bluuebunny/crossref_metadata_2025 huggingface dataset:
Pituitary Action of Cytokines: Focus on BMP-4 and gp130 Family
Authors: Giacomini Damiana , Acuña Matías , Gerez Juan , Nagashima Alberto Carbia , Silberstein Susana , Páez-Pereda Marcelo , Labeur Marta , Theodoropoulou Marily , Renner Ulrich , Stalla Günter K. , Arzt Eduardo
Published: April 2007

The anterior pituitary can develop benign tumors of different sizes, classified as micro- and macroadenomas, frequently associated with high levels of hormone production, leading to different associated syndromes like Cushing’s disease, acromegaly or prolactinomas. Much work has been done in order to understand the signaling pathways and the factors and hormones involved in the pituitary tumorigenic process. In recent years, much evidence has been collected and it is now well documented that cytokines of the gp130 family, such as interleukin-6, that use gp130 as a common signaling protein stimulate not only the proliferation but also the hormone secretion of pituitary cells. Experiments in vivo have shown that the overexpression of the gp130 receptor resulted in pituitary abnormal growth. Moreover, it has been recently described that bone morphogenetic protein-4 (BMP-4), a member of the TGF-β family, has a stimulatory role on lactosomatotropic cells promoting the development of prolactinomas but it has an inhibitory action on the corticotropic lineage. This inhibitory action prevents Cushing’s disease progression. Furthermore, BMP-4 mediates the antiproliferative action of retinoic acid in these cells. The present review highlights the most recent work about gp130 and TGF-β cytokine families and their role in pituitary tumorigenesis.
Hormonal Signaling and Pituitary Adenomas
Authors: Spada Anna , Lania Andrea , Mantovani Giovanna
Published: April 2007

In recent years the demonstration that human pituitary adenomas are monoclonal in origin provides further evidence that pituitary neoplasia arise from the replication of a single mutated cell in which growth advantage results from either activation of proto-oncogenes or inactivation of tumor suppressor genes. Mutations in common oncogenes and tumor suppressor genes are only exceptionally involved in pituitary tumors. Since pituicytes may proliferate in response to hypothalamic neurohormones, locally produced growth factors and peripheral hormones, it has been speculated that dysregulation of the signaling molecules that constitute these pathways may confer growth advantage to the target cell, finally resulting in tumor formation. The only mutational change so far recognized to be unequivocally associated with pituitary tumors occur in the Gsα gene (GNAS1) and cause constitutive activation of the cAMP-dependent pathway. However, other components of pituitary-specific pathways are frequently altered in their expression and activity. This review will focus on the possible impact of G proteins and other components of hormone signaling on pituitary tumorigenesis.
Clozapine-Induced Alteration of Glucose Homeostasis in the Rat: The Contribution of Hypothalamic-Pituitary-Adrenal Axis Activation
Authors: Tulipano Giovanni , Rizzetti Cristina , Bianchi Irene , Fanzani Alessandro , Spano PierFranco , Cocchi Daniela
Published: April 2007

Background/Aims: To our knowledge, a suitable animal model to investigate how atypical antipsychotics may induce diabetes in patients has not received much attention. Methods: We investigated the effects of acute as well as subchronic administration of clozapine on food intake, body weight gain, glucose tolerance and insulin secretion in response to glucose in Sprague-Dawley rats. We then evaluated the effects of clozapine on corticosterone secretion and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) and phosphoenolpyruvate carboxykinase (PEPCK) expression in the liver. We investigated the in vitro effects of clozapine on glucose uptake and development of differentiated myotubes in skeletal muscle cell (C2C12) cultures. Results: Clozapine administration caused hyperglycemia (p < 0.05) in female rats. In male rats, the increase of plasma glucose levels after clozapine injection was not statistically significant. The increase of plasma insulin concentrations and the intraperitoneal glucose tolerance test results proved that clozapine reduced insulin sensitivity in female rats. These endocrine and metabolic effects of clozapine were not related to changes in feeding behavior of fat accumulation. We observed a stimulatory effect of clozapine on corticosterone (p < 0.01) secretion in both female and male rats. Chronic clozapine administration upregulated PEPCK and 11β-HSD-1 expression in rat liver. Clozapine did not inhibit basal and insulin-induced glucose transport in murine myotubes but it was able to antagonize the stimulatory effect of α-methyl-5-hydroxytryptamine on glucose uptake. Conclusion: Clozapine induces sex-related alterations of glucose homeostasis and insulin sensitivity in rodents. We discussed the possible contribution of clozapine-induced activation of HPA and clozapine antagonistic activity at peripheral 5-HT2A receptors to the observed metabolic alterations.
Plasticity in the Melanotrope Neuroendocrine Interface of Xenopus laevis
Authors: Jenks Bruce G. , Kidane Adhanet H. , Scheenen Wim J.J.M. , Roubos Eric W.
Published: April 2007

Melanotrope cells of the amphibian pituitary pars intermedia produce α-melanophore-stimulating hormone (α-MSH), a peptide which causes skin darkening during adaptation to a dark background. The secretory activity of the melanotrope of the South African clawed toad Xenopus laevis is regulated by multiple factors, both classical neurotransmitters and neuropeptides from the brain. This review concerns the plasticity displayed in this intermediate lobe neuroendocrine interface during physiological adaptation to the environment. The plasticity includes dramatic morphological plasticity in both pre- and post-synaptic elements of the interface. Inhibitory neurons in the suprachiasmatic nucleus, designated suprachiasmatic melanotrope-inhibiting neurons (SMINs), possess more and larger synapses on the melanotrope cells in white than in black-background adapted animals; in the latter animals the melanotropes are larger and produce more proopiomelanocortin (POMC), the precursor of α-MSH. On a white background, pre-synaptic SMIN plasticity is reflected by a higher expression of inhibitory neuropeptide Y (NPY) and is closely associated with postsynaptic melanotrope plasticity, namely a higher expression of the NPY Y1 receptor. Interestingly, melanotrope cells in such animals also display higher expression of the receptors for thyrotropin-releasing hormone (TRH) and urocortin 1, two neuropeptides that stimulate α-MSH secretion. Possibly, in white-adapted animals melanotropes are sensitized to neuropeptide stimulation so that, when the toad moves to a black background, they can immediately initiate α-MSH secretion to achieve rapid adaptation to the new background condition. The melanotrope cell also produces brain-derived neurotrophic factor (BDNF), which is co-sequestered with α-MSH in secretory granules within the cells. The neurotrophin seems to control melanotrope cell plasticity in an autocrine way and we speculate that it may also control presynaptic SMIN plasticity.
NATO's International Security Role in the Terrorist Era
Authors: Nevers Renée de
Published: April 2007

