共查询到20条相似文献，搜索用时 15 毫秒
1.
Eleni V. Pappa Aikaterini A. Zompra Zoi Diamantopoulou Zinovia Spyranti George Pairas Fotini N. Lamari Panagiotis Katsoris George A. Spyroulias Paul Cordopatis 《Peptide Science》2012,98(6):525-534
Lamprey gonadotropin‐releasing hormone type III (lGnRH‐III) is an isoform of GnRH isolated from the sea lamprey (Petromyzon marinus) with negligible endocrine activity in mammalian systems. Data concerning the superior direct anticancer activity of lGnRH‐III have been published, raising questions on the structure–activity relationship. We synthesized 21 lGnRH‐III analogs with rational amino acid substitutions and studied their effect on PC3 and LNCaP prostate cancer cell proliferation. Our results question the importance of the acidic charge of Asp6 for the antiproliferative activity and indicate the significance of the stereochemistry of Trp in positions 3 and 7. Furthermore, conjugation of an acetyl‐group to the side chain of Lys8 or side chain cyclization of amino acids 1‐8 increased the antiproliferative activity of lGnRH‐III demonstrating that the proposed salt bridge between Asp6 and Lys8 is not crucial. Conformational studies of lGnRH‐III were performed through NMR spectroscopy, and the solution structure of GnRH‐I was solved. In solution, lGnRH‐III adopts an extended backbone conformation in contrast to the well‐defined β‐turn conformation of GnRH‐I. © 2012 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 98: 525–534, 2012. 相似文献
2.
Gil Fridkin Shai Rahimipour Nurit Ben-Aroya Aviva Kapitkovsky Susanna Di-Segni Masha Rosenberg Irina Kustanovich Yitzhak Koch Chaim Gilon Mati Fridkin 《Journal of peptide science》2006,12(2):106-115
Five linear analogs of GnRH containing a p-aminophenylalanine (Pap) residue in their sequence and their six corresponding azo-bridged cyclic derivatives were synthesized. The precyclic peptides were prepared on solid-support, while azo-cyclization was performed in solution by diazotization of the p-aminophenylalanine residue followed by intramolecular coupling of the formed diazo salt with either tyrosine or histidine side chains present in the sequence. All peptides were examined for their binding ability to the GnRH receptor expressed on rat pituitary membranes and for their LH-release activity from dispersed rat pituitary cells. Linear analogs 1 i.e [Pap(5)] GnRH and 3, i.e. [Tyr(3), Pap(5)] GnRH, were found to bind to the GnRH receptors only slightly less avidly than native GnRH. Their cyclization, however, led to a marked reduction in the binding capacity, i.e. from IC(50) of 10(-9) M to the 10(-7) M range, and in biopotency, i.e. LH-release. All other linear and cyclic peptides were found to bind selectively to the GnRH receptor only in the low microM range. Only peptide 1 was found comparable to native GnRH in respect to LH-release activity and thus may potentially be a good agonist of the parent peptide. Peptides 1-4, the most potent GnRH receptor binders, were examined for their conformational properties using CD. Cyclic-azo peptides 2 and 4 were further evaluated by NMR spectroscopy in solution combined with molecular modeling. The structural information obtained explains in part the GnRH-like biological activity observed. 相似文献
3.
Susanna Di-Segni Cesare Giordano Shai Rahimipour Nurit Ben-Aroya Yitzhak Koch Mati Fridkin 《Journal of peptide science》2005,11(1):45-52
With the aim of producing long-acting analogs of gonadotropin releasing hormone (GnRH), four analogs, containing -X(6) (aa)psi(CH(2)SO(2)NH)-Leu(7) building unit (X(aa)=Gly, Ala, Val or Phe), and a reduced-size analog [Des-Tyr(5)]-GnRH which includes the unit Phe(5)psi(CH(2)SO(2)NH)-Leu(6), and [beta-Ala(6)]-GnRH were synthesized. The peptides were evaluated for their capacity to induce LH-release from rat pituitary cells and to withstand proteolysis by pituitary-derived enzymes, compared with the parent peptide GnRH. Albeit stable toward enzymatic degradation, the sulfonamido containing peptides were only marginally bioactive. [beta-Ala(6)]-GnRH, however, induced LH-release and bound to pituitary receptors nearly as efficiently as GnRH. This analog was also highly stable toward proteolysis suggesting that it may serve as a long-acting GnRH-analog. 相似文献
4.
