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Biomedical subjects

M Zdravkovic

Publications and source records attributed to M Zdravkovic.

At least 19 recordsLinked to original sources
PubMed2006

Five weeks of treatment with the GLP-1 analogue liraglutide improves glycaemic control and lowers body weight in subjects with type 2 diabetes.

AIMS: Effects of the long acting GLP-1 analogue--liraglutide in subjects with type 2 diabetes. METHODS: 144 type 2 diabetic subjects on metformin treatment (1000 mg BID) were randomised to 5 weeks of treatment (double-blind) with metformin plus liraglutide, liraglutide or metformin, or metformin plus glimepiride (open label). The dose of liraglutide was increased weekly from 0.5 to 2 mg OD. RESULTS: Liraglutide added to metformin monotherapy was associated with a significant reduction in fasting serum glucose (FSG) (-3.9 mM -4.9; -2.9) (primary objective), and HbA1c levels (-0.8% -1.2; -0.4). Furthermore, liraglutide in combination with metformin vs. metformin plus glimepiride significantly reduced FSG (-1.2 mM -2.2; -0.2). In addition, body weight was significantly lower in the metformin plus liraglutide vs. the metformin plus glimepiride group (-2.9 kg -3.6; -2.1). There were no biochemically confirmed episodes of hypoglycaemia with liraglutide treatment. Nausea was the most frequently reported adverse event following liraglutide therapy, it was transient in nature, and led to withdrawal of only 4% of the subjects. CONCLUSIONS: Using a weekly dose-titration liraglutide is well tolerated up to 2 mg daily. While liraglutide caused transient gastrointestinal side effects, this rarely interfered with continuing treatment. An improvement in FSG over that in control groups was seen for liraglutide as an add-on to metformin. In the latter case, body weight was reduced in comparison to metformin plus glimepiride. Liraglutide is a promising drug for the treatment of type 2 diabetes.

Adult↗
PubMed2003

Oral administration of the growth hormone secretagogue NN703 in adult patients with growth hormone deficiency.

OBJECTIVE: Little is known of the usefulness of GH secretagogues (GHSs) in GH-deficient (GHD) adults. The objective of this study was to determine the number of responders to treatment with NN703 in GHD adults. DESIGN: A multicentre, randomized, double-blind, and placebo-controlled study. PATIENTS: Ninety-seven GHD adults were included. MEASUREMENTS: The GH response before and after 1 week of oral treatment with NN703 (n = 83) or placebo (n = 14) was determined. The first and last dose of NN703 was 3 mg/kg, whereas the dose of NN703 was 1.5 mg/kg/day during the 6 days between the first and last doses. Furthermore, all 97 patients received 1 micro g/kg GH-releasing hormone (GHRH) 3 weeks after the last dose of NN703. RESULTS: Serum GH peak and area under curve (AUC) values after the first NN703 administration were greater than those after placebo administration (P < 0.05). However, after correction for the lower body mass index (BMI) in the NN703 group, this difference lost statistical significance. After 1 week of therapy, GH peak and AUC values were similar following the final doses of NN703 and placebo. Serum peak and AUC values of other anterior pituitary hormones were similar between the NN703 and placebo groups both after the first and last administration of study drug. Nine of the 83 patients (11%) responded with a serum peak GH concentration >or= 5 micro g/l after the first and/or last NN703 administration, whereas no patient responded after placebo administration. Serum IGF-I was unaffected by 1-week NN703 treatment, whereas serum IGFBP-3 was increased (P < 0.05 vs. placebo) also after correction for BMI. Mean serum peak GH concentration after GHRH administration was 2.1 micro g/l (+/-0.3, SEM), which was higher than that after the first NN703 administration (1.32 +/- 0.3, P < 0.05). CONCLUSION: NN703 administration was generally well tolerated. Eleven per cent of the GHD adult patients responded with a peak GH response >or= 5 micro g/l after the first and/or last administration of oral NN703. Although a majority of GHD adults will not respond to NN703, the present results suggest that oral NN703 treatment could be useful in some adult patients with moderately severe GHD. These patients may be identified by a test dose of GHS.

