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ABSTRACT: Structural determinants underlying signaling specificity in the tumor necrosis factor receptor superfamily (TNFRSF) are poorly characterized, and it is unclear whether different signaling outputs can be genetically dissociated. The p75 neurotrophin receptor (p75(NTR)), also known as TNFRSF16, is a key regulator of trophic and injury responses in the nervous system. Here, we describe a genetic approach for dissecting p75(NTR) signaling and deciphering its underlying logic. Structural determinants important for regulation of cell death and NF-κB and RhoA pathways were identified in the p75(NTR) death domain (DD). Proapoptotic and prosurvival pathways mapped onto nonoverlapping epitopes, demonstrating that different signaling outputs can be genetically separated in p75(NTR). Dissociation of c-Jun kinase (JNK) and caspase-3 activities indicated that JNK is necessary but not sufficient for p75(NTR)-mediated cell death. RIP2 recruitment and RhoGDI release were mechanistically linked, indicating that competition for DD binding underlies crosstalk between NF-κB and RhoA pathways in p75(NTR) signaling. These results provide insights into the logic of p75(NTR) signaling and pave the way for a genetic dissection of p75(NTR) function and physiology.
Cell reports. 12/2012;
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George Notas,
Vassilia-Ismini Alexaki,
Marilena Kampa,
Vassiliki Pelekanou,
Ioannis Charalampopoulos,
Sanaa Sabour-Alaoui,
Iosif Pediaditakis,
Valérie Dessirier, Achille Gravanis,
Efstathios N Stathopoulos,
Andreas Tsapis,
Elias Castanas
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ABSTRACT: The TNF superfamily ligands APRIL and BAFF bind with different affinity to two receptors, BCMA and TACI, and induce cell survival and/or proliferation, whereas BAFF also binds specifically to BAFFR. These molecules were considered specific for the immune system. Recently, however, they were also found in epithelial and mesenchymal noncancerous and cancerous tissues and cell lines. In this article, we report that hepatocellular carcinoma (HCC) cell lines HepG2 and Hep3B and HCC specimens express APRIL and BAFF and their receptors BCMA and BAFFR, but not TACI; APRIL/BCMA is enhanced in HCC, compared with normal liver tissue. In contrast to previous reports, APRIL binding to BCMA decreases cell proliferation by inducing G(2)/M cell cycle arrest, whereas BAFF has no effect on cell growth. HCC cells therefore represent a rare system in which these two ligands (APRIL and BAFF) exert a differential effect and may serve as a model for specific APRIL/BCMA actions. We show that the effect of APRIL is mediated via BCMA, which does not activate the classical NF-κB pathway, whereas it induces a novel signaling pathway, which involves JNK2 phosphorylation, FOXO3A activation, and GADD45 transcription. In addition, JNK2 mediates the phosphorylation of Akt, which is activated but does not participate in the antiproliferative effect of APRIL. Furthermore, transcriptome analysis revealed that APRIL modifies genes specifically related to cell cycle modulation, including MCM2/4/5/6, CDC6, PCNA, and POLE2. Our data, therefore, identify a novel APRIL/BCMA signaling pathway in HCC and suggest that APRIL could have a pleiotropic role in tumor biology.
The Journal of Immunology 10/2012; · 5.79 Impact Factor
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ABSTRACT: The aim of the present study was to investigate the neuroprotective properties of the endogenous neurosteroid dehydroepiandrosterone (DHEA) in an in vivo model of retinal excitotoxicity, and the involvement of Nerve Growth Factor (NGF) in its actions. Adult Sprague-Dawley rats (250-300 g) received intravitreally (RS)-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide (AMPA; 42 nmol/eye) alone or in combination with DHEA (10(-8), 10(-7), 10(-6) M), or PBS (50 mM, control group). To examine the involvement of NGF and its TrkA receptor in the pharmacological effects of DHEA, animals received AMPA and NGF (60 pg/eye) in the absence or presence of a TrkA receptor inhibitor (Calbiochem 648450, 10(-6) M) or AMPA, DHEA (10(-6) M) and TrkA receptor inhibitor (10(-6), 10(-5) M). Immunohistochemistry studies [choline acetyltransferase (ChAT), brain nitric oxide synthetase (bNOS), calbindin, and TUNEL] and fluorescence-activated cell sorting (FACS) were used to examine retinal cell loss and protection. TrkA receptor immunoreactivity (-IR) and colocalization studies with relevant markers were also performed. AMPA (42 nmol) treatment resulted in a loss of bNOS, ChAT and calbindin immunoreactivities 24 h after its administration. DHEA, administered intravitreally, protected the retina from excitotoxicity in a dose-dependent manner. This effect was mimicked by NGF, and reversed by the NGF TrkA receptor inhibitor. The TrkA receptor is expressed in ganglion cells of rat retina. TUNEL staining and FACS analysis substantiated the neuroprotective actions of DHEA. These results demonstrate for the first time that the neurosteroid DHEA, administered intravitreally, protects the retina from AMPA excitotoxicity. An NGF TrkA receptor mechanism appears to be involved in this neuroprotection.