Apoptosis is the biological process by which follicular cells are eliminated in atretic follicles. The aim of the present study was to examine the in vitro effect of a GnRH-a (leuprolide acetate, LA) and its interactions with FSH, dibutyryl cAMP, and growth factors (IGF-I, EGF, and FGF) on follicular apoptosis in early antral ovarian follicles obtained from prepubertal DES- treated rats. Follicles cultured 24 hr in the absence of hormones showed spontaneous onset of apoptotic DNA fragmentation. The presence of FSH suppressed the spontaneous onset of apoptotic DNA fragmentation (75-85%). Quantitative estimation of DNA cleavage from ovarian follicles revealed no significant changes in DNA fragmentation after in vitro LA treatment (1-100 ng/ml). However, coincubation with LA interfered partially with the effects of FSH on apoptosis suppression. This apoptosis suppression was also obtained by treatment with dibutyryl cAMP (80%), and was partially prevented by the presence of LA in the cultures. Follicles were cultured 24 hr with FGF, EGF, or IGF-I, and these factors suppressed DNA fragmentation (70, 60, and 70% respectively), while the presence of LA (100 ng/ml) in the culture medium prevented this effect. In conclusion, we show that the rescue from apoptotic DNA fragmentation produced in early antral follicles by FSH, cAMP, and growth factors, is prevented by coincubation with LA. This GnRH analog would thus interfere in the pathway of FSH, cAMP and/or growth factors by an as yet unknown mechanism. 相似文献
5.
The LH-releasing activity of GnRH and nine synthetic GnRH derivatives was tested in pituitary monolayer cell culture prepared from female rats. D-amino acid-substituted analogs were found to be 12 to 18-fold as active as GnRH, while D-amino acid GnRH-[1-9]-ethylamide analogs showed 15 to 38-fold activity as compared to GnRH. Dehydroproline-GnRH was equipotent with the parent compound. Asp(A)6-GnRH-EA was less active than GnRH and it was a partial agonist only. All peptides stimulated intracellular cAMP content of the cultured cells at 1 hr and 4 hr of incubation. A nearly uniform 1.8 to 2-fold increase above basal cAMP could be observed with all peptides tested at their maximally active concentrations. However, no correlation could be established between the relative LH-releasing activities and cAMP-elevating potencies of the peptides. The findings suggest that cAMP may not be involved in overall LH-release by GnRH but leave the possibility open that cAMP could be involved in certain steps of mobilizing compartmentalized LH pools of pituitary gonadotrophs. 相似文献
6.
7.
The present study aims at quantification of gonadotropin releasing hormone (GnRH) by radioimmunoassay, relative expression of its mRNA by real-time PCR accompanied by its cellular localization in the rat ovary by immunonohistochemistry (IHC) during different time points of pregnancy. To determine the involvement of endogenous ovarian GnRH in receptor mediated local autocrine/paracrine functions within the ovary, the cell specific localization of the classical receptor for GnRH (GnRHR) in the ovary by IHC and expression pattern of its mRNA were studied during pregnancy. Receptor expression during each time point within the ovary was reconfirmed by Western blot analysis accompanied by densitometric analysis of the signal intensity. Results reveal that the content of ovarian GnRH reaches its maximum on Day 20. The densitometric analysis of GnRHR receptor expression from Western blot study exhibits a decreasing trend by Day 20. Presence of GnRH and GnRHR mRNA in the ovary indicates the local synthesis of both ligand and receptor in the rat ovary. Differential expression of GnRH/GnRHR in the corpus luteum throughout pregnancy strengthens the hypothesis of the involvement of ovarian GnRH in local ovarian functions by receptor-mediated mechanisms. The expression of GnRH and GnRHR in the atretic antral follicles is indicative of the possible involvement of this decapeptide in processes like follicular atresia. The expression of GnRH/GnRHR in the nonatretic antral follicles and their oocytes requires further in-depth investigation. Collectively, this study for the first time reveals the presence of endogenous ovarian GnRH/GnRHR supporting their possible involvement in local autocrine/paracrine functions during pregnancy. 相似文献
8.
