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Sample records for possibly involves kallikrein

  1. Increased circulating levels of tissue kallikrein in systemic sclerosis correlate with microvascular involvement

    PubMed Central

    Del Rosso, A; Distler, O; Milia, A; Emanueli, C; Ibba-Manneschi, L; Guiducci, S; Conforti, M; Generini, S; Pignone, A; Gay, S; Madeddu, P; Matucci-Cerinic, M

    2005-01-01

    Background: In systemic sclerosis (SSc) the lack of an angiogenic response to hypoxia may be due to inappropriate synthesis of angiogenic and angiostatic factors. Tissue kallikrein (t-kallikrein), regulating the kallikrein-kinin system and acting on the microcirculation, is a potent angiogenic agent, and kallistatin is its natural inhibitor. Objective: To evaluate, in patients with SSc, t-kallikrein and kallistatin levels and their correlation with clinical features and measures of microvascular involvement. Patients and methods: Serum levels of t-kallikrein and kallistatin (ELISA) and t-kallikrein skin expression (immunohistochemistry) were studied in patients with SSc, and evaluated for subset (dSSc or lSSc), clinical and immunological features, and microvascular involvement (ulcers, telangiectasias, nailfold videocapillaroscopy). Results: Circulating levels of t-kallikrein were higher in SSc than in controls (p<0.001). T-kallikrein did not differ between lSSc and dSSc, although it was higher in lSSc than in controls (p<0.001).T-kallikrein levels were higher in patients with early and active capillaroscopic pattern than in those with late pattern (p = 0.019 and 0.023). Patients with giant capillaries and capillary microhaemorrhages had higher t-kallikrein concentrations than patients with architectural derangement (p = 0.04). No differences in kallistatin levels were detected between patients with SSc and controls, or between lSSc and dSSc. In early SSc skin, the presence of t-kallikrein was found in endothelial and in perivascular inflammatory cells, while no staining in skin of advanced SSc was detected. Conclusion: T-kallikrein levels are increased in patients with SSc, particularly in lSSc, and are associated with early and active capillaroscopic patterns. T-kallikrein may play a part in SSc microvascular changes. PMID:15708892

  2. Involvement of Kallikrein-Related Peptidases in Normal and Pathologic Processes

    PubMed Central

    Stefanini, Ana Carolina B.; da Cunha, Bianca Rodrigues; Henrique, Tiago; Tajara, Eloiza H.

    2015-01-01

    Human kallikrein-related peptidases (KLKs) are a subgroup of serine proteases that participate in proteolytic pathways and control protein levels in normal physiology as well as in several pathological conditions. Their complex network of stimulatory and inhibitory interactions may induce inflammatory and immune responses and contribute to the neoplastic phenotype through the regulation of several cellular processes, such as proliferation, survival, migration, and invasion. This family of proteases, which includes one of the most useful cancer biomarkers, kallikrein-related peptidase 3 or PSA, also has a protective effect against cancer promoting apoptosis or counteracting angiogenesis and cell proliferation. Therefore, they represent attractive therapeutic targets and may have important applications in clinical oncology. Despite being intensively studied, many gaps in our knowledge on several molecular aspects of KLK functions still exist. This review aims to summarize recent data on their involvement in different processes related to health and disease, in particular those directly or indirectly linked to the neoplastic process. PMID:26783378

  3. Exogenous kallikrein protects against diabetic nephropathy.

    PubMed

    Liu, Wenjuan; Yang, Yeping; Liu, Yemei; Lu, Xiaolan; Guo, Shizhe; Wu, Meng; Wang, Meng; Yan, Linling; Wang, Qinghua; Zhao, Xiaolong; Tong, Xian; Hu, Ji; Li, Yiming; Hu, Renming; Stanton, Robert C; Zhang, Zhaoyun

    2016-11-01

    The kallikrein-kinin system has been shown to be involved in the development of diabetic nephropathy, but specific mechanisms are not fully understood. Here, we determined the renal-protective role of exogenous pancreatic kallikrein in diabetic mice and studied potential mechanisms in db/db type 2 diabetic and streptozotocin-induced type 1 diabetic mice. After the onset of diabetes, mice were treated with either pancreatic kallikrein (db/db+kallikrein, streptozotocin+kallikrein) or saline (db/db+saline, streptozotocin+saline) for 16 weeks, while another group of streptozotocin-induced diabetic mice received the same treatment after onset of albuminuria (streptozotocin'+kallikrein, streptozotocin'+saline). Db/m littermates or wild type mice were used as non-diabetic controls. Pancreatic kallikrein had no effects on body weight, blood glucose and blood pressure, but significantly reduced albuminuria among all three groups. Pathological analysis showed that exogenous kallikrein decreased the thickness of the glomerular basement membrane, protected against the effacement of foot process, the loss of endothelial fenestrae, and prevented the loss of podocytes in diabetic mice. Renal fibrosis, inflammation and oxidative stress were reduced in kallikrein-treated mice compared to diabetic controls. The expression of kininogen1, tissue kallikrein, kinin B1 and B2 receptors were all increased in the kallikrein-treated compared to saline-treated mice. Thus, exogenous pancreatic kallikrein both prevented and ameliorated diabetic nephropathy, which may be mediated by activating the kallikrein-kinin system.

  4. [Therapy of male fertility disorders with kallikrein].

    PubMed

    Schill, W B

    1976-11-26

    An overview of the use of kallikrein to treat male sterility is presented. Kallikrein was shown to increase sperm motility in both in vivo and in vitro studies. The vitality and longevity of the sperm are also enhanced. These effects are due to the stimulation of the intracellular concentration of cyclical adenosonemonophosphates in the sperm. Quinine receptors on the sperm surface are assumed to be the mechanism responsible for the kallikrein effect. Kallikrein stimulates spermal penetration of cervical mucus by about 80% and causes a significant increase in total sperm output 3 months from the beginning of treatment. After 2 months of use, kallikrein leads to an increase in the number of normally formed spermatozoa in the ejaculate. Kallikrein is indicated in cases of asthenospermia and oligozoospermia, in some cases of teratozoospermia, in cases of the vegetative-functional congestion syndrome desecribed by Hoffmann, and is recommended in cases of testicular parenchyme damage involving tubulus function. Parenteral administration involves 40 KE (1KE=8mcg) thrice weekly, oral administration 300-600 KE daily. Kallikrein is added directly to the ejaculate in instrumental insemination in cases of therapy-resistant decrease in motility associated with asthenospermia or oligozoospermia. Concentrations of 5 KE per ml ejaculate are used in such cases. Chronic infection, especially in the genital area, and the incidence of dizziness during therapy are contraindications to kellikrein use.

  5. Involvement of the renal kallikrein-kinin system in K(+)-induced diuresis and natriuresis in anesthetized rats.

    PubMed

    Suzuki, T; Katori, M; Fujita, T; Kumagai, Y; Majima, M

    2000-07-07

    Intravenous infusion of a high-K(+) solution (67.5 mM KCl, 67.5 mM NaCl) to anesthetized rats increased urine volume by 47.6% after 60 min, compared with infusion of a Na(+) solution (135 mM NaCl). This treatment also increased urinary excretion of Na(+) by 32.2%, in parallel with an increase in excretion of K(+) or Cl(-). Urinary excretion of kallikrein increased within 60 min after the start of K(+) infusion. A bradykinin B(2) receptor antagonist, 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-me thylamino ]-2,6-dichlorobenzyloxy]-2-methylquinoline (FR173657; 1.0 mg/kg, i.v. ), inhibited the K(+)-induced diuresis and natriuresis by 41.0% and 26.7%, respectively. These results indicate that K(+) load induces diuresis and natriuresis through the renal kallikrein-kinin system in rats.

  6. Plasma half-life and organ uptake ratio of radiolabeled glandular kallikrein in control and nephrectomized rats

    SciTech Connect

    Nishimura, K.; Iwata, T.; Kokubu, T.

    1986-01-01

    The purified rat urinary kallikrein was radiolabeled by lactoperoxidase method and by chloramine T method. Plasma half-life of radiolabeled kallikrein was 5.06 +/- 0.59 (n = 5) min in control rats and 5.24 +/- 0.42 (n = 5) min in nephrectomized rats. There was no difference between two groups. From autoradiogram, main metabolic organs of radiolabeled kallikrein were liver, kidney and spleen. Total uptake of radiolabeled kallikrein in ech organ was the highest in liver (73.2%). The uptake per g tissue of radiolabeled kallikrein in each organ was high in liver (33.0%), kidney (31.4%) and spleen (21.1%). These results suggest that the active kallikrein is metabolized mainly in the liver, and kidney is not so an important organ to metabolize or to eliminate the active kallikrein in plasma. In order to clarify the mode of existence of active kallikrein in plasma, the following experiment was done by using disc gel electrophoresis. Radioactive profile of radiolabeled kallikrein showed one peak (Rf = 1.0), but radiolabeled kallikrein mixed with rat plasma showed two peaks, that is small peak (Rf = 1.0), and main peak (RF = 0.5). The most of radiolabeled kallikrein was bound to plasma protein and only five per cent was in free form. Furthermore, the binding of radiolabeled kallikrein to plasma protein was interfered by the addition of active kallikrein. These results suggest the possibility of existence of kallikrein binding protein in plasma.

  7. Kallikreins - the melting pot of activity and function

    PubMed Central

    Kalinska, Magdalena; Meyer-Hoffert, Ulf; Kantyka, Tomasz; Potempa, Jan

    2015-01-01

    The human tissue kallikrein and kallikrein-related peptidases (KLKs), encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles. Because of the broad spectrum of processes that are modulated by kallikreins, these proteases are the subject of extensive investigations. This review brings together basic information about the biochemical properties affecting enzymatic activity, with highlights on post-translational modifications, especially glycosylation. Additionally, we present the current state of knowledge regarding the physiological functions of KLKs in major human organs and outline recent discoveries pertinent to the involvement of kallikreins in cell signaling and in viral infections. Despite the current depth of knowledge of these enzymes, many questions regarding the roles of kallikreins in health and disease remain unanswered. PMID:26408415

  8. Crystallization and preliminary crystallographic studies of human kallikrein 7, a serine protease of the multigene kallikrein family

    PubMed Central

    Fernández, Israel S.; Ständker, Ludger; Forssmann, Wolf-Georg; Giménez-Gallego, Guillermo; Romero, Antonio

    2007-01-01

    Human kallikreins are a group of serine proteases of high sequence homology whose genes are grouped as a single cluster at chromosome 19. Although the physiological roles of kallikreins are generally still unknown, members of the kallikrein family have been clearly implicated in pathological situations such as cancer and psoriasis. Human kallikrein 7 (hK7) has been shown to be involved in pathological keratinization, psoriasis and ovarian cancer. In order to gain insight into the molecular structure of this protein, hK7 was crystallized after recombinant production in its folded and active form using a periplasmic secretion vector in Escherichia coli. The crystals belonged to the rhombohedral space group H32 and diffracted to 2.8 Å. The phase problem was solved by molecular replacement using the mouse kallikrein-related protein neuropsin. Completion of the model and structure refinement are under way. PMID:17671364

  9. Kallikrein-related Peptidase-8 (KLK8) Is an Active Serine Protease in Human Epidermis and Sweat and Is Involved in a Skin Barrier Proteolytic Cascade

    PubMed Central

    Eissa, Azza; Amodeo, Vanessa; Smith, Christopher R.; Diamandis, Eleftherios P.

    2011-01-01

    Kallikrein-related peptidase-8 (KLK8) is a relatively uncharacterized epidermal protease. Although proposed to regulate skin-barrier desquamation and recovery, the catalytic activity of KLK8 was never demonstrated in human epidermis, and its regulators and targets remain unknown. Herein, we elucidated for the first time KLK8 activity in human non-palmoplantar stratum corneum and sweat ex vivo. The majority of stratum corneum and sweat KLK8 was catalytically active, displaying optimal activity at pH 8.5 and considerable activity at pH 5. We also showed that KLK8 is a keratinocyte-specific protease, not secreted by human melanocytes or dermal fibroblasts. KLK8 secretion increased significantly upon calcium induction of terminal keratinocyte differentiation, suggesting an active role for this protease in upper epidermis. Potential activators, regulators, and targets of KLK8 activity were identified by in vitro kinetic assays using pro-KLK8 and mature KLK8 recombinant proteins produced in Pichia pastoris. Mature KLK8 activity was enhanced by calcium and magnesium ions and attenuated by zinc ions and by autocleavage after Arg164. Upon screening KLK8 cleavage of a library of FRET-quenched peptides, trypsin-like specificity was observed with the highest preference for (R/K)(S/T)(A/V) at P1-P1′-P2′. We also demonstrated that KLK5 and lysyl endopeptidase activate latent pro-KLK8, whereas active KLK8 targets pro-KLK11, pro-KLK1, and LL-37 antimicrobial peptide activation in vitro. Together, our data identify KLK8 as a new active serine protease in human stratum corneum and sweat, and we propose regulators and targets that augment its involvement in a skin barrier proteolytic cascade. The implications of KLK8 elevation and hyperactivity in desquamatory and inflammatory skin disease conditions remain to be studied. PMID:20940292

  10. Parental Involvement in Education: Possibilities and Limitations.

    ERIC Educational Resources Information Center

    Khan, Mir Baiz

    1996-01-01

    Examines parental involvement in school affairs as a means to forge school-community partnerships in education. Identifies fundamental barriers to meaningful parental involvement and suggests possible solutions, such as parent empowerment, administrators' support, home-school interdependency, awareness of current research, reorganized structures,…

  11. Crystallization and preliminary crystallographic studies of human kallikrein 7, a serine protease of the multigene kallikrein family

    SciTech Connect

    Fernández, Israel S.; Ständker, Ludger; Forssmann, Wolf-Georg; Giménez-Gallego, Guillermo; Romero, Antonio

    2007-08-01

    The cloning, expression, purification and crystallization of recombinant human kallikrein 7, directly synthesized in the active form in E. coli, is described. Diffraction data were collected to 2.8 Å resolution from native crystals. Human kallikreins are a group of serine proteases of high sequence homology whose genes are grouped as a single cluster at chromosome 19. Although the physiological roles of kallikreins are generally still unknown, members of the kallikrein family have been clearly implicated in pathological situations such as cancer and psoriasis. Human kallikrein 7 (hK7) has been shown to be involved in pathological keratinization, psoriasis and ovarian cancer. In order to gain insight into the molecular structure of this protein, hK7 was crystallized after recombinant production in its folded and active form using a periplasmic secretion vector in Escherichia coli. The crystals belonged to the rhombohedral space group H32 and diffracted to 2.8 Å. The phase problem was solved by molecular replacement using the mouse kallikrein-related protein neuropsin. Completion of the model and structure refinement are under way.

  12. Tissue kallikrein proteolytic cascade pathways in normal physiology and cancer.

    PubMed

    Pampalakis, Georgios; Sotiropoulou, Georgia

    2007-09-01

    Human tissue kallikreins (KLKs or kallikrein-related peptidases) are a subgroup of extracellular serine proteases that act on a wide variety of physiological substrates, while they display aberrant expression patterns in certain types of cancer. Differential expression patterns lead to the exploitation of these proteins as new cancer biomarkers for hormone-dependent malignancies, in particular. The prostate-specific antigen or kallikrein-related peptidase 3 (PSA/KLK3) is an established tumor marker for the diagnosis and monitoring of prostate cancer. It is well documented that specific KLK genes are co-expressed in tissues and in various pathologies suggesting their participation in complex proteolytic cascades. Here, we review the currently established knowledge on the involvement of KLK proteolytic cascades in the regulation of physiological and pathological processes in prostate tissue and in skin. It is well established that the activity of KLKs is often regulated by auto-activation and subsequent autolytic internal cleavage leading to enzymatic inactivation, as well as by inhibitory serpins or by allosteric inhibition by zinc ions. Redistribution of zinc ions and alterations in their concentration due to physiological or pathological reasons activates specific KLKs initiating the kallikrein cascade(s). Recent studies on kallikrein substrate specificity allowed for the construction of a kallikrein interaction network involved in semen liquefaction and prostate cancer, as well as in skin pathologies, such as skin desquamation, psoriasis and cancer. Furthermore, we discuss the crosstalks between known proteolytic pathways and the kallikrein cascades, with emphasis on the activation of plasmin and its implications in prostate cancer. These findings may have clinical implications for the underlying molecular mechanism and management of cancer and other disorders in which KLK activity is elevated.

  13. The renal kallikrein-kinin system: its role as a safety valve for excess sodium intake, and its attenuation as a possible etiologic factor in salt-sensitive hypertension.

    PubMed

    Katori, Makoto; Majima, Masataka

    2003-02-01

    The distal tubules of the kidney express the full set of the components of the kallikrein-kinin system, which works independently from the plasma kallikrein-kinin system. Studies on the role of the renal kallikrein-kinin system, using congenitally kininogen-deficient Brown-Norway Katholiek rats and also bradykinin B2 receptor knockout mice, revealed that this system starts to function and to induce natriuresis and diuresis when sodium accumulates in the body as a result of excess sodium intake or aldosterone release, for example, by angiotensin II. Thus, it can be hypothesized that the system works as a safety valve for sodium accumulation. The large numbers of studies on hypertensive animal models and on essential hypertensive patients, particularly those with salt sensitivity, indicate a tendency toward the reduced excretion of urinary kallikrein, although this reduction is modified by potassium intake and impaired renal function. We hypothesize that the reduced excretion of the renal kallikrein may be attributable to a genetic defect of factor(s) in renal kallikrein secretion process and may cause salt-sensitive hypertension after salt intake.

  14. Therapeutic modulation of tissue kallikrein expression.

    PubMed

    Campbell, Duncan J

    2016-12-01

    The kallikrein kinin system has cardioprotective actions and mediates in part the cardioprotection produced by angiotensin converting enzyme inhibitors and angiotensin type 1 receptor blockers. Additional approaches to exploit the cardioprotective effects of the kallikrein kinin system include the administration of tissue kallikrein and kinin receptor agonists. The renin inhibitor aliskiren was recently shown to increase cardiac tissue kallikrein expression and bradykinin levels, and to reduce myocardial ischemia-reperfusion injury by bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanisms. Thus, aliskiren represents a prototype drug for the modulation of tissue kallikrein expression for therapeutic benefit.

  15. Involvement of DDAH/ADMA/NOS/cGMP and COX-2/PTGIS/cAMP Pathways in Human Tissue Kallikrein 1 Protecting Erectile Function in Aged Rats

    PubMed Central

    Tang, Zhe; Rao, Ke; Wang, Tao; Chen, Zhong; Wang, Shaogang; Liu, Jihong; Wang, Daowen

    2017-01-01

    Our previous studies had reported that Human Tissue Kallikrein 1 (hKLK1) preserved erectile function in aged transgenic rats, while the detailed mechanism of hKLK1 protecting erectile function in aged rats through activation of cGMP and cAMP was not mentioned. To explore the latent mechanism, male wild-type Sprague-Dawley rats (WTR) and transgenic rats harboring the hKLK1 gene (TGR) were fed to 4 and 18 months old and divided into four groups: young WTR (yWTR) as the control, aged WTR (aWTR), aged TGR (aTGR) and aged TGRs with HOE140 (aTGRH). Erectile function of all rats was evaluated by cavernous nerve electrostimulation method and measured by the ratio of intracavernous pressure/ mean arterial pressure (ICP/MAP) in rats. Expression levels of cAMP and cGMP were assessed, and related signaling pathways were detected by western blot, immunohistochemistry and RT-PCR. Our experiment results showed erectile function of the aWTR group and aTGRH group was lower compared with those of other two groups. Also, expression levels of cAMP and cGMP were significantly lower than those of other two groups. Moreover, expressions of related signaling pathways including DDAH/ADMA/NOS/cGMP and COX-2/PTGIS/cAMP were also downregulated in the corpus cavernosum of rats in aWTR group. Our finding revealed hKLK1 played a protective role in age-related ED. The DDAH/ADMA/NOS/cGMP and COX-2/PTGIS/cAMP pathways that were linked to the mechanism hKLK1 could increase the levels of cGMP and cAMP, which might provide novel therapy targets for age-related ED. PMID:28103290

  16. Inhibitors of Kallikrein in Human Plasma

    PubMed Central

    McConnell, David J.

    1972-01-01

    Human plasma was fractionated by ammonium sulfate precipitation, DEAE-cellulose chromatography, and Sephadex G-200 gel filtration to determine which method would give the greatest number of clearly separable kallikrein inhibitory peaks. With G-200 gel filtration three peaks could be separated which were demonstrated to contain α2-macroglobulin, C1̄ inactivator, and α1-antitrypsin. No other kallikrein inhibitors could be identified. The fractions containing C1̄ inactivator and α2-macroglobulin appeared to be more effective against kallikrein than that containing α1-antitrypsin. A patient with hereditary angioneurotic edema was shown to have an abnormal C1̄ inactivator protein capable of interfering with kallikrein's biologic, but not its esterolytic activity. Heat-treated human plasma, a commonly used source of kininogen for experiments with kallikrein, was shown to have kallikrein inhibitory activity. PMID:4113391

  17. Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice

    NASA Astrophysics Data System (ADS)

    Meneton, Pierre; Bloch-Faure, May; Hagege, Albert A.; Ruetten, Hartmut; Huang, Wei; Bergaya, Sonia; Ceiler, Debbie; Gehring, Doris; Martins, Isabelle; Salmon, Georges; Boulanger, Chantal M.; Nussberger, Jürg; Crozatier, Bertrand; Gasc, Jean-Marie; Heudes, Didier; Bruneval, Patrick; Doetschman, Tom; Ménard, Joël; Alhenc-Gelas, François

    2001-02-01

    Tissue kallikrein is a serine protease thought to be involved in the generation of bioactive peptide kinins in many organs like the kidneys, colon, salivary glands, pancreas, and blood vessels. Low renal synthesis and urinary excretion of tissue kallikrein have been repeatedly linked to hypertension in animals and humans, but the exact role of the protease in cardiovascular function has not been established largely because of the lack of specific inhibitors. This study demonstrates that mice lacking tissue kallikrein are unable to generate significant levels of kinins in most tissues and develop cardiovascular abnormalities early in adulthood despite normal blood pressure. The heart exhibits septum and posterior wall thinning and a tendency to dilatation resulting in reduced left ventricular mass. Cardiac function estimated in vivo and in vitro is decreased both under basal conditions and in response to βadrenergic stimulation. Furthermore, flow-induced vasodilatation is impaired in isolated perfused carotid arteries, which express, like the heart, low levels of the protease. These data show that tissue kallikrein is the main kinin-generating enzyme in vivo and that a functional kallikrein-kinin system is necessary for normal cardiac and arterial function in the mouse. They suggest that the kallikrein-kinin system could be involved in the development or progression of cardiovascular diseases.