Administration, Oral↗
PubMed2002

The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1), a polypeptide hormone secreted by the l-cells in the gastrointestinal tract, has shown promising effects as a new treatment modality for patients with Type II (non-insulin-dependent) diabetes mellitus. However, the pharmacokinetic profile of native GLP-1 with a rapid elimination has limited its therapeutic potential. NN2211 is a fatty acid derivative of GLP-1, which pre-clinically has shown a protracted pharmacokinetic profile, while maintaining its biological activity. This study aimed to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of NN2211 in healthy male subjects following seven days treatment. METHODS: In a double-blind, randomized, dose escalation, placebo controlled study, healthy male subjects were enrolled at five consecutive dose levels of NN2211 (1.25, 5.0, 7.5, 10.0, 12.5 microg/kg). Six subjects were allocated at random at each dose level to active or placebo treatment with a ratio of 2:1. Dosing with NN2211 was performed on day 1, and days 5-11. The 84-h pharmacokinetics and 24-h glucose and insulin profiles were assessed on day 1 and day 11. RESULTS: Following s. c. administration the half-life of NN2211 was found to be 12.6 +/- 1.1 h, with a subsequent accumulation index after a daily dose for seven days of 1.4-1.5. There were dose-proportional increases in exposure (AUC and C(max)) with increasing doses. Overall, there were no statistically significant differences from placebo in the 24-h glucose and insulin profiles. In subjects treated with NN2211 rather than placebo, there was a higher incidence of adverse events, most notably dizziness and adverse events related to the gastrointestinal system. There were no serious adverse events but three subjects were nonetheless withdrawn because of dizziness, fever and nausea. There were no clinically relevant changes in vital signs, ECG parameters, physical examination or safety laboratory parameters. A significantly lower diuresis was observed in the actively treated subjects, without a clinically relevant change in packed cell volume. CONCLUSIONS/INTERPRETATION: This study shows NN2211 has a pharmacokinetic profile supporting a daily dose in human beings, but also that subjects treated with NN2211 rather than placebo, had a higher incidence of adverse events, most notably dizziness and adverse events related to the gastrointestinal system.

Adolescent↗
PubMed2001

The pharmacokinetics, pharmacodynamics, safety and tolerability following 7 days daily oral treatment with NN703 in healthy male subjects.

The aim of the present study was to assess the safety, pharmacokinetics and pharmacodynamics (including specificity) of NN703 (tabimorelin), a growth hormone (GH) secretagogue, in healthy male subjects following treatment for 7 days once-daily. This was a randomized, double-blind and placebo-controlled study with four active dose levels: 1.71, 3.0, 4.5 and 6.86 mg/kg body weight. There was a dose-related increase for GH area under the curve (AUC) (0-12 h) and GH C(max)(0--12 h); these were significantly higher on both days 1 and 7 as compared with placebo treatment (P = 0.04 to P< 0.0001); however, an overall significant decrease in GH release was found from day 1 to day 7 (P< 0.001). Insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) increased at all dose levels (including placebo); however, a significantly higher increase as compared with placebo treatment was observed at the three highest dose levels for IGF-I (P = 0.04--0.0006) and at the highest dose level for IGFBP-3 (P = 0.03). There was no statistically significant increase in AUC (0-5 h) for follicle-stimulating hormone, luteinizing hormone and cortisol between active and placebo treatment for day 1 or 7. On day 1 only, a statistically significant increase in AUC (0--5 h) was found for prolactin at 1.71 and 6.86 mg/kg (P< 0.05), for thyroid-stimulating hormone (TSH) at 3.0 mg/kg (P< 0.01) and for adrenocorticotrophic hormone (ACTH) at 4.5 mg/kg (P< 0.05); however, no dose--response relationship was observed for TSH or ACTH. In addition, a statistically significant decrease in AUC (0--5 h) for ACTH (3.0 and 6.86 mg/kg) and cortisol (1.71 mg/kg) was observed on day 7 (P< 0.05). Thus, NN703 is a promising candidate for treatment of absolute or relative GH deficiency.

Administration, Oral↗
PubMed2001

Pharmacokinetic and pharmacodynamic modeling of NN703, a growth hormone secretagogue, after a single po dose to human volunteers.