Previous work in our laboratory has shown agkistin, a snake venom metalloproteases (SVMPs) from the venom of Agkistrodon halys, possesses antiplatelet aggregation activity. In this study, we further examined the antiangiogenic activity of agkistin-s, the disintegrin domain of agkistin. Recombinant agkistin-s was produced in Escherichia coli by subcloning its cDNA into pET28a vector, and the effect of purified agkistin-s was evaluated. At the concentration of 0.5-1.5 microM, the recombinant agkistin-s exhibited inhibitory activities on the bovine aortic endothelial cells (BAECs) migration and proliferation in a dose-dependent manner. In addition, it exhibited an effective antiangiogenic effect when assayed by using the 10-day-old embryo chick CAM model and effectively inhibits the tube-like structure formation. Furthermore, it potently induced BAECs apoptosis as examined by flow cytometric assays. 相似文献
9.
Kim S Lee SH Kim JH Jeong YW Hashem MA Koo OJ Park SM Lee EG Hossein MS Kang SK Lee BC Hwang WS 《Molecular reproduction and development》2006,73(12):1523-1530
Insulin-like growth factor (IGF)-I is a receptor-mediated autocrine and/or paracrine growth and/or survival factor for mammalian embryo development. It is known to promote the growth and development of mouse preimplantation embryos. The present study was designed to investigate the effects of IGF-I (50 ng/ml), anti-IGF-I receptor antibody (50 ng/ml) and their combination on porcine preimplantation embryo development. Furthermore, the mechanism underlying the embryotropic effects of IGF-I was evaluated by monitoring the incidence of apoptosis and expression of apoptosis-related genes. In both in vitro fertilized (IVF) and somatic cell nuclear transfer (SCNT) embryos, culturing with IGF-I increased the rate of blastocyst formation and this embryotrophic effect was neutralized by culturing with IGF-I along with anti-IGF-I receptor (IGF-IR) antibody. Culturing IVF and SCNT embryos with IGF-I significantly increased the number of total cells in blastocysts and decreased the number of apoptotic nuclei. These effects of IGF-I were also neutralized by culturing with IGF-I along with anti-IGF-IR antibody. Expression of the anti-apoptotic Bcl-2 gene was increased, while expression of the pro-apoptotic Bax was decreased in both IVF and SCNT embryos cultured with IGF-I. In both IVF and SCNT embryos, anti-IGF-IR antibody along with IGF-I neutralized the effect of IGF-I on expression of Bcl-2 and Bax genes. In conclusion, the present study demonstrated that IGF-I through its specific receptors improved the developmental competence of IVF and SCNT embryos by decreasing the incidence of apoptosis and regulating apoptosis-related genes in porcine preimplantation embryos. 相似文献
10.
GnRH in physiological concentrations is highly degradable by both soluble and particulate fractions of rat ovarian homogenate in vitro. The two proteolytic enzyme activities differ strongly by the soluble activity showing a dithiothreitol optimum, high inhibition by diisopropyl fluorophospate (ki=0.7 μM), and a relatively high affinity (Km=1.1 μM) as opposed to the particulate fraction (Ki=3.5 mM and Km=150 μM, respectively). The results of this study show that the rat ovary is differently endowed with GnRH-degrading activity at different sites. The involvement of these in terminating the biological activity of the hormone on the ovary may possibly depend on its exact pathway in this GnRH-target organ. 相似文献
11.