  18. Studies on kallikrein in the duct systems of the salivary glands of the cat

    PubMed Central

    Shnitka, †T. K.; Maranda, B.; Rodrigues, J. A. A.; Schachter, M.; Weinberg, J.

    1978-01-01

    unevenly distributed and were concentrated in only a few lobules of the gland. Specific immunofluorescence was seen only in sections containing striated ducts. 4. The possible physiological role of kallikrein in the salivary glands is discussed. ImagesPlate 1A, BCDPlate 3 PMID:349133

  19. Clearance and metabolism of glandular kallikrein in the rat

    SciTech Connect

    Rabito, S.F.; Seto, M.; Maitra, S.R.; Carretero, O.A.

    1985-06-01

    This study was undertaken to characterize the clearance of circulating rat glandular kallikrein and to determine the contribution of various organs and the urinary excretion to the removal of glandular kallikrein from the bloodstream. The authors injected either active /sup 125/I-kallikrein or kallikrein inactivated with phenylmethylsulfonyl fluoride (/sup 125/I-PMSF-kallikrein) intravenously into intact or nephrectomized rats and then studied the disappearance rate of trichloroacetic acid (TCA)-precipitable radioactivity from the circulation. Inactivation by PMSF markedly reduced the binding of kallikrein to plasma protease inhibitors. The removal rate of the acid-precipitable radioactivity fit a biexponential curve for both active and inactive kallikrein. In the intact rats approximately 50% of the radioactivity was removed from the circulation 30 min after the injection of active /sup 125/I-kallikrein. Removal of the kidneys did not significantly affect the clearance of active kallikrein. On the other hand, inactive /sup 125/I-PMSF-kallikrein was removed from blood faster than active /sup 125/I-kallikrein in normal animals. Approximately 50% of the radioactivity was removed from the circulation 8 min after the injection, and the half-life of inactive /sup 125/I-PMSF-kallikrein was markedly prolonged by bilateral nephrectomy. Active /sup 125/I-kallikrein was taken up by tissues, particularly the liver and the kidney. In urine, less than 2% of the radioactivity was excreted in 60 min as TCA-precipitable material. The authors concluded that glandular kallikrein is cleared rapidly from the circulation of the rat, probably in the form of a complex with a plasma protease inhibitor.

  20. Factors affecting the secretion of submandibular salivary kallikrein in cats.

    PubMed

    Garrett, J R; Smith, R E; Kyriacou, K; Kidd, A; Liao, J

    1987-07-01

    Glandular kallikrein has been assessed in submandibular saliva, homogenates and plasma by the fluorimetric substrate D-Val-Leu-Arg-7-amino-4-trifluoromethylcoumarin (AFC) and histochemically in tissue sections by the 4-methoxy-2-naphthylamide (MNA) analogue. Nerve stimulation was used to produce salivary secretion. Parasympathetic saliva contained low concentrations of kallikrein, independently of any circulating catecholamines from the adrenals. Sympathetic saliva contained very high concentrations of kallikrein; the amounts in individual drops rapidly reached a peak then declined gradually. Adrenergic blocking drugs during mixed parasympathetic and sympathetic stimulation showed that beta-adrenergic effects normally increase the secretion of kallikrein in response to the alpha-adrenergic influence from sympathetic nerve impulses. Small amounts of a glandular kallikrein-like activity are present in the plasma. Effluent blood from the submandibular gland before, during and after stimulation of either nerve gave no indication that submandibular kallikrein passes from the glandular compartment to the blood under conditions of unobstructed salivary flow. Excision of the chorda tympani indicated that parasympathetic nerve impulses are required for the normal resynthesis of submandibular kallikrein. The secretion of salivary kallikrein is essentially an exocrine function but its role in the saliva remains obscure. The results suggest that sudden mobilization of kallikrein may occur at times into the saliva and that a separate population of adrenergic axons, under separate central control, may pass to the striated ducts specially for this purpose.

  1. Plasma Kallikrein Inhibitors in Cardiovascular Disease: An Innovative Therapeutic Approach.

    PubMed

    Kolte, Dhaval; Shariat-Madar, Zia

    2016-01-01

    Plasma prekallikrein is the liver-derived precursor of the trypsin-like serine protease plasma kallikrein, and circulates in plasma bound to high molecular weight kininogen. Plasma prekallikrein is activated to plasma kallikrein by activated factor XII or prolylcarboxypeptidase. Plasma kallikrein regulates the activity of multiple proteolytic cascades in the cardiovascular system such as the intrinsic pathway of coagulation, the kallikrein-kinin system, the fibrinolytic system, the renin-angiotensin system, and the complement pathways. As such, plasma kallikrein plays a central role in the pathogenesis of thrombosis, inflammation, and blood pressure regulation. Under physiological conditions, plasma kallikrein serves as a cardioprotective enzyme. However, its increased plasma concentration or hyperactivity perpetuates cardiovascular disease (CVD). In this article, we review the biochemistry and cell biology of plasma kallikrein and summarize data from preclinical and clinical studies that have established important functions of this serine protease in CVD states. Finally, we propose plasma kallikrein inhibitors as a novel class of drugs with potential therapeutic applications in the treatment of CVDs.

  2. Kallikrein-related peptidases (KLKs) and the hallmarks of cancer.

    PubMed

    Filippou, Panagiota S; Karagiannis, George S; Musrap, Natasha; Diamandis, Eleftherios P

    2016-08-01

    The kallikrein-related peptidases (KLKs) represent the largest family of serine proteases within the human genome and are expressed in various tissues. Although they regulate several important physiological functions, KLKs have also been implicated in numerous pathophysiological processes, including cancer. Growing evidence describing the deregulation of KLK expression and secretion, as well as activation in various malignancies, has uncovered their potential as mediators of cancer progression, biomarkers of disease and as candidate therapeutic targets. The diversity of signalling pathways and proteolytic cascades involving KLKs and their downstream targets appears to affect cancer biology through multiple mechanisms, including those related to the hallmarks of cancer. The aim of this review is to provide an update on the importance of KLK-driven molecular pathways in relation to cancer cell traits associated with the hallmarks of cancer and to highlight their potential in personalized therapeutics.

  3. Possible involvement of poly(A) in protein synthesis.

    PubMed Central

    Jacobson, A; Favreau, M

    1983-01-01

    The experiments of this paper have re-evaluated the possibility that poly(A) is involved in protein synthesis by testing whether purified poly(A) might competitively inhibit in vitro protein synthesis in rabbit reticulocyte extracts. We have found that poly(A) inhibits the rate of translation of many different poly(A)+ mRNAs and that comparable inhibition is not observed with other ribopolymers. Inhibition by poly(A) preferentially affects the translation of adenylated mRNAs and can be overcome by increased mRNA concentrations or by translating mRNPs instead of mRNA. The extent of inhibition is dependent on the size of the competitor poly(A) as well as on the translation activity which a lysate has for poly(A)+ RNA. In light of our results and numerous experiments in the literature, we propose that poly(A) has a function in protein synthesis and that any role in the determination of mRNA stability is indirect. Images PMID:6137807

  4. Plasma Kallikrein Promotes Epidermal Growth Factor Receptor Transactivation and Signaling in Vascular Smooth Muscle through Direct Activation of Protease-activated Receptors*

    PubMed Central

    Abdallah, Rany T.; Keum, Joo-Seob; Lee, Mi-Hye; Wang, Bing; Gooz, Monika; Luttrell, Deirdre K.; Luttrell, Louis M.; Jaffa, Ayad A.

    2010-01-01

    The kallikrein-kinin system, along with the interlocking renin-angiotensin system, is a key regulator of vascular contractility and injury response. The principal effectors of the kallikrein-kinin system are plasma and tissue kallikreins, proteases that cleave high molecular weight kininogen to produce bradykinin. Most of the cellular actions of kallikrein (KK) are thought to be mediated by bradykinin, which acts via G protein-coupled B1 and B2 bradykinin receptors on VSMCs and endothelial cells. Here, we find that primary aortic vascular smooth muscle but not endothelial cells possess the ability to activate plasma prekallikrein. Surprisingly, exposing VSMCs to prekallikrein leads to activation of the ERK1/2 mitogen-activated protein kinase cascade via a mechanism that requires kallikrein activity but does not involve bradykinin receptors. In transfected HEK293 cells, we find that plasma kallikrein directly activates G protein-coupled protease-activated receptors (PARs) 1 and 2, which possess consensus kallikrein cleavage sites, but not PAR4. In vascular smooth muscles, KK stimulates ADAM (a disintegrin and metalloprotease) 17 activity via a PAR1/2 receptor-dependent mechanism, leading sequentially to release of the endogenous ADAM17 substrates, amphiregulin and tumor necrosis factor-α, metalloprotease-dependent transactivation of epidermal growth factor receptors, and metalloprotease and epidermal growth factor receptor-dependent ERK1/2 activation. These results suggest a novel mechanism of bradykinin-independent kallikrein action that may contribute to the regulation of vascular responses in pathophysiologic states, such as diabetes mellitus. PMID:20826789

  5. Effect of glandular kallikrein on distal bicarbonate transport. Role of basolateral Cl-/HCO3- exchanger and vacuolar H(+)-ATPase.

    PubMed

    Manucha, W; Vallés, P

    1999-12-01

    The luminal membrane of collecting duct cells, specially the intercalated cells, is normally exposed to active kallikrein. This is due to the specific localization of renal kallikrein in the connecting tubule cells. We have previously reported inhibition of distal bicarbonate secretion by renal kallikrein. The present study was performed to evaluate the participation of basolateral Cl-/HCO3- exchanger and luminal H(+)-ATPase activity of cortical collecting duct segments (CCD) in the mechanism involved in the inhibition of bicarbonate secretion induced by the enzyme. The effect of orthograde injections of 1 microgram/ml (250 U/6.3 mg) pig pancreatic kallikrein, in the absence and presence of 1 mM DIDS (stilbene-disulfonic acid) in the renal tubule system, was evaluated. Urine fractions were collected after two-minutes stop-flow. Changes in the urine fraction (Fr) related to those in free-flow urine samples (Ff) were related to the respective polyfructosan (Inutest) ratio. Renal kallikrein activity (Fr:Ff kallikrein/Fr:Ff polyfructosan) increased significantly in the first 120 microliters urine fraction collected after glandular 1 microgram/ml kallikrein, P < 0.05, (first stop-flow) and after glandular 1 microgram/ml kallikrein plus 1 mM. DIDS P < 0.05 (second stop flow). Bicarbonate secretion rate (Fr:Ff HCO3-/Fr:Ff polyfructosan) of collecting ducts was significantly reduced in the first 120 microliters urine fraction collected, related to control, during the first and second stop-flow periods. No difference was shown in bicarbonate excretion between the first 120 microliters urine fractions collected after administration of glandular kallikrein and glandular kallikrein plus DIDS. To measure H(+)-ATPase activity, rat microdissected cortical collector tubules (CCD) were incubated in the presence of increasing glandular kallikrein doses (A: 93, B: 187 and C: 375 mU/200 microL) in the presence of ouabain (4 microM) and omeprazole (100 microM) to inhibit Na

  6. Clonidine and Cortical Plasticity: Possible Evidence for Noradrenergic Involvement.

    DTIC Science & Technology

    1984-10-31

    D 616 CLONIDINE AND CORTICAL PLASTICITY POSSIBLE EVIDENCE / FOR NORADRENERGIC IN..(U) BROWIN UNIV PROVIDENCE RICENTER FOR NEURAL SCIENCE S B NELSON...plasticity in kitten visual cortex, we monocularly deprived kittens while administering the at-2 adrenergic agonist clonidine (CLON). To avoid bias in...Distribution/ AvailabilitY Codes Avail and/or Dist Special I. S N 0102- LF. 014- 6601 SECuRITY CLASSIVrCATION OF TMIS PA*S St’e DOI@ MAIN Clonidine and Cortical

  7. Pre-stimulation of the kallikrein system in cisplatin-induced acute renal injury: An approach to renoprotection

    SciTech Connect

    Aburto, Andrés; Barría, Agustín; Cárdenas, Areli; Carpio, Daniel; Figueroa, Carlos D.; Burgos, Maria E.; Ardiles, Leopoldo

    2014-10-15

    Antineoplastic treatment with cisplatin is frequently complicated by nephrotoxicity. Although oxidative stress may be involved, the pathogenic mechanisms responsible for renal damage have not been completely clarified. In order to investigate the role of the renal kinin system in this condition, a group of rats was submitted to high potassium diet to stimulate the synthesis and excretion of tissue kallikrein 1 (rKLK1) previous to an intraperitoneal injection of 7 mg/kg cisplatin. A significant reduction in lipoperoxidation, evidenced by urinary excretion of malondialdehyde and renal immunostaining of hidroxy-nonenal, was accompanied by a decline in apoptosis. Coincident with these findings we observed a reduction in the expression of renal KIM-1 suggesting that renoprotection may be occurring. Stimulation or indemnity of the renal kinin system deserves to be evaluated as a complementary pharmacological measure to diminish cisplatin nephrotoxicity. - Highlights: • Mechanisms of cisplatin-induced-renal damage have not been completely clarified. • Cisplatin induces oxidative stress and apoptosis. • The renal kallikrein-kinin system is protective in experimental acute renal damage. • Kallikrein stimulation reduces oxidative stress and apoptosis induced by cisplatin. • Protection of the kallikrein-kinin system may reduce cisplatin toxicity.

  8. Evidence suggesting possible SCA1 gene involvement in schizophrenia

    SciTech Connect

    Diehl, S.R.; Wange, S.; Sun, C.

    1994-09-01

    Several findings suggest a possible role for the SCA1 gene on chromosome 6p in some cases of schizophrenia. First, linkage analyses in Irish pedigrees provided LOD scores up to 3.0 for one model tested using microsatellites closely linked to SCA1. Reanalysis of these data using affected sibpair methods yielded a significant result (p = 0.01) for one marker. An attempt to replicate this linkage finding was made using 44 NIMH families (206 individuals, 80 affected) and 12 Utah families (120 individuals, 49 affected). LOD scores were negative in these new families, even allowing for heterogeneity, as were results using affected sibpair methods. However, one Utah family provided a LOD score of 1.3. We also screened the SCA1 trinucleotide repeat to search for expansions characteristic of this disorder in these families and in 38 additional unrelated schizophrenics. We found 1 schizophrenic with 41 repeats, which is substantially larger than the maximum size of 36 repeats observed in previous studies of several hundred controls. We are now assessing whether the distribution of SCA1 repeats differs significantly in schizophrenia versus controls. Recent reports suggest possible anticipation in schizophrenia (also characteristic of SCA1) and a few cases of psychiatric symptoms suggesting schizophrenia have been observed in the highly related disorder DRPLA (SCA2), which is also based on trinucleotide repeat expansion. These findings suggest that further investigations of this gene and chromosome region may be a priority.

  9. Accumulation of α-synuclein in dementia with Lewy bodies is associated with decline in the α-synuclein-degrading enzymes kallikrein-6 and calpain-1.

    PubMed

    Miners, J Scott; Renfrew, Ruth; Swirski, Marta; Love, Seth

    2014-12-05

    Kallikrein-6 and calpain-1 are amongst a small group of proteases that degrade α-synuclein. We have explored the possibility that reduction in the level or activity of these enzymes contributes to the accumulation of α-synuclein in Lewy body diseases. We measured calpain-1 activity by fluorogenic activity assay, kallikrein-6 level by sandwich ELISA, and levels of α-synuclein and α-synuclein phosphorylated at serine 129 (α-synuclein-P129), in post-mortem brain tissue in pure dementia with Lewy bodies (DLB, n=12), Alzheimer's disease (AD, n=20) and age-matched controls (n=19). Calpain-1 activity was significantly reduced in DLB within the cingulate and parahippocampal cortex, regions with highest α-synuclein and α-synuclein-P129 load, and correlated inversely with the levels of α-synuclein and α-synuclein-P129. Calpain-1 was unaltered in the thalamus and frontal cortex, regions with less α-synuclein pathology. Kallikrein-6 level was reduced in the cingulate cortex in the DLB cohort, and correlated inversely with α-synuclein and α-synuclein-P129. Kallikrein-6 was also reduced in DLB in the thalamus but not in relation to α-synuclein or α-synuclein-P129 load and was unaltered in the frontal and parahippocampal cortex. In SH-SY5Y cells overexpressing wild-type α-synuclein there was partial co-localisation of kallikrein-6 and calpain-1 with α-synuclein, and siRNA-mediated knock-down of kallikrein-6 and calpain-1 increased the amount of α-synuclein in cell lysates. Our results indicate that reductions in kallikrein-6 and calpain-1 may contribute to the accumulation of α-synuclein in DLB.

  10. Various Possible Toxicants Involved in Thyroid Dysfunction: A Review

    PubMed Central

    Bajaj, Jagminder K.; Salwan, Poonam

    2016-01-01

    About 300 million people across the world suffer from thyroid gland dysfunction. Environmental factors play an important role in causation of autoimmune thyroid diseases in susceptible individuals. Genetics contributes to 70% of the risk. In order to reduce the risk, we need to understand the association of environmental agents with thyroid dysfunction. These factors are especially relevant for those at increased risk due to positive family history. The ideal study to see the impact of a thyroid toxicant consists of directly measuring the degree of exposure to toxicant in an individual with his thyroid status. Knowledge of various factors influencing thyroid dysfunction can help in interpreting the results of such studies in a better way. This article is an attempt to highlight the various possible toxicants affecting thyroid function so that adequate measures can be undertaken to control excessive exposure in future to reduce the prevalence of thyroid disorders. PMID:26894086

  11. Possible involvement of queuine in regulation of cell proliferation.

    PubMed

    Pathak, Chandramani; Jaiswal, Yogesh K; Vinayak, Manjula

    2007-01-01

    An increase in cell number is one of the most prominent characteristics of cancer cells. This may be caused by an increase in cell proliferation or decrease in cell death. Queuine is one of the modified base which is found at first anticodon position of specific tRNAs. It is ubiquitously present throughout the living system except mycoplasma and yeast. The tRNAs of Q-family are completely modified to Q-tRNAs in terminally differentiated somatic cells, however hypomodification of Q-tRNA is closely associated with cell proliferation and malignancy. Queuine participates at various cellular functions such as regulation of cell proliferation, cell signaling and alteration in the expression of growth associated proto-oncogenes. Like other proto-oncogenes bcl2 is known to involve in cell survival by inhibiting apoptosis. Queuine or Q-tRNA is suggested to inhibit cell proliferation but the mechanism of regulation of cell proliferation by queuine or Q-tRNA is not well understood. Therefore, in the present study regulation in cell proliferation by queuine in vivo and in vitro as well as the expression of cell death regulatory protein Bcl2 are investigated. For this DLAT cancerous mouse, U87 cell line and HepG2 cell line are treated with different concentrations of queuine and the effect of queuine on cell proliferation and apoptosis are studied. The results indicate that queuine down regulates cell proliferation and expression of Bcl2 protein, suggesting that queuine promotes cell death and participates in the regulation of cell proliferation.

  12. Possible involvement of ghrelin on pain threshold in obesity.

    PubMed

    Guneli, Ensari; Gumustekin, Mukaddes; Ates, Mehmet

    2010-03-01

    Pain threshold (or perception) can increase or decrease according to some factors like gender, depression or individual differences. Also, previous studies showed that pain threshold can change in obesity but, these studies on the effects of obesity on pain threshold have given controversial results. In the obese people who were exposed to pain stimulation to determined pain threshold, an increased pain threshold was observed. Contrarily, in the studies using electrophysiological test had lower pain threshold, which indicates a reverse correlation between degree of overweight and the threshold of the nociceptive reflex. These studies indicate possible interrelationships between the endogenous opioids, nociception and obesity or eating behavior. Nevertheless, its mechanism is still unclear. The endocrine changes that play an important role in obesity can lead an increase or decrease in pain threshold. There are a few researches about these hormonal factors which are related to pain pathways, that they are nociceptive (like leptin) or antinociceptive effect (like ghrelin, orexin A and B). Ghrelin is one of the hormones which is related to obesity. There are studies which prove the relationship between this hormone and the systems that play a role in pain modulation in the brain. However, there is no previous knowledge about the effects of ghrelin on pain threshold in obesity. But, many strong evidence are present to hypothesise that ghrelin may have effects on pain threshold. Obesity and fasting are the two main situations in which ghrelin secretion is mostly modified. Circulating ghrelin levels negatively correlate with BMI, meaning increased ghrelin secretion during fasting, malnutrition, cachexia, and in anorexia nervosa and reduced ghrelin secretion in obesity. Therefore, we have the opinion that ghrelin play an important role in obesity-pain relationship and/or regulate other systems that are related to pain pathway. Based on the above analyses, we propose a

  13. Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis.