What role does NATO play in combating terror? NATO's missions have expanded dramatically since the end of the Cold War, and most of the United States’ closest allies are members of the alliance. Nevertheless, NATO plays, at best, a supportive role in U.S. efforts to combat terrorism. The alliance contributes to preventive and defensive missions to address the threat of terrorism, and its consequence management plans aim to respond to terrorist attacks and to mitigate their effects. But many of the essential activities of the fight against terrorism occur outside NATO, through bilateral cooperation or loose coalitions of the willing. Three factors help to explain NATO's minor role in combating terrorism: shifts in alignments and threat perceptions caused by systemic changes, the alliance's limited military capabilities, and the nature of the fight against terror itself. Over time the consequences of NATO's limited role could be severe. If NATO's strongest members do not seek to address their core security threats within the alliance, NATO may have difficulty sustaining its military value.
The African Union's Capacity in Promoting Good Governance
Authors: Kingah Sevidzem Stephen
Published: April 2007

In the spirit of the Constitutive Act of the African Union we must work for a continent characterized by democratic principles and institutions which guarantee popular participation and provide for good governance. Through our actions, let us proclaim to the world that this is a continent of democracy, a continent of democratic institutions and culture. Indeed, a continent of good governance, where the people participate and the rule of law is upheld.
Industrial and Innovation Policy in Europe: The Effects on Growth and Sustainability
Authors: Korres George M.
Published: April 2007

Industrial policy is a highly controversial issue. The European Union (EU) justifies its industrial policy on the grounds of common problems across countries, its capacity to coordinate and reduce duplication of efforts, its capacity to control and limit member-state subsidies to industries, and its mandate for foreign trade and competition policy. Technology policy has been relatively successful in certain fields such as telecommunications or traffic control systems. In other fields, such as microelectronics and computers, the results have been mixed. Formulating a coherent industrial policy remains a highly complicated venture because there are a number of conflicts that are difficult to resolve. This article attempts to review the role and the implementation of industrial and innovation policies in the EU. Moreover, it will attempt to examine and analyze the effects of these policies on convergence and cohesion for the European member-states.
Rethinking Cortical Organization
Authors: Graziano Michael S.A. , Aflalo Tyson N.
Published: April 2007

One way to understand the topography of the cerebral cortex is that “like attracts like.” The cortex is organized to maximize nearest neighbor similarity. This principle can explain the separation of the cortex into discrete areas that emphasize different information domains. It can also explain the maps that form within cortical areas. However, because the cortex is two-dimensional, when a parameter space of much higher dimensionality is reduced onto the cortical sheet while optimizing nearest neighbor relationships, the result may lack an obvious global ordering into separate areas. Instead, the topography may consist of partial gradients, fractures, swirls, regions that resemble separate areas in some ways but not others, and in not a lack of topographic maps but an excess of maps overlaid on each other, no one of which seems to be entirely correct. Like a canvas in a gallery of modern art that no two observers interpret the same way, this lack of obvious ordering of high-dimensional spaces onto the cortex might then result in some scientific controversy over the true organization. In this review, the authors suggest that at least some sectors of the cortex do not have a simple global ordering and are better understood as a result of a reduction of a high-dimensional space onto the cortical sheet. The cortical motor system may be an example of this phenomenon. The authors discuss a model of the lateral motor cortex in which a reduction of many parameters onto a simulated cortical sheet results in a complex topographic pattern that matches the actual monkey motor cortex in surprising detail. Some of the ambiguities of topography and areal boundaries that have plagued the attempt to systematize the lateral motor cortex are explained by the model. NEUROSCIENTIST the attempt to syste 13(2):138—147, 2007.
Endocannabinoids and Synaptic Function in the CNS
Authors: Hashimotodani Yuki , Ohno-Shosaku Takako , Kano Masanobu
Published: April 2007

Marijuana affects neural functions through the binding of its active component (Δ9-THC) to cannabinoid receptors in the CNS. Recent studies have elucidated that endogenous ligands for cannabinoid receptors, endocannabinoids, serve as retrograde messengers at central synapses. Endocannabinoids are produced on demand in activity-dependent manners and released from postsynaptic neurons. The released endocannabinoids travel backward across the synapse, activate presynaptic CB1 cannabinoid receptors, and modulate presynaptic functions. Retrograde endocannabinoid signaling is crucial for certain forms of short-term and long-term synaptic plasticity at excitatory or inhibitory synapses in many brain regions, and thereby contributes to various aspects of brain function including learning and memory. Molecular identities of the CB1 receptor and enzymes involved in production and degradation of endocannabinoids have been elucidated. Anatomical studies have demonstrated unique distributions of these molecules around synapses, which provide morphological bases for the roles of endocannabinoids as retrograde messengers. CB1-knockout mice exhibit various behavioral abnormalities and multiple defects in synaptic plasticity, supporting the notion that endocannabinoid signaling is involved in various aspects of neural function. In this review article, the authors describe molecular mechanisms of the endocannabinoid-mediated synaptic modulation and its possible physiological significance. NEUROSCIENTIST 13(2):127—137, 2007.
Cationic Surfactants Induce Apoptosis in Normal and Cancer Cells
Authors: ENOMOTO RIYO , SUZUKI CHIE , OHNO MASATAKA , OHASI TOSHINORI , FUTAGAMI RYOKO , ISHIKAWA KEIKO , KOMAE MIKA , NISHINO TAKAYUKI , KONISHI YASUO , LEE EIBAI
Published: April 2007