Neuropharmacology 04/2012; 62(5-6):2106-17. · 4.81 Impact Factor
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European Journal of Clinical Investigation 03/2012; 42(10):1146. · 3.02 Impact Factor
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European Journal of Clinical Investigation 03/2012; 42(3):231-2. · 3.02 Impact Factor
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ABSTRACT: The neurosteroid dehydroepiandrosterone (DHEA) exerts a portion of its neuroprotective effects by directly interacting with the nerve growth factor (NGF) receptors TrkA and p75(NTR) to induce prosurvival signaling. DHEA is an intermediate in the biosynthesis of estrogens and androgens that affects the endocrine system and potentially increases the risk for developing estrogen- and androgen-dependent tumors. We have synthesized 17-spiro analogs of DHEA that lack estrogenic or androgenic properties and bind to and activate NGF receptors, thus exerting potent neuroprotective effects without the tumor risk. These synthetic DHEA derivatives may serve as lead molecules to develop small agonists of NGF receptors that can penetrate the blood-brain barrier (microneurotrophins) with potential applications in the treatment of neurodegenerative diseases. The neuroprotective properties of microneurotrophins are now being tested in various animal models of neurodegenerative diseases.
Science Signaling 01/2012; 5(246):pt8. · 7.50 Impact Factor
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Marianna Ioannou,
Themis Alissafi,
Iakovos Lazaridis,
George Deraos,
John Matsoukas, Achille Gravanis,
Vasileios Mastorodemos,
Andreas Plaitakis,
Arlene Sharpe,
Dimitrios Boumpas,
Panayotis Verginis
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ABSTRACT: There is a need in autoimmune diseases to uncover the mechanisms involved in the natural resolution of inflammation. In this article, we demonstrate that granulocytic myeloid-derived suppressor cells (G-MDSCs) abundantly accumulate within the peripheral lymphoid compartments and target organs of mice with experimental autoimmune encephalomyelitis prior to disease remission. In vivo transfer of G-MDSCs ameliorated experimental autoimmune encephalomyelitis, significantly decreased demyelination, and delayed disease onset through inhibition of encephalitogenic Th1 and Th17 immune responses. Exposure of G-MDSCs to the autoimmune milieu led to up-regulation of the programmed death 1 ligand that was required for the G-MDSC-mediated suppressive function both in vitro and in vivo. Importantly, myeloid-derived suppressor cells were enriched in the periphery of subjects with active multiple sclerosis and suppressed the activation and proliferation of autologous CD4(+) T cells ex vivo. Collectively, this study revealed a pivotal role for myeloid-derived suppressor cells in the regulation of multiple sclerosis, which could be exploited for therapeutic purposes.