    PubMed

    Banerji, Aleena; Busse, Paula; Shennak, Mustafa; Lumry, William; Davis-Lorton, Mark; Wedner, Henry J; Jacobs, Joshua; Baker, James; Bernstein, Jonathan A; Lockey, Richard; Li, H Henry; Craig, Timothy; Cicardi, Marco; Riedl, Marc; Al-Ghazawi, Ahmad; Soo, Carolyn; Iarrobino, Ryan; Sexton, Daniel J; TenHoor, Christopher; Kenniston, Jon A; Faucette, Ryan; Still, J Gordon; Kushner, Harvey; Mensah, Robert; Stevens, Chris; Biedenkapp, Joseph C; Chyung, Yung; Adelman, Burt

    2017-02-23

    Background Hereditary angioedema with C1 inhibitor deficiency is characterized by recurrent, unpredictable swelling episodes caused by uncontrolled plasma kallikrein generation and excessive bradykinin release resulting from cleavage of high-molecular-weight kininogen. Lanadelumab (DX-2930) is a new kallikrein inhibitor with the potential for prophylactic treatment of hereditary angioedema with C1 inhibitor deficiency. Methods We conducted a phase 1b, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients with hereditary angioedema with C1 inhibitor deficiency were randomly assigned in a 2:1 ratio to receive either lanadelumab (24 patients) or placebo (13 patients), in two administrations 14 days apart. Patients assigned to lanadelumab were enrolled in sequential dose groups: total dose of 30 mg (4 patients), 100 mg (4 patients), 300 mg (5 patients), or 400 mg (11 patients). The pharmacodynamic profile of lanadelumab was assessed by measurement of plasma levels of cleaved high-molecular-weight kininogen, and efficacy was assessed by the rate of attacks of angioedema during a prespecified period (day 8 to day 50) in the 300-mg and 400-mg groups as compared with the placebo group. Results No discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All

  14. The kallikrein-kinin system in diabetic nephropathy

    PubMed Central

    Tomita, Hirofumi; Sanford, Ryan B.; Smithies, Oliver; Kakoki, Masao

    2012-01-01

    Diabetic nephropathy is the major cause of end-stage renal disease worldwide. Although the renin-angiotensin system has been implicated in the pathogenesis of diabetic nephropathy, angiotensin I-converting enzyme (ACE) inhibitors have a beneficial effect on diabetic nephropathy independently of their effects on blood pressure and plasma angiotensin II levels. This suggests that the kallikrein-kinin system (KKS) is also involved in the disease. To study the role of the KKS in diabetic nephropathy, mice lacking either the bradykinin B1 receptor (B1R) or the bradykinin B2 receptor (B2R) have been commonly used. However, because absence of either receptor causes enhanced expression of the other, it is difficult to determine the precise functions of each receptor. This difficulty has recently been overcome by comparing mice lacking both receptors with mice lacking each receptor. Deletion of both B1R and B2R reduces nitric oxide (NO) production and aggravates renal diabetic phenotypes, relevant to either lack of B1R or B2R, demonstrating that both B1R and B2R exert protective effects on diabetic nephropathy presumably via NO. Here, we review previous epidemiological and experimental studies, and discuss novel insights regarding the therapeutic implications of the importance of the KKS in averting diabetic nephropathy. PMID:22318421

  15. Urinary kallikrein activity of workers exposed to lead.

    PubMed Central

    Boscolo, P; Porcelli, G; Cecchetti, G; Salimei, E; Iannaccone, A

    1978-01-01

    Two groups of men of different age ranges and with the same period of lead exposure were selected for study in a recently opened car-battery factory. Two other groups of age-matched men, not exposed to heavy metals in their work, were used as controls. Morning urines were collected from control and exposed groups for determination of urinary kallikrein activity, urinary delta-amino-levulinic acid (ALA) and lead levels. The environmental lead levels and the urinary ALA and lead values indicated that exposure in the factory was not heavy. The older group of lead-exposed workers showed greatly reduced urinary kallikrein activity compared with that of the age-matched controls. In contrast, the younger group did not show any significant alteration in urinary kallikrein excretion. PMID:698136

  16. Tissue kallikrein activation of the epithelial Na channel

    PubMed Central

    Patel, Ankit B.; Chao, Julie

    2012-01-01

    Epithelial Na Channels (ENaC) are responsible for the apical entry of Na+ in a number of different epithelia including the renal connecting tubule and cortical collecting duct. Proteolytic cleavage of γ-ENaC by serine proteases, including trypsin, furin, elastase, and prostasin, has been shown to increase channel activity. Here, we investigate the ability of another serine protease, tissue kallikrein, to regulate ENaC. We show that excretion of tissue kallikrein, which is secreted into the lumen of the connecting tubule, is stimulated following 5 days of a high-K+ or low-Na+ diet in rats. Urinary proteins reconstituted in a low-Na buffer activated amiloride-sensitive currents (INa) in ENaC-expressing oocytes, suggesting an endogenous urinary protease can activate ENaC. We next tested whether tissue kallikrein can directly cleave and activate ENaC. When rat ENaC-expressing oocytes were exposed to purified tissue kallikrein from rat urine (RTK), ENaC currents increased threefold in both the presence and absence of a soybean trypsin inhibitor (SBTI). RTK and trypsin both decreased the apparent molecular mass of cleaved cell-surface γ-ENaC, while immunodepleted RTK produced no shift in apparent molecular mass, demonstrating the specificity of the tissue kallikrein. A decreased effect of RTK on Xenopus ENaC, which has variations in the putative prostasin cleavage sites in γ-ENaC, suggests these sites are important in RTK activation of ENaC. Mutating the prostasin site in mouse γ-ENaC (γRKRK186QQQQ) abolished ENaC activation and cleavage by RTK while wild-type mouse ENaC was activated and cleaved similar to that of the rat. We conclude that tissue kallikrein can be a physiologically relevant regulator of ENaC activity. PMID:22622459

  17. Human plasma kallikrein-kinin system: Physiological and biochemical parameters

    PubMed Central

    Bryant, J.W.; Shariat-Madar, z

    2016-01-01

    The plasma kallikrein-kinin system (KKS) plays a critical role in human physiology. The KKS encompasses coagulation factor XII (FXII), the complex of prekallikrein (PK) and high molecular weight kininogen (HK). The conversion of plasma to kallikrein by the activated FXII and in response to numerous different stimuli leads to the generation of bradykinin (BK) and activated HK (HKa, an antiangiogenic peptide). BK is a proinflammatory peptide, a pain mediator and potent vasodilator, leading to robust accumulation of fluid in the interstitium. Systemic production of BK, HKa with the interplay between BK bound-BK receptors and the soluble form of HKa are key to angiogenesis and hemodynamics. KKS has been implicated in the pathogenesis of inflammation, hypertension, endotoxemia, and coagulopathy. In all these cases increased BK levels is the hallmark. In some cases, the persistent production of BK due to the deficiency of the blood protein C1-inhibitor, which controls FXII, is detrimental to the survival of the patients with hereditary angioedema (HAE). In others, the inability of angiotensin converting enzyme (ACE) to degrade BK leads to elevated BK levels and edema in patients on ACE inhibitors. Thus, the mechanisms that interfere with BK liberation or degradation would lead to blood pressure dysfunction. In contrast, anti-kallikrein treatment could have adverse effects in hemodynamic changes induced by vasoconstrictor agents. Genetic models of kallikrein deficiency are needed to evaluate the quantitative role of kallikrein and to validate whether strategies designed to activate or inhibit kallikrein may be important for regulating whole-body BK sensitivity. PMID:19689262

  18. Nucleotide sequence of cloned cDNA for human pancreatic kallikrein.

    PubMed

    Fukushima, D; Kitamura, N; Nakanishi, S

    1985-12-31

    Cloned cDNA sequences for human pancreatic kallikrein have been isolated and determined by molecular cloning and sequence analysis. The identity between human pancreatic and urinary kallikreins is indicated by the complete coincidence between the amino acid sequence deduced from the cloned cDNA sequence and that reported partially for urinary kallikrein. The active enzyme form of the human pancreatic kallikrein consists of 238 amino acids and is preceded by a signal peptide and a profragment of 24 amino acids. A sequence comparison of this with other mammalian kallikreins indicates that key amino acid residues required for both serine protease activity and kallikrein-like cleavage specificity are retained in the human sequence, and residues corresponding to some external loops of the kallikrein diverge from other kallikreins. Analyses by RNA blot hybridization, primer extension, and S1 nuclease mapping indicate that the pancreatic kallikrein mRNA is also expressed in the kidney and sublingual gland, suggesting the active synthesis of urinary kallikrein in these tissues. Furthermore, the tissue-specific regulation of the expression of the members of the human kallikrein gene family has been discussed.

  19. Structural studies of human urinary kallikrein (urokallikrein).

    PubMed

    ole-MoiYoi, O K; Spragg, J; Austen, K F

    1979-07-01

    Human urinary kallikrein (urokallikrein) has been purified by affinity chromatography with aprotinin coupled to CH-Sepharose and by gel filtration. The isolation procedure, which was performed under mild conditions, was completed in a 36-hr period and yielded an overall recovery of more than 75% and a purification of 1727-fold. Homogeneity of the urokallikrein was demonstrated by three criteria: the coincidence of the stained protein band and functional urokallikrein in duplicate gels after alkaline disc gel electrophoresis; the appearance of a single stained band of molecular weight 48,000 on sodium dodecyl sulfate/polyacrylamide gel electrophoresis of reduced and unreduced enzyme; and the finding of a single amino-terminal residue, namely alanine after dansylation and acid hydrolysis of purified enzyme. The Km of urokallikrein on N alpha-p-tosyl-L-arginine methyl ester was 400 microM, and the Vmax was 194 mumol/min per mg of protein, which is higher than that observed with any previous preparations. The molecular weight of 48,700 determined on gel filtration and the molecular weight of 48,000 observed by sodium dodecyl sulfate/polyacrylamide gel electrophoresis are in good agreement with the molecular weight of 48,213 calculated from the amino acid composition. The finding of a molecular weight higher than those previously reported, namely 27,000-43,500, the increased functional activity on tosylarginine methyl ester, and the detection of a single amino-terminal residue are consistent with the isolation of a more native protein by the procedure described in this paper.

  20. The Kallikrein Inhibitor from Bauhinia bauhinioides (BbKI) shows antithrombotic properties in venous and arterial thrombosis models.

    PubMed

    Brito, Marlon V; de Oliveira, Cleide; Salu, Bruno R; Andrade, Sonia A; Malloy, Paula M D; Sato, Ana C; Vicente, Cristina P; Sampaio, Misako U; Maffei, Francisco H A; Oliva, Maria Luiza V

    2014-05-01

    The Bauhinia bauhinioides Kallikrein Inhibitor (BbKI) is a Kunitz-type serine peptidase inhibitor of plant origin that has been shown to impair the viability of some tumor cells and to feature a potent inhibitory activity against human and rat plasma kallikrein (Kiapp 2.4 nmol/L and 5.2 nmol/L, respectively). This inhibitory activity is possibly responsible for an effect on hemostasis by prolonging activated partial thromboplastin time (aPTT). Because the association between cancer and thrombosis is well established, we evaluated the possible antithrombotic activity of this protein in venous and arterial thrombosis models. Vein thrombosis was studied in the vena cava ligature model in Wistar rats, and arterial thrombosis in the photochemical induced endothelium lesion model in the carotid artery of C57 black 6 mice. BbKI at a concentration of 2.0 mg/kg reduced the venous thrombus weight by 65% in treated rats in comparison to rats in the control group. The inhibitor prolonged the time for total artery occlusion in the carotid artery model mice indicating that this potent plasma kallikrein inhibitor prevented thrombosis.

  1. Critical Role for PAR1 in Kallikrein 6-Mediated Oligodendrogliopathy

    PubMed Central

    Burda, Joshua E.; Radulovic, Maja; Yoon, Hyesook; Scarisbrick, Isobel A.

    2014-01-01

    Kallikrein 6 (Klk6) is a secreted serine protease preferentially expressed by oligodendroglia in CNS white matter. Elevated levels of Klk6 occur in actively demyelinating multiple sclerosis (MS) lesions and in cases of spinal cord injury (SCI), stroke and glioblastoma. Taken with recent evidence establishing Klk6 as a CNS-endogenous activator of protease-activated receptors (PARs), we hypothesized that Klk6 activates a subset of PARs to regulate oligodendrocyte physiology and potentially pathophysiology. Here, primary oligodendrocyte cultures derived from wild type or PAR1-deficient mice and the murine oligodendrocyte cell line, Oli-neu, were used to demonstrate that Klk6 mediates loss of oligodendrocyte processes and impedes morphological differentiation of oligodendrocyte progenitor cells (OPCs) in a PAR1-dependent fashion. Comparable gliopathy was also elicited by the canonical PAR1 agonist, thrombin, as well as PAR1-activating peptides (PAR1-APs). Klk6 also exacerbated ATP-mediated oligodendrogliopathy in vitro, pointing to a potential role in augmenting excitotoxicity. In addition, Klk6 suppressed the expression of proteolipid protein (PLP) RNA in cultured oligodendrocytes by a mechanism involving PAR1-mediated Erk1/2 signaling. Microinjection of PAR1 agonists, including Klk6 or PAR1-APs, into the dorsal column white matter of PAR+/+ but not PAR−/− mice promoted vacuolating myelopathy and a loss of immunoreactivity for myelin basic protein (MBP) and CC-1+ oligodendrocytes. These results demonstrate a functional role for Klk6-PAR1 signaling in oligodendroglial pathophysiology and suggest that PAR1 or PAR1-agonists may represent new targets to moderate demyelination and to promote myelin regeneration in cases of CNS white matter injury or disease. PMID:23832758

  2. Immunoreactive glandular kallikrein in rat plasma: a radioimmunoassay for its determination

    SciTech Connect

    Rabito, S.F.; Scicli, A.G.; Kher, V.; Carretero, O.A.

    1982-04-01

    A radioimmunoassay (RIA) has been developed to measure immunoreactive glandular kallikrein in rat plasma. To prevent the binding of radioactive kallikrein to plasma inhibitors, /sup 125/I-kallikrein was inactivated with phenylmethylsulfonyl fluoride (PMSF), a procedure that maintained /sup 125/I-kallikrein immunoreactivity. Different volumes of plasma displaced /sup 125/I-PMSF-kallikrein in a parallel fashion to the kallikrein standard curve. The sensitivity of the RIA was 200 pg, and the recovery of nonradioactive active kallikrein added to plasma was 58.7%. The concentration of immunoreactive glandular kallikrein in normal rat plasma averaged 47.1 +/- 1.7 (SE) ng/ml. Bilateral nephrectomy caused a threefold increase in circulating glandular kallikrein (50 +/- 2.7 to 167 +/- 7 ng/ml; P < 0.001). Removal of the submandibular and sublingual glands signficantly decreased its concentration from 52 +/- 2.3 to 34 +/- 1.6 ng/ml (P < 0.001). Immunoreactive glandular kallikrein was higher in the submandibular gland vein than in arterial blood (venous; 94 +/- 10.5; arterial: 64 +/- 6.3 ng/ml; P < 0.05) and was lower in the renal venous blood (venous: 44 +/- 2.2; arterial: 53 +/- 2.6 ng/ml; P < 0.05). In conclusion, this study shows that the use of /sup 125/I-PMSF-kallikrein as tracer prevents the interference in the RIA caused by plasma protease inhibitors. It also indicates that the submandibular gland is an important source of the immunoreactive glandular kallikrein in rat plasma and that the kidney probably participates in its metabolism. Glandular kallikrein released by the submandibular gland into the circulation may participate in regulating local blood flow before it is inactivated by plasma inhibitors.

  3. A role for plasma kallikrein-kinin system activation in the synovial recruitment of endothelial progenitor cells in arthritis

    PubMed Central

    Dai, Jihong; Agelan, Alexis; Yang, Aizhen; Zuluaga, Viviana; Sexton, Daniel; Colman, Robert W.; Wu, Yi

    2012-01-01

    Objective To examine whether the activation of plasma kallikrein-kinin system (KKS) mediates synovial recruitment of endothelial progenitor cells (EPCs) in arthritis. Methods EPCs were isolated from Lewis rat bone marrow and characterized by the expression of progenitor cell lineage markers and functional property. EPCs were intravenously injected into Lewis rats bearing arthritis, their recruitment and formation of de novo blood vessels in inflamed synovium were evaluated. The role of plasma KKS was examined using a plasma kallikrein inhibitor EPI-KAL2 and an anti-kallikrein antibody 13G11. Transendothelial migration (TEM) assay was used to determine the role of bradykinin and its receptor in EPC mobilization. Results Lewis rat EPCs exhibited strong capacities to form tubes and vacuoles, and expressed higher level of bradykinin type 2 receptor (B2R) and progenitor cell markers CD34 and Sca-1. In Lewis rats bearing arthritis, EPCs were recruited into inflamed synovium at acute phase and formed de novo blood vessels. Inhibition of plasma kallikrein by EPI-KAL2 and 13G11 significantly suppressed synovial recruitment of EPCs and hyperproliferation of synovial cells. Bradykinin concentration-dependently stimulated TEM of EPCs, which was mediated by B2R, as the knockdown of B2R by silencing RNA completely blocked bradykinin-stimulated TEM. Moreover, bradykinin selectively upregulated the expression of homing receptor C-X-C chemokine receptor type 4 (CXCR-4) in EPCs. Conclusion These observations demonstrate a novel role for plasma KKS activation in the synovial recruitment of EPCs in arthritis, acting via kallirein activation and B2R-dependent mechanisms. B2R might be involved in the mobilization of EPCs via upregulation of CXCR-4. PMID:22739815

  4. Induction of salivary kallikreins by the diet containing a sweet-suppressive peptide, gurmarin, in the rat.

    PubMed

    Yamada, Ayako; Nakamura, Yuki; Sugita, Daigo; Shirosaki, Shinya; Ohkuri, Tadahiro; Katsukawa, Hideo; Nonaka, Kazuaki; Imoto, Toshiaki; Ninomiya, Yuzo

    2006-07-28

    Gymnema sylvestre (gymnema) contains gurmarin that selectively inhibits responses to sweet substances in rodents. The present study investigated possible interaction between gurmarin and the submandibular saliva in rats fed diet containing gymnema. Electrophoretic analyses demonstrated that relative amounts of two proteins in the saliva clearly increased in rats fed the gymnema diet. However, rats previously given section of the bilateral glossopharyngeal nerve showed no such salivary protein induction. Analyses of amino acid sequence indicate that two proteins are rat kallikrein 2 (rK2) and rat kallikrein 9 (rK9). rK2 and rK9, a family of serine proteases, have a striking resemblance of cleavage site in the protein substrates. Interestingly, gurmarin possesses comparable residues with those rK2 and rK9 prefer. The kallikreins significantly inhibited immunoreaction between gurmarin and antigurmarin antiserum. These results suggest that rK2 and rK9 increased by chemosensory information for the gymnema diet via the glossopharyngeal nerve might cleave gurmarin or at least cause specific binding with it.

  5. Human kallikrein 6 activity is regulated via an autoproteolytic mechanism of activation/inactivation.

    PubMed

    Bayés, Alex; Tsetsenis, Theodoros; Ventura, Salvador; Vendrell, Josep; Aviles, Francesc X; Sotiropoulou, Georgia

    2004-06-01

    Human kallikrein 6 (protease M/zyme/neurosin) is a serine protease that has been suggested to be a serum biomarker for ovarian cancer and may also be involved in pathologies of the CNS. The precursor form of human kallikrein 6 (pro-hK6) was overexpressed in Pichia pastoris and found to be autoprocessed to an active but unstable mature enzyme that subsequently yielded the inactive, self-cleavage product, hK6 (D81-K244). Site-directed mutagenesis was used to investigate the basis for the intrinsic catalytic activity and the activation mechanism of pro-hK6. A single substitution R80 --> Q stabilized the activity of the mature enzyme, while substitution of the active site serine (S197 --> A) resulted in complete loss of hK6 proteolytic activity and facilitated protein production. Our data suggest that the enzymatic activity of hK6 is regulated by an autoactivation/autoinactivation mechanism. Mature hK6 displayed a trypsin-like activity against synthetic substrates and human plasminogen was identified as a putative physiological substrate for hK6, as specific cleavage at the plasminogen internal bond S460-V461 resulted in the generation of angiostatin, an endogenous inhibitor of angiogenesis and metastatic growth.

  6. Kinins produced from bovine colostrum by kallikrein and saliva

    PubMed Central

    Guth, Paul S.