The objective of this study was to describe the pharmacokinetics and pharmacodynamics of NN703, a growth hormone (GH)-releasing secretagogue, after po administration to healthy human male subjects. The study was designed as a randomized, placebo-controlled, double-blind, dose-escalating, single-dose trial of NN703 covering eight dose levels. Each of the dose levels had 6 subjects on active treatment and 2 subjects on placebo. NN703 was administered po as a solution. Blood samples for serum concentrations of NN703 and GH were collected before dosing and up to 24 hours after dosing. Serum concentrations of NN703 were determined using a validated analytical method, based on solid-phase extraction and LC/MS/MS detection. A two-compartmental model with zero-order input was used to describe the pharmacokinetics of NN703. The parameters of the elimination phase were fitted simultaneously, whereas the parameters describing the absorption phase were allowed to vary between the dose levels. The pharmacodynamics of NN703 was described by use of an indirect-response model containing both a threshold value and a modulator for the development of tolerance. It was concluded that the absorption of NN703 after po administration was nonlinear; the bioavailability increased with the dose. The serum concentration of NN703 required for half-maximal stimulation of GH was determined to be 485 ng/ml. The proposed indirect-response model requiring a threshold concentration and development of tolerance provided a useful mean of quantifying the effects of NN703. Furthermore, the development of tolerance shown based on pharmacokinetic/pharmacodynamic modeling of single-dose data presented here has been confirmed following multiple dosing in healthy male subjects.

Administration, Oral↗
PubMed2001

Bioequivalence and relative bioavailability of three estradiol and norethisterone acetate-containing hormone replacement therapy tablets.

OBJECTIVE: The primary objective was to demonstrate bioequivalence between the estrogen components ofActivelle (1 mg estradiol (E2) + 0.5 mg norethisterone acetate (NETA)) and the combined phase of Novofem (1 mg E2 + 1 mg NETA) and between the NETA components of the combined phase of Novofem (1 mg E2 + 1 mg NETA) and Trisequens (2 mg E2 + 1 mg NETA). SUBJECTS, MATERIALS AND METHODS: The study design was double-blind, randomized, three-way, balanced six-sequence cross-over. The washout period was 14 days between treatments. Single doses of the above-described tablets were administered in the morning following an overnight fast to 24 healthy postmenopausal or bilaterally oophorectomized women. Plasma concentration profiles of E2, estrone (E1; pharmacologically active metabolite of E2) and norethindrone (NET: NET was determined since NETA is very rapidly metabolized to NET) were measured over 72 h, and 36 h, respectively. For the two former substances a baseline correction was performed by subtracting the mean of two predose measurements from the concentrations measured after dosing. RESULTS: One subject dropped out of the study, completing only one treatment sequence; therefore, the results are based on 23 subjects. The baseline-corrected E2 and E1 AUC0-t (Novofem)/AUC0-t (Activelle) ratios were 105% and 100%, respectively; and the Cmax ratios 100% and 105%, respectively. Identical median tmax was observed for E2 (6 h) and for E1 (5 h). The NET AUC0-t (Novofem)/AUC0-t (Trisequens) ratio was 95%, and the corresponding Cmax ratio 98%. The median tmax for Novofem was 0.75 h and for Trisequens 1.0 h. CONCLUSION: Bioequivalence was demonstrated for E2, E1 and NET in accordance with the study objectives.

Administration, Oral↗
PubMed2000

The pharmacokinetics, pharmacodynamics, safety and tolerability of a single dose of NN703, a novel orally active growth hormone secretagogue in healthy male volunteers.

