Biomedical subjects

Antonis Makrigiannakis

Publications and source records attributed to Antonis Makrigiannakis.

At least 19 recordsLinked to original sources

PubMed2007

Peripheral corticotropin-releasing hormone is produced in the immune and reproductive systems: actions, potential roles and clinical implications.

Corticotropin-releasing hormone (CRH), the principal regulator of the hypothalamic-pituitary-adrenal axis, has been identified in various organ systems, including the immune and the female and male reproductive systems. CRH-like immunoreactivity has been reported in peripheral inflammatory sites and in a number of reproductive organs, including the ovaries, endometrial glands, decidualized endometrial stroma, placenta, decidua, and the testes. Therefore, "immune" and "reproductive" CRH are forms of "tissue" CRH; i.e., CRH found in peripheral tissues. Immune CRH plays a direct immunomodulatory role as an autocrine/paracrine mediator of inflammation. Immune CRH participates in several experimental inflammations and, in humans, in inflamed tissues from patients with autoimmune and inflammatory diseases. One of the early effects of immune CRH is the degranulation of mast cells and the release of histamine and several inflammatory cytokines. Reproductive CRH is regulating reproductive functions with an inflammatory component, such as ovulation, luteolysis, decidualization, implantation, and early maternal tolerance. Placental CRH participates in the physiology of pregnancy and the onset of labor. Circulating placental CRH is responsible for the physiologic hypercortisolism of the latter half of pregnancy. Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explain the blues/depression and increased autoimmune phenomena observed during this period.

Animals↗

PubMed2007

Mechanisms of implantation.

Successful embryo implantation in mammals requires the co-ordinated development of a blastocyst competent to implant and an adhesive endometrium. Given the indispensable role of implantation for the furtherance of the species, a number of molecular mechanisms have evolved to regulate the process. A variety of molecules, produced by embryo as well as maternal tissue participates in the cross-talk between the implanting blastocyst and the endometrium. The interplay between the various molecules and the routes in which they are involved is beginning to be elucidated. Because impaired implantation represents the most important limiting factor in the establishment of pregnancy, it is believed that research in the field will allow clinicians to improve the respective rates. This paper reviews certain groups of molecules that are considered to have key roles in the mechanisms of implantation.

Animals↗

PubMed2006

FSH receptor gene polymorphisms have a role for different ovarian response to stimulation in patients entering IVF/ICSI-ET programs.

PURPOSE: To examine the frequency distribution of the Ser680Asn polymorphism of the follicle-stimulating hormone receptor (FSHR) gene in ovarian dysfunction (OD) infertile women, "poor responders" (PR) and "good responders" (GR). METHODS: The hormonal profiles and treatment of all patients were analyzed and FSHR polymorphism was examined by PCR and RFLP. Women from all groups were classified as Asn/Asn, Asn/Ser, and Ser/Ser genotypes. RESULTS: The frequency distribution of Ser/Ser, Asn/Ser and Asn/Asn variants in OD patients was 45.5, 22.7, and 31.8%, respectively. Day 3 FSH levels in OD and GR patients were higher in Ser/Ser and Asn/Asn subgroups. Asn/Ser carriers from OD and GR groups provided more follicles and oocytes compared to other allelic variants. CONCLUSIONS: GR patients carry more often the Asn/Ser genotype. The latter is correlated with more follicles and oocytes in both OD and GR patients. The Ser/Ser variant might be related to higher serum FSH levels, while the Asn/Ser with lower.

Adult↗

PubMed2006

Hormonal and cytokine regulation of early implantation.

Implantation of the blastocyst into the endometrium is a delicately controlled process and a prerequisite for the furtherance of the mammalian species. A complex network of molecules is involved in preparing both the endometrium and blastocyst for a successful interaction. However, the exact molecular steps are poorly understood. Studies so far have shown that disruption of certain pathways results in fertility defects. Impaired implantation is currently considered to be the most important limiting factor for the establishment of viable pregnancies in assisted reproduction. It is expected that elucidating the molecular background of the process will enable accurate diagnosis and effective treatment of infertility.