    1959-01-01

    Substances capable of stimulating smooth muscle are produced on the incubation of bovine colostrum with urinary kallikrein or calf saliva. These substances, called urine- and saliva-colostrokinin, have been differentiated from kallidin, substance A and similar smooth muscle activating agents. Saliva-colostrokinin is likely to be formed in the suckling calf. Further, as colostrum became milk, the ability to form colostrokinin diminished. A function for saliva-colostrokinin in the newborn is suggested. PMID:13830444

  7. Human kallikrein 5: a potential novel serum biomarker for breast and ovarian cancer.

    PubMed

    Yousef, George M; Polymeris, Mary-Ellen; Grass, Linda; Soosaipillai, Antoninus; Chan, Pak-Cheung; Scorilas, Andreas; Borgoño, Carla; Harbeck, Nadia; Schmalfeldt, Barbara; Dorn, Julia; Schmitt, Manfred; Diamandis, Eleftherios P

    2003-07-15

    The kallikrein family is a group of 15 serine protease genes clustered on chromosome 19q13.4. Human kallikrein (hK) gene 5 (KLK5) is a member of this family and encodes for a secreted serine protease (hK5). KLK5 was shown to be differentially expressed at the mRNA level in breast and ovarian cancer. Until now, detection of hK5 protein in either biological fluids or tissues has not been described due to lack of suitable reagents and methods. The aim of this study was to develop immunological reagents and a sensitive and specific fluorometric immunoassay (ELISA) for hK5, to examine the presence of hK5 in human tissues and biological fluids, and to study the possible clinical utility of hK5 as a biomarker for endocrine-related malignancies. Recombinant hK5 protein was produced and purified using a Pichia pastoris yeast expression system. The protein was used as an immunogen to generate mouse and rabbit polyclonal anti-hK5 antibodies. A sandwich-type microplate immunoassay (ELISA) was developed using these antibodies, coupled with a time-resolved fluorometric detection technique. The ELISA assay was then used to measure hK5 in various biological fluids, tissue extracts, and serum samples from normal individuals and patients with various malignancies. The hK5 ELISA immunoassay has a lower detection limit of 0.1 micro g/liter, is specific for hK5, and has no cross-reactivity with other homologous kallikreins. The dynamic range is 0.1-25 micro g/liter, and within-run and between-run coefficients of variation within this range are <10%. hK5 is found in many tissues, with the highest expression levels seen in the skin, breast, salivary gland, and esophagus. hK5 is present at relatively high levels in milk of lactating women. Whereas the levels of hK5 are almost undetectable in serum of normal individuals (male and female) and patients with diverse malignancies, higher concentrations were found in a proportion of patients with ovarian (69%) and breast (49%) cancer. High

  8. Functional stability and structural transitions of Kallikrein: spectroscopic and molecular dynamics studies.

    PubMed

    Dalal, Sayli; Mhashal, Anil; Kadoo, Narendra; Gaikwad, Sushama M

    2017-02-01

    Kallikrein, a physiologically vital serine protease, was investigated for its functional and conformational transitions during chemical (organic solvents, Gdn-HCl), thermal, and pH induced denaturation using biochemical and biophysical techniques and molecular dynamics (MD) simulations approach. The enzyme was exceptionally stable in isopropanol and ethanol showing 110% and 75% activity, respectively, after 96 h, showed moderate tolerance in acetonitrile (45% activity after 72 h) and much lower stability in methanol (40% activity after 24 h) (all the solvents [90% v/v]). Far UV CD and fluorescence spectra indicated apparent reduction in compactness of KLKp structure in isopropanol system. MD simulation studies of the enzyme in isopropanol revealed (1) minimal deviation of the structure from native state (2) marginal increase in radius of gyration and solvent accessible surface area (SASA) of the protein and the active site, and (3) loss of density barrier at the active site possibly leading to increased accessibility of substrate to catalytic triad as compared to methanol and acetonitrile. Although kallikrein was structurally stable up to 90 °C as indicated by secondary structure monitoring, it was functionally stable only up to 45 °C, implicating thermolabile active site geometry. In GdnHCl [1.0 M], 75% of the activity of KLKp was retained after incubation for 4 h, indicating its denaturant tolerance. A molten globule-like structure of KLKp formed at pH 1.0 was more thermostable and exhibited interesting structural transitions in organic solvents. The above results provide deeper understanding of functional and structural stability of the serine proteases at molecular level.

  9. The possible involvement of NMDA glutamate receptor in the etiopathogenesis of bipolar disorder.

    PubMed

    Fountoulakis, Konstantinos N

    2012-01-01

    Glutamate is the most abundant excitatory neurotransmitter in the brain and the ionotropic NMDA receptor is one of the major classes of its receptors, thought to play an important role in schizophrenia and mood disorders. The current systematic review summarized the evidence concerning the involvement of NMDA receptors in the pathophysiology of bipolar disorder. Genetic studies point to the genes encoding the NMDA 1, 2A and 2B subunits while neuropathological studies suggest a possible region specific decrease in the density of NMDA receptor and more consistently a reduced NMDA-mediated glutamatergic activity in patients with bipolar disorder in the frame of slower NMDA kinetics because of lower contribution of NR2A subunits. However the literature is poor and incomplete; future research is necessary to elucidate the mechanisms underlying bipolar disorder and its specific relationship to a possible NMDA malfunction and to explore the possibility of developing novel therapeutic agents.

  10. Possible involvement of infection with human coronavirus 229E, but not NL63, in Kawasaki disease.

    PubMed

    Shirato, Kazuya; Imada, Yoshio; Kawase, Miyuki; Nakagaki, Keiko; Matsuyama, Shutoku; Taguchi, Fumihiro

    2014-12-01

    Although human coronavirus (HCoV)-NL63 was once considered a possible causative agent of Kawasaki disease based on RT-PCR analyses, subsequent studies could not confirm the result. In this study, this possibility was explored using serological tests. To evaluate the role of HCoV infection in patients with Kawasaki disease, immunofluorescence assays and virus neutralizing tests were performed. Paired serum samples were obtained from patients with Kawasaki disease who had not been treated with γ-globulin. HCoV-NL63 and two antigenically different isolates of HCoV-229E (ATCC-VR740 and a new isolate, Sendai-H) were examined as controls. Immunofluorescence assays detected no difference in HCoV-NL63 antibody positivity between the patients with Kawasaki disease and controls, whereas the rate of HCoV-229E antibody positivity was higher in the patients with Kawasaki disease than that in controls. The neutralizing tests revealed no difference in seropositivity between the acute and recovery phases of patients with Kawasaki disease for the two HCoV-229Es. However, the Kawasaki disease specimens obtained from patients in recovery phase displayed significantly higher positivity for Sendai-H, but not for ATCC-VR740, as compared to the controls. The serological test supported no involvement of HCoV-NL63 but suggested the possible involvement of HCoV-229E in the development of Kawasaki disease.

  11. Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?

    PubMed Central

    Basha, Basma; Samuel, Samson Mathews; Triggle, Chris R.; Ding, Hong

    2012-01-01

    The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications. PMID:22474423

  12. Endothelial dysfunction in diabetes mellitus: possible involvement of endoplasmic reticulum stress?

    PubMed

    Basha, Basma; Samuel, Samson Mathews; Triggle, Chris R; Ding, Hong

    2012-01-01

    The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications.

  13. Possible Involvement of Photoperiodic Regulation in Reproductive Endocrine System of Female Olive Flounder Paralichthys olivaceus

    PubMed Central

    Kim, Hyun Chul; Lee, Chi Hoon; Hur, Sung Pyu; Kim, Byeong Hoon; Park, Jun Young; Lee, Young Don

    2015-01-01

    This study investigated possible involvement of photoperiodic regulation in reproductive endocrine system of female olive flounder. To investigate the influence on brain-pituitary axis in endocrine system by regulating photoperiod, compared expression level of Kisspeptin and sbGnRH mRNA in brain and FSH-β, LH-β and GH mRNA in pituitary before and after spawning. Photoperiod was treated natural photoperiod and long photoperiod (15L:9D) conditions from Aug. 2013 to Jun. 2014. Continuous long photoperiod treatment from Aug. (post-spawning phase) was inhibited gonadal development of female olive flounder. In natural photoperiod group, the Kiss2 expression level a significant declined in Mar. (spawning period). And also, FSH-β, LH-β and GH mRNA expression levels were increasing at this period. However, in long photoperiod group, hypothalamic Kiss2, FSH-β, LH-β and GH mRNA expression levels did not show any significant fluctuation. These results suggest that expression of hypothalamic Kiss2, GtH and GH in the pituitary would change in response to photoperiod and their possible involvement of photoperiodic regulation in reproductive endocrine system of the BPG axis. PMID:25949205

  14. Possible Involvement of Photoperiodic Regulation in Reproductive Endocrine System of Female Olive Flounder Paralichthys olivaceus.

    PubMed

    Kim, Hyun Chul; Lee, Chi Hoon; Hur, Sung Pyu; Kim, Byeong Hoon; Park, Jun Young; Lee, Young Don

    2015-03-01

    This study investigated possible involvement of photoperiodic regulation in reproductive endocrine system of female olive flounder. To investigate the influence on brain-pituitary axis in endocrine system by regulating photoperiod, compared expression level of Kisspeptin and sbGnRH mRNA in brain and FSH-β, LH-β and GH mRNA in pituitary before and after spawning. Photoperiod was treated natural photoperiod and long photoperiod (15L:9D) conditions from Aug. 2013 to Jun. 2014. Continuous long photoperiod treatment from Aug. (post-spawning phase) was inhibited gonadal development of female olive flounder. In natural photoperiod group, the Kiss2 expression level a significant declined in Mar. (spawning period). And also, FSH-β, LH-β and GH mRNA expression levels were increasing at this period. However, in long photoperiod group, hypothalamic Kiss2, FSH-β, LH-β and GH mRNA expression levels did not show any significant fluctuation. These results suggest that expression of hypothalamic Kiss2, GtH and GH in the pituitary would change in response to photoperiod and their possible involvement of photoperiodic regulation in reproductive endocrine system of the BPG axis.

  15. Contribution of the Kallikrein/Kinin System to the Mediation of ConA-Induced Inflammatory Ascites.

    PubMed

    Baintner, Károly

    2016-03-01

    Intraperitoneal administration of concanavalin A (ConA, 25 mg/kg b.w.), a cell-binding plant lectin was used for inducing inflammatory ascites, and potential inhibitors were tested in 1 h and 2.5 h experiments, i.e. still before the major influx of leucocytes. At the end of the experiment the peritoneal fluid was collected and measured. The ConA-induced ascites was significantly (p<0.01) and dose-dependently inhibited by icatibant (HOE-140), a synthetic polypeptide antagonist of bradykinin receptors. Aprotinin, a kallikrein inhibitor protein also had significant (p<0.01), but less marked inhibitory effect. L-NAME, an inhibitor of NO synthesis, and atropine methylnitrate, an anticholinergic compound, were ineffective. It is concluded, that the kallikrein/kinin system contributes to the mediation of the ConA-induced ascites by increasing subperitoneal vascular permeability, independent of the eventual vasodilation produced by NO. It is known, that membrane glycoproteins are aggregated by the tetravalent ConA and the resulting distortion of membrane structure may explain the activation of the labile prekallikrein. Complete inhibition of the ConA-induced ascites could not be achieved by aprotinin or icatibant, which indicates the involvement of additional mediators.

  16. Kallikrein and Renin in the Membrane Fractions of the Rat Kidney.

    DTIC Science & Technology

    1980-05-23

    and Renin _____ ___ i.;? - 2 SUMMARY Plasma membrane (P-H) and endoplasmic reticulum (ER) enriched fractions were isolated from the homogenized rat...The inhibitor of proteases, p-methylsulfonylfluoride inhibited 77-80% all kallikrein preparations at 3 w*1 concentration . Activation of renin Renin ...fold although only at a concentration 5-10 times higher than used with kallikrein. The relative rate of activation of renin in the ER fraction was

  17. Melatonin in humans: Possible involvement in SIDS, and use in contraceptives

    NASA Technical Reports Server (NTRS)

    Wurtman, Richard J.; Lynch, Harry J.; Sturner, William Q.

    1991-01-01

    Relatively few tools exist for assessing the possible involvement of melatonin in normal or abnormal physiologlcal and behavioral states. One cannot perform the classic ablation experiment of endocrinologists by cavalierly removing the human's pineal, nor derive the same effect pharmacologically by administering a drug which blocks the actions of the indole on its receptors (because no such drugs, demonstrated to work in humans, exist). About all that can be done is to administer the melatonin and see what happens, or measure its levels in a body fluid and determine whether its temporal patterns track those of the physiological or behavioral variable being examined. The clinical state of Sudden Infant Death Syndrome (SIDS) which apparently is associated with abnormalities in melatonin concentrations within body fluids obtained at autopsy is described. New data which suggest that exogenous melatonin has sufficient antigonadal potency to allow it to replace estrogen and, acting in combination with norethisterone, serve as a useful contraceptive agent is summarized.

  18. The Possible Mechanisms Involved in Degradation of Patulin by Pichia caribbica

    PubMed Central

    Zheng, Xiangfeng; Yang, Qiya; Zhang, Hongyin; Cao, Jing; Zhang, Xiaoyun; Apaliya, Maurice Tibiru

    2016-01-01

    In this work, we examined the mechanisms involved in the degradation of patulin by Pichia caribbica. Our results indicate that cell-free filtrate of P. caribbica reduced patutlin content. The heat-killed cells could not degrade patulin. However, the live cells significantly reduced the concentration of the patulin. In furtherance to this, it was observed that patulin was not detected in the broken yeast cells and cell wall. The addition of cycloheximide to the P. caribbica cells decreased the capacity of degradation of patulin. Proteomics analyses revealed that patulin treatment resulted in an upregulated protein which was involved in metabolism and stress response processes. Our results suggested that the mechanism of degradation of patulin by P. caribbica was not absorption; the presence of patulin can induce P. caribbica to produce associated intracellular and extracellular enzymes, both of which have the ability to degrade patulin. The result provides a new possible method that used the enzymes produced by yeast to detoxify patulin in food and feed. PMID:27735830

  19. Cholecystokinin impact on rainbow trout glucose homeostasis: possible involvement of central glucosensors.

    PubMed

    Polakof, Sergio; Míguez, Jesus M; Soengas, José L

    2011-12-10

    Although the role of cholecystokinin (CCK) on fish appetite regulation has been widely studied, its involvement in the regulation of glucose metabolism had been little explored to date. In the present study we have carried out different experimental approaches to study CCK effects in rainbow trout (a so-called 'glucose intolerant' fish species) glucose homeostasis. We have found that for the first time in a vertebrate species, systemic or central CCK administration causes hyperglycemia, which is at least in part related to the presence of an ancestral gut-brain axis in which CCK is involved. By using capsaicin we have found that part of the action of CCK on glucose homeostasis is mediated by vagal and splanchnic afferents. Changes in hepatic metabolism after systemic CCK administration suggest that the effects are not directly taking place on the liver, but probably in other tissues, while after the central CCK administration, the glycogenolytic response observed in liver could be mediated by the activation of the sympathetic system. In hypothalamus and hindbrain changes elicited by CCK-8 treatment are likely related to the glucosensor response to the increased glycemia and/or vagal/splanchnic afferences whereas in hindbrain a possible action through specific CCK-1 receptors cannot be excluded. All these processes result in changes in metabolic parameters related with glucose homeostasis control. Further studies are needed to fully understand the role of this peptide on glucose homeostasis control in fish.

  20. Neurotoxicity of endocrine disruptors: possible involvement in brain development and neurodegeneration.

    PubMed

    Masuo, Yoshinori; Ishido, Masami

    2011-01-01

    Environmental chemicals that act as endocrine disruptors do not appear to pose a risk to human reproduction; however, their effects on the central nervous systems are less well understood. Animal studies suggested that maternal exposure to endocrine-disrupting chemicals (EDC) produced changes in rearing behavior, locomotion, anxiety, and learning/memory in offspring, as well as neuronal abnormalities. Some investigations suggested that EDC exert effects on central monoaminergic neurons, especially dopaminergic neurons. Our data demonstrated that EDC attenuate the development of dopaminergic neurons, which might be involved in developmental disorders. Perinatal exposure to EDC might affect neuronal plasticity in the hippocampus, thereby potentially modulating neuronal development, leading to impaired cognitive and memory functions. Endocrine disruptors also attenuate gender differences in brain development. For example, the locus ceruleus is larger in female rats than in males, but treatments with bisphenol-A (BPA) enlarge this region in males. Some reports indicated that EDC induce hypothyroidism, which might be evidenced as abnormal brain development. Endocrine disruptors might also affect mature neurons, resulting in neurodegenerative disorders such as Parkinson's disease. The current review focused on alterations in the brain induced by EDC, specifically on the possible involvement of EDC in brain development and neurodegeneration.

  1. Involvement of Renin-Angiotensin System in Retinopathy of Prematurity - A Possible Target for Therapeutic Intervention

    PubMed Central

    Nath, Madhu; Chandra, Parijat; Halder, Nabanita; Singh, Baskar; Deorari, Ashok Kumar; Kumar, Atul; Azad, Rajvardhan; Velpandian, Thirumurthy

    2016-01-01

    Objective Examining the Retinal Renin Angiotensin System (RRAS) in the ROP neonates and analyzing the possibility of modulating the RRAS to prevent the progression in Oxygen Induced Retinopathy (OIR) model. Method Vitreous of ROP patients (n = 44, median age 5.5 months) was quantified for RRAS components, VEGF, HIF-1α and compared with age matched control. The involvement of RRAS in ROP was tested in the rat model of OIR and compared with normoxia. Expressions of RAS components, VEGF and HIF-1α in retina were analyzed using qPCR and retinal structure and function was also analyzed. Effect of Angiotensin Converting Enzyme Inhibitor (ACEI) and Angiotensin Receptor Blocker (ARB) was evaluated and compared with Bevacizumab which served as a positive control. Drug penetration into retina was confirmed by liquid chromatography coupled ESI-tandem mass spectroscopy (LC-MS/MS). Results Multifold increase in the expression of RAS components in human vitreous and rat retina showed their involvement in ROP. ERG & fundus studies in OIR revealed the altered function of retina and were successfully prevented by ARB (telmisartan), ACEI (lisinopril) and bevacizumab. Retinal analysis revealed the presence of ACEI and ARB in their therapeutic levels. Conclusion This study for the first time demonstrates the upregulated level of RAS components in human ROP vitreous and further that the pharmacological intervention in RRAS can functionally and structurally preserve retina against the progression of ROP in the OIR model. PMID:28033392

  2. A phenomenographic analysis of first-year engineering students' experiences with problems involving multiple possible solutions

    NASA Astrophysics Data System (ADS)

    Dringenberg, Emily A.

    Engineers are expected to solve problems that are ill-structured. These problems are presented with a lack of necessary information and allow for different ways of engaging with the problem; they are open-ended and involve multiple possible solutions with multiple means of evaluation. In order to allow maximum time for students to develop skills for solving such problems, undergraduate engineering programs can introduce such problems during the first year of students' education, in the form of cornerstone design tasks. This provides students with more opportunities to develop their ability to engage with ill-structured problems, which are characteristic of engineering work. Researchers have documented variation within both the behavior and perceptions of students' early experiences with design problems. General themes include novice-like design behavior, discomfort with lack of information, difficulty with problem scoping, and resistance to ambiguity. To build on these generalizations of students' experiences, a more thorough understanding of the variation in how students experience this phenomenon of engaging with ill-structured problems is needed to design effective learning environments. This work presents the qualitatively different ways that engineering students experience problems with multiple possible solutions during their first year of engineering studies. Using phenomenography as the methodological framework, data were collected through in-depth, semi-structured interviews with 27 first-year engineering students. The iterative, phenomenographic analysis resulted in seven descriptive categories for the ways participants experienced problems involving multiple possible solutions. The names of these categories represent the different foci of the students' experiences: completion, transition, iteration, organization, collaboration, reasoning, and growth. These categories are organized along two crucial dimensions of variation: reaction to ambiguity and role

  3. Possible involvement of polyphenols and polyamines in salt tolerance of almond rootstocks.

    PubMed

    Zrig, Ahlem; Tounekti, Taïeb; Vadel, Ahmedou Mohamed; Ben Mohamed, Hatem; Valero, Daniel; Serrano, María; Chtara, Chaker; Khemira, Habib

    2011-11-01

    Leaf physiological and biochemical adaptive strategies and more particularly the possible involvement of polyamines and polyphenols in salt stress tolerance were investigated. Three almond rootstocks (GN15, GF677 and bitter almond) were subjected to 0, 25, 50 and 75 mM NaCl for 30 days. The dry mass of leaves, stems and roots decreased with increasing salt concentration in the irrigation solution regardless of genotype. Photosynthetic assimilation rate decreased in the three almond rootstocks, but more so in GF677 and bitter almond. The accumulation of toxic ions was greater in the leaves than in the roots in all genotypes. GN15 accumulated less Na(+) and Cl(-) than GF677 and bitter almond. GF677 accumulated polyphenols, but had less anthocyanin and antioxidant activity in its leaves compared to bitter almond. It seems that GN15 was more able to tolerate the excess of toxic ions using anthocyanins which are abundant in its red leaves and free polyamines for a more efficient response to stress. However, most of the antioxidant activity was found in the leaves and was lower in the roots. Given that the upper part of the tree will be of a different cultivar after grafting, this advantage may not be relevant for the tree's survival. GF677 showed a different antioxidant strategy; it maintained a stable carotenoids content and accumulated polyphenols in its leaves. The three rootstocks used different strategies to deal with the excess of salt in the growth medium.