The aim of the present study was to investigate the pharmacodynamics, pharmacokinetics, safety and tolerability of a single dose of NN703 (tabimorelin), a growth hormone secretagogue in healthy male subjects. The study design was double blind, randomized and placebo-controlled, with eight escalating dose levels (0.05-12 mg/kg bodyweight (BW)). NN703 was well tolerated by the subjects. The GH area under the curve (AUC) (0-24 h) was significantly higher when compared to placebo for the three highest dose levels (3.0 mg/kg: P = 0.027, 6.0 mg/kg: P = 0.0023, 12 mg/kg: P< 0.0001), and for GH maximal concentration C(max)the four highest dose levels were also significantly higher when compared to placebo (1.5 mg/kg: P = 0.04, 3.0 mg/kg: P = 0.0143, 6.0 mg/kg: P = 0.0053, 12 mg/kg: P = 0.0007). Furthermore, there was a significant increase in IGF-1 levels when compared to placebo for the 6.0 and 12.0 mg/kg BW dose levels (P< 0. 0001). Statistical analysis comparing the AUC (0-24 h) of the NN703 (four highest dose levels) and placebo-treated groups showed no significant increases following NN703 for ACTH, LH, FSH, TSH, prolactin, and cortisol, however, subtle individual changes were noted in ACTH, cortisol and prolactin at doses above 3.0 mg/kg. In conclusion, NN703 is a promising potential candidate for treatment of GH deficiency/insufficiency.

Administration, Oral↗
PubMed1997

Epstein-Barr virus permissively infects human syncytiotrophoblasts in vitro and induces replication of human T cell leukemia-lymphoma virus type I in dually infected cells.

Epstein-Barr virus (EBV) and human immunodeficiency virus type 1 (HIV-1), as well as human T-cell leukemia-lymphoma virus type I (HTLV-I), may interact in the pathogenesis of human retroviral infections. The placental syncytiotrophoblast layer represents a barrier protecting the fetal compartment from exposure to retroviruses. We studied the interactions of EBV with HIV-1 and HTLV-I in human term syncytiotrophoblast cells to investigate the significance of double infections in transplacental transmission of human retroviruses. We found that syncytiotrophoblast cells could be productively infected with EBV. Dual infection of the cells with EBV and HTLV-I resulted in full replication cycle of otherwise latent HTLV-I. In contrast, the restricted permissiveness of syncytiotrophoblasts for HIV-1 was not influenced by coinfection of the cells with EBV. Infection of syncytiotrophoblast cells with EBV, but not HTLV-I, induced interleukin-2 and interleukin-6 secretion, and augmented secretion occurred on coinfection with both viruses. Coinfection of syncytiotrophoblast cells with EBV and HTLV-I induced tumor necrosis factor-beta and transforming growth factor-beta 1 secretion, but infection with either virus alone did not lead to secretion of these cytokines. Permissive replication cycle of HTLV-I was induced by the EBV immediate-early gene product Zta. Pseudotype formation between EBV and HTLV-I in coinfected syncytiotrophoblast cells was not found. Our data suggest that activation of HTLV-I gene expression by EBV in coinfected syncytiotrophoblast cells may be a mechanism for transplacental transmission of HTLV-I.

Animals↗
PubMed1997

High interferon alpha levels in placenta, maternal, and cord blood suggest a protective effect against intrauterine herpes simplex virus infection.

Interferons (IFN) are produced by the placenta during pregnancy, and they can be detected in the maternal and fetal blood. Although the antiviral potential of IFNs is well established, it remains unclear whether the IFNs associated with pregnancy can prevent transplacental spread of viral infection. The present study was undertaken in order to determine the possible protective effect of placentally produced IFN-alpha on fetal acquisition of herpes simplex virus (HSV). Nine mothers with a known history of genital HSV infection were studied. In five cases IFN-alpha was detected in the placenta, maternal, and fetal blood, whereas in three cases IFN-alpha could not be detected. in the remaining case, IFN-alpha was found only in the maternal blood. As corroborated by the serological evidence of early HSV infection in the cord blood, the single case of vertical HSV transmission was observed in the group of IFN nonproducers. Furthermore, virus transmission did not occur in cases where IFN-alpha was present in the placenta and simultaneously in the maternal and fetal circulations. Thus, the present data indicate that high levels of IFN during pregnancy may protect the fetus from acquiring a possibly fatal intrauterine HSV infection.

C-Reactive Protein↗
PubMed1997

Role of the Fas/Fas ligand pathway in apoptotic cell death induced by the human T cell lymphotropic virus type I Tax transactivator.