Zhou J Rothman VL Sargiannidou I Dimitrov S Qiu C Smith E Sheffield J Sharma M Tuszynski GP 《Journal of cellular biochemistry》2004,92(1):125-146
Thrombospondin-1 (TSP-1) is a matrix protein that has been implicated in mechanisms of tumor progression. Our laboratory previously showed that the CSVTCG (cys-ser-val-thr-cys-gly) sequence of TSP-1 functioned as a tumor cell adhesion domain and CSVTCG peptides as well as an anti-peptide antibody possessed anti-metastatic activity in a murine model of lung metastasis. In a subsequent study, a putative TSP-1 binding protein from lung carcinoma was isolated by CSVTCG-peptide affinity chromatography. In this study, we present the full-length cDNA of this binding protein isolated from a prostate cancer cell (PC3-NI) cDNA library. The purified recombinant protein, termed angiocidin, is a potent inhibitor of tumor growth of Lewis Lung carcinoma in vivo and tumor invasion and angiogenesis in vitro. In addition, the recombinant protein inhibits tumor and endothelial cell proliferation and induces apoptosis. The activity of angiocidin both in vivo and in vitro is partially dependent on its TSP-1 binding activity, since an angiocidin deletion mutant missing a high affinity-binding site for TSP-1 failed to inhibit tumor growth in vivo and was less active in its anti-tumor and anti-angiogenic activities in vitro. These results suggest that the anti-tumor activity of TSP-1 reported in many studies may be mediated in part by binding proteins such as angiocidin. Such proteins may function as tumor-suppressor proteins, which limit the growth of tumors by inhibiting angiogenesis and cell matrix interaction. 相似文献
12.
M. P. Rivera‐Fillat F. Reig E. M. Martínez M. R. Grau‐Oliete 《Journal of peptide science》2010,16(7):315-321
New therapies in cancer treatment are focusing on multifaceted approaches to starve and kill tumors utilizing both antiangiogenic and chemotherapeutic compounds. In this work, we searched for a peptide vector that would home liposomes both to endothelial and tumor cells. [Abu6]TSPB and [Abu6]TSPA, aspartimide analogs of natural sequences of TSP‐1 and TSP‐2, respectively, were tested for adhesion of tumor and endothelial cells, in vivo and in vitro antiangiogenic effects, and in vivo antitumor action. Both peptides support the adhesion of both types of cells, but only [Abu6]TSPA inhibits the angiogenesis in vivo, and [Abu6]TSPA‐targeted L ‐DOX decreases by 58% (P < 0.008) the HT29 tumor growth in nude mice. The improvement in the doxorubicin antitumor effect should be attributed to the antiangiogenic effect of [Abu6]TSPA, since [Abu6]TSPB, despite being a good ligand for both cell types, had no effect on tumor growth. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
13.
M. A. Forniés M. Carrillo E. Mañanós L. A. Sorbera Y. Zohar† S. Zanuy‡ 《Journal of fish biology》2003,63(1):73-89
The in vivo and in vitro potency of native and modified forms of gonadotropin releasing hormone (GnRH) to release luteotropic hormone (LH) was studied in sea bass Dicentrarchus labrax in particular the hypothalamic fish‐specific sea bream GnRH form (sbGnRH) and the general mesoencephalic form chicken GnRH‐II (cGnRH‐II). The potencies of the natives and their analogs (GnRHas) were referred to that of [D‐Ala6, Pro9Net]‐mGnRHa (LHRHa) at equivalent doses. Analogs of the native peptides [D‐Arg6, Pro9Net]‐cGnRH‐II, [D‐Ala6, Pro9Net]‐cGnRH‐II, [D‐Trp6, Pro9Net]‐sbGnRH and [D‐Ala6, Pro9Net]‐sbGnRH were effective in inducing in vivo LH release (at 15 µg kg?1 body mass), exhibiting longer lasting activity than their corresponding native forms. Injection of sbGnRH and cGnRH‐II provoked a small but significant peak of circulating LH at 1·5 h after treatment (a.t.) decreasing down to basal levels at 4 h a.t. [D‐Arg6, Pro9Net]‐cGnRH‐II, [D‐Ala6, Pro9Net]‐cGnRH‐II and [D‐Ala6, Pro9Net]‐mGnRHa evoked a higher and a more sustained elevation of LH, peaking at 12 h a.t. and returning to basal levels between 48 and 72 h a.t. [D‐Trp6, Pro9Net]‐sbGnRH and [D‐Ala6, Pro9Net]‐sbGnRH also induced