  4. Effect of Diazepam on Severity of Acute Pancreatitis: Possible Involvement of Peripheral Benzodiazepine Receptors

    PubMed Central

    Abed, Alireza; Minaiyan, Mohsen; Safaei, Azadeh; Taheri, Diana

    2013-01-01

    Acute pancreatitis is a lethal inflammatory condition of pancreas with high mortality rate. There is a pressing need for research to explore active agents and novel mechanisms involving in the treatment of pancreatitis. Clinical studies have shown after the initial acinar cell injury plasma levels of pro-inflammatory cytokines are elevated in patients with acute pancreatitis and the degree of cytokine elevation correlates with disease severity. Diazepam may decrease interleukin release from macrophages, suppress neutrophil activities, and exhibit anti-inflammatory effects. So it is expected that in vivo pretreatment of acute pancreatitis with different doses of diazepam can attenuate its severity. Thus, we evaluated the effects of diazepam, intraperitoneally (5, 10, and 20 mg/kg i.p.), intracerebroventricularly (ICV 10 μg), and concurrently with flumazenil (1 mg/kg) on cerulein-induced acute pancreatitis in mice. Interestingly, the pretreatment with diazepam (5 mg/kg i.p.) reduced significantly the inflammatory response of acute pancreatitis by ameliorating pancreatic edema, amylase and lipase serum levels, myeloperoxidase activity, pancreatic TNF-alpha, and pathological alteration compared to control group. Diazepam i.c.v. was ineffective, suggesting that central benzodiazepine receptors have no significant role in this property. These results demonstrate that pretreatment with diazepam exhibits anti-inflammatory property in cerulein-induced acute pancreatitis possibly through peripheral benzodiazepine receptors. PMID:23956866

  5. Ultraviolet-induced transformation of keratinocytes: possible involvement of long interspersed element-1 reverse transcriptase.

    PubMed

    Banerjee, Gautam; Gupta, Nishma; Tiwari, Jyoti; Raman, Govindarajan

    2005-02-01

    The normal human keratinocyte cell line, HaCaT, was transformed using multiple doses of ultraviolet (UV)A+B (UVA, 150-200 mJ/cm(2) and UVB, 15-20 mJ/cm(2) x 6). Malignant transformation was confirmed by upregulation of Cyclin D1 (mRNA) and formation of colonies on soft agar. To identify the genes involved in this transformation process, we have done rapid amplification of polymorphic DNA using RNA from unexposed and multiple-exposed cells. Six percent PAGE showed several differentially regulated genes in exposed cells compared with unexposed cells. Total 19 genes were identified, cloned and sequenced. Three of these 19 cloned genes showed 99% homology at both DNA and protein levels to a stretch of 540 bp (180 aa) of long interspersed element (LINE)-1 reverse transcriptase (RT) open reading frame (ORF-2). Colonies from soft agar showed upregulation of this gene compared with non-colonized (lawn on soft agar) cells as detected by RT-PCR. This data implicates LINE-1 RT (ORF-2) in UV-induced malignancy and can possibly be used as a marker for the diagnosis of UV-induced skin cancer.

  6. Protein phosphatase and kinase activities possibly involved in exocytosis regulation in Paramecium tetraurelia.

    PubMed

    Kissmehl, R; Treptau, T; Hofer, H W; Plattner, H

    1996-07-01

    In Paramecium tetraurelia cells synchronous exocytosis induced by aminoethyldextran (AED) is accompanied by an equally rapid dephosphorylation of a 63 kDa phosphoprotein (PP63) within 80 ms. In vivo, rephosphorylation occurs within a few seconds after AED triggering. In homogenates (P)P63 can be solubilized in all three phosphorylation states (phosphorylated, dephosphorylated and rephosphorylated) and thus tested in vitro. By using chelators of different divalent cations, de- and rephosphorylation of PP63 and P63 respectively can be achieved by an endogenous protein phosphatase/kinase system. Dephosphorylation occurs in the presence of EDTA, whereas in the presence of EGTA this was concealed by phosphorylation by endogenous kinase(s), thus indicating that phosphorylation of P63 is calcium-independent. Results obtained with protein phosphatase inhibitors (okadaic acid, calyculin A) allowed us to exclude a protein serine/threonine phosphatase of type I (with selective sensitivity in Paramecium). Protein phosphatase 2C is also less likely to be a candidate because of its requirement for high Mg2+ concentrations. According to previous evidence a protein serine/threonine phosphatase of type 2B (calcineurin; CaN) is possibly involved. We have now found that bovine brain CaN dephosphorylates PP63 in vitro. Taking into account the specific requirements of this phosphatase in vitro, with p-nitrophenyl phosphate as a substrate, we have isolated a cytosolic phosphatase of similar characteristics by combined preparative gel electrophoresis and affinity-column chromatography. In Paramecium this phosphatase also dephosphorylates PP63 in vitro (after 32P labelling in vivo). Using various combinations of ion exchange, affinity and hydrophobic interaction chromatography we have also isolated three different protein kinases from the soluble fraction, i.e. a cAMP-dependent protein kinase (PKA), a cGMP-dependent protein kinase (PKG) and a casein kinase. Among the kinases tested, PKA

  7. Achyranthes aspera Attenuates epilepsy in experimental animals: possible involvement of GABAergic mechanism.

    PubMed

    Viswanatha, Gollapalle Lakshminarayanashastry; Venkataranganna, Marikunte V; Prasad, Nunna Bheema Lingeswara; Godavarthi, Ashok

    2017-03-06

    The present study was aimed to examine the possible anticonvulsant property of aerial parts of Achyranthes aspera using various experimental models of epilepsy in mice. Petroleum ether extract of aerial parts of A. aspera (PeAA), methanolic eAA (MeAA) and aqueous eAA (AeAA) was initially evaluated against six-hertz seizure model in mice, based on the outcomes the effective extract was further evaluated against maximal electroshock (MES) and pentylenetetrazole (PTZ) models in mice. In addition, the potent extract was evaluated against the PTZ model by co-administering with flumazenil (FMZ), and also evaluated for its effect on GABA levels in brain and NMDA-induced lethality in mice. Furthermore, the probable locomotor deficit-inducing property of the extract was evaluated by actophotometer test in mice. In results, only MeAA showed protection against six-hertz-induced seizures in mice, based on these outcomes only MeAA was evaluated in MES and PTZ models. Notably, the MeAA (200, 400 and 800 mg/kg) has offered mild and dose dependent protection against MES and PTZ-induced seizures in mice. Alongside, the MeAA (400 mg/kg) showed a significant increase in GABA levels in the brain compared to control, and in line with these findings the anti-PTZ effect of MeAA (400 mg/kg, p.o.) was blocked when co-administered with flumazenil (5 mg/kg, i.p.). However, the MeAA has not shown significant protection against NMDA-induced mortality and also did not cause significant change in locomotor activity compared to before treatment. These findings suggest that MeAA possess mild anticonvulsant activity and the outcomes further confirmed the involvement of GABAergic mechanism behind the anticonvulsant activity of MeAA.

  8. The involvement and possible mechanism of NR4A1 in chondrocyte apoptosis during osteoarthritis

    PubMed Central

    Shi, Xinge; Ye, Hui; Yao, Xuedong; Gao, Yanzheng

    2017-01-01

    Osteoarthritis (OA) is a joint disease caused by the breakdown of joint cartilage and underlying bone, and places great burdens to daily life of patients. Nuclear orphan receptor nuclear receptor subfamily 4, group A, member 1 (NR4A1) is vital for cell apoptosis, but little is known about its role in OA. This study aims to reveal the expression and function of NR4A1 during OA chondrocyte apoptosis. NR4A1 expression by qRT-PCR and western blot, and chondrocyte apoptosis by TUNEL assay were detected in normal and OA joint cartilage. NR4A1 was located in cartilage sections by immunohistofluorescence. Chondrocytes from normal joint cartilage were cultured in vitro for interleukin 6 (IL6) or tumor necrosis factor (TNF) treatment and si-NR4A1 transfection, after which the possible mechanism involving NR4A1 was analyzed. Results showed that NR4A1 expression and chondrocyte apoptosis were significantly elevated in OA cartilage (P < 0.05 and P < 0.01). NR4A1 was located in nuclei of normal cartilage chondrocytes, but was translocated to mitochondria and co-located with B-cell lymphoma 2 in OA chondrocytes. NR4A1 expression in cultured chondrocytes could be promoted by both IL6 and TNF treatment. si-NR4A1 partly reduced TNF-induced cell apoptosis. Inhibiting p38 by SB203580 could decrease TNF-induced NR4A1 to some extent, while inhibiting JNK could not. So NR4A1 is likely to facilitate OA chondrocyte apoptosis, which is associated with p38 MAPK and mitochondrial apoptosis pathway. This study provides a potential therapeutic target for OA treatment and offers information for regulatory mechanisms in OA. PMID:28337303

  9. Kallikrein 6 regulates early CNS demyelination in a viral model of multiple sclerosis.

    PubMed

    Scarisbrick, Isobel A; Yoon, Hyesook; Panos, Michael; Larson, Nadya; Blaber, Sachiko I; Blaber, Michael; Rodriguez, Moses

    2012-09-01

    Kallikrein 6 (Klk6) is a secreted serine protease that is elevated in active multiple sclerosis lesions and patient sera. To further evaluate the involvement of Klk6 in chronic progressive demyelinating disease, we determined its expression in the brain and spinal cord of SJL mice infected with Theiler's murine encephalomyelitis virus (TMEV) and assessed the effects of Klk6-neutralizing antibodies on disease progression. Klk6 RNA expression was elevated in the brain and spinal cord by 7 days postinfection (dpi). Thereafter, Klk6 expression persisted primarily in the spinal cord reaching a peak of fivefold over controls at mid-chronic stages (60 dpi-120 dpi). Significant elevations in Klk6 RNA were also induced in splenocytes stimulated with viral capsid proteins in vitro and in activated human acute monocytic leukemia cells. Klk6-neutralizing antibodies reduced TMEV-driven brain and spinal cord pathology and delayed-type hypersensitivity (DTH) responses when examined at early chronic time points (40 dpi). Reductions in spinal cord pathology included a decrease in activated monocytes/microglia and reductions in the loss of myelin basic protein (MBP). By 180 dpi, pathology scores no longer differed between groups. These findings point to regulatory activities for Klk6 in the development and progression of central nervous system (CNS) inflammation and demyelination that can be effectively targeted through the early chronic stages with neutralizing antibody.

  10. Effect of various concentrations of caffeine, pentoxifylline, and kallikrein on hyperactivation of frozen bovine semen.

    PubMed

    Barakat, Ibrahim A H; Danfour, Mohamed A; Galewan, Fatma A M; Dkhil, Mohamed A

    2015-01-01

    Caffeine, pentoxifylline, and kallikrein are substances that affect the efficiency of sperms in the fertilization process; however, they have not been adequately studied. The present study aimed to examine the influence of caffeine, kallikrein, and pentoxifylline on sperm motility in bovine as well as investigate their optimum concentrations for increasing the movement of sperms in bovine. Frozen bovine sperms were thawed in universal IVF medium supplemented with 1, 5, and 10 mM caffeine or pentoxifylline or 1, 4, and 8 U/mL kallikrein and were then incubated for 30 min. Treated semen parameters were analyzed using a computer assisted semen analyzer (CASA). Data analysis showed that the mean values concerning progression and motility of sperm increased in caffeine and pentoxifylline treatments when compared with the kallikrein group. The obtained results revealed that kallikrein is not necessary for the improvement of bovine sperm motility. Additionally, our results revealed that 5 mM from caffeine was the best concentration added to the medium, followed by 1 or 5 mM from pentoxifylline. Therefore, it is concluded from the present study that caffeine has hyperactivation efficacy at 5 mM concentration compared to other treatments.

  11. Tissue kallikrein permits early renal adaptation to potassium load.

    PubMed

    El Moghrabi, Soumaya; Houillier, Pascal; Picard, Nicolas; Sohet, Fabien; Wootla, Bharath; Bloch-Faure, May; Leviel, Françoise; Cheval, Lydie; Frische, Sebastian; Meneton, Pierre; Eladari, Dominique; Chambrey, Régine

    2010-07-27

    Tissue kallikrein (TK) is a serine protease synthetized in renal tubular cells located upstream from the collecting duct where renal potassium balance is regulated. Because secretion of TK is promoted by K+ intake, we hypothesized that this enzyme might regulate plasma K+ concentration ([K+]). We showed in wild-type mice that renal K+ and TK excretion increase in parallel after a single meal, representing an acute K+ load, whereas aldosterone secretion is not modified. Using aldosterone synthase-deficient mice, we confirmed that the control of TK secretion is aldosterone-independent. Mice with TK gene disruption (TK-/-) were used to assess the impact of the enzyme on plasma [K+]. A single large feeding did not lead to any significant change in plasma [K+] in TK+/+, whereas TK-/- mice became hyperkalemic. We next examined the impact of TK disruption on K+ transport in isolated cortical collecting ducts (CCDs) microperfused in vitro. We found that CCDs isolated from TK-/- mice exhibit net transepithelial K+ absorption because of abnormal activation of the colonic H+,K+-ATPase in the intercalated cells. Finally, in CCDs isolated from TK-/- mice and microperfused in vitro, the addition of TK to the perfusate but not to the peritubular bath caused a 70% inhibition of H+,K+-ATPase activity. In conclusion, we have identified the serine protease TK as a unique kalliuretic factor that protects against hyperkalemia after a dietary K+ load.

  12. Kinins— The Kallikrein-Kinin System and Oxidative Stress

    PubMed Central

    Kayashima, Yukako; Smithies, Oliver; Kakoki, Masao

    2012-01-01

    Purpose of review The Kallikrein-kinin system (KKS) constitutes a complex multi-enzyme cascade that produces several bioactive kinin peptides and their derivatives including bradykinin. In addition to the classical notion of the KKS as a potent vasodilator and a mediator of inflammatory responses, recent studies suggest a link between the KKS and oxidative stress. A number of established mouse model with altered levels of KKS components opened the way to evaluate precise functions of the KKS. Here we review recent findings on the role of the KKS in cardiovascular diseases and chronic kidney diseases, and discuss potential benefits of KKS activation in these diseases. Recent findings Deletion of both B1R and B2R in a diabetic mouse model exacerbates its renal phenotypes, suggesting that the KKS exerts protective effects on diabetic nephropathy by suppressing oxidative stress, presumably via nitric oxide (NO) and prostaglandins (PGs). Summary Accumulating evidence has highlighted the importance of the KKS as a protective system against oxidative stress and organ damage in the heart and kidney. The activation of the KKS by ACE inhibitors and vasopeptidase inhibitors is likely to be beneficial in senescence-associated cardiovascular diseases and chronic kidney diseases. PMID:22048723

  13. Investigation of possible involvement of several genes related to development of hepatocarcinogenesis in rats.

    PubMed

    Todaka, N; Higashi, K; Yan, Y; Abe, T; Yamashiro, K; Hiai, H

    2000-06-01

    A comparative study on the possible involvement of several genes in the susceptibility of chemical carcinogenesis was carried out using carcinogen-resistant DRH rat and -sensitive Donryu and F344 rats. Previously, we observed that the induction of glutathione S-transferase placental form (GST-P) in the liver of Donryu rats by 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) was significantly greater than that of DRH rats. In the present study, we tentatively determined base sequences of the enhancer region including GPE-I and GPE-II (GST-P enhancers I and II) of GST-P genes of DRH, Donryu and F344 rats, but we did not observe any nucleotide polymorphism around these regions. Furthermore, the mRNA levels of silencer binding protein (NFA-1) for the GST-P promoter of rat liver were also similar in the DRH and Donryu rats. Since clonal expansion of putative preneoplastic GST-P-positive foci in the DRH rat liver was significantly suppressed during 3'-Me-DAB administration, we examined whether two opposite growth controlling factors, TGF-alpha and TGF-beta, may participate in such suppression of growth. It was supposed that mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R), at least in part, activates TGF-beta preproprotein. However, we observed that the levels of M6P/IGF2R mRNA in the livers of DRH were not higher than those of Donryu rats after being fed 3'-Me-DAB for 8 weeks. Another important factor in the carcinogenesis is insulin-like growth factor II itself. Although liver tumors induced by 3'-Me-DAB in F344 had high levels of IGF-II mRNA, little IGF-II gene expression existed in normal adult livers of Donryu, F344 and DRH rats. High levels of IGF-II mRNA were detected similarly in the livers of neonates from all these three strains of rats. Finally, we detected a significant increase of AFP (alpha-fetoprotein) mRNA in the livers of Donryu rats around 6 to 8 weeks from the start of 3'-Me-DAB feeding, which is in parallel with detrimental effects

  14. Immigrant Parent Involvement in U.S. Schools: Current Practices and Future Possibilities

    ERIC Educational Resources Information Center

    Aleixo, Marina Bandeira

    2012-01-01

    This dissertation examines how parent involvement expectations are communicated and enacted in interactions at one small urban high school. Through detailed descriptions of school interactions between supporting staff and immigrant parents, this study examines how parent involvement expectations are understood and perceived. Although scholarly…

  15. Pregnant rats treated with a serotonin precursor have reduced fetal weight and lower plasma volume and kallikrein levels.

    PubMed

    Salas, Sofía P; Giacaman, Andrea; Romero, William; Downey, Patricio; Aranda, Eduardo; Mezzano, Diego; Vío, Carlos P

    2007-10-01

    Pregnant women with preeclampsia have increased serotonin levels, suggesting a possible role of this amine in abnormal pregnancy. With the hypothesis that an increase in serotonin would reduce volume expansion and cause fetal growth restriction, we evaluated the maternal and fetal effects of the administration of the serotonin precursor 5-hidroxytryptophan (5-HTP) to Sprague-Dawley rats. At pregnancy day 13 (n=19) or in random cycle nonpregnant rats (n=10), animals were assigned to a single injection of 5-HTP (100 mg/kg IP) or to a control group. Animals were studied at day 21, after overnight urinary collection. Additional pregnant rats received ketanserin (1 mg/kg), a 5-HT(2) receptor antagonist, 1 hour before 5-HTP injection. In pregnant rats, 5-HTP lowered plasma volume (control: 22+/-1.1; 5-HTP: 17+/-0.7 mL; P<0.001) and creatinine clearance, whereas serum creatinine and urinary protein excretion were increased; no changes were observed in nonpregnant rats. Systolic blood pressure did not change significantly. Urinary kallikrein activity and plasma aldosterone levels decreased only in pregnant animals. Fetal (control: 5.5+/-0.1; 5-HTP: 4.2+/-0.2 g; P<0.001) and placental weights were reduced. In nonpregnant and pregnant animals, 5-HTP caused profound renal morphological alterations and decreased kallikrein immunostaining. Preadministration of ketanserin abolished all of the changes associated with the use of 5-HTP. These data indicate that the administration of a serotonin precursor to pregnant rats limits plasma volume expansion and fetal growth via 5-HT(2) receptors, suggesting a possible role for serotonin in abnormal pregnancy. We postulate that an increased vascular resistance, both at the placental and renal levels, mediates these effects.

  16. Role of tissue kallikrein-kininogen-kinin pathways in the cardiovascular system.

    PubMed

    Sharma, Jagdish N

    2006-04-01

    All the components of the kallikrein-kinin system are located in the cardiac muscle, and its deficiency may lead to cardiac dysfunction. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischemia, myocardial infarction and left ventricular hypertrophy have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental for the induction of cardiovascular-related diseases. The cardioprotective property of the angiotensin converting enzyme inhibitors is primarily mediated via kinin-releasing pathway, which may cause regression of the left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating hypertension, cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders.

  17. Partial genetic deficiency in tissue kallikrein impairs adaptation to high potassium intake in humans.

    PubMed

    Monteiro, Joana S; Blanchard, Anne; Curis, Emmanuel; Chambrey, Régine; Jeunemaitre, Xavier; Azizi, Michel

    2013-12-01

    Inactivation of the tissue kallikrein gene in mice impairs renal handling of potassium due to enhanced H, K-ATPase activity, and induces hyperkalemia. We investigated whether the R53H loss-of-function polymorphism of the human tissue kallikrein gene affects renal potassium handling. In a crossover study, 30 R53R homozygous and 10 R53H heterozygous healthy males were randomly assigned to a low-sodium/high-potassium or a high-sodium/low-potassium diet to modulate tissue kallikrein synthesis. On the seventh day of each diet, participants were studied before and during a 2-h infusion of furosemide to stimulate distal potassium secretion. Urinary kallikrein activity was significantly lower in R53H than in R53R subjects on the low-sodium/high-potassium diet and was similarly reduced in both genotypes on high-sodium/low-potassium. Plasma potassium and renal potassium reabsorption were similar in both genotypes on an ad libitum sodium/potassium diet or after 7 days of a high-sodium/low-potassium diet. However, the median plasma potassium was significantly higher after 7 days of low-sodium/high-potassium diet in R53H than in R53R individuals. Urine potassium excretion and plasma aldosterone concentrations were similar. On the low-sodium/high-potassium diet, furosemide-induced decrease in plasma potassium was significantly larger in R53H than in R53R subjects. Thus, impaired tissue kallikrein stimulation by a low-sodium/high-potassium diet in R53H subjects with partial tissue kallikrein deficiency highlights an inappropriate renal adaptation to potassium load, consistent with experimental data in mice.

  18. Possible involvement of parotid beta-adrenergic receptors in the etiology of sialadenosis.

    PubMed

    Chilla, R; Witzemann, V; Opaitz, M; Arglebe, C

    1981-01-01

    The concentration of beta-adrenergic receptors was determined in rat and human parotid glands, in normal tissue as well as after sympathetic denervation of the rat, and in human sialadenosis. Receptor levels were clearly elevated after denervation of the rat and in sialadenosis. The possible implications of these findings for the etiology of human sialadenosis are discussed.