Animals↗

PubMed2006

Premature ovarian failure, endothelial dysfunction and estrogen-progestogen replacement.

Cardiovascular disease, including coronary artery disease, stroke and peripheral vascular disease, is the leading cause of death among women. Vascular endothelial dysfunction is an early marker of atherosclerosis. Women with premature ovarian failure (or premature menopause) present an increased risk for cardiovascular disease, which might be attributed to the early onset of vascular endothelial dysfunction, associated with sex steroid deficiency. Cyclical estrogen and progestogen therapy has been shown to restore endothelial function in these young women. Further research is required to assess primarily the long-term effects of hormone replacement therapy on cardiovascular and overall prognosis in young women with premature ovarian failure, as well as the effects of different doses, duration and routes of hormone administration in these women.

Adult↗

PubMed2006

Corticotropin-releasing hormone modulates human trophoblast invasion through carcinoembryonic antigen-related cell adhesion molecule-1 regulation.

Abnormalities in the process of trophoblast invasion may result in abnormal placentation. Both the embryonic trophoblast and maternal decidua produce corticotropin-releasing hormone (CRH), which promotes implantation. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is expressed in extravillous trophoblasts (EVTs) of normal human placenta, may also function in tro-phoblast/endometrial interactions. We investigated whether locally produced CRH plays a role in trophoblast invasion, primarily by regulating CEACAM1 expression. We examined cultures of freshly isolated human EVTs, which express CEACAM1, and an EVT-based hybridoma cell line, which is devoid of endogenous CEACAM1. CRH inhibited EVT invasion in Matrigel invasion assays, and this effect was blocked by the CRH receptor type 1 (CRHR1)-specific antagonist antalarmin. Additionally, CRH decreased CEACAM1 expression in EVTs in a dose-dependent manner. After transfection of the hybridoma cell line with a CEACAM1 expression vector, the invasiveness of these cells was strongly enhanced. This effect was inhibited by addition of blocking monoclonal antibody against CEACAM1. Furthermore, blocking of endogenous CEACAM1 in EVTs inhibited the invasive potential of these cells. Taken together these findings suggest that CRH inhibits trophoblast invasion by decreasing the expression of CEACAM1 through CRHR1, an effect that might be involved in the pathophysiology of clinical conditions, such as preeclampsia and placenta accreta.

Antigens, CD↗

PubMed2005

Predictors of endothelial dysfunction in young women with polycystic ovary syndrome.

CONTEXT: Women with polycystic ovary syndrome (PCOS) may be at increased risk for cardiovascular disease. Endothelial dysfunction is an early marker of atherosclerosis. OBJECTIVES: The objectives of this study were to 1) compare endothelial function in young women with PCOS and regularly menstruating control women, and 2) to identify the determinants of endothelial function and investigate its relationship with body mass index in women with PCOS. DESIGN: This was a cross-sectional study. SETTING: This study was conducted at a tertiary cardiovascular research center. PATIENTS: Sixty-two young women with PCOS (mean age, 22.7 yr) and 17 control women, matched as a group for age and body mass index, were studied. Twenty-three women with PCOS were lean, 21 were overweight, and 18 were obese. MAIN OUTCOME MEASURES: Endothelium-dependent and -independent vascular function was assessed by measuring flow-mediated dilation (FMD) and nitrate-mediated dilation in the brachial artery (diameter change during hand hyperemia and after sublingual glyceryl trinitrate administration, respectively). RESULTS: FMD and nitrate-mediated dilation were significantly lower in PCOS than in control women (reduced by approximately 50 and 25%, respectively; both P < 0.0005). Insulin resistance, total testosterone, and total cholesterol were independent predictors of FMD, accounting for 21, 10, and 9% of the variance, respectively (P < 0.005 for all). A trend of deterioration in FMD from lean to overweight and obese PCOS women was observed, but differences among groups were not statistically significant. CONCLUSIONS: Women with PCOS have significant endothelial dysfunction at an early age (i.e. early 20s), and largely independent of obesity. This suggests that women with PCOS are at increased risk for early onset cardiovascular disease and may gain particular benefit from measures to improve endothelial function.