Abstract:  Cationic surfactants, such as benzalkonium chloride and benzethonium chloride, possess quaternary ammonium salt. These surfactants have antimicrobial action and are used as a preservative and an antiseptic. The positively charged polar head of cationic surfactants seems to play a role in the antimicrobial action of these compounds. Recently, benzalkonium chloride in eye drops has been reported to induce apoptosis in conjunctival cells. Here, we examined whether various types of surfactants including anionic and amphoteric surfactants induce apoptosis or not in mammalian cells. Antimicrobial cationic surfactants induced apoptosis at lower concentration than its critical micelle concentration (CMC) in rat thymocytes. Other quaternary ammonium surfactants, such as cetyltrimethylammonium bromide, similarly increased biochemical and morphological features of apoptosis, whereas both anionic and amphoteric surfactants had no significant effect on these apoptotic features. These results suggest that the positive charge of quaternary ammonium surfactants is involved with onset of the apoptotic process. The treatment of benzethonium chloride also led to apoptotic cell death in Jurkat cells. These results indicate that cationic surfactants induce apoptosis in the normal and cancer cells.
Bcl‐2 Expression in Oral Squamous Cell Carcinoma
Authors: POPOVIĆ B. , JEKIĆ B. , NOVAKOVIĆ I. , LUKOVIĆ L.J. , TEPAVČEVIĆ Z. , JURIŠIĆ V. , VUKADINOVIĆ M. , MILAŠIN J.
Published: April 2007

Abstract:  Apoptosis is a genetically regulated process involved in tissue size regulation, morphogenesis, and elimination of genetically damaged cells. A pallet of genes is involved in the control of apoptosis, such as bcl‐2 family whose oncogenic potential has been demonstrated in oral tumorigenesis. Different members of bcl‐2 family may promote or inhibit apoptosis by synthesizing anti‐ and proapoptotic proteins. One of antiapoptotic proteins, bcl‐2, with a crucial role in apoptosis regulation was the object of our study. By means of immunohistochemistry we estimated the level of overexpression of bcl‐2 proteins in a series of the 26 formalin fixed, paraffin‐embedded samples of oral squamous cell carcinoma (OSCC). Analyzed tumors originated from different sites of oral cavity; 7/26 belonged to stage II, 14/26 to stage III, and 5/26 to stage IV. Immunoreactivity was scored according to the percentage and intensity of positive cytoplasmic bcl‐2 staining. All tumors had low percentage of positively stained bcl‐2 cells, with mean values for lower/higher intensity of 8.3 ± 2.5/34.4 ± 7, 7.5 ± 1.1/31.9 ± 4.3, and 8.4 ± 5.8/31.5 ± 5.8 within stages II, III, and IV, respectively. Low level of bcl‐2 expression in our sample seems to be associated with higher survival rate: 77% for the 5‐year follow‐up period. Comparing clinicopathologic and risk factors data within each and between three groups of analyzed tumors (lip–tongue P= 0.58, tongue–floor of the mouth, P= 0.21, lip–floor of the mouth, P= 0.50) there was no significant difference. However, our results suggest that the level of bcl‐2 expression could be a valuable predictor of tumor behavior and disease outcome.
Effect of Distinct Anticancer Drugs on the Phosphorylation of p53 Protein at Serine 46 in Human MCF‐7 Breast Cancer Cells
Authors: WȨSIERSKA‐GA̧DEK JÓZEFA , GUEORGUIEVA MARIETA , HERBACEK IRENE , RANFTLER CARMEN
Published: April 2007

Abstract:  Roscovitine (ROSC), a potent cyclin‐dependent kinase inhibitor (CDI), inactivates cyclin‐dependent kinase (CDK)2 resulting in the arrest of human MCF‐7 breast cancer cells in G2 phase of the cell cycle. We have recently observed a strong activation of wild‐type (wt) p53 protein in human MCF‐7 breast cancer cells upon treatment with ROSC implicating that upregulated p53 might additionally modulate the primary action of ROSC. ROSC stabilized wt p53 protein resulting in a marked extension of its half‐life. Since ROSC exhibits low cytotoxicity, it seems to upregulate p53 protein in a way different from DNA damage. ROSC induced phosphorylation of p53 protein at serine 46. Therefore, we decided to examine whether other anticancer drugs are also able to induce phosphorylation of wt p53 protein at serine 46. Exposure of MCF‐7 cells to doxorubicin (DOX) at doses inducing a strong G2 arrest resulted in a weak upregulation of p53. No site‐specific phosphorylation of p53 at serine 46 was detected. These results indicate that p53 activation is dispensable for DOX‐induced G2 arrest. Moreover, the pattern of p53 phosphorylation strongly depends on the type of the stimulating factor.
Aromatase Expression Was Not Detected by Immunohistochemistry in Endometrial Cancer
Authors: JEON YONG‐TARK , PARK SO YEON , KIM YONG‐BEOM , KIM JAE WEON , PARK NOH‐HYUN , KANG SOON‐BEOM , LEE HYO‐PYO , SONG YONG‐SANG
Published: April 2007