  19. The Regulation of Nucleolin Expression in Prostrate Epithelial Cells; Possible Involvement of MYC

    DTIC Science & Technology

    2002-01-01

    physical state. Therefore it is possible that while a specific portion of Nucleolin can interact with H1 in such a way as to promote DNA condensation...phosphorylation is unnecessary in a cell like S cerevisiae in which no nuclear division accompanies cytokinesis (Ginisty et al 1999). The authors...the nucleolus dissipates and the nuclear envelope breaks down. Whether or not this localization function is related to the phosphorylation-dependent

  20. Estrogen receptor beta, a possible tumor suppressor involved in ovarian carcinogenesis

    PubMed Central

    Lazennec, Gwendal

    2006-01-01

    Ovarian cancer is one of the leading cause of death from gynecological tumors in women. Several lines of evidence suggest that estrogens may play an important role in ovarian carcinogenesis, through their receptors, ERα and ERβ. Interestingly, malignant ovarian tumors originating from epithelial surface constitute about 90% of ovarian cancers and expressed low levels of ERβ, compared to normal tissues. In addition, restoration of ERβ in ovarian cancer cells, leads to strong inhibition of their proliferation and invasion, while apoptosis is enhanced. In this manuscript, recent data suggesting a possible tumor-suppressor role for ERβ in ovarian carcinogenesis are discussed. PMID:16399219

  1. Misfolded proteins activate Factor XII in humans, leading to kallikrein formation without initiating coagulation

    PubMed Central

    Maas, Coen; Govers-Riemslag, José W.P.; Bouma, Barend; Schiks, Bettina; Hazenberg, Bouke P.C.; Lokhorst, Henk M.; Hammarström, Per; ten Cate, Hugo; de Groot, Philip G.; Bouma, Bonno N.; Gebbink, Martijn F.B.G.

    2008-01-01

    When blood is exposed to negatively charged surface materials such as glass, an enzymatic cascade known as the contact system becomes activated. This cascade is initiated by autoactivation of Factor XII and leads to both coagulation (via Factor XI) and an inflammatory response (via the kallikrein-kinin system). However, while Factor XII is important for coagulation in vitro, it is not important for physiological hemostasis, so the physiological role of the contact system remains elusive. Using patient blood samples and isolated proteins, we identified a novel class of Factor XII activators. Factor XII was activated by misfolded protein aggregates that formed by denaturation or by surface adsorption, which specifically led to the activation of the kallikrein-kinin system without inducing coagulation. Consistent with this, we found that Factor XII, but not Factor XI, was activated and kallikrein was formed in blood from patients with systemic amyloidosis, a disease marked by the accumulation and deposition of misfolded plasma proteins. These results show that the kallikrein-kinin system can be activated by Factor XII, in a process separate from the coagulation cascade, and point to a protective role for Factor XII following activation by misfolded protein aggregates. PMID:18725990

  2. Biodegradation of ivory (natural apatite): possible involvement of fungal activity in biodeterioration of the Lewis Chessmen.

    PubMed

    Pinzari, Flavia; Tate, James; Bicchieri, Marina; Rhee, Young Joon; Gadd, Geoffrey Michael

    2013-04-01

    Fungal biodeterioration of ivory was investigated with in vitro inoculation of samples obtained from boar and walrus tusks with the fungi Aspergillus niger and Serpula himantioides, species of known geoactive abilities. A combination of light and scanning electron microscopy together with associated analytical techniques was used to characterize fungal interactions with the ivory, including changes in ivory composition, dissolution and tunnelling, and the formation of new biominerals. The research was aimed at providing further understanding of the potential roles of fungi in the colonization and deterioration of ivory in terrestrial environments, but also contributes to our knowledge regarding the possible origins of the surface damage observed on early medieval sculptures made largely from walrus tusks, referred to as 'the Lewis hoard of gaming pieces', that were presumably produced for playing chess. The experiments have shown that the possibility of damage to ivory being caused by fungi is realistic. Scanning electron microscopy revealed penetration of fungal hyphae within cracks in the walrus tusk that showed also widespread tunnelling by fungal hyphae as well as 'fungal footprints' where the surface was etched as a consequence of mycelial colonization. Similar phenomena were observed with boar tusk ivory, while production of metabolites could lead to complete dissolution of the sample. Colonization of ivory and/or exposure to fungal activity lead to extensive secondary biomineral formation, and this was identified as calcium oxalate, mainly as the monohydrate, whewellite.

  3. A Gene Island with Two Possible Configurations Is Involved in Chromatic Acclimation in Marine Synechococcus

    PubMed Central

    Humily, Florian; Partensky, Frédéric; Six, Christophe; Farrant, Gregory K.; Ratin, Morgane; Marie, Dominique; Garczarek, Laurence

    2013-01-01

    Synechococcus, the second most abundant oxygenic phototroph in the marine environment, harbors the largest pigment diversity known within a single genus of cyanobacteria, allowing it to exploit a wide range of light niches. Some strains are capable of Type IV chromatic acclimation (CA4), a process by which cells can match the phycobilin content of their phycobilisomes to the ambient light quality. Here, we performed extensive genomic comparisons to explore the diversity of this process within the marine Synechococcus radiation. A specific gene island was identified in all CA4-performing strains, containing two genes (fciA/b) coding for possible transcriptional regulators and one gene coding for a phycobilin lyase. However, two distinct configurations of this cluster were observed, depending on the lineage. CA4-A islands contain the mpeZ gene, encoding a recently characterized phycoerythrobilin lyase-isomerase, and a third, small, possible regulator called fciC. In CA4-B islands, the lyase gene encodes an uncharacterized relative of MpeZ, called MpeW. While mpeZ is expressed more in blue light than green light, this is the reverse for mpeW, although only small phenotypic differences were found among chromatic acclimaters possessing either CA4 island type. This study provides novel insights into understanding both diversity and evolution of the CA4 process. PMID:24391958

  4. Osteopontin, a protein with cytokine-like properties: a possible involvement in pemphigus vulgaris.

    PubMed

    Baroni, A; De Filippis, A; Buommino, E; Satriano, R A; Cozza, V

    2012-04-01

    Pemphigus is an autoimmune blistering disease characterized by severe and chronic course, histopathologically characterized by infiltration of a large quantity of eosinophils, neutrophils, and activated Th1 and Th2 cells around the blister. Polarization of Th cells to Th1 or Th2 phenotypes, a critical aspect of cell-mediated immunity, is influenced by production of early cytokines, including osteopontin. To determine the involvement of osteopontin in pemphigus vulgaris patients in active stage of the disease, auto-antibodies to desmoglein-1 and desmoglein-3 and plasmatic osteopontin levels were examined by ELISA tests. In this work, significant plasmatic level of osteopontin in PV patients with active stage of disease were found particularly in those patients with both skin and oral pemphigus. OPN might drive the immune responses playing an important role in pemphigus onset.

  5. Exercise Influence on Hippocampal Function: Possible Involvement of Orexin-A

    PubMed Central

    Chieffi, Sergio; Messina, Giovanni; Villano, Ines; Messina, Antonietta; Esposito, Maria; Monda, Vincenzo; Valenzano, Anna; Moscatelli, Fiorenzo; Esposito, Teresa; Carotenuto, Marco; Viggiano, Andrea; Cibelli, Giuseppe; Monda, Marcellino

    2017-01-01

    In the present article, we provide a brief review of current knowledge regarding the effects induced by physical exercise on hippocampus. Research involving animals and humans supports the view that physical exercise, enhancing hippocampal neurogenesis and function, improves cognition, and regulates mood. These beneficial effects depend on the contribute of more factors including the enhancement of vascularization and upregulation of growth factors. Among these, the BDNF seems to play a significant role. Another putative factor that might contribute to beneficial effects of exercise is the orexin-A. In support of this hypothesis there are the following observations: (1) orexin-A enhances hippocampal neurogenesis and function and (2) the levels of orexin-A increase with physical exercise. The beneficial effects of exercise may represent an important resource to hinder the cognitive decline associated with the aging-related hippocampal deterioration and ameliorate depressive symptoms. PMID:28261108

  6. Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

    PubMed Central

    Wang, Juan; Zhang, Hai-yan; Tang, Xi-can

    2009-01-01

    Vascular dementia (VaD) is a progressive neurodegenerative disease with a high prevalence. Several studies have recently reported that VaD patients present cholinergic deficits in the brain and cerebrospinal fluid (CSF) that may be closely related to the pathophysiology of cognitive impairment. Moreover, cholinergic therapies have shown promising effects on cognitive improvement in VaD patients. The precise mechanisms of these cholinergic agents are currently not fully understood; however, accumulating evidence indicates that these drugs may act through the cholinergic anti-inflammatory pathway, in which the efferent vagus nerve signals suppress pro-inflammatory cytokine release and inhibit inflammation, although regulation of oxidative stress and energy metabolism, alleviation of apoptosis may also be involved. In this paper, we provide a brief overview of the cholinergic treatment strategy for VaD and its relevant mechanisms of anti-inflammation. PMID:19574993

  7. Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms.

    PubMed

    Srinivasan, Padmanabhan; Kapadia, Rubina; Biswas, Arundhati; Said, Hamid M

    2014-11-01

    Chronic exposure to alcohol affects different physiological aspects of pancreatic acinar cells (PAC), but its effect on the uptake process of biotin is not known. We addressed this issue using mouse-derived pancreatic acinar 266-6 cells chronically exposed to alcohol and wild-type and transgenic mice (carrying the human SLC5A6 5'-promoter) fed alcohol chronically. First we established that biotin uptake by PAC is Na(+) dependent and carrier mediated and involves sodium-dependent multivitamin transporter (SMVT). Chronic exposure of 266-6 cells to alcohol led to a significant inhibition in biotin uptake, expression of SMVT protein, and mRNA as well as in the activity of the SLC5A6 promoter. Similarly, chronic alcohol feeding of wild-type and transgenic mice carrying the SLC5A6 promoter led to a significant inhibition in biotin uptake by PAC, as well as in the expression of SMVT protein and mRNA and the activity of the SLC5A6 promoters expressed in the transgenic mice. We also found that chronic alcohol feeding of mice is associated with a significant increase in the methylation status of CpG islands predicted to be in the mouse Slc5a6 promoters and a decrease in the level of expression of transcription factor KLF-4, which plays an important role in regulating SLC5A6 promoter activity. These results demonstrate, for the first time, that chronic alcohol exposure negatively impacts biotin uptake in PAC and that this effect is exerted (at least in part) at the level of transcription of the SLC5A6 gene and may involve epigenetic/molecular mechanisms.

  8. Possible involvement of miRNAs in tropism of Parvovirus B19.

    PubMed

    Anbarlou, Azadeh; AkhavanRahnama, Mahshid; Atashi, Amir; Soleimani, Masoud; Arefian, Ehsan; Gallinella, Giorgio

    2016-03-01

    Human Parvovirus B19 (PVB19) is one of the most important pathogens that targets erythroid lineage. Many factors were mentioned for restriction to erythroid progenitor cells (EPCs). Previous studies showed that in non-permissive cells VP1 and VP2 (structural proteins) mRNAs were detected but could not translate to proteins. A bioinformatics study showed that this inhibition might be due to specific microRNAs (miRNAs) present in non-permissive cells but not in permissive EPCs. To confirm the hypothesis, we evaluated the effect of miRNAs on VP expression. CD34(+) HSCs were separated from cord blood. Then, CD34(+) cells were treated with differentiation medium to obtain CD36(+) EPCs. To evaluate the effect of miRNAs on VP expression in MCF7 and HEK-293 cell lines (non-permissive cells) and CD36(+) EPCs, dual luciferase assay was performed in presence of shRNAs against Dicer and Drosha to disrupt miRNA biogenesis. QRT-PCR was performed to check down-regulation of Dicer and Drosha after transfection. All measurements were done in triplicate. Data means were compared using one-way ANOVAs. MicroRNA prediction was done by the online microRNA prediction tools. No significant difference was shown in luciferase activity of CD36(+) EPCs after co-transfection with shRNAs, while it was significant in non-permissive cells. Our study revealed that miRNAs may be involved in inhibition of VP expression in non-permissive cells, although further studies are required to demonstrate which miRNAs exactly are involved in regulation of PVB19 replication.

  9. Zuclopenthixol facilitates memory retrieval in rats: possible involvement of noradrenergic and serotonergic mechanisms.

    PubMed

    Khalifa, Amani E

    2003-07-01

    Although disturbed memory function often coexists with psychosis, the cognitive effects of antipsychotic medications with diverse pharmacodynamic properties are rarely investigated. The neurocognitive profile of zuclopenthixol, a thioxanthene dopaminergic antagonist and a conventional neuroleptic agent, has yet to be investigated despite the effect of the drug on a variety of neurotransmitter systems involved in mediation of learning and memory processes. In this study, the effect of zuclopenthixol was tested on memory retrieval 24 h after training using an inhibitory avoidance task in rats. Acute administration of zuclopenthixol (0.7 and 1.4 mg/kg i.p.) before retrieval testing increased step-through latency during the test session. The same doses of zuclopenthixol did not affect the ambulatory activity of rats in the openfield test and therefore the facilitatory effect of the drug on memory function could not be confounded with any motoric properties. This study also investigated the effect of zuclopenthixol on cortical and hippocampal monoaminergic neurotransmitters' levels together with acetylcholinesterase enzyme (AChE) activity, both of which are known to be important in control of cognitive function. Administration of zuclopenthixol (0.7 and 1.4 mg/kg i.p.) neither affected dopamine (DA) level nor AChE activity in rat cortex and hippocampus. On the other hand, the lower dose of zuclopenthixol elevated cortical norepinephrine (NE) level, while the higher dose elevated both cortical and hippocampal NE level together with hippocampal serotonin (5-HT) level. These results may suggest the involvement of adrenergic and serotonergic mechanisms in the facilitatory effect of zuclopenthixol on retrieval memory. Zuclopenthixol may therefore be a better alternative than other commonly used antipsychotic medications reported to impair cognitive function of schizophrenic patients.

  10. Local bone interaction between renin-angiotensin system and kallikrein-kinin system in diabetic rat

    PubMed Central

    Li, Yong; Shen, Guang-Si; Yu, Chen; Li, Guang-Fei; Shen, Jun-Kang; Xu, You-Jia; Gong, Jian-Ping

    2015-01-01

    Objective: This study was performed to investigate bone deteriorations and the involvement of skeletal renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) of male rat in response to the hyperglycemia. Methods: The biomarkers in serum and urine were measured by ELISA kit, and tibias were taken for the measurement on gene, protein expression and histological analysis, feumrs were taken for the measurement on biomechanical parameters and micro-CT. Results: The DM1 showed the decreased level of osteocalcin, testosterone and FGF-23, and the increased level of serum CTX as compared to those of vehicle group. The H&E staining showed remarkable bone deteriorations, including increased disconnections and separation of trabecular bone among growth plate and joint cartilage in DM1 group. Biomechanically, the maximum load, maximum stress, and strain parameter of DM1 group was significantly lower than control group. Type 1 diabetic mice displayed bone loss shown the reduction of bone volume/total volume, trabecular number, trabecular thickness and bone mineral density. The STZ injection significantly up-regulated mRNA expression of AT1R, AGT, renin, renin-receptor, and ACE, and the expression of AT2R, B1R and B2R were down-regulated in tibia of rat in hyperglycemia group. The protein expression of renin, ACE and Ang II were significantly up-regulated, and AT2R, B1R and B2R were down-regulated in DM1 group. Conclusions: The treatment of hyperglycemia was detrimental to bone as compared to the vehicle group, and the underlying mechanism was mediated, at least partially, through down-regulation of KSS activity and up-regulation of RAS activity in local bone. PMID:25973045

  11. Possible involvement of galectin-3 in microglial activation in the hippocampus with trimethyltin treatment.

    PubMed

    Yang, Miyoung; Kim, Juhwan; Kim, Taehyub; Kim, Sung-Ho; Kim, Jong-Choon; Kim, Jeongtae; Takayama, Chitoshi; Hayashi, Akinobu; Joo, Hong-Gu; Shin, Taekyun; Moon, Changjong

    2012-12-01

    Trimethyltin (TMT) is an organotin neurotoxicant with effects that are selectively localized to the limbic system (especially the hippocampus), which produces memory deficits and temporal lobe seizures. Galectin-3 (Gal-3) is a beta-galactoside-binding lectin that is important in cell proliferation and regulation of apoptosis. The present study evaluated the temporal expression of Gal-3 in the hippocampus of adult BALB/c mice after TMT treatment (i.p., 2.5mg/kg). Western blotting analyses showed that Gal-3 immunoreactivity began to increase days after treatment; the immunoreactivity peaked significantly within days after treatment but significantly declined between days 4 and 8. Immunohistochemical analysis indicated that Gal-3 expression was very rare in the hippocampi of vehicle-treated controls. However, Gal-3 immunoreactivity appeared between 2 and 8 days after TMT treatment and was primarily localized to the hippocampal dentate gyrus (DG), in which neuronal degeneration occurred. The immunoreactivity was detected predominantly in most of the Iba1-positive microglia and in some GFAP-positive astrocytes of the hippocampal DG. Furthermore, Gal-3 expression co-localized with the pro-inflammatory enzymes cyclooxygenase-2 and inducible nitric oxide synthase in the hippocampal DG. Therefore, we suggest that Gal-3 is involved in the inflammatory process of neurodegenerative disorder induced by organotin intoxication.

  12. Oxytocin is involved in the proconvulsant effects of Sildenafil: Possible role of CREB.

    PubMed

    Khoshneviszadeh, Mahsima; Rahimian, Reza; Fakhfouri, Gohar; Payandemehr, Borna; Khodagholi, Fariba; Ejtemaei Mehr, Shahram; Dehpour, Ahmad Reza

    2016-08-10

    Sildenafil is a phosphodiesterase type 5 inhibitor mainly used for male erectile dysfunction. One of rare yet serious adverse effects of Sildenafil is its potential to decrease seizure threshold. Ample evidence suggests that Sildenafil exerts central effects through induction of Oxytocin (OT) secretion and CREB phosphorylation. The aim of the present study is to evaluate potential roles of OT and CREB in the proconvulsant effects of Sildenafil. The Pentylenetetrazole-induced seizure was used as a standard convulsion model in this study. OT release and pCREB expression were evaluated in the hippocampus of mice using ELISA and western blot assays, respectively. Our results showed that Sildenafil at the dose of 10mgkg(-1) or higher, significantly decreased seizure threshold. Pretreatment with a non-effective dose of OT, potentiated while OT receptor antagonist, Atosiban, reversed fully the proconvulsant effects of Sildenafil (5mgkg(-1)). At biochemical inspection, Sildenafil markedly increased CREB which was attenuated by coadministration of Atosiban. The present study shows for the first time that OT release and the subsequent CREB phosphorylation are involved in the proconvulsant effects of acute Sildenafil treatment in an experimental model of seizure.

  13. Renal allograft rejection: possible involvement of lymphokine-activated killer cells.

    PubMed Central

    Kirby, J A; Forsythe, J L; Proud, G; Taylor, R M

    1989-01-01

    Human renal allograft tissue was recovered at transplant nephrectomy from three patients with irreversible loss of graft function. This tissue was disaggregated and separated into two fractions on the basis of particle size. Fraction 1 contained glomeruli and developed a mixed outgrowth containing adherent epithelial and mesangial cells after a limited period of culture. Fraction 2 contained fragments of renal tubules and produced monolayers of tubular epithelial cells during culture. A population of lymphoid cells was observed to grow from the primary disaggregate into medium supplemented with recombinant human interleukin-2 (IL-2). After culture for 5 days these lymphoid cells were predominantly CD3-positive and carried both class II major histocompatibility antigens (MHC) and the CD25 IL-2 receptor. Culture of peripheral blood-derived mononuclear cells with IL-2 caused the generation of lymphokine-activated killer (LAK) cells; these cells were able to lyse both glomerular and tubular cells grown from nephrectomy tissue without showing MHC antigen restriction. The lymphoid cells grown from renal allograft tissue showed a similar lytic potential for both renal cells prepared from the same nephrectomy specimen and from third party renal tissue. It is possible that any LAK cells formed within a renal allograft by the action of IL-2 may contribute to the tissue destruction observed during graft rejection. Images Figure 2 PMID:2661417

  14. Possible involvement of P-glycoprotein in the biliary excretion of grepafloxacin.

    PubMed

    Zhao, Ying Lan; Cai, Shao Hui; Wang, Li; Kitaichi, Kiyoyuki; Tatsumi, Yasuaki; Nadai, Masayuki; Yoshizumi, Hideo; Takagi, Kenji; Takagi, Kenzo; Hasegawa, Takaaki

    2002-03-01

    1. In the present study, we have examined the effects of the quinolones norfloxacin (NFLX), enoxacin (ENX), ofloxacin (OFLX), tosufloxacin (TFLX), lomefloxacin (LFLX), sparfloxacin (SPFX) and grepafloxacin (GPFX) on the efflux of doxorubicin from mouse leukaemia P388/ADR cells expressing P-glycoprotein. The relationship between their partition coefficients (hydrophobicity) and effluxing potencies was also elucidated. 2. Both TFLX and SPFX strongly increased the intracellular accumulation of doxorubicin (5 micromol/L) in P388/ADR cells, but had no effect on P388/S cells not expressing P-glycoprotein. The rank of order of the potency of the quinolones (TFLX > SPFX > GPFX > NFLX) was not related directly to their hydrophobicity. These results suggest that some quinolones can reverse anticancer drug resistance. 3. Because GPFX is more highly excreted into the bile than other known quinolones, the effects of doxorubicin (10 mg/kg) or the well-known inhibitors of P-glycoprotein, namely cyclosporine A (10 mg/kg) and erythromycin (100 mg/kg), on the biliary excretion of GPFX at steady state was studied in rats. 4. Doxorubicin, cyclosporine A and erythromycin significantly decreased the biliary clearance of GPFX. Cyclosporine A and erythromycin had a much stronger inhibitory effect on the biliary excretion of GPFX than doxorubicin. These results suggest the possibility that GPFX is, at least in part, excreted into the bile by a P-glycoprotein-mediated transport mechanism.