a significant surge of LH in plasma at 4 h a.t. turning to the basal levels at 24 h a.t. These rises, however, were of less amplitude and duration than the observed after treatment with cGnRH‐II analogs and [D‐Ala6, Pro9Net]‐mGnRHa. The in vitro stimulation of dispersed pituitary cells with the different native and modified forms of GnRH resulted in a dose‐dependent increase in the quantity of LH released at 24 h a.t. [D‐Arg6, Pro9Net]‐cGnRH‐II and [D‐Ala6, Pro9Net]‐cGnRH‐II induced the highest response of LH in vitro release followed by salmon GnRH (sGnRH), [D‐Ala6, Pro9Net]‐mGnRHa and [D‐Trp6, Pro9Net]‐sbGnRH. The lowest activity was exhibited by sbGnRH. Collectively, the in vitro biological activity (compared by their EC50) can be ordered as follows: [D‐Arg6, Pro9Net]‐cGnRH‐II > [D‐Ala6, Pro9Net]‐cGnRH‐II > sGnRH > [D‐Ala6, Pro9Net]‐mGnRHa > [D‐Trp6, Pro9Net]‐sbGnRH > [D‐Ala6, Pro9Net]‐sbGnRH > cGnRH‐II > sbGnRH. 相似文献
14.
Chandana Das 《Journal of biosciences》1985,7(2):203-206
Chronic administration of a potent gonadotropin releasing hormone inhibits ovulation in women. The suppression of gonadal
function during long term treatment with the GnRH analogues is ascribable to inhibition of gonadotropin secretion caused by
the down regulatory action of the decapeptide at the pituitary level. Reduced progesterone production with premature onset
of menstruation has been observed in women injected with the agonist during the midluteal phase. The decapeptide however,
has no effect onin vitro human ovarian steroidogenesis. Specific receptors for GnRH have been located on rodent ovarian cells, but corpora lutea of
rhesus monkey and human ovaries seem to lack these receptors. The luteolytic effect in women thus appears to be central in
origin and not a direct effect on the corpus luteum. Recently, a superactive agonist of GnRH given around the peri-implantation
period has been shown to terminate pregnancy in baboons. Monoclonal antibodies against GnRH administered during the same period
in a fertile cycle also abrogated pregnancy in these animals. Using immuno-enzymatic techniques GnRH has been localized on
the placenta. GnRH also exerts a stimulatory effect on hCG production by the placental villi maintained in culture. Addition
of anti-luteinizing hormone releasing hormone antibodies blocks this effect completely. It seems that placenta is the only
other tissue besides the pituitary where GnRH has probably a regulatory role in the human female. 相似文献
15.
16.
17.
Stem cell factor (SCF) is essential for the development of primordial follicles. One of its functions is to prevent oocytes from apoptosis. However, the underlying mechanism remains largely unknown. By using cultured ovaries that are rich in primordial follicles, the anti-apoptotic action of SCF and the potential signal transduction pathways were investigated. The apoptosis was evaluated by means of in situ 3'-end labeling. The expressions of proteins were analyzed with immunohistochemistry and Western blot. The data showed that SCF significantly prevented oocytes from apoptosis in the cultured organs. Addition of a specific pharmacological inhibitor of PI3K abolished the anti-apoptotic action of SCF while that of a MEK inhibitor did not. The phosphorylation of two mitogen activated protein kinases (MAPKs) (p42 and p44) and AKT, the respective substrates of MEK and PI3K, were enhanced by SCF treatment. Not surprisingly, the MAPK activation occurred only in theca cells. The expressions of apoptosis-related gene products, the Bcl-2 family proteins, in response to SCF treatment were also investigated. While SCF up-regulated the expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL, it did the opposite to the pro-apoptotic factor Bax. The PI3K inhibitor reversed the regulation of SCF on Bcl-xL and Bax but not on Bcl-2. Therefore, it seemed that SCF initiated an anti-apoptotic signal starting from its membrane receptor c-kit to Bcl-2 family members through PI3K/AKT and other signaling cascades in the oocytes of primordial follicles. 相似文献
18.