Two distinct human diseases have been described in association with human T cell lymphotropic virus type I (HTLV-I) infection: adult T cell leukaemia and tropical spastic paraparesis/HTLV-I-associated myelopathy. Although comprehensive understanding of specific mechanisms underlying pathogenesis of either disease has not yet been achieved, the viral regulatory protein Tax is believed to play a significant role. Previous studies demonstrated the potential of Tax to transform host cells. Here, it is shown that the Tax transactivator has in addition the potential to induce T cell death by apoptosis. Using an inducible system (Jurkat cell line JPX-9), significant apoptotic cell death upon Tax expression was observed. In an attempt to detect the cellular genes mediating this effect, it was found that induction of Tax was associated with marked upregulation of the Fas ligand (FasL) gene. Tax-induced apoptosis was inhibited when the Fas/FasL pathway was interrupted by YVAD-cmk, the inhibitor of ICE-like proteases. Transient expression experiments provided additional support for the putative role of endogenous FasL in Tax-induced apoptosis. Upon cotransfection with Tax-expressing plasmid, the transcriptional activity of the FasL promoter was found to be significantly upregulated in Jurkat cells and several other cell lines, as measured by reporter gene expression. Furthermore, cotransfection using different Tax mutants demonstrated that both CREB and NF-kappaB activation domains of Tax protein were required for the transactivation to take effect.

Adult↗
PubMed1996

Isolated serratus anterior paralysis: a simple surgical procedure to reestablish scapulo-humeral dynamics.

We present an original surgical technique for the treatment of an isolated paralysis of the serratus anterior muscle. We used this technique on six patients in whom nonoperative treatment failed. We fixed the inferior angle of the scapula at approximately 35 degrees of lateral position with synthetic ribbon: not to the rib behind the inferior scapular angle but to the next lower rib, usually the eighth. Therefore the scapula was not fixed directly to the pectoral cage, but over a loop of 2-2.5 cm in length. This is the crux of the procedure, because this "loose" fixation enables lateral movement of the scapula and complete painless arm elevation without scapular winging. The follow-up period was 1-7 years (mean, 4 years and 9 months). The clinical results were "excellent" for five patients and "very good" in one patient. We recommend this procedure for its excellent restoration of shoulder function.

Adult↗
PubMed1996

Functional characteristics of human trophoblast interferons.

Human trophoblast populations from first-and third-trimester placentas produce interferons (IFNs) in the presence of growth factors (CSF and PDGF) or when infected with virus. The highly invasive extravillous trophoblast population produced a higher level of IFNs (three- to eightfold, P < 0.05) than the noninvasive villous trophoblast population when stimulated with growth factors and/or virus. The level of IFN produced was dependent on the type of trophoblast population, the type of inducer and the stage of differentiation of the trophoblasts. Tandem immunoaffinity chromatography of the virus-induced trophoblast IFNs resulted in the isolation of trophoblast IFN-alpha and -beta types. The purified trophoblast IFNs have antiviral, antiproliferative and immunoregulatory properties. Furthermore, the trophoblast IFNs inhibited the expression of proto-oncogenes such as EGF-R, c-erbB2 and c-fms reported to be involved in normal trophoblast growth and differentiation. These data suggest essential roles of interferons in normal human development during pregnancy.

Antiviral Agents↗
PubMed1996

Isolation and characterization of human placental trophoblast subpopulations from first-trimester chorionic villi.