The Journal of Immunology 12/2011; 188(3):1136-46. · 5.79 Impact Factor
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ABSTRACT: The neurosteroid dehydroepiandrosterone (DHEA), produced by neurons and glia, affects multiple processes in the brain, including neuronal survival and neurogenesis during development and in aging. We provide evidence that DHEA interacts with pro-survival TrkA and pro-death p75(NTR) membrane receptors of neurotrophin nerve growth factor (NGF), acting as a neurotrophic factor: (1) the anti-apoptotic effects of DHEA were reversed by siRNA against TrkA or by a specific TrkA inhibitor; (2) [(3)H]-DHEA binding assays showed that it bound to membranes isolated from HEK293 cells transfected with the cDNAs of TrkA and p75(NTR) receptors (K(D): 7.4 ± 1.75 nM and 5.6 ± 0.55 nM, respectively); (3) immobilized DHEA pulled down recombinant and naturally expressed TrkA and p75(NTR) receptors; (4) DHEA induced TrkA phosphorylation and NGF receptor-mediated signaling; Shc, Akt, and ERK1/2 kinases down-stream to TrkA receptors and TRAF6, RIP2, and RhoGDI interactors of p75(NTR) receptors; and (5) DHEA rescued from apoptosis TrkA receptor positive sensory neurons of dorsal root ganglia in NGF null embryos and compensated NGF in rescuing from apoptosis NGF receptor positive sympathetic neurons of embryonic superior cervical ganglia. Phylogenetic findings on the evolution of neurotrophins, their receptors, and CYP17, the enzyme responsible for DHEA biosynthesis, combined with our data support the hypothesis that DHEA served as a phylogenetically ancient neurotrophic factor.
PLoS Biology 04/2011; 9(4):e1001051. · 11.45 Impact Factor
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ABSTRACT: Amyloid-β protein precursor (AβPP) is a ubiquitously expressed glycoprotein, which under physiological conditions can be cleaved following two alternative routes; the non-amyloidogenic and the amyloidogenic pathway. Shift of AβPP processing in favor of the amyloidogenic pathway is a key event in the pathogenesis of Alzheimer's disease (AD). Among the factors that regulate AβPP processing, nerve growth factor (NGF) appears to play an important role; abnormal NGF signaling has been implicated in the onset of AD. In the present study, we used PC12 cells to study the effects of NGF on AβPP processing and provide evidence that NGF, through binding to its high affinity receptor, TrkA moderately down-regulates the expression of the β-secretase β-site AβPP cleaving enzyme-1 and, most importantly, upregulates the expression of two enzymes with α-secretase activity, a disintegrin and metalloprotease-17 and to a greater extent matrix metalloproteinase-9 (MMP9) in a phosphoinositide kinase-3 dependent manner. Finally, we demonstrate that MMP9 actively participates in NGF-induced α-secretase cleavage of AβPP, thus it contributes to the shift of AβPP processing towards the non-amyloidogenic pathway precluding the formation of neurotoxic Aβ peptides.
Journal of Alzheimer's disease: JAD 02/2011; 24(4):705-19. · 3.74 Impact Factor
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ABSTRACT: Corticotropin-releasing hormone, or factor, (CRH or CRF) exerts important biological effects in multiple peripheral tissues via paracrine/autocrine actions. The aim of our study was to assess the effects of endogenous CRH in the biology of mouse and human skin fibroblasts, the primary cell type involved in wound healing. We show expression of CRH and its receptors in primary fibroblasts, and we demonstrate the functionality of fibroblast CRH receptors by induction of cAMP. Fibroblasts genetically deficient in Crh (Crh-/-) had higher proliferation and migration rates and compromised production of IL-6 and TGF-β1 compared to the wildtype (Crh+/+) cells. Human primary cultures of foreskin fibroblasts exposed to the CRF(1) antagonist antalarmin recapitulated the findings in the Crh-/- cells, exhibiting altered proliferative and migratory behavior and suppressed production of IL-6. In conclusion, our findings show an important role of fibroblast-expressed CRH in the proliferation, migration, and cytokine production of these cells, processes associated with the skin response to injury. Our data suggest that the immunomodulatory effects of CRH may include an important, albeit not explored yet, role in epidermal tissue remodeling and regeneration and maintenance of tissue homeostasis.