Abstract:  Several studies suggested that aromatase could play an important role in tumor progression and prognosis in endometrial cancer because androstenedione is converted to estrogen by the enzyme. For better understanding of the aromatase expression in endometrial cancer and its relation to diverse clinicopathological parameters, we conducted this study. This study was carried out with 141 endometrial cancer patients, all of whom had undergone operations in our institution from 1993 to 2002. Paraffin‐embedded tissue blocks were sectioned and immunostained with monoclonal antiaromatase antibody using human placental tissue as positive control. Clinicopathological variables of all patients were also reviewed. Despite quite a high aromatase expression in positive control, there was no endometrial cancer specimen showing the enzyme expression. Our result, although needs further investigation on the cause of the difference from other studies, suggested that aromatase might not have an important role in endometrial cancer.
Lack of Association of the Cyclooxygenase‐2 and Inducible Nitric Oxide Synthase Gene Polymorphism with Risk of Cervical Cancer in Korean Population
Authors: LEE TAEK SANG , JEON YONG TARK , KIM JAE WEON , PARK NOH HYUN , KANG SOON BEOM , LEE HYO PYO , SONG YONG SANG
Published: April 2007

Abstract:  Currently, many studies have shown that nitric oxide (NO) and prostaglandin (PG) are main inflammatory mediators involved in a variety of pathophysiological processes including inflammation and carcinogenesis. In this article, we explored the possible association of polymorphisms, of two representative inflammatory mediators, with the risk for cervical cancer. This study included 176 cases of histologically confirmed invasive cervical cancer, and 172 healthy controls. Allele frequency of 12 single‐nucleotide polymorphisms (SNPs) of cyclooxygenase‐2 (COX‐2) and COX5 of the inducible nitric oxide synthase (iNOS) genes in 43 different normal populations were analyzed. We found that 14 of 17 showed a monomorphic or minimal minor allele frequency; therefore, we did not continue with additional analysis. Three SNPs (2 for COX‐2, 1 for iNOS) were chosen for the study. Genotyping of three SNPs (SNP‐rs5275 in the untranslated region of exon 10 and rs5277 in the coding region of exon 3 of COX‐2, and iNOS Ser608Leu allele C/T polymorphism within exon 16 of the iNOS reductase domain) was performed. No significant increase was found in any of the genotypes of the COX‐2 or iNOS in the cancer group. We investigated the possible correlation between the genotypes and the clinicopathologic parameters of cervical cancer. No significant association of the genotypes studied was found with respect to clinical stage, lymph node (LN) status, histologic type, or parametrial invasion. Our data did not reveal an association between COX‐2 and iNOS polymorphisms with cervical cancer in Korean women.
Viability of a Human Melanoma Cell after Single and Combined Treatment with Fotemustine, Dacarbazine, and Proton Irradiation
Authors: PETROVIĆ IVAN M. , KORIĆANAC LELA B. , TODOROVIĆ DANIJELA V. , RISTIĆ‐FIRA ALEKSANDRA M. , VALASTRO LUCIA M. , PRIVITERA GIUSEPPE , CUTTONE GIACOMO
Published: April 2007

Abstract:  Viability of human HTB140 melanoma cells after being exposed to fotemustine (FM) and dacarbazine (DTIC) as well as to proton irradiation was studied. Effects of 100 and 250 μM drugs were assessed after incubation of 6, 24, 48, 72, and 96 h. Irradiations were performed with 62 MeV therapeutic protons, delivering to the cell monolayer single doses of 2, 4, 8, 12, and 16 Gy. Viability was evaluated 7 days after irradiation. Inactivation level was estimated using microtetrasolium (MTT) and sulforhodamine B (SRB) assays. Combined effects of each drug and protons, were carried out using the same drug concentrations. Proton doses applied were those used in therapy, that is, 12 and 16 Gy. With the increase of drug concentration or irradiation dose, level of cell inactivation reached approximately 60%, 48 h after drug treatment or 7 days after irradiation at 16 Gy. Considering the rate of drug concentrations used, as well as the level of doses applied, it appears that HTB140 cells are more resistant to proton irradiation than to alkylating agents tested. The combined treatment with FM or DTIC and protons did not show significant changes of cell viability as compared to the effects of single agents. Since the time point for measuring cumulative effects of drug and irradiation was 48 h post irradiation, it seems that the obtained level of viability could be attributed primarily to the effects of drugs.
Erufosine
Authors: ZAHARIEVA M.M. , KONSTANTINOV S.M. , PILICHEVA B. , KARAIVANOVA M. , BERGER M.R.
Published: April 2007

Abstract:  The ether lipid analog erufosine (erucylphospho‐N,N,N,‐trimethylpropylammonium, ErPC3) has high activity against leukemic cells without affecting the normal hematopoiesis. It belongs to the group of alkylphosphocholines (APC) that are inhibitors of protein kinase C and phospholipase C. However, the mechanism of action of erufosine remains rather unclear. We focused on combination effects with the tyrosine kinase inhibitor imatinib mesylate (gleevec, former STI‐571 or CGP‐57148) against two chronic myeloid leukemia (CML)‐derived cell lines (K‐562 and BV‐173). The influence of erufosine on proteins involved in the phosphatidylinositol‐3‐phosphate pathway and on expression of the retinoblastoma protein Rb was studied, the latter being a key component for cell cycle entry and progression in mammalian cells. The consecutive treatment of K‐562 and BV‐173 cells with erufosine (2.5, 5, 15, 30 μM) and imatinib mesylate (0.05, 0.1 μM) led to synergism as measured by the MTT‐dye reduction assay and this is reason to hypothesize that such combinations could be beneficial for relapsed patients with drug‐resistant disease. Whole cell lysates from K‐562 and BV‐173 were investigated for the expression of Rb, PKB/Akt, pAkt, and p27 by Western blot. Erufosine caused decreases of pAkt and CML fusion protein p210 (BCR‐ABL) protein expression, but induced the Rb protein expression in K‐562 cells. A parallel increase in p27 level was observed after 24 and 48 h treatment. These alterations in signal transduction could be an explanation for the drug interaction found. Furthermore, Rb is a substrate of caspases and is cleaved during apoptosis as already evidenced for BV‐173 cells. Our experimental findings suggest that erufosine acts through induction of changes in protein signaling and especially through Rb induction. This unique mode of action makes it an attractive partner for combination therapies, for example, in combination with imatinib mesylate for treatment of CML.
Is the Distribution of Selenium and Zinc in the Sublocations of Spermatozoa Regulated?
Authors: BERTELSMANN HOLGER , SIEME HARALD , BEHNE DIETRICH , KYRIAKOPOULOS ANTONIOS
Published: April 2007