  15. Possible involvement of delta-6-desaturase in control of melanoma growth by gamma-linolenic acid.

    PubMed

    Gardiner, N S; Duncan, J R

    1991-03-01

    This study examined the effects of linoleic acid (LA) and gamma-linolenic acid (GLA) on BL6 melanoma growth in cell culture and of safflower oil (SFO) which contains LA and evening primrose oil (EPO) which contains GLA, on melanoma growth when grown in mice. The delta-6-desaturase activity of the melanoma cells in the two systems was also examined and an attempt made to relate the activity of the enzyme to the effects of GLA on cell and tumour growth. LA and GLA were found to be equipotent in inhibiting growth of the in vitro cultured BL6 cells which were found to contain an appreciable level of delta-6-desaturase activity. EPO was however found to be a more potent promoter of in vivo melanoma growth in mice than SFO. Melanomas grown in mice were found to lack delta-6-desaturase activity suggesting that the EPO diet, by providing GLA, was able to compensate for the loss of enzyme activity in the melanomas. The possibility that melanomas in mice have a requirement for GLA for growth while in in vitro cultured cells excess GLA inhibits the growth of the cells through an increase in lipid peroxidation is discussed.

  16. Possible involvement of leptin and leptin receptor in developing gastric adenocarcinoma

    PubMed Central

    Zhao, Liang; Shen, Zhi-Xiang; Luo, He-Sheng; Shen, Lei

    2005-01-01

    AIM: To investigate the expression of leptin and leptin receptor (ob-R) in intestinal-type gastric cancer and precancerous lesions, and to explore the possible mechanism and role of the leptin system in developing intestinal-type gastric adenocarcinoma. METHODS: Immunohistochemistry was performed to examine the expression of leptin and leptin receptor in archival samples of gastric adenocarcinoma and preneoplastic lesions, including intestinal metaplasia and mild to severe gastric epithelial dysplasia. Positive staining was identified and percentage of positive staining was graded. RESULTS: Dual expression of leptin and leptin receptor were detected in 80% (16/20) intestinal metaplasia, 86.3% (25/30) mild gastric epithelial dysplasia, 86.7% (26/30) moderate gastric epithelial dysplasia, 93.3% (28/30) severe gastric epithelial dysplasia, 91.3% (55/60) intestinal-type gastric adenocarcinoma and 30.0% (9/30) diffuse-type gastric carcinoma. The percentage of dual expression of leptin and leptin receptor in intestinal-type gastric adenocarcinoma was significantly higher than that in diffuse-type gastric adenocarcinoma (χ2 = 37.022, P<0.01). CONCLUSION: Our results indicate the presence of an autocrine loop of leptin system in the development of intestinal-type gastric adenocarcinoma. PMID:16437696

  17. A Novel DBL-Domain of the P. falciparum 332 Molecule Possibly Involved in Erythrocyte Adhesion

    PubMed Central

    Moll, Kirsten; Kaneko, Osamu; Nilsson, Sandra; Winter, Gerhard; Haeggström, Malin; Pan, Weiqing; Berzins, Klavs; Wahlgren, Mats; Chen, Qijun

    2007-01-01

    Plasmodium falciparum malaria is brought about by the asexual stages of the parasite residing in human red blood cells (RBC). Contact between the erythrocyte surface and the merozoite is the first step for successful invasion and proliferation of the parasite. A number of different pathways utilised by the parasite to adhere and invade the host RBC have been characterized, but the complete biology of this process remains elusive. We here report the identification of an open reading frame (ORF) representing a hitherto unknown second exon of the Pf332 gene that encodes a cysteine-rich polypeptide with a high degree of similarity to the Duffy-binding-like (DBL) domain of the erythrocyte-binding-ligand (EBL) family. The sequence of this DBL-domain is conserved and expressed in all parasite clones/strains investigated. In addition, the expression level of Pf332 correlates with proliferation efficiency of the parasites in vitro. Antibodies raised against the DBL-domain are able to reduce the invasion efficiency of different parasite clones/strains. Analysis of the DBL-domain revealed its ability to bind to uninfected human RBC, and moreover demonstrated association with the iRBC surface. Thus, Pf332 is a molecule with a potential role to support merozoite invasion. Due to the high level of conservation in sequence, the novel DBL-domain of Pf332 is of possible importance for development of novel anti-malaria drugs and vaccines. PMID:17534427

  18. Brain Glycogen Decreases During Intense Exercise Without Hypoglycemia: The Possible Involvement of Serotonin.

    PubMed

    Matsui, Takashi; Soya, Shingo; Kawanaka, Kentaro; Soya, Hideaki

    2015-07-01

    Brain glycogen stored in astrocytes, a source of lactate as a neuronal energy source, decreases during prolonged exercise with hypoglycemia. However, brain glycogen dynamics during exercise without hypoglycemia remain unknown. Since intense exercise increases brain noradrenaline and serotonin as known inducers for brain glycogenolysis, we hypothesized that brain glycogen decreases with intense exercise not accompanied by hypoglycemia. To test this hypothesis, we employed a well-established acute intense exercise model of swimming in rats. Rats swam for fourteen 20 s bouts with a weight equal to 8 % of their body mass and were sacrificed using high-power (10 kW) microwave irradiation to inactivate brain enzymes for accurate detection of brain glycogen and monoamines. Intense exercise did not alter blood glucose, but did increase blood lactate levels. Immediately after exercise, brain glycogen decreased and brain lactate increased in the hippocampus, cerebellum, cortex, and brainstem. Simultaneously, serotonin turnover in the hippocampus and brainstem mutually increased and were associated with decreased brain glycogen. Intense swimming exercise that does not induce hypoglycemia decreases brain glycogen associated with increased brain lactate, implying an importance of glycogen in brain energetics during intense exercise even without hypoglycemia. Activated serotonergic regulation is a possible underlying mechanism for intense exercise-induced glycogenolysis at least in the hippocampus and brainstem.

  19. Regional intestinal absorption and biliary excretion of fluvastatin in the rat: possible involvement of mrp2.

    PubMed

    Lindahl, Anders; Sjöberg, Asa; Bredberg, Ulf; Toreson, Helena; Ungell, Anna-Lena; Lennernäs, Hans

    2004-01-01

    The first purpose of this study was to investigate the in vivo absorption, biliary secretion, and first-pass effect of fluvastatin following regional intestinal dosing in the rat. We also examined the membrane transport mechanisms and made in silico predictions of the relative importance of various intestinal regions to the human absorption of fluvastatin. Fluvastatin was administered intravenously (2, 10, and 20 micromol/kg) and into the duodenum (1.46, 2.92, 7.32, and 14.6 micromol/kg), jejunum (14.6 micromol/kg), ileum (1.46 and 14.6 mciromol/kg), and colon (1.46 and 14.6 micromol/kg) as a solution to conscious rats. In a separate group of rats, bile was collected after an i.v. dose of fluvastatin (2 micromol/kg). In the Caco-2 model the bidirectional transport of fluvastatin (16 microM) was investigated with and without various efflux inhibitors (verapamil, vinblastine, probenecid, and indomethacin, 160 microM). The human in vivo absorption of fluvastatin from an oral immediate release tablet and that from an oral extended release tablet (both 40 mg) were simulated in GastroPlus. Neither the dose nor the intestinal region influenced the bioavailability of fluvastatin significantly. The rate of absorption was, however, affected by both the dose and the site of administration; duodenum = jejunum > colon > ileum, and higher following the high dose. Increasing the i.v. dose from 2 to 20 micromol/kg decreased the clearance (26 +/- 3 to 12 +/- 1 mL/min/kg), the hepatic extraction (66 +/- 8 to 30 +/- 2%), and the volume of distribution (7.3 +/- 0.3 to 2.1 +/- 0.7 L/kg) for fluvastatin (p < 0.05). Neither bile cannulation nor bile sampling affected the pharmacokinetics. Fluvastatin was secreted into the bile, probably by active transport. The in vitro permeability for fluvastatin was high (>10 x 10(-6) cm/s). Indomethacin, but not the other inhibitors, affected the transport in both directions suggesting mrp2 to be involved. In silico, 93% of the dose was absorbed from

  20. Age-related differences in experimental stroke: possible involvement of mitochondrial dysfunction and oxidative damage.

    PubMed

    Li, Nanlin; Kong, Xiangwei; Ye, Ruidong; Yang, Qianzi; Han, Junliang; Xiong, Lize

    2011-06-01

    Age is the single most important risk factor for cerebral stroke. Unfortunately, the effect of age on ischemic brain damage is less clear. In this study, we sought to examine the potential influence of aging on the histologic and functional outcomes after ischemia. Juvenile (4 weeks of age), young adult (4 months of age), mid-aged (11-12 months of age), and aged (18-19 months of age) mice were subjected to transient middle cerebral artery occlusion. There was no remarkable difference of infarct volume on postoperative days 1 and 3. However, on postoperative day 7, aged mice exhibited significantly worsened infarct volume compared with juvenile and young mice. Intriguingly, the increase of infarct volume was most prominent in the striatal area rather than in cortex. Accordingly, aged mice displayed a slower and incomplete functional recovery after stroke. We further evaluated the effects of aging on the oxidative damage and mitochondrial dysfunction following ischemia. Brain tissues were assayed for lipid, DNA, and protein peroxidation products, mitochondrial enzyme activities, mitochondrial membrane potential, production of reactive oxygen species, and antioxidant activities. Aging was associated with declined mitochondrial function and antioxidant detoxification following ischemia, thereby inducing a deteriorated oxidative damage. Regional subanalyses demonstrated that, in accordance with infarct area, the pro-oxidant/antioxidant imbalance occurred more prominently in subcortical areas. Collectively, these findings suggest mitochondria-mediated oxidative damage may be involved in the age-related aggravated injury in subcortical areas. Mitochondrial protection could be a promising target for neuroprotective therapy, especially in the aged population.

  1. Enzyme activity alteration by cadmium administration to rats: the possibility of iron involvement in lipid peroxidation.

    PubMed

    Casalino, E; Sblano, C; Landriscina, C

    1997-10-15

    The specific activities of D-3-hydroxybutyrate dehydrogenase (BDH) and glutamate dehydrogenase (GDH) are reduced in the liver and kidney of rats intoxicated with 2.5 mg Cd/kg body wt and sacrificed after 24 h; conversely ketone-body concentration is strongly increased in both of these organs and blood. In the same animals a great stimulation of antioxidant enzymes glutathione reductase and glutathione peroxidase occurs. The prooxidant state induced by cadmium in liver mitochondria and microsomes is unaffected by superoxide dismutase, catalase, or mannitol, whereas it is completely blocked by vitamin E thus excluding the involvement of reactive oxygen species in this process. The mechanism by which cadmium induces lipid peroxidation has been investigated by measuring the effect of this metal on liposomes. Ninety-minute treatment of liposomes with CdCl2 does not induce any lipid peroxidation. In contrast, Fe2+ ions under the same conditions cause strong liposome peroxidation. It has also been observed that cadmium promotes a time-dependent iron release from biological membranes. When lipid peroxidation is induced by a low concentration (5 microM) of FeCl2, in place of CdCl2, the characteristics of this process and the sensitivity to the various antioxidants used are similar to those observed with Cd. From these results we conclude that the prooxidative effect of cadmium is an indirect one since it is mediated by iron. With regard to the inhibitory effect on BDH and GDH following cadmium intoxication, it does not appear to be imputable to lipid peroxidation since in vitro investigations indicate that the presence of vitamin E does not remove the inhibition at all.

  2. Bacopa monnieri ameliorates memory deficits in olfactory bulbectomized mice: possible involvement of glutamatergic and cholinergic systems.

    PubMed

    Le, Xoan Thi; Pham, Hang Thi Nguyet; Do, Phuong Thi; Fujiwara, Hironori; Tanaka, Ken; Li, Feng; Van Nguyen, Tai; Nguyen, Khoi Minh; Matsumoto, Kinzo

    2013-10-01

    This study investigated the effects of alcoholic extract of Bacopa monnieri (L.) Wettst. (BM) on cognitive deficits using olfactory bulbectomized (OBX) mice and the underlying molecular mechanisms of its action. OBX mice were treated daily with BM (50 mg/kg, p.o.) or a reference drug, tacrine (2.5 mg/kg, i.p.), 1 week before and continuously 3 days after OBX. Cognitive performance of the animals was analyzed by the novel object recognition test, modified Y maze test, and fear conditioning test. Brain tissues of OBX animals were used for neurochemical and immunohistochemical studies. OBX impaired non-spatial short-term memory, spatial working memory, and long-term fair memory. BM administration ameliorated these memory disturbances. The effect of BM on short-term memory deficits was abolished by a muscarinic receptor antagonist, scopolamine. OBX downregulated phosphorylation of synaptic plasticity-related signaling proteins: NR1 subunit of N-methyl-D-aspartate receptor, glutamate receptor 1 (GluR1), and calmodulin-dependent kinase II but not cyclic AMP-responsive element binding protein (CREB), and reduced brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus. OBX also reduced choline acetyltransferase in the hippocampus and cholinergic neurons in the medial septum, and enlarged the size of lateral ventricle. BM administration reversed these OBX-induced neurochemical and histological alterations, except the decrease of GluR1 phosphorylation, and enhanced CREB phosphorylation. Moreover, BM treatment inhibited ex vivo activity of acetylcholinesterase in the brain. These results indicate that BM treatment ameliorates OBX-induced cognition dysfunction via a mechanism involving enhancement of synaptic plasticity-related signaling and BDNF transcription and protection of cholinergic systems from OBX-induced neuronal damage.

  3. Effects of hypergravity exposure on the developing central nervous system: possible involvement of thyroid hormone

    NASA Technical Reports Server (NTRS)

    Sajdel-Sulkowska, E. M.; Li, G. H.; Ronca, A. E.; Baer, L. A.; Sulkowski, G. M.; Koibuchi, N.; Wade, C. E.

    2001-01-01

    The present study examined the effects of hypergravity exposure on the developing brain and specifically explored the possibility that these effects are mediated by altered thyroid status. Thirty-four timed-pregnant Sprague-Dawley rats were exposed to continuous centrifugation at 1.5 G (HG) from gestational Day 11 until one of three key developmental points: postnatal Day (P) 6, P15, or P21 (10 pups/dam: 5 males/5 females). During the 32-day centrifugation, stationary controls (SC, n = 25 dams) were housed in the same room as HG animals. Neonatal body, forebrain, and cerebellum mass and neonatal and maternal thyroid status were assessed at each time point. The body mass of centrifuged neonates was comparatively lower at each time point. The mass of the forebrain and the mass of the cerebellum were maximally reduced in hypergravity-exposed neonates at P6 by 15.9% and 25.6%, respectively. Analysis of neonatal plasma suggested a transient hypothyroid status, as indicated by increased thyroid stimulating hormone (TSH) level (38.6%) at P6, while maternal plasma TSH levels were maximally elevated at P15 (38.9%). Neither neonatal nor maternal plasma TH levels were altered, suggesting a moderate hypothyroid condition. Thus, continuous exposure of the developing rats to hypergravity during the embryonic and neonatal periods has a highly significant effect on the developing forebrain and cerebellum and neonatal thyroid status (P < 0.05, Bonferroni corrected). These data are consistent with the hypothesized role of the thyroid hormone in mediating the effect of hypergravity in the developing central nervous system and begin to define the role of TH in the overall response of the developing organism to altered gravity.

  4. Avian circannual clocks: adaptive significance and possible involvement of energy turnover in their proximate control.

    PubMed

    Wikelski, Martin; Martin, Lynn B; Scheuerlein, Alex; Robinson, Maisha T; Robinson, Nuriya D; Helm, Barbara; Hau, Michaela; Gwinner, Eberhard

    2008-01-27

    Endogenous circannual clocks are found in many long-lived organisms, but are best studied in mammal and bird species. Circannual clocks are synchronized with the environment by changes in photoperiod, light intensity and possibly temperature and seasonal rainfall patterns. Annual timing mechanisms are presumed to have important ultimate functions in seasonally regulating reproduction, moult, hibernation, migration, body weight and fat deposition/stores. Birds that live in habitats where environmental cues such as photoperiod are poor predictors of seasons (e.g. equatorial residents, migrants to equatorial/tropical latitudes) rely more on their endogenous clocks than birds living in environments that show a tight correlation between photoperiod and seasonal events. Such population-specific/interspecific variation in reliance on endogenous clocks may indicate that annual timing mechanisms are adaptive. However, despite the apparent adaptive importance of circannual clocks, (i) what specific adaptive value they have in the wild and (ii) how they function are still largely untested. Whereas circadian clocks are hypothesized to be generated by molecular feedback loops, it has been suggested that circannual clocks are either based upon (i) a de-multiplication ('counting') of circadian days, (ii) a sequence of interdependent physiological states, or (iii) one or more endogenous oscillators, similar to circadian rhythms. We tested the de-multiplication of days (i) versus endogenous regulation hypotheses (ii) and (iii) in captive male and female house sparrows (Passer domesticus). We assessed the period of reproductive (testicular and follicular) cycles in four groups of birds kept either under photoperiods of LD 12L:12D (period length: 24h), 13.5L:13.5D (27 h), 10.5L:10.5D (23 h) or 12D:8L:3D:1L (24-h skeleton photoperiod), respectively, for 15 months. Contrary to predictions from the de-multiplication hypothesis, individuals experiencing 27-h days did not differ (i.e. did

  5. In vitro cleavage by asbestos fibers of the fifth component of human complement through free-radical generation and kallikrein activation.

    PubMed

    Governa, M; Amati, M; Valentino, M; Visonà, I; Fubini, B; Botta, G C; Volpe, A R; Carmignani, M

    2000-04-14

    Chrysotile and crocidolite fibers incubated in normal human plasma (NHP) generated from the C5 component of complement C5a-type fragments that stimulated polymorphonuclear leukocyte (PMN) chemotaxis. Absorption of NHP with antiserum against C5a totally abolished neutrophil chemotactic activity. Asbestos fibers also produced C5a small peptides in the presence of ethylene glycol bis(beta-aminoethyl ether) N,N,N'N'-tetraacetic acid (EGTA) but not ethylene diamine tetraacetic acid (EDTA). Activation of C5 was significantly inhibited when asbestos fibers were pretreated with iron chelators such as sodium dithionite (DTN), deferoxamine (DFX), or ascorbate (AA). Concentration-related inhibition of C5 activation was also observed when asbestos fibers were added concurrently to plasma in the presence of DFX, 1,3-dimethyl-2-thiourea (DMTU), a strong hydroxyl scavenger, or aprotinin (APR), a specific protease inhibitor. Further, chrysotile and crocidolite significantly increased plasma kallikrein activity. Data demonstrate that asbestos-induced C5 activation plays a role in inflammatory reactions characteristic of asbestosis through mechanisms involving iron ions, hydroxyl radicals, and oxidized C5-ike fragments. The ferrous ions present at the asbestos fiber surface trigger this activation and catalyze, via Fenton reaction, the production of hydroxyl radicals, which in turn convert native C5 to an oxidized C5-like form. This product is then cleaved by kallikrein, activated by the same asbestos fibers, yielding an oxidized C5a with the same functional properties as C5a.

  6. Tissue kallikrein promotes neovascularization and improves cardiac function by the Akt-glycogen synthase kinase-3β pathway

    PubMed Central

    Yao, Yu-Yu; Yin, Hang; Shen, Bo; Smith, Robert S.; Liu, Yuying; Gao, Lin; Chao, Lee; Chao, Julie

    2008-01-01

    Aims We investigated the role of the Akt-glycogen synthase kinase (GSK)-3β signalling pathway in mediating the protective effects of tissue kallikrein on myocardial injury by promoting angiogenesis and blood flow in rats after myocardial infarction (MI). Methods and results Human tissue kallikrein gene in an adenoviral vector, with or without co-administration of dominant-negative Akt (Ad.DN-Akt) or constitutively active GSK-3β (Ad.GSK-3βS9A), was injected into rat myocardium after MI. The expression of recombinant human kallikrein in rat heart significantly improved cardiac function and reduced infarct size 10 days after gene delivery. Kallikrein administration significantly increased myocardial blood flow as well as capillary and arteriole densities in the infarcted myocardium. Kallikrein increased cardiac Akt and GSK-3β phosphorylation in conjunction with decreased GSK-3β activity and the upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2). All of kallikrein’s effects on the myocardium were abrogated by Ad.DN-Akt and Ad.GSK-3βS9A. Moreover, in cultured human aortic endothelial cells, tissue kallikrein stimulated capillary tube formation and promoted cell migration; however, these effects were blocked by Ad.DN-Akt, Ad.GSK-3βS9A, icatibant (a kinin B2 receptor antagonist), Tki (a VEGF receptor tyrosine kinase inhibitor), and a neutralizing VEGF antibody. In addition, tissue kallikrein decreased GSK-3β activity via the phosphatidylinositol 3-kinase-Akt pathway and enhanced VEGF and VEGFR-2 expression in endothelial cells. Conclusion These data provide the first direct evidence that tissue kallikrein protects against acute-phase MI by promoting neovascularization, restoring regional blood flow and improving cardiac function through the kinin B2 receptor-Akt-GSK-3β and VEGF signalling pathways. PMID:18689794

  7. Use of different derivatives of D-Val-Leu-Arg for studying kallikrein activities in cat submandibular glands and saliva.