PLoS ONE 01/2011; 6(7):e21654. · 4.09 Impact Factor
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Theodora Calogeropoulou,
Nicolaos Avlonitis,
Vassilios Minas,
Xanthippi Alexi,
Athanasia Pantzou,
Ioannis Charalampopoulos,
Maria Zervou,
Varvara Vergou,
Efrosini S Katsanou,
Iakovos Lazaridis,
Michael N Alexis, Achille Gravanis
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ABSTRACT: DHEA analogues with modifications at positions C3 or C17 were synthesized and evaluated for neuroprotective activity against the neural-crest-derived PC12 cell model of serum deprivation-induced apoptosis. The most potent compounds were the spiro-epoxy derivatives 17beta-spiro[5-androstene-17,2'-oxiran]-3beta-ol (20), (20S)-3beta,21-dihydroxy-17beta,20-epoxy-5-pregnene (23), and (20R)-3beta,21-dihydroxy-17alpha,20-epoxy-5-pregnene (27) with IC(50) values of 0.19 +/- 0.01, 99.0 +/- 4.6, and 6.4 +/- 0.3 nM, respectively. Analogues 20, 23, and 27, up to the micromolar range of concentrations, were unable to activate estrogen receptor alpha and beta (ERalpha and ERbeta) or to interfere with ER-dependent gene expression significantly. In addition, they were unable to stimulate the growth of Ishikawa, MCF-7, and LNCaP cells. Our results suggest that the spiro-epoxyneurosteroid derivatives 20, 23, and 27 may prove to be lead molecules for the synthesis of novel neuroprotective agents.
Journal of Medicinal Chemistry 11/2009; 52(21):6569-87. · 4.80 Impact Factor
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ABSTRACT: Although the epidermis is importantly affected by steroid hormones, little is known about the effects of dehydroepiandrosterone (DHEA) on human keratinocytes, in spite of its abundance in human serum. Here, we demonstrate for the first time a protective role of DHEA against apoptosis in keratinocytes, using non-cancerous immortalized human HaCaT cells. We show that DHEA transmits its signal via specific G protein-coupled, membrane binding sites and inhibits apoptosis, through prevention of mitochondrial disruption and altered balance of Bcl-2 proteins. DHEA conjugated to the membrane impermeable molecule BSA, as well as DHEA-S, the most abundant form of DHEA in human serum exhibit similar anti-apoptotic effect. Our data provide new insights in the treatment of the epidermis with steroid hormones in apoptosis-related conditions.
Experimental Cell Research 05/2009; 315(13):2275-83. · 3.58 Impact Factor
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ABSTRACT: SNP-typing strategies involve an exponential amplification step, an allele discrimination reaction and detection of the products. Usually, allele discrimination is performed after amplification. Tetra-primer PCR allows allele discrimination during the amplification step, thereby avoiding additional genotyping reactions. However, to date, electrophoresis is the only method used for detection of tetra-primer PCR products. We report a dipstick test that enables visual detection of tetra-primer PCR products within minutes without instruments. The method is applied to the genotyping of CYP2C19*2 (c.681G>A) and CYP2D6*4 (g.3465G>A).
A pair of external primers amplifies a segment encompassing the SNPs. Biotinylated inner primers have a 3 -mismatch and pair off with the external primers to guide a bidirectional amplification that generates allele-specific fragments. The products are hybridized briefly with poly(dA)-tailed probes and applied to the DNA biosensor, which is then immersed in the appropriate buffer. As the buffer migrates along the biosensor, the hybrids are captured from streptavidin at the test zone and interact with oligo(dT)-functionalized gold nanoparticles leading to the formation of a red line. Another red line is formed at the control zone to indicate proper function of the sensor.
We genotyped 55 samples for CYP2C19*2 and 49 samples for CYP2D6*4. The accuracy of this method was confirmed by sequencing and electrophoresis.
The unique advantages of the proposed method are its simplicity and low cost. Contrary to electrophoresis, hybridization provides sequence confirmation of amplified fragments. The dry-reagent dipstick format minimizes the requirements for highly qualified personnel.
Pharmacogenomics 03/2009; 10(3):495-504. · 3.97 Impact Factor
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ABSTRACT: Upon binding of the corticotropin-releasing factor (CRF) analog sauvagine to the type 1 CRF receptor (CRF(1)), the amino-terminal portion of the peptide has been shown to lie near Lys257 in the receptor's second extracellular loop (EL2). To test the hypothesis that EL2 residues play a role in the binding of sauvagine to CRF(1) we carried out an alanine-scanning mutagenesis study to determine the functional role of EL2 residues (Leu251 to Val266). Only the W259A, F260A, and W259A/F260A mutations reduced the binding affinity and potency of sauvagine. In contrast, these mutations did not seem to significantly alter the overall receptor conformation, in that they left unchanged the affinities of the ligands astressin and antalarmin that have been suggested to bind to different regions of CRF(1). The W259A, F260A, and W259A/F260A mutations also decreased the affinity of the endogenous ligand, CRF, implying that these residues may play a common important role in the binding of different peptides belonging to CRF family. Parallel amino acid deletions of the two peptides produced ligands with various affinities for wild-type CRF(1) compared with the W259A, F260A, and W259A/F260A mutants, supporting the interaction between the amino-terminal residues 8 to 10 of sauvagine and the corresponding region in CRF with EL2 of CRF(1). This is the first time that a specific region of CRF(1) has been implicated in detailed interactions between the receptor and the amino-terminal portion of peptides belonging to the CRF family.