Abstract:  In the sperm nuclei, of mammalian species selenium has been found only in the form of sperm nuclei glutathione peroxidase (snGPx) where it is most likely bound to the chromatin of spermatozoa. Over 80% of selenium in sperm is bound to the selenoprotein phospholipid hydroperoxide glutathione peroxidase (PHGPx) in the midpiece of rat sperm. Zinc in sperm is mainly contained in the outer dense fiber (ODF) proteins of the flagella of mammalian spermatozoa. In the sperm nuclei, zinc is predominately located in the chromatin to the protamine proteins. In order to investigate if the insertion of zinc and selenium in sperm chromatin is regulated, the element concentrations were determined in equine spermatozoa and purified sperm nuclei. We found a significant positive correlation between the selenium concentration in equine spermatozoa and sperm nuclei. The same finding was obtained for the zinc concentration in spermatozoa and sperm nuclei. The results assume that the distribution of selenium and zinc in spermatozoa is regulated by cell signaling pathways and in this way determining the selenium and zinc amount in the chromatin of spermatozoa.
Expression and Protective Role of Heme Oxygenase‐1 in Delayed Myocardial Preconditioning
Authors: JANCSÓ GÁBOR , CSEREPES BARBARA , GASZ BALÁZS , BENKÓ LÁSZLÓ , BORSICZKY BALÁZS , FERENC ANDREA , KÜRTHY MÁRIA , RÁCZ BOGLÁRKA , LANTOS JÁNOS , GÁL JÁNOS , ARATÓ ENDRE , SÍNAYC LÓSZLÓ , WÉBER GYÖRGY , RÓTH ERZSÉBET
Published: April 2007

Abstract:  In the study the authors aimed to demonstrate the expression and protective effect of heme oxygenase‐1 (HO‐1) in the delayed preconditioning (PC) on cultured myocardiac cells. Neonatal rat cardiac myocytes were exposed to ischemic (ischemic medium [IM] for 20 min) and pharmacological (adenosine, epinephrine, opioid) PC. Twenty‐four hours later cells were subjected to a simulated ischemia (SI
)—culturing for 3 h in IM, followed by 2‐h reperfusion in normal medium‐–and then lactate dehydrogenase (LDH), live/death ratio, and apoptosis were measured. For demonstrating the protective role of HO‐1, its enzymatic activity was competitively inhibited by administration of zinc protoporphyrin IX (ZnPPIX), and HO‐1 synthesis was blocked with HO‐1 siRNA. Cells in control group were cultured under normoxic conditions. In SI group, cells underwent only an SI without PC. HO‐1 expression in all of the groups was demonstrated with immunostaining. Our results showed a significant decrease of LDH release, apoptosis, and cell death in PC groups versus SI group, which has been risen in ZnPPIX‐ and HO‐1 siRNA‐treated groups. HO‐1 immunostaining showed an appreciable HO‐1 expression in PC groups, which was abolished with HO‐1 siRNA administration, but not in ZnPPIX group. The results therefore suggest that HO‐1 expression increases in both ischemic and pharmacological PC, and HO‐1 has cellular protective effect against cell death and apoptosis in ischemia‐reperfusion‐induced oxidative injury.
Expression of Insulin Signaling Transmitters and Glucose Transporters at the Protein Level in the Rat Testis
Authors: KOKK KERSTI , VERÄJÄNKORVA ESKO , WU XIAO‐KE , TAPFER HELLE , PÕLDOJA ELLE , SIMOVART HELLE‐EVI , PÖLLÄNEN PASI
Published: April 2007

Abstract:  Insulin receptor substrate (IRS) proteins are key mediators in insulin signaling from the insulin receptor. It takes place through receptor‐mediated tyrosine phosphorylation of IRS proteins. The aim of the present article is to demonstrate the distribution of IRS 1–3, glucose transporters 1–4 (GLUT 1–4), signal regulatory protein 1α (SIRP1α), PKB, and PI 3‐kinase in the rat testis to see if signal transduction mediated by these proteins is active in testicular cells. Wistar rats were used as donors of testis tissue. Expression of these genes was studied at the protein level by using immunohistochemistry and Western blotting. IRS‐1, IRS‐2, GLUT 1, GLUT 2, GLUT 3, and SIRP1α were strongly expressed in the Sertoli cells (except GLUT 1), early spermatocytes, peritubular myoid cells, macrophage‐like interstitial cells, and testicular endothelial cells in all the testes investigated by immunohistochemistry. IRS‐2 was also expressed in the Leydig cells. Immunoblotting experiments demonstrated the presence of about 26–67 kDa reactive with anti‐ IRS‐1, IRS‐2, GLUT 1, GLUT 2, GLUT 3, PKB, and SIRP1α. The present results suggest that proteins like insulin and certain cytokines using IRS‐1, IRS‐2, GLUT 1, GLUT 2, GLUT 3, PKB, and SIRP1α in their signal transduction can have effects on the different types of testicular cells in the rat.
Small GTPase Ras and Rho Expression in Rat Osteoblasts during Spaceflight
Authors: KUMEI YASUHIRO , SHIMOKAWA HITOYATA , OHYA KEI'ICHI , KATANO HISAKO , AKIYAMA HIDEO , HIRANO MASAHIKO , MORITA SADAO
Published: April 2007