A method for the simultaneous preparation of highly enriched human placental trophoblast populations (villous and extravillous) from first-trimester placental villi (5 to 12 weeks) by using sequential trypsinization, percoll gradient centrifugation, and negative selection with anti-CD9 immunomagnetic separation is described. The purification method resulted in the isolation of four distinct trophoblast populations identified on the basis of morphology and phenotyping: (i) mononuclear villous cytotrophoblast cells which, through differentiation, become committed to syncytium formation; (ii) an extravillous trophoblast population which appeared as a "crazy pavement" and, with subsequent subculturing, differentiated morphologically to mononuclear cells; (iii) an extravillous trophoblast fraction which fused to form multinucleated trophoblast giant cells; and (iv) floating intermediate extravillous trophoblast cells which fused together to form cell clumps and which further differentiated to a mononuclear anchoring intermediate extravillous trophoblast. Short-term cultures of the freshly isolated cell fractions consisted of heterogeneous trophoblasts at different differentiation stages as determined by their varied biochemical and morphological properties. All the isolated trophoblast populations expressed the cytokeratin intermediate filament and the epithelium-specific cell-cell adhesion molecule E-cadherin. The isolated villous trophoblasts in culture expressed integrins alpha 6 and beta 4 and reduced levels of beta 1 subunits, whereas the proliferating extravillous trophoblast cultures expressed alpha 1, alpha 3, and alpha 5 and high levels of beta 1 integrin subunits, vitronectin receptor (alpha V beta 3/beta 5), and major histocompatibility complex class 1 molecules. Furthermore, the isolated trophoblast populations secreted metalloproteases (such as type IV collagenases [mainly 72- and 92-kDa enzymes, i.e., gelatinases A and B]) and urokinase plasminogen activator, as evaluated by substrate gel zymography. This method of isolation should facilitate in vitro studies of trophoblast proliferation, differentiation, invasion, virus interactions, cytokenesis, and immunology.

Cadherins↗
PubMed1996

Cervical ripening and induction of delivery by local administration of prostaglandin E2 gel or vaginal tablets is equally effective.

BACKGROUND: Prostaglandin E2 for local application has been widely used for preinduction cervical ripening in cases presenting with an unfavorable cervical state. The optimal way of administering prostaglandin E2, however, remains unclear. The aim of this study was to compare the effect of multiple application of 0.5 mg Minprostin intracervical Gel to the effect of 3 mg Minprostin vaginal tablets in priming the uterine cervix and inducing labor in an open, prospective, randomised study. METHODS: PGE2 was applied up to three times a day for two days until ripening was obtained or labor induced. In case no progress took place amniotomy was performed and i.v. oxytocin stimulation one hour later if necessary. A total of 208 pregnant women, consecutively admitted for induction of delivery, with Bishop Scores 0-5, were included. RESULTS: Minprostin gel (group I) and Minprostin tablets (group II) were equally effective in ripening the cervix. Delivery within 48 hours was achieved in 59% and 63% respectively. The mean number of applications was 2.6 (s.d. 1.6) and 2.7 (s.d. 1.3) respectively. In case more than four doses were required no further effect was seen on delivery rates. Rates of cesarean section (performed in 15% and 18% respectively), labor induction (3%/1%), drop outs (14%/12%) and failed inductions (10%/5%) were comparable. Patients in group I had a significantly lower demand for analgesia. A significantly shorter induction-delivery interval in group II was seen in patients with preinduction Bishop scores 3-5 compared to patients with Bishop scores 0-2. Side effects were few. Both procedures appear safe. CONCLUSIONS: Cervical ripening and induction of delivery by local administration of prostaglandin E2 gel or vaginal tablets in cases presenting with an unfavorable cervical state is equally effective.

Cervix Uteri↗
PubMed1996

Altered expression of the tumor suppressor/oncoprotein p53 in SV40 Tag-transformed human placental trophoblast and malignant trophoblast cell lines.

The expression of the tumor suppressor/oncoprotein p53 has been investigated in normal human placental villous trophoblast, in vitro propagated invasive extravillous trophoblast, SV40 tumor antigen (Tag)-immortalized extravillous trophoblast, human cytomegalovirus (hCMV)-infected syncytiotrophoblast and malignant trophoblast (choriocarcinoma) cell lines (JAR, JEG-3 and BeWo) using quantitative enzyme-linked immunosorbent assay (ELISA) and Western immunoblot methods using monoclonal antibodies specific for wild-type and mutant p53. The normal villous and extravillous trophoblast cells expressed low levels of the wild-type p53 protein, whereas normal terminally differentiated multinucleated syncytiotrophoblast cells, as well as hCMV-infected syncytiotrophoblast, showed a higher expression of the wild-type p53 protein. SV40 Tag-immortalized invasive trophoblast cells also showed a high expression of the wild-type p53 protein which remained complexed with the Tag protein. All the choriocarcinoma cell lines over expressed the mutant form of the p53 protein. The increased expression of p53 protein in the SV40 Tag-immortalized invasive trophoblast and choriocarcinoma cells paralleled with increased expression of the mouse double minute 2 (mdm2) oncogenic protein. Transforming growth factor (TGF)-beta inhibited proliferation of normal extravillous trophoblast cells. The antiproliferative effects of TGF-beta were reduced in SV40 Tag-immortalized cells and non-detectable in choriocarcinoma cell lines JAR, BeWo and JEG-3. The inactivation of p53 owing to complexing with Tag in the immortalized premalignant trophoblast and p53 mutation in the malignant trophoblast may be responsible for their aberrant proliferation and refractoriness to antiproliferative effects of TGF-beta observed in these cells as compared to the normal trophoblast. These results may suggest the role of p53 protein in trophoblast differentiation, transformation and tumorigenesis.