Marta Clariano Vanda Marques João Vaz Salma Awam Marta B. Afonso Maria Jesus Perry Cecília MP Rodrigues 《化学与生物多样性》2023,20(3):e202300222
Curcumin has a plethora of biological properties, making this compound potentially effective in the treatment of several diseases, including cancer. However, curcumin clinical use is compromised by its poor pharmacokinetics, being crucial to find novel analogs with better pharmacokinetic and pharmacological properties. Here, we aimed to evaluate the stability, bioavailability and pharmacokinetic profiles of monocarbonyl analogs of curcumin. A small library of monocarbonyl analogs of curcumin 1a–q was synthesized. Lipophilicity and stability in physiological conditions were both assessed by HPLC-UV, while two different methods assessed the electrophilic character of each compound monitored by NMR and by UV-spectroscopy. The potential therapeutic effect of the analogs 1a–q was evaluated in human colon carcinoma cells and toxicity in immortalized hepatocytes. Our results showed that the curcumin analog 1e is a promising agent against colorectal cancer, with improved stability and efficacy/safety profile. 相似文献
19.
Seto J Seto Y Iino M Komatsu T Katagiri K Hagino A Aso H Katoh K Sasaki Y Obara Y 《Cell biology international》2001,25(9):893-899
We examined the effects of IGF-I (1-1000 ng/ml) on cell proliferation in LM2d6 mouse fibroblast cells at 0.1, 1.0 and 5.0% fetal bovine serum (FBS). In medium containing 0.1% FBS, treatment of LM2d6 cells with IGF-I significantly reduced the cell number in a dose- and time-dependent manner, whereas no effects were seen at 1 or 5% FBS. Treatment of the cells with 0.1% FBS for 72 h caused DNA laddering and nuclear condensation. However, Scatchard analysis for IGF-I binding sites on the cells revealed that both the number and the affinity of IGF-I receptors were not greater than that of Balb/3T3 cells. Furthermore, the apoptotic action of Long (R(3))-IGF-I, an analogue of IGF-I that has a reduced affinity for IGF binding proteins, was not greater than that of IGF-I. Taken together, we conclude that IGF-I reduces cell proliferation at low levels of FBS due to the induction of apoptosis. This effect is probably not caused by an excess production of IGF binding proteins in LM2d6 cells. 相似文献
20.
Both neurons and glia succumb to programmed cell death (PCD) when deprived of growth factors at critical periods in development or following injury. Insulin‐like growth factor‐I (IGF‐I) prevents apoptosis in neurons in vitro. To investigate whether IGF‐I can protect Schwann cells (SC) from apoptosis, SC were harvested from postnatal day 3 rats and maintained in serum‐containing media until confluency. When cells were switched to serum‐free defined media (DM) for 12–72 h, they underwent PCD. Addition of insulin or IGF‐I prevented apoptosis. Bisbenzamide staining revealed nuclear condensation and formation of apoptotic bodies in SC grown in DM alone, but SC grown in DM plus IGF‐I had normal nuclear morphology. The phosphatidylinositol 3‐kinase (PI 3‐K) inhibitor LY294002 blocked IGF‐I–mediated protection. Caspase‐3 activity was rapidly activated upon serum withdrawal in SC, and the caspase inhibitor BAF blocked apoptosis. These results suggest that IGF‐I rescues SC from apoptosis via PI 3‐K signaling which is upstream from caspase activation. © 1999 John Wiley & Sons, Inc. J Neurobiol 41: 540–548, 1999 相似文献