Abstract:  Rat osteoblasts were cultured for 4 and 5 days aboard a space shuttle and solubilized after a 24‐h treatment with 1α,25 dihydroxyvitamin D3. The quantitative RT‐PCR determined the mRNA levels of signaling molecules upstream and downstream Ras. The small GTPase is activated by guanine nucleotide exchange protein (GEF) and deactivated by GTPase‐activating protein (GAP). When external stimuli are transduced into intracellular signals, various pathways are recruited: focal adhesion kinase (FAK) is associated with integrin‐β, and directs tyrosine phosphorylation of downstream substrates, including phospholipase C‐γ (PLC‐γ) and son of sevenless (SOS, a Ras GEF). The mRNA levels of FAK and PLC‐γ1 and ‐γ2 in the flight cultures were increased 150% and 250% of the ground controls. The SOS mRNA levels in the flight cultures were increased 520% and 320% of the ground controls. Signals via G protein–coupled receptors are transmitted through PLC‐β and Ras GRF (another Ras GEF). Activated Ras then stimulates Raf, mitogen‐activated protein kinase (MAPK) cascades. The mRNA levels of Raf, extracellular signal‐regulated protein kinase of MAPK family (ERK‐1 and ‐2), and PLC‐β were increased during spaceflight. Rho GAP expression in the flight cultures was increased twofold of the ground controls. Since Rho GAP deactivates Rho, microgravity may suppress Rho signals, regulating actin filament rearrangement. Microgravity signals may involve two pathways (G protein–coupled receptor‐mediated pathway and tyrosine phosphorylation‐mediated pathway) that activate Ras, Raf, and MAPK cascades in rat osteoblasts.
Generation of ΔTAp73 Proteins by Translation from a Putative Internal Ribosome Entry Site
Authors: SAYAN A. EMRE , ROPERCH JEAN‐PIERRE , SAYAN BERNA S. , ROSSI MARIO , PINKOSKI M.J. , KNIGHT RICHARD A. , WILLIS ANNE E. , MELINO GERRY
Published: April 2007

Abstract:  p73 belongs to a family of transcription factors, including p53 and p63, that mediate response to DNA damage and cellular stress by inducing DNA repair, cell cycle arrest, and apoptosis. TP73 gene contains two promotors and several splice variants resulting in up to 24 possible permutations of p73 proteins which underlies the complexity of the family and its regulatory mechanisms. p73 variants lacking the N‐terminal, denoted as ΔTAp73, are not transcriptionally competent and they act in a dominant negative fashion over TAp73. ΔTAp73 isoforms can be generated by alternative promotor usage, giving rise to ΔNp73, or alternative splicing of exons 2, 3 or 2, and 3 together. Such transcript isoforms potentially produce oncogenic proteins and they were shown to be present in primary tumors and tumor‐derived cell lines. We investigated the possibility of additional mechanisms by which p73 protein could be regulated and discovered a putative internal ribosome entry site (IRES) in exon 2. Translation initiation of TAp73 mRNA results in a ΔNp73‐like peptide, thus demonstrating an additional mechanism whereby a ΔTA p73 protein is produced from a transcript originally generated from the P1 promotor of the p73 gene.
A New Transcript Splice Variant of the Human Glucocorticoid Receptor
Authors: TURNER JONATHAN D. , SCHOTE ANDREA B. , KEIPES MARC , MULLER CLAUDE P.
Published: April 2007

Abstract:  All human glucocorticoid receptor (hGR) isoforms are encoded by the NR3C1 gene consisting of seven core exons (exons 2–8) common to all protein isoforms. The gene has two major exon 8‐9 splice variants and a 5′‐UTR consisting of 11 alternative splice variants. The N‐terminal region of the hGR includes a tau 1 transactivation domain that interacts with proteins in the basal transcriptional apparatus, including the TATA box‐binding protein. Here, we report the existence and the tissue distribution of a novel splice variant, hGRΔ313‐338, with a 26 residue (78 bp) deletion in this N‐terminal region encoded by exon 2, between amino acids 313 and 338. The hGRΔ313‐338 observed at the mRNA level represents a transcript variant encoding a smaller protein isoform detected by WB with a predicted deletion between the tau 1 domain and the DNA‐binding domain (DBD) encoded by exons 3 and 4. Previous studies in transgenic mice showed that the removal of the entire exon 2 covering both the tau 1 transactivation domain and our deleted region produced a functional receptor albeit with an altered glucocorticoid‐induced gene transcription pattern. Interestingly, the deleted residues show a number of potential phosphorylation sites including serine 317, known to be phosphorylated. It is thought that phosphorylation plays an important role in transactivation action of hGR. Thus, we hypothesize that hGRΔ313‐338 represents a hGR isoform with an altered glucocorticoid‐induced transactivation profile.
The Analgesic Effect of Tribulus terrestris Extract and Comparison of Gastric Ulcerogenicity of the Extract with Indomethacine in Animal Experiments
Authors: HEIDARI M.R. , MEHRABANI M. , PARDAKHTY A. , KHAZAELI P. , ZAHEDI M.J. , YAKHCHALI M. , VAHEDIAN M.
Published: April 2007