Adult↗

PubMed2005

Osteopontin is colocalized with the adhesion molecule CEACAM1 in the extravillous trophoblast of the human placenta and enhances invasion of CEACAM1-expressing placental cells.

CONTEXT: The human placenta is a complex tissue and possesses, through its capacity to proliferate and to invade maternal tissue, qualities that are usually found in malignant tumors. Osteopontin (OPN) and CEACAM1 may regulate these processes. OBJECTIVE: The present study was designed to investigate the expression pattern of OPN in the human placental components and to correlate it with CEACAM1 expression and function in placental cell invasiveness. DESIGN: Immunohistochemistry with an OPN-specific antibody and immunofluorescence were performed on normal placental samples to investigate the expression pattern of OPN and CEACAM1 in the human placenta. Extravillous trophoblast (EVT) hybridoma cells transfected with CEACAM1 and stimulated with OPN were studied using the Matrigel invasion assay. RESULTS: All placentae presented very strong expression of OPN in the EVT at the invasion front, where it colocalized with CEACAM1. In addition, OPN was also present in the villous trophoblast, with strongest expression in the cytotrophoblast of the first trimester. Transfection with CEACAM1 followed by stimulation with OPN resulted in increased invasiveness of EVT hybridoma cells. CONCLUSION: The present study shows the first systematic analysis of OPN expression pattern in the human placenta showing strong expression in the EVT at the invasion front. Colocalization of OPN with CEACAM1 in the EVT indicates that they might act together to regulate invasiveness at the maternal-fetal interface. Using an in vitro model, we also demonstrated increased cellular invasiveness after OPN treatment. We speculate that OPN and CEACAM1 may act as a functional complex involved in the regulation of placental invasiveness.

Antigens, CD↗

PubMed2005

Regulation of progesterone production in human term trophoblasts in vitro by CRH, ACTH and cortisol (prednisolone).

BACKGROUND: In most mammals, onset of labor is accompanied with progesterone withdrawal. In humans, cortisol blockade of progesterone is a possible mechanism involved in the initiation of labor. Therefore, aim of the study was to clarify the effect of CRH, ACTH and cortisol (prednisolone) on the release of progesterone by term trophoblast cells in vitro. METHODS: Cytotrophoblast cells were prepared from human term placentas by standard dispersion of villous tissue followed by a percoll gradient centrifugation step. Trophoblasts were incubated with CRH, ACTH as well as with prednisolone. RESULTS: The release of progesterone is decreased in CRH- and ACTH-treated trophoblast cell cultures compared to untreated trophoblast cells. Addition of prednisolone in varying concentrations leads to an increase of trophoblast progesterone production. CONCLUSIONS: The results suggest that CRH and ACTH directly modulate the endocrine function of trophoblasts in culture by downregulating progesterone production. Prednisolone on the other hand showed a stimulating effect on progesterone production in term trophoblast cells in vitro. Because blockade of progesterone is a possible mechanism involved in initiation of labor, we may speculate that CRH and ACTH are directly involved in the auto- or paracrine regulation of this procedure.

Adrenocorticotropic Hormone↗

PubMed2005

Factors controlling blastocyst implantation.

Establishment of early pregnancy is promoted by a complex network of signalling molecules that mediate cell-to-cell and cell-to-extracellular matrix communications, in order to manifest controlled invasion of the trophectoderm and successful implantation. During the period known as the 'window of implantation', the endometrium expresses specialized proteins, many of which exhibit potential use as markers of endometrial receptivity. Trophoblast differentiation to the invasive phenotype also depends on the up-regulation of certain peptides and the down-regulation of others. Disruption of each pathway is theoretically possible, and studies in animal models suggest that implantation defects result when the function of these proteins is blocked. Indeed, the implantation process is currently considered the most important limiting factor for the establishment of viable pregnancy. The present overview of the literature reports critical families of molecules located at the embryo-maternal interface and describes the mechanisms of interplay and control. Since these factors are crucial to the process of implantation, targeting them might be a valuable contraceptive tool. Conversely, induction of specific peptides may prove to be beneficial in certain infertility cases.