Molecular pharmacology 02/2009; 75(4):793-800. · 4.53 Impact Factor
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ABSTRACT: Dehydroepiandrosterone (DHEA) protects neural crest-derived PC12 cells from serum deprivation-induced apoptosis via G protein-associated specific plasma membrane-binding sites (mDBS). Here, we studied the signaling pathways involved in the pro-survival effects of DHEA-mediated activation of the mDBS binding sites. Membrane impermeable DHEA-bovine serum albumin (BSA) conjugate induced an acute phosphorylation of the prosurvival kinases Src, protein kinase A (PKA), MEK1/2/ERK1/2, and PI3K/Akt in serum deprived PC12 cells in parallel to an elevation of intracellular cAMP. The physiological significance of these findings was further assessed in a series of experiments using several selective pro-survival kinase inhibitors. Our combined findings suggest that the following sequence of events may take place following activation of mDBS binding sites: DHEA-BSA induces an acute but transient sequential phosphorylation of the pro-survival kinases Src/PKC(a/b)/MEK1/2/ERK1/2 which, in their turn, activate transcription factors cAMP responsive element binding protein and nuclear factor kappa B which induce the expression of the anti-apoptotic Bcl-2 genes. In parallel, DHEA-BSA increases intracellular cAMP, and the subsequent phosphorylation of PKA kinase and of cAMP responsive element binding protein. Finally, DHEA-BSA induces phosphorylation of PI3K/Akt kinases which, subsequently, lead to phosphorylation/deactivation of the pro-apoptotic Bad. Our findings suggest that the neurosteroid DHEA affects neural crest-derived cell survival by multiple pro-survival signaling pathways comprising an integrated system of non-genomic and genomic mechanisms.
Journal of Neurochemistry 01/2009; 107(5):1457-69. · 4.06 Impact Factor
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ABSTRACT: Neurons and glia in the central nervous system express the necessary enzymes for the synthesis of neurosteroids that are produced in concentrations high enough to exert paracrine effects. Synthesis of brain neurosteroids declines with age, during stressful conditions (including major depression, chronic psychological stress), and in chronic inflammatory and neurodegenerative diseases. Recent reports associate the decrease of brain neurosteroids to neuronal dysfunction and degeneration. This review summarizes the recent findings on how the most studied neurosteroids (dehydroepiandrosterone, pregnenolone and their sulphate esters, progesterone and allopregnanolone) affect neuronal survival, neurite outgrowth and neurogenesis; furthermore, this review discusses potential applications of these neurosteroids in the therapeutic management of neurodegenerative conditions, including that of age-related brain atrophy.
Trends in Endocrinology and Metabolism 10/2008; 19(8):300-7. · 8.11 Impact Factor
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ABSTRACT: In this study we describe a novel Rho small GTPase dependent pathway that elicits apoptotic responses controlled by actin reorganization in hormone-sensitive LNCaP- and hormone insensitive DU145-prostate cancer cells stimulated with membrane androgen receptor selective agonists. Using an albumin-conjugated steroid, testosterone-BSA, we now show significant induction of actin polymerization and apoptosis that can be reversed by actin disrupting agents in both cell lines. Testosterone-BSA triggered RhoA/B and Cdc42 activation in DU145 cells followed by stimulation of downstream effectors ROCK, LIMK2 and ADF/destrin. Furthermore, dominant-negative RhoA, RhoB or Cdc42 mutants or pharmacological inhibitors of ROCK inhibited both actin organization and apoptosis in DU145 cells. Activation of RhoA/B and ROCK was also implicated in membrane androgen receptor-dependent actin polymerization and apoptosis in LNCaP cells. Our findings suggest that Rho small GTPases are major membrane androgen receptor effectors controlling actin reorganization and apoptosis in prostate cancer cells.