Abstract: 
Tribulus terrestris has been used in traditional medicine for relieving rheumatic pain and as an analgesic plant for a long time. In this investigation the analgesic effect of methanolic extract of this plant on male albino mice was evaluated by formalin and tail flick test. Extraction of the fruits of the plant was done by two different methods (suxheletion and percolation) with methanol 80%. The percolated extract was injected intraperitoneally in mice at 50, 100, 200, 400, and 800 mg/kg. The results showed that a dose of 100 mg/kg of percolated extract had the highest significant analgesic effect compared to the control group (P < 0.01) in formalin and tail flick test. There is no significant difference in the analgesic effect of suxheleted and percolated extract. The analgesic effect of the extract was lower than morphine, 2.5 mg/kg in both tests, and higher than ASA 300 mg/kg in chronic phase of pain in formalin test (P < 0.05). Pretreatment of animal with naloxone did not change the analgesia induced by the plant extract in both tests, therefore the involvement of opioid receptor in the analgesic effect of this plant was excluded. The results of ulcerogenic studies indicate that the gastric ulcerogenecity of plant extract is lower than the indomethacin in the rat's stomach. It can therefore be concluded that T. terrestris extract has a suitable analgesic effect and further studies are required to produce a more effective product of this plant to substitute for conventional analgesic drugs.
Antioxidative Effects of Plant Polyphenols
Authors: JEFREMOV VIKTOR , ZILMER MIHKEL , ZILMER KERSTI , BOGDANOVIC NENAD , KARELSON ELLO
Published: April 2007

Abstract:  The antioxidant potency of three natural polyphenols, resveratrol, curcumin, and genistein, was compared by using the two human models: oxymodified with H2O2 and homocysteine (Hcy) G proteins in the postmortem frontal cortex (FC) membranes of age‐matched control and Alzheimer's disease (AD) subjects; and Cu2+‐induced oxidation of plasma low‐density lipoproteins (LDL). In Co, 3–10 μM polyphenols dose‐dependently depressed the G protein 25% stimulation induced by 10 μM H2O2 or 500 μM Hcy. Resveratrol revealed significantly higher antioxidativity than curcumin or genistein. In AD, the antioxidativity of polyphenols showed no significant differences. Polyphenols (1 μM) significantly increased the LDL oxidation lag time (oxyresistance) as compared with control, the effect of resveratrol being most potent. Due to the dual antioxidant mechanism, the investigated polyphenols, particularly resveratrol, should have preferences for the preventive‐therapeutic use in age‐related oxidative stress‐based pathologies.
Jaceosidin, a Pharmacologically Active Flavone Derived from Artemisia argyi, Inhibits Phorbol‐Ester‐Induced Upregulation of COX‐2 and MMP‐9 by Blocking Phosphorylation of ERK‐1 and ‐2 in Cultured Human Mammary Epithelial Cells
Authors: JEONG MIN A , LEE KI WON , YOON DO‐YOUNG , LEE HYONG JOO
Published: April 2007

Abstract:  Elevated levels of cyclooxygenase‐2 (COX‐2) and matrix metalloproteinases (MMPs) are frequently found in various types of cancerous and transformed cells, with recent studies implicating the upregulation of COX‐2 and MMPs in the development of breast cancer. This article investigated the effects of jaceosidin (4′,5,7‐trihydroxy‐3′,6‐dimethoxyflavone) isolated from Artemisia argyi on the upregulation of COX‐2 and MMP‐9 induced by the tumor promotor 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) in MCF10A human breast epithelial cells (MCF10A cells). Treatment of MCF10A cells with TPA induced the upregulation of COX‐2 and MMP‐9, and this was attenuated by jaceosidin treatment. Jaceosidin also inhibited the invasive and migrative phenotypes of MCF10A cells induced by TPA. Furthermore, jaceosidin blocked the TPA‐induced phosphorylation of extracellular signal‐regulated protein kinase‐1 and ‐2 (ERK‐1 and ‐2), which is one of the signaling molecules regulating COX‐2 and MMP. These results suggest that jaceosidin inhibits the TPA‐induced upregulation of COX‐2 and MMP‐9 by blocking ERK‐1 and ‐2 phosphorylation in human breast epithelial cells, which may be indicative of its chemopreventive potential.
Effects of Selenium Diet on Expression of Selenoproteins in the Lung of the Rat
Authors: BUKALIS KATARZYNA , ALBER DOROTHEA , BUKALIS GREGOR , BEHNE DIETRICH , KYRIAKOPOULOS ANTONIOS
Published: April 2007

Abstract:  In the present article the radiotracer techniques have been combined with biochemical separation procedures to investigate the effects of changes in the selenium status on the expression of the selenium‐containing proteins in the lung and their subcellular fractions. Subcellular separation of the lung has been achieved by differential ultracentrifugation. The selenium‐containing proteins in these compartments have been investigated by labeling of rats in vivo with 75Se, gel electrophoretic separation of the proteins, and autoradiographic detection of the tracer. In the lung of the selenium‐deficient animals, the selenium administered was used predominantly to restore the levels of the selenoproteins, while in the lung of the selenium‐sufficient animals most of the selenium retained was incorporated into the glutathione peroxidase. Also, higher activity of this enzyme has been found in the lung of the selenium‐sufficient animals. The differences in the specific incorporation of the element in the selenium deficiency into different compounds suggested that there are different metabolic pathways for selenium, strongly dependent on its status.
Involvement of AMPK Signaling Cascade in Capsaicin‐Induced Apoptosis of HT‐29 Colon Cancer Cells
Authors: KIM YOUNG MIN , HWANG JIN‐TAEK , KWAK DONG WOOK , LEE YUN KYUNG , PARK OCK JIN
Published: April 2007