Animals↗
PubMed1995

Basal and interferon-induced 2',5'-oligoadenylate synthetase activity in human placental trophoblast and trophoblast-derived malignant cell lines.

Human placental trophoblasts produce interferon (tro-IFNs) when stimulated with viral inducers. Since the antiviral and cellular functions of IFNs are partly mediated by the 2',5'-oligoadenylate synthetase (2-5A synthetase) pathway, the aim of the present study was to determine the basal and IFN-induced levels of 2-5A synthetase in villous trophoblast cultures. A considerable basal level of 2-5A synthetase was observed in syncytiotrophoblast cultures from both first and third trimester. In contrast no basal activity was detectable in placental fibroblast- and trophoblast-derived malignant cell lines (Far, FEG-3, and BeWo). Stimulation with tro-IFN-beta, -alpha and leucocyte-IFN (leu-IFN)-alpha increased the enzyme activity in first and third trimester human syncytiotrophoblast cultures. Treatment with recombinant-IFN (rec-IFN)-gamma significantly enhanced 2-5A synthetase activity in first trimester syncytiotrophoblast, but had no effect on third trimester syncytiotrophoblast. Tro-IFN-beta, -alpha and leu-IFN-alpha induced high levels of 2-5A synthetase activity in placental fibroblast, BeWo and FEG-3 cell-lines, whereas rec-IFN-gamma treatment did not induce 2-5A synthetase activity in any of these cells. No detectable 2-5A synthetase activity was found in the Far cell line. The capability of cells deriving from the fetoplacental unit to raise an antiviral response by the induction of 2-5A synthetase may be important in defending the fetus against viral infection from the mother. Furthermore 2-5A synthetase in cells of the fetoplacental unit may play a role in their normal growth and development.

2',5'-Oligoadenylate Synthetase↗
PubMed1995

Bidirectional enhancing activities between human T cell leukemia-lymphoma virus type I and human cytomegalovirus in human term syncytiotrophoblast cells cultured in vitro.

The syncytiotrophoblast layer of the human placenta has an important role in limiting transplacental viral spread from mother to fetus. Human cytomegalovirus (HCMV) is capable of establishing a latent infection in syncytiotrophoblast cells, with restriction of gene expression to immediate-early and early proteins. We analyzed the extent of replication of human T cell leukemia-lymphoma virus type I (HTLV-I) in human term syncytiotrophoblasts infected with HTLV-I alone or coinfected with HTLV-I and HCMV. Although syncytiotrophoblasts could be infected with cell-free HTLV-I, no viral protein expression was found in the singly infected cells. On the contrary, coinfection of the cells with HTLV-I and HCMV resulted in simultaneous replication of both viruses. Bidirectional enhancing activities between HTLV-I and HCMV were mediated primarily by the Tax and immediate-early proteins, respectively. The stimulatory effect of HTLV-I Tax on HCMV replication appeared to be mediated partly by tumor necrosis factor beta and transforming growth factor beta-1. We observed formation of pseudotypes with HTLV-I nucleocapsids within HCMV envelopes, whereas HCMV was not pseudotyped by HTLV-I envelopes in dually infected syncytiotrophoblast cells. Our data suggest that in vivo dual infection of syncytiotrophoblast cells with HTLV-I and HCMV may facilitate the transplacental transmission of both viruses.

Antibodies, Monoclonal↗