-treated cells, however both IL-1 alpha and TNF-alpha induced higher amounts of IL-8 mRNA in a dose- and time-dependent manner. Non-treated mesothelial cells in culture also produced and secreted IL-8 protein quantified by ELISA, but again higher concentrations were induced by IL-1 alpha and TNF-alpha treatment. In conclusion, we found that IL-8 concentrations were elevated in peritoneal fluids from women with endometriosis. Cultured mesothelial cells expressed cytokine-inducible IL-8 mRNA and secreted IL-8 protein. The regulated expression of this angiogenic factor may play a role in pathogenesis of endometriosis.

Ascitic Fluid↗
PubMed1995

Modulation of leukemia inhibitory factor gene expression and protein biosynthesis in human endometrium.

Implantation is the process by which the blastocyst becomes intimately connected with the maternal endometrium/decidua. The independently developing preimplantation blastocyst then becomes dependent on the maternal environment for its continued development. Although the factors involved in the regulation of blastocyst implantation are incompletely understood, recent studies strongly suggest a critical role for leukemia inhibitory factor (LIF) in mice. We showed previously that LIF acts on human trophoblasts to shift their differentiation toward the anchoring phenotype by increasing the synthesis of fibronectin. In the present study, we first evaluated the temporal expression of LIF in the human endometrium in order to gain further insights into the role of LIF in human implantation. We established the LIF is expressed in the endometrium in a menstrual cycle-dependent manner. The most abundant LIF messenger ribonucleic acid (mRNA) levels are observed in the mid- and late-luteal phase samples. LIF mRNA was also present in decidual tissues of first trimester of pregnancy, but levels were lower than those found in the midluteal endometrium. We then investigated the regulation of LIF expression in human endometrial cells in culture by cytokines, steroid hormones, and growth factors. We could not show any direct stimulatory evidence of steroid hormones (estradiol and progestins) on LIF mRNA expression or protein production by endometrial cells in culture. On the other hand, we showed that interleukin-1, tumor necrosis factor-alpha, platelet-derived growth factor, epidermal growth factor, and transforming growth factor-beta are potent inducers of LIF expression in endometrial stromal cells in culture in a concentration- and time-dependent manner. Interferon-gamma acted to inhibit LIF expression induced by these cytokines. In contrast, we found high constitutive and relatively less regulated levels of LIF mRNA in the endometrial gland cells. The timing of the expression of LIF in the endometrium suggests a potential role in the implantation. The regulation of the expression of LIF may have an important role in the physiological and pathological processes involving human implantation.

Adult↗