Abstract:  Adenosine monophosphate (AMP)‐activated protein kinase (AMPK) is activated during ATP‐depleting metabolic states, such as hypoxia, heat shock, oxidative stress, and exercise. As a highly conserved heterotrimeric kinase that functions as a major metabolic switch to maintain energy homeostasis, AMPK has been shown to exert as an intrinsic regulator of mammalian cell cycle. Moreover, AMPK cascade has emerged as an important pathway implicated in cancer control. In this article, we have investigated the effects of capsaicin on apoptosis in relation to AMPK activation in colon cancer cell.
Capsaicin‐induced apoptosis was revealed by the presence of nucleobodies in the capsaicin‐treated HT‐29 colon cancer cells. Concomitantly, the activation of AMPK and the increased expression of the inactive form of acetyl‐CoA carboxylase (ACC) were detected in capsaicin‐treated colon cancer cells. We showed that both capsaicin and 5′‐aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribonucleoside (AICAR), an AMPK activator possess the AMPK‐ activating capacity as well as apoptosis‐inducing properties.
Evidence of the association between AMPK activation and the increased apoptosis in HT‐29 colon cancer cells by capsaicin treatment, and further findings of the correlation of the activated AMPK and the elevated apoptosis by cotreatment of AICAR and capsaicin support AMPK as an important component of apoptosis, as well as a possible target of cancer control.
Peonidin Inhibits Phorbol‐Ester–Induced COX‐2 Expression and Transformation in JB6 P+ Cells by Blocking Phosphorylation of ERK‐1 and ‐2
Authors: KWON JUNG YEON , LEE KI WON , HUR HAENG JEON , LEE HYONG JOO
Published: April 2007

Abstract:  Abnormal upregulation of cyclooxygenase‐2 (COX‐2) has been frequently observed in various types of transformed and cancerous cells. Numerous anti‐inflammatory agents have been shown to exert chemopreventive effects by targeting COX‐2, a rate‐limiting enzyme involved in the inflammatory process. Anthocyanins are naturally occurring polyphenolic compounds that endow various fruits, vegetables, and plants with intense colors. Peonidin is another representative anthocyanidin, but its chemopreventive potential has not been fully described. This article investigated the effect of peonidin on 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced COX‐2 expression and transformation in JB6 P+ mouse epidermal cells (JB6 P+ cells). Treatment of JB6 P+ cells with peonidin inhibited TPA‐induced COX‐2 expression, and also decreased TPA‐induced neoplastic transformation and blocked TPA‐induced phosphorylation of extracellular signal‐regulated kinases (ERKs) in the cells. The inhibition of the signaling mechanism regulating the activation of ERKs strongly suggests that peonidin exhibits chemopreventive as well as anti‐inflammatory activities.
Inhibitory Effects of 7‐Carboxymethyloxy‐3′,4′,5‐Trimethoxy Flavone (DA‐6034) on Helicobacter pylori‐Induced NF‐κB Activation and iNOS Expression in AGS Cells
Authors: LEE JEONG‐SANG , KIM HYUN‐SOO , HAHM KI‐BAIK , SOHN MI‐WON , YOO MOOHI , JOHNSON JEFFREY A. , SURH YOUNG‐JOON
Published: April 2007

Abstract:  The Helicobacter pylori were identified by Marshall and Warren in 1984. H. pylori survive in the forbidding harsh acid environment of the stomach and duodenum by hiding in the mucus layer and neutralizing gastric acid in its local surrounding environment. Multiple lines of evidence suggest that H. pylori infection is one of the primary causes of gastritis and peptic ulcer, which are provoked by oxidative stress and inflammation. More than 50% of the world's population is infected by this bacterium. The H. pylori‐induced inflammation has been implicated in the pathogenesis and progression of gastric cancer. DA‐6034 (7‐carboxymethyloxy‐3′,4′,5‐trimethoxy flavone) is a synthetic flavonoid known to possess anti‐inflammatory activity. It has been reported that oral administration of DA‐6034 suppresses the inflammatory bowel disease (IBD) in animal models. In this article, we attempted to examine the effect of DA‐6034 on H. pylori‐induced inflammation in human gastric cancer (AGS) cells by targeting NF‐κB and extracellular signal‐regulated kinase (ERK), a representative MAPK.
KG‐135 Inhibits COX‐2 Expression by Blocking the Activation of JNK and AP‐1 in Phorbol Ester–Stimulated Human Breast Epithelial Cells
Authors: PARK SIN‐AYE , KIM EUN‐HEE , NA HYE‐KYUNG , SURH YOUNG‐JOON
Published: April 2007

Abstract:  Ginsenosides, ingredients of ginseng, have a wide array of pharmacologic effects. Especially, ginsenosides Rk1, Rg3, and Rg5 derived from heat‐processed ginseng have been shown to possess substantial anti‐tumor‐promoting effects. KG‐135 is a formulated complex that contains several antitumorigenic ginsenosides, such as Rk1, Rg3, Rg5, Rk2, Rk3, Rs3, Rs4, Rs5, Rs6, Rs7, etc. The present article was aimed at evaluating the chemopreventive as well as anti‐inflammatory effects of KG‐135 in the human breast epithelial cell line (MCF‐10A). One of the well‐recognized molecular targets for chemoprevention is cyclooxygenase‐2 (COX‐2) that is abnormally upregulated in many premalignant and malignant tissues and cells. In this study, we found that KG‐135 inhibited COX‐2 expression in MCF‐10A cells stimulated with a prototype tumor promotor 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA). Since the transcription factor activator protein‐1 (AP‐1) plays a role in tumor promotion and is also known to regulate COX‐2 induction, we attempted to determine the effect of KG‐135 on TPA‐induced activation of AP‐1. Cotreatment with KG‐135 resulted in a decrease in TPA‐induced DNA binding of AP‐1. In addition, KG‐135 inhibited TPA‐induced phosphorylation of c‐Jun N‐terminal kinases (JNK) that regulates COX‐2 expression in MCF‐10A cells. The JNK inhibitor SP600125 attenuated COX‐2 expression in TPA‐treated MCF‐10A cells. Taken together, the above findings suggest that KG‐135 inhibits TPA‐induced COX‐2 expression in MCF‐10A cells by blocking the JNK/AP‐1 signaling pathway.