Corticotropin-Releasing Hormone↗

PubMed2005

Novel trends in follicular development, atresia and corpus luteum regression: a role for apoptosis.

During ovarian follicular development in humans, only a limited number of follicles mature and ovulate. The vast majority of follicles stop developing after the formation of an antrum and then undergo atresia. The few that are selected to become ovulatory follicles are transformed into corpora lutea following ovulation. The lifespan of the corpus luteum is also limited. In each oestrus/menstrual cycle, corpora lutea regress and are eliminated by a progress called luteolysis. During atresia and luteolysis, granulosa and lutein cells undergo apoptosis. It is believed that there are many signal transduction pathways that control apoptosis in order to suppress full maturation of too many follicles and to protect the dominant follicle from the apoptotic process prior the ovulation. Such interplay between different factors, some of them produced in the ovary, may modulate apoptosis of corpus luteum cells, in order to preserve the function of the corpus luteum during pregnancy or to eliminate the old corpora lutea of the previous cycle. The present review reports a number of factors that regulate follicular atresia and corpus luteum regression, via apoptotic pathways. Elucidation of apoptotic mechanisms may lead to prevention of female infertility or other pathological conditions.

Animals↗

PubMed2005

Prolactin receptor mRNA expression in oocytes and preimplantation mouse embryos.

Prolactin was first identified as an anterior pituitary lobe hormone, responsible for the regulation of mammary gland growth and development. Prolactin receptors have been localized in a number of peripheral tissues, including tissues involved in reproduction. Studies with knockout animals have shown that prolactin receptor deficient mice present reproductive defects, whereas prolactin promotes the developmental potential of preimplantation mouse and rat embryos in vitro. To better understand the role of prolactin in the process of reproduction and early embryo development in mice, the expression of the four transcript variants of prolactin receptor was examined in the first stages of mouse embryo development. Prolactin long receptor mRNA was expressed in all stages examined, that is in cumulus cells, oocytes, zygotes, 2-cell embryos, 4-cell embryos, morulae and blastocysts. Prolactin receptor type S1 mRNA was observed only in cumulus cells, while S2 mRNA was present in cumulus cells, oocytes, zygotes and 2-cell embryos. S3 mRNA was expressed only in cumulus cells and oocytes. These results indicate that different isoforms of prolactin receptors may be present in the various stages of mouse preimplantation embryo and may play an important role in the control of its growth and development.

Animals↗

PubMed2004

Chemoprophylactic and bactericidal efficacy of 80 mg gentamicin in a single and once-daily dosing.

OBJECTIVE: The objective was to examine the biodistribution, the chemoprophylactic, and the bactericide efficacy of 80-mg gentamicin single or once-daily dosing. STUDY DESIGN: Ninety-six patients who had had cesarean section or gynecological surgery received 80 mg gentamicin for chemoprophylaxis. A second group of 92 patients with Gram-negative infection received once-daily 80-mg gentamicin intramuscularly, combined with cefoxitin or ceforanide, for 5 days. Gentamicin serum and tissue concentration was determined 1 h after the first administration. RESULTS: The chemoprophylactic efficacy of gentamicin was 93.7%. The treatment efficacy was high in patients with chorioamnionitis and endometritis (92.9%), moderate in those with wound infection (69.5%), and less effective in those with septicemia (55.6%). Twenty-six percent of patients continued with antibiotics for infection control. The mean serum level was 4.48+/-0.49 and 5.56+/-0.66 microg/ml in obstetrical and gynecological patients respectively (p>0.05). Serum levels >4 microg/ml were achieved in 91% of patients. CONCLUSIONS: A single dose of 80 mg gentamicin offers chemoprophylaxis and achieves therapeutic serum-concentrations 1 h after administration. The 5-day combination of once-daily 80 mg gentamicin with a second-generation cephalosporin is effective in patients with chorioamnionitis and endometritis, but only moderately effective in those with wound infections and septicemia.