Experimental Cell Research 08/2008; 314(17):3162-74. · 3.58 Impact Factor
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ABSTRACT: Most genotyping methods for known single-nucleotide polymorphisms (SNPs) are based on hybridization with allele-specific probes, oligonucleotide ligation reaction (OLR), primer extension or invasive cleavage. OLR offers superior specificity because it involves two recognition events; namely, the hybridization of an allele-specific probe and a common probe to adjacent positions on target DNA. OLR products can be detected by microtiter well-based colorimetric, time-resolved fluorimetric or chemiluminometric assays, electrophoresis, microarrays, microspheres, and homogeneous fluorimetric or colorimetric assays. We have developed a simple, robust, and low-cost disposable biosensor in dry-reagent format, which allows visual genotyping with no need for instrumentation. The OLR mixture contains a biotinylated common probe and an allele-specific probe with a (dA)(20) segment at the 3'-end. OLR products are denatured and applied to the biosensor next to gold nanoparticles that are decorated with oligo(dT) strands. The sensor is immersed in the appropriate buffer and all components migrate by capillary action. The OLR product is captured by immobilized streptavidin at the test zone (TZ) of the sensor and hybridizes with the oligo(dT) strands of the nanoparticles. A characteristic red line is generated due to the accumulation of nanoparticles. The excess nanoparticles are captured by immobilized oligo(dA) at the control zone of the strip, giving a second red line. We have applied successfully the proposed OLR-dipstick assay to the genotyping of four SNPs in the drug-metabolizing enzyme genes CYP2D6 ((*)3 and (*)4) and CYP2C19 ((*)2 and (*)3). The results were in agreement with direct sequencing.
Human Mutation 06/2008; 29(8):1071-8. · 5.69 Impact Factor
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ABSTRACT: Pregnancy represents a major challenge to the maternal immune system since it has to tolerate the semi-allograft fetus. Indeed, the success of pregnancy requires an appropriate immunological interaction between the mother and the fetus. Furthermore, evidence suggests that some pregnancy complications, such as spontaneous abortions, preeclampsia and intrauterine growth restriction, are associated with abnormal maternal-fetal immune responses. Corticotropin-releasing hormone (CRH), a 41-amino acid peptide originally found in the hypothalamus, appears to have a fundamental role in the mechanisms responsible for the implantation and maintenance of human pregnancy. Reproductive CRH is a form of tissue CRH (CRH found in peripheral tissues), analogous to the immune CRH detected in peripheral inflammatory sites. Reproductive CRH has been identified in the endometrial glands, the decidualized endometrial stroma and the placental trophoblast, synctiotrophoblast and decidua. Reproductive CRH participates in various reproductive functions with an inflammatory component, where it serves as an autocrine/paracrine modulator. The immunological mechanisms contributing to the establishment and maintenance of pregnancy are not fully understood. The present article focuses on the potential roles of CRH on the physiology and pathophysiology of pregnancy and highlights its participation in implantation, early fetal immunotolerance and parturition.
Expert Review of Endocrinology & Metabolism 04/2008; 3(3):315-325.
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ABSTRACT: Dehydroepiandrosterone (DHEA) is synthesized in the adrenals and the brain. Additionally, DHEA is produced at high concentrations
in the human embryo enhancing neuronal development. Its production rate and levels in serum, brain and adrenals decrease gradually
with advancing age. This decline was associated to age-related neuronal dysfunction and degeneration, suggesting a neuroprotective
effect of endogenous DHEA against noxious agents. This hypothesis is substantiated by experimental findings showing that DHEA
protect neural crest derived cells against serum deprivation-induced apoptosis with EC50 1.8 nM. This potent antiapoptotic
effect of DHEA is mediated by G-protein coupled specific membrane binding sites, the subsequent activation of prosurvival
kinases Src and PKC and transcription factors CREB and NF-κB, upstream effectors of the antiapoptotic Bcl-2 proteins. These
findings suggest that DHEA may act as an endogenous neuroprotective factor, during development and in adulthood. The decline
of DHEA levels during ageing may leave the brain unprotected against neurotoxic challenges. The DHEA specific membrane binding
sites conferring neuroprotection offer a new target for developing synthetic DHEA analogs with antiapoptotic and neuroprotective
properties, deprived of endocrine toxicity.
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