Adult↗

PubMed2004

Role of immunoreceptor tyrosine-based inhibitory motifs of PECAM-1 in PECAM-1-dependent cell migration.

Platelet endothelial cell adhesion molecule (PECAM-1), a transmembrane glycoprotein, has been implicated in angiogenesis, with recent evidence indicating the involvement of PECAM-1 in endothelial cell motility. The cytoplasmic domain of PECAM-1 contains two tyrosine residues, Y663 and Y686, that each fall within an immunoreceptor tyrosine-based inhibitory motif (ITIM). When phosphorylated, these residues together mediate the binding of the protein tyrosine phosphatase SHP-2. Because SHP-2 has been shown to be involved in the turnover of focal adhesions, a phenomenon required for efficient cell motility, the association of this phosphatase with PECAM-1 via its ITIMs may represent a mechanism by which PECAM-1 might facilitate cell migration. Studies were therefore done with cell transfectants expressing wild-type PECAM or mutant PECAM-1 in which residues Y663 and Y686 were mutated. These mutations eliminated PECAM-1 tyrosine phosphorylation and the association of PECAM-1 with SHP-2 but did not impair the ability of the molecule to localize at intercellular junctions or to bind homophilically. However, in vitro cell motility and tube formation stimulated by the expression of wild-type PECAM-1 were abrogated by the mutation of these tyrosine residues. Importantly, during wound-induced migration, the number of focal adhesions as well as the level of tyrosine phosphorylated paxillin detected in cells expressing wild-type PECAM-1 were markedly reduced compared with control cells or transfectants with mutant PECAM-1. These data suggest that, in vivo, the binding of SHP-2 to PECAM-1, via PECAM-1's ITIM domains, promotes the turnover of focal adhesions and, hence, endothelial cell motility.

Amino Acid Motifs↗

PubMed2004

Expression pattern of the activating protein-1 family of transcription factors in the human placenta.

The human placenta is a tissue with a unique capacity for rapid, but--as opposed to malignant tumours--tightly controlled proliferation and invasion capacity. The members of the activating protein-1 (AP-1) family of transcription factors are key regulators of cellular proliferation, differentiation and invasion processes in many systems and could, thus, play an important role in regulating these processes in the human placenta as well. In the present study, we used immunohistochemistry with specific antibodies against all members of the AP-1 family (c-Jun, JunB, JunD and c-Fos, FosB, Fra-1, Fra-2) to investigate their expression pattern and tissue localization in the human placenta. With the exception of c-Jun, which was expressed in a small fraction of villous cytotrophoblast nuclei and JunD, expressed in some syncytiotrophoblast nuclei, all other members of the AP-1 family were completely absent from villous cyto- and syncytiotrophoblast. Interestingly, most AP-1 factors were expressed in the intermediate (extravillous) trophoblast, with expression being strongest for JunD and Fra2 (100% of nuclei showing strong expression), followed by c-Jun (80% positive nuclei), c-Fos and FosB (50% positive nuclei). This was true for samples of both first trimester and later pregnancy. These data show that, in the human placenta, the AP-1 transcription factors are specifically expressed in the intermediate (extravillous) trophoblast, were they could be implicated in regulating proliferation, differentiation and/or expression of invasion-specific molecules, such as matrix metalloproteinases, which have been shown to be regulated by AP-1 in vitro and are expressed by the invasive trophoblast.

Blotting, Western↗

PubMed2004

Reproductive functions of corticotropin-releasing hormone. Research and potential clinical utility of antalarmins (CRH receptor type 1 antagonists).

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis exerts a complex, mostly inhibitory, effect on the female reproductive system. In addition, the principal regulator of this axis, the hypothalamic neuropeptide corticotropin-releasing hormone (CRH) and its receptors have been identified in most female reproductive tissues, including the ovary, uterus, and placenta. Furthermore, CRH is secreted in peripheral inflammatory sites where it exerts strong inflammatory actions. Antalarmins (CRH receptor type 1 antagonists) have been used to elucidate the roles of CRH in stress, inflammation and reproduction. METHOD OF STUDY: We review existing data on the effects of CRH in the female reproductive system. RESULTS: Ovarian CRH participates in female sex steroid production, follicular maturation, ovulation and luteolysis. Uterine CRH participates in decidualization, implantation, and early maternal tolerance. Placental CRH participates in the physiology of pregnancy and the onset of parturition. Circulating placental CRH is secreted mostly during the latter half of pregnancy and is responsible for the concurrently increasing physiologic hypercortisolism of this period. After labor and delivery, this hypercortisolism is ensued by a transient suppression of hypothalamic CRH secretion, which may explain the postpartum blues and depression and the increased autoimmune manifestations depression of period, the postpartum period. CONCLUSIONS: These data show that CRH is present in female reproductive tissues, and is regulating key reproductive functions with an inflammatory component, such as ovulation, luteolysis, implantation, and parturition.

Animals↗

PubMed2003

Expression pattern of the CCAAT/enhancer-binding proteins C/EBP-alpha, C/EBP-beta and C/EBP-delta in the human placenta.

The human trophoblast has the capacity to invade maternal tissue in a controlled fashion and to produce a wide range of hormones. The transcription factors belonging to the CCAAT/enhancer-binding protein (C/EBP) family are regulators of intracellular processes and mediators of hormone action. C/EBP binding sites have been described in the promoters of several placenta-expressed target genes. In the present study, we used immunohistochemistry and Western-blot analysis to investigate the expression pattern of the three most important members of this family, C/EBP-alpha, -beta, and -delta, in the normal human placenta as well as in isolated trophoblast cell populations. We found C/EBP-alpha and C/EBP-beta expression in the villous syncytiotrophophoblast (ST) and the extravillous (intermediate) trophoblast (EVT), but it was absent from the villous cytotrophoblast (CT). Interestingly, expression of C/EBP-beta continued to be very strong up to the third trimester of pregnancy, especially in the ST. C/EBP-delta showed overall lower expression levels, stronger only in the EVT, while CT/ST showed very low/negative expression. These data show for the first time the expression pattern and tissue localization of C/EBP factors in the human placenta, indicating that these factors (especially C/EBP-beta) may play important roles in the regulation of placenta-specific genes and processes.

Blotting, Western↗

PubMed2003

Expression of the high-mobility group protein HMGI(Y) in human trophoblast: potential role in trophoblast invasion of maternal tissue.

The high-mobility group protein HMGI(Y) is a member of a family of non-histone chromosomal proteins, which have been implicated in the regulation of inducible gene transcription, integration of retroviruses into chromosomes and induction of neoplastic transformation and metastatic progression in cancer cells. The human trophoblast is a tissue that shares proliferation capacity and invasiveness with neoplastic tissues, but in which these processes are tightly regulated. In the present study, we analyzed the expression of HMGI(Y) in the human placenta using immunohistochemistry. We found expression of HMGI(Y), with nuclear localization, in the villous cytotrophoblast (vCT), which is a highly proliferative cell type. In contrast, the majority of the nuclei of the villous syncytiotrophoblast, a terminally differentiated tissue, was negative. Interestingly, expression of HMGI(Y) was strongest in anchoring villi at the implantation site and in extravillous (intermediate) trophoblast (EVT) invading the maternal decidua. As vCT cells differentiate to become EVT, the HMGI(Y) protein appears to switch from a nuclear to a cytoplasmic localization. Expression of HMGI(Y) in isolated trophoblast populations in primary cell culture was also confirmed using Western-blot analysis. This study shows for the first time expression and localization of HMGI(Y) in the subpopulations of placental tissue.

Blotting, Western↗