    PubMed

    Garrett, J R; Kidd, A; Kyriacou, K; Smith, R E

    1985-07-01

    Glandular kallikrein shows a special selectivity for D-Val-Leu-Arg-4-methoxy-2-naphthylamide in comparison with other potential oligopeptide substrates and it provides a useful histochemical substrate, although the reaction may not always be specific. However, in cat submandibular saliva, a biochemical assay using the closely related D-Val-Leu-Arg-7-amino-4-trifluoromethylcoumarin (AFC) as substrate, which affords more sensitive detection, showed that soya bean trypsin inhibitor causes no inhibition. This indicates that there are unlikely to be contaminating enzymes competing for the substrate in this body fluid. Support for this observation has been gained by the useful new enzyme overlay membrane technique for fluorescent assessment of reactive bands of enzymes after isoelectric focusing, using membranes of cellulose acetate impregnated with D-Val-Leu-Arg-AFC. Comparison of results after isoelectric focusing of purified cat submandibular kallikrein with samples of cat submandibular saliva confirmed that the substrate is monospecific for kallikrein in saliva of the cat. This knowledge has enabled us to start assessing the dynamics of the secretion of kallikrein by the gland. Testing individual drops of saliva has shown that an amazingly rapid mobilization of kallikrein occurs in high concentrations on sympathetic nerve stimulation. The corresponding oligopeptide-based inhibitor D-Val-Leu-Arg-chloromethyl ketone was found to be strongly inhibitory of the amidase reaction by kallikrein but showed a low specificity for kallikrein. Nevertheless, its effects have been tested in vivo by the intravascular route and it caused an increase in the resting salivary vascular resistance whether administered close-arterially or intravenously. Thus, it would seem that a kallikrein-like protease does influence the background tone in the vessels and the source of this enzyme is thought to be mast cells.

  8. Human plasma kallikrein and tissue kallikrein binding to a substrate based on the reactive site of a factor Xa inhibitor isolated from Bauhinia ungulata seeds.

    PubMed

    Oliva, M L; Andrade, S A; Batista, I F; Sampaio, M U; Juliano, M; Fritz, H; Auerswald, E A; Sampaio, C A

    1999-12-01

    Kunitz type Bauhinia ungulata factor Xa inhibitor (BuXI) was purified from B. ungulata seeds. BuXI inactivates factor Xa and human plasma kallikrein (HuPK) with Ki values of 18.4 and 6.9 nM, respectively. However, Bauhinia variegata trypsin inhibitor (BvTI) which is 70% homologous to BuXI does not inhibit factor Xa and is less efficient on HuPK (Ki = 80 nM). The comparison between BuXI and BvTI reactive site structure indicates differences at Met59, Thr66 and Met67 residues. The hydrolysis rate of quenched fluorescence peptide substrates based on BuXI reactive site sequence, Abz-VMIAALPRTMFIQ-EDDnp (leading peptide), by HuPK and porcine pancreatic kallikrein (PoPK) is low, but hydrolysis is enhanced with Abz-VMIAALPRTMQ-EDDnp, derived from the leading peptide shortened by removing the dipeptide Phe-Ileu from the C-terminal portion, for HuPK (Km = 0.68 microM, k(cat)/Km = 1.3 x 10(6) M(-1) s(-1)), and the shorter substrate Abz-LPRTMQ-EDDnp is better for PoPK (Km = 0.66 microM, k(cat)/Km = 2.2 x 10(3) M(-1) s(-1)). The contribution of substrate methionine residues to HuPK and PoPK hydrolysis differs from that observed with factor Xa. The determined Km and k(cat) values suggest that the substrates interact with kallikreins the same as an enzyme and inhibitor interacts to form complexes.

  9. Kallikrein genes are associated with lupus and glomerular basement membrane–specific antibody–induced nephritis in mice and humans

    PubMed Central

    Liu, Kui; Li, Quan-Zhen; Delgado-Vega, Angelica M.; Abelson, Anna-Karin; Sánchez, Elena; Kelly, Jennifer A.; Li, Li; Liu, Yang; Zhou, Jinchun; Yan, Mei; Ye, Qiu; Liu, Shenxi; Xie, Chun; Zhou, Xin J.; Chung, Sharon A.; Pons-Estel, Bernardo; Witte, Torsten; de Ramón, Enrique; Bae, Sang-Cheol; Barizzone, Nadia; Sebastiani, Gian Domenico; Merrill, Joan T.; Gregersen, Peter K.; Gilkeson, Gary G.; Kimberly, Robert P.; Vyse, Timothy J.; Kim, Il; D’Alfonso, Sandra; Martin, Javier; Harley, John B.; Criswell, Lindsey A.; Wakeland, Edward K.; Alarcón-Riquelme, Marta E.; Mohan, Chandra

    2009-01-01

    Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody–induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that may be responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody–induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family, which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody–induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms, some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody–induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody–induced nephritis and lupus. PMID:19307730

  10. Beneficial effect of berberine on hepatic insulin resistance in diabetic hamsters possibly involves in SREBPs, LXRα and PPARα transcriptional programs.

    PubMed

    Liu, Xuhan; Li, Guosheng; Zhu, Hua; Huang, Lan; Liu, Yali; Ma, Chunmei; Qin, Chuan

    2010-01-01

    The "lipotoxicity" hypothesis holds that fat-induced hepatic insulin resistance (FIHIR) may play a major role in the pathogenesis of type 2 diabetes. Berberine has been reported to have antidiabetic properties. However, the molecular mechanisms for this action are not fully clarified. Therefore, we will investigate the gene expression alterations involved in the therapeutic effect of berberine on FIHIR in diabetic hamsters and possible mechanisms. In this study, type 2 diabetic hamsters were induced by high-fat diet with streptozotocin injection. After 9 weeks of berberine-treatment, the gene expression alterations involved in the therapeutic molecular mechanisms of berberine on FIHIR will be studied by microarray technology and real time RT-PCR. Our study demonstrates berberine significantly improved fat-induced insulin resistance and diabetic phenotype in type 2 diabetic hamsters. The alterations of certain metabolism related genes and their main regulators: Liver X receptor (LXR) α, Peroxisome proliferator-activated receptor (PPAR) α and Sterol regulatory element-binding protein (SREBPs) are observed in the liver of treated and untreated diabetic hamsters. Compared with diabetic hamsters, the increased mRNA levels of LXRα and PPARα and the decreased mRNA levels of SREBPs are observed in berberine-treated diabetic hamster. The statistical significance of the expression of hepatic LXRα, SREBPs and PPARα and their certain target genes is found between treated and untreated diabetic hamsters. These results suggest that altered hepatic SREBPs, LXRα and PPARα transcriptional programs possibly involve in the therapeutic mechanisms of berberine on FIHIR in type 2 diabetic hamsters.

  11. Effect of metoprolol on 24-hour urinary excretion of adrenal steroids and kallikrein in patients with essential hypertension.

    PubMed Central

    Fritschka, E.; Gotzen, R.; Kittler, R.; Schöneshöfer, M.

    1984-01-01

    Treatment of fifteen patients with essential hypertension over four weeks using the beta 1-adrenoceptor blocking agent, metoprolol, resulted in a decrease in 24 h urinary excretion of kallikrein and aldosterone along with a decrease in plasma renin activity. There was no significant change in 24 h excretion rates of the free adrenal steroids deoxycorticosterone, 18-OH-deoxycorticosterone, corticosterone, cortisol or 18-OH-corticosterone during treatment, which were not significantly different from excretion rates of normal males, thus excluding inhibitory effects of adrenal steroids on urinary kallikrein activity. A positive correlation was found between plasma renin activity and urinary excretion of kallikrein during the control period and after 2 weeks on metoprolol, supporting the assumption of a preserved link between the renin-angiotensin-aldosterone system and the renal excretion of kallikrein in these patients. The decrease in kallikrein excretion during beta 1-adrenoceptor blockade in patients with essential hypertension may be explained by a reduction in sympathetic tone and by reduced activity of the renin-aldosterone system. PMID:6367871

  12. Purification and preliminary characterization of a plasma kallikrein inhibitor isolated from sea hares Aplysia dactylomela Rang, 1828.

    PubMed

    González, Y; Araujo, M S; Oliva, M L V; Sampaio, C A M; Chávez, M A

    2004-02-01

    An inhibitor active against pancreatic trypsin was found in the crude extract from the sea hares Aplysia dactylomelaRang, 1828. A stronger inhibitory activity against human plasma kallikrein was detectable after treating this extract at 60 degrees C, for 30 min. The plasma kallikrein inhibitor (AdKI) purification was achieved by acetone fractionation (80%) v/v, ion-exchange chromatography on Mono Q column and gel filtration chromatography on Superdex 75 column (FPLC system). By the latter a molecular mass of 2900 Da was estimated. The purified inhibitor strongly inhibits human plasma kallikrein with a K(i) value of 2.2 x 10(-10)M, while human plasmin and pancreatic trypsin were inhibited with K(i) values of 1.8 x 10(-9) and 4.7 x 10(-9)M, respectively. Chymotrypsin, pancreatic elastase, pancreatic kallikrein and thrombin are not inhibited. The effect of AdKI on plasma kallikrein was confirmed by the prolongation of activated partial thromboplastin time, using a clotting time assay. The inhibitor did not affect prothrombin time or thrombin time. AdKi is a more specific inhibitor than other serine proteinase inhibitors from marine invertebrates.

  13. Initial study on the possible mechanisms involved in the effects of high doses of perfluorooctane sulfonate (PFOS) on prolactin secretion.

    PubMed

    Salgado, R; Pereiro, N; López-Doval, S; Lafuente, A

    2015-09-01

    Perfluorooctane sulfonate (PFOS) is a fluorinated organic compound. This chemical is neurotoxic and can alter the pituitary secretion. This is an initial study aimed at knowing the toxic effects of high doses of PFOS on prolactin secretion and the possible mechanisms involved in these alterations. For that, adult male rats were orally treated with 3.0 and 6.0 mg of PFOS/kg body weight (b.w.)/day for 28 days. At the end of the treatment, the serum levels of prolactin and estradiol as well as the concentration of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and gamma-aminobutyric acid (GABA) were quantified in the anterior and in the mediobasal hypothalamus. PFOS, at the administered doses, reduced prolactin and estradiol secretion, increased the concentration of dopamine and GABA in the anterior hypothalamus, and decreased the ratios DOPAC/dopamine and HVA/dopamine in this same hypothalamic area. The outcomes reported in this study suggest that (1) high doses of PFOS inhibit prolactin secretion in adult male rats; (2) only the periventricular-hypophysial dopaminergic (PHDA) neurons seem to be involved in this inhibitory effect but not the tuberoinfundibular dopaminergic (TIDA) and the tuberohypophysial dopaminergic (THDA) systems; (3) GABAergic cells from the paraventricular and supraoptic nuclei could be partially responsible for the PFOS action on prolactin secretion; and finally (4) estradiol might take part in the inhibition exerted by elevated concentration of PFOS on prolactin release.

  14. Studies on Bronchodilator Activity of Salvia officinalis (Sage): Possible Involvement of K(+) Channel Activation and Phosphodiesterase Inhibition.

    PubMed

    Gilani, Anwarul-Hassan; Rehman, Najeeb-Ur; Khan, Aslam; Alkharfy, Khalid M

    2015-06-01

    The aqueous methanolic extract of the aerial parts of Salvia officinalis (So.Cr) was studied to provide possible underlying mechanism(s) for its medicinal use in asthma using the in vivo bronchodilatory assay and isolated tracheal preparations. S. officinalis (1-10 mg/kg) dose-dependently inhibited carbachol (CCh)-induced bronchospasm in anesthetized rats with three-fold greater potency than the positive control, aminophylline. In tracheal preparations, So.Cr inhibited the low K(+) (25 mM)-induced contractions. Pretreatment of the tissues with 4-aminopyridine reversed the inhibitory effect of the plant extract against low K(+) , whereas glibenclamide did not show any effect, thus showing the involvement of voltage-sensitive K(+) channels. When tested against the CCh-induced pre-contractions for the involvement of any additional mechanism, interestingly, the extract showed a dose-dependent (0.03-0.1 mg/mL) inhibitory effect and shifted the inhibitory concentration response curves of isoprenaline to the left, thus showing phosphodiesterase enzyme inhibitory-like action, similar to that of papaverine. These results indicate that the crude extract of S. officinalis possesses bronchodilatory activity mediated predominantly via activation of voltage-dependent K(+) channels and inhibition of phosphodiesterase enzyme; thus, this study provides sound pharmacological basis for its medicinal use in hyperactive airways disorders such as asthma and cough. Copyright © 2015 John Wiley & Sons, Ltd.

  15. Transsynaptic modality codes in the brain: possible involvement of synchronized spike timing, microRNAs, exosomes and epigenetic processes

    PubMed Central

    Smythies, John; Edelstein, Lawrence

    2013-01-01

    This paper surveys two different mechanisms by which a presynaptic cell can modulate the structure and function of the postsynaptic cell. We first present the evidence that this occurs, and then discuss two mechanisms that could bring this about. The first hypothesis relates to the long lasting effects that the spike patterns of presynaptic axons may exert by modulating activity–inducible programs in postsynaptic cells. The second hypothesis is based on recently obtained evidence that, the afferent neuron at the neuromuscular junction buds off exosomes at its synapse and carries a cargo of Wg and Evi, which are large molecular transsynaptic signaling agents (LMTSAs). Further evidence indicates that many types of neurons bud off exosomes containing payloads of various lipids, proteins, and types of RNA. The evidence suggests that they are transmitted across the synapse and are taken up by the postsynaptic structure either by perisynaptic or exosynaptic mechanisms, thus mediating the transfer of information between neurons. To date, the molecular hypothesis has been limited to local interactions within the synapse of concern. In this paper, we explore the possibility that this represents a mechanism for information transfer involving the postsynaptic neuron as a whole. This entails a review of the known functions of these molecules in neuronal physiology, together with an estimate of the possible types of information they could carry and how they might affect neurocomputations. PMID:23316146

  16. Possible involvement of nitric oxide in morphine-induced miosis and reduction of intraocular pressure in rabbits.

    PubMed

    Bonfiglio, Vincenza; Bucolo, Claudio; Camillieri, Giovanni; Drago, Filippo

    2006-03-18

    The role of mu3 opioid receptors in morphine-induced intraocular pressure (IOP) lowering effect and miosis was evaluated in conscious, dark-adapted New Zealand white (NZW) rabbits using a masked-design study. IOP and pupil diameter (PD) measurements were taken at just before and 0.5, 1, 2, 4, 6 h after monolateral instillation of morphine (10, 50 and 100 microg/30 microl) as compared to vehicle administered in the contralateral eye. Morphine-induced ocular effects were challenged by a pre-treatment with the non-selective opioid receptor antagonist, naloxone (100 microg/30 microl), the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME, 1%, 30 microl), or the non-selective mu3 opioid receptor inhibitor, reduced L-glutathione (GSH, 1%, 30 microl). Morphine induced a dose-dependent decrease in IOP and PD. Pre-treatment with naloxone totally prevented morphine-induced decrease in IOP and miosis. Ocular administration of L-NAME or GSH alone failed to affect IOP or PD of NZW rabbits. However, pre-treatment with either drugs significantly reduced, but not totally prevented ocular effects of morphine. These results suggest that biochemical mechanisms related to nitric oxide release are involved, at least in part, in morphine effects on the eye. Since the mu3 opioid receptor subtype is able to release nitric oxide and is sensitive to inactivation by GSH, it may be possible that mu3 opioid receptors are involved in morphine-induced miosis and reduction in IOP.

  17. Possible involvement of sigma-1 receptors in the anti-immobility action of bupropion, a dopamine reuptake inhibitor.

    PubMed

    Dhir, Ashish; Kulkarni, S K

    2008-08-01

    Sigma receptors particularly, sigma-1 subtype is known to modulate the release of catecholamines in the brain and may participate in the mechanism of action of various antidepressants. The present study investigated the possible involvement of sigma receptors in modulating the anti-immobility-like effect of bupropion (a dopamine reuptake inhibitor) using the forced swim test (FST) in mice. Bupropion produced dose-dependent (10-40 mg/kg, i.p.) reduction in immobility period and the ED(50) value was found to be 18.5 (7.34-46.6) mg/kg, i.p. (+)-Pentazocine (2.5 mg/kg, i.p.), a high-affinity sigma-1 receptor agonist, produced synergistic response when it was co-administered with a subeffective dose of bupropion (10 mg/kg, i.p.). On the contrary, pretreatment with progesterone (10 mg/kg, s.c.), a sigma-1 receptor antagonist neurosteroid, rimcazole (5 mg/kg, i.p.), another sigma-1 receptor antagonist, or BD 1047 (1 mg/kg, i.p.), a novel sigma-1 receptor antagonist, reversed the anti-immobility effects of bupropion (20 mg/kg, i.p.). The various modulators used in the study did not show any effect per se on locomotor activity except bupropion which at a higher dose (15-40 mg/kg, i.p.) significantly increased the locomotor activity. The results for the first time demonstrated the involvement of sigma-1 receptors in the anti-immobility effects of bupropion.

  18. The kallikrein gene 5 splice variant 2 is a new biomarker for breast and ovarian cancer.

    PubMed

    Yousef, George M; White, Nicole M A; Kurlender, Lisa; Michael, Iacovos; Memari, Nader; Robb, John-Desmond; Katsaros, Dionyssios; Stephan, Carsten; Jung, Klaus; Diamandis, Eleftherios P

    2004-01-01

    The presence of more than one mRNA form for the same gene is common among kallikreins, and many of the kallikrein splice variants may hold significant clinical value. The human kallikrein gene 5 (KLK5) is a member of the human kallikrein gene family of serine proteases on chromosome 19q13.4. KLK5 has been shown to be differentially expressed in a variety of endocrine tumors including ovarian, breast and prostate cancer. Utilizing Expressed Sequence Tag database analysis and reverse transcriptase polymerase chain reaction, we identified a new alternatively spliced form of KLK5(KLK5-splice variant 2, KLK5-SV2). This variant mRNA is 1,438 bp in length; formed of 195 bp of 5' untranslated region, 882 bp of protein coding sequence and a 3' untranslated region of 326 nucleotides. KLK5-SV2 has 7 exons, the first 2 of which are untranslated, and 6 intervening introns. KLK5-SV2 is different from the classic form of the KLK5 mRNA in its 5' untranslated region, where the first 5' untranslated exon of the classic form is split into 2 exons with an intervening intron of 135 nucleotides. KLK5-SV2 is expressed in a variety of tissues, with higher expression levels in the mammary gland, cervix, salivary gland and trachea. The steroid hormone receptor-positive breast cancer cell line BT-474 was used to examine the effect of different steroids on the expression levels of KLK5-SV2. Expression levels were significantly higher after stimulation with androgens, but not estrogens, progestins, aldosterone or corticosteroids. While relatively high levels of expression were found in all 10 normal breast tissues examined, no expression was detected in 16 breast cancer tissues, and expression was significantly lower than normal in the remaining 4 cancers. Expression levels comparable to normal were found in only 1 breast cancer cell line. Weak to no expression was detected in 3 other breast cancer cell lines. KLK5-SV2 was not detectable in any of the 10 normal ovarian tissues examined. It was

  19. Coordinated steroid hormone-dependent and independent expression of multiple kallikreins in breast cancer cell lines.

    PubMed

    Paliouras, Miltiadis; Diamandis, Eleftherios P

    2007-03-01

    The regulation of gene expression by steroid hormones plays an important role in the normal development and function of many organs, as well in the pathogenesis of endocrine-related cancers. Previous experiments have shown that many kallikrein genes are under steroid hormone regulation in breast cancer cell lines. We here examine the coordinated expression of multiple kallikrein genes in several breast cancer cell lines after steroid hormone stimulation. Breast cancer cell lines were treated with various steroid hormones and kallikrein (KLK/hK) expression of hK3 (prostate-specific antigen, PSA), hK5, hK6, hK7, hK8, hK10, hK11, hK13, and hK14 was analyzed at the RNA level via RT-PCR and at the protein level by immunofluorometric ELISA assays. We identified several distinct hK hormone-dependent and hormone-independent expression patterns. Hormone-specific modulation of expression was seen for several kallikreins in BT-474, MCF-7, and T-47D cell lines. hK6 was specifically up-regulated upon estradiol treatment in all three cell lines whereas PSA expression was induced by dihydrotestosterone (DHT) and norgestrel stimulation in BT-474 and T-47D. hK10, hK11, hK13, and hK14 were specifically up-regulated by DHT in T-47D and by estradiol in BT-474 cells. Bioinformatic analysis of upstream proximal promoter sequences for these hKs did not identify any recognizable hormone-response elements (HREs), suggesting that the coordinated activation of these four hKs represents a unique expression "cassette", utilizing a common hormone-dependent mechanism. We conclude that groups of human hKs are coordinately expressed in a steroid hormone-dependent manner. Our data supports clinical observations linking expression of multiple hKs with breast cancer prognosis.

  20. Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity II. Possible involvement of the gamma-glutamyl cycle.

    PubMed

    Stern, Stephan T; Bruno, Mary K; Horton, Robert A; Hill, Dennis W; Roberts, Jeanette C; Cohen, Steven D

    2005-01-15

    Acetaminophen (APAP) nephrotoxicity has been observed both in humans and research animals. Our recent investigations have focused on the possible involvement of glutathione-derived APAP metabolites in APAP nephrotoxicity and have demonstrated that administration of acetaminophen-cysteine (APAP-CYS) potentiated APAP-induced renal injury with no effects on APAP-induced liver injury. Additionally, APAP-CYS treatment alone resulted in a dose-responsive renal GSH depletion. This APAP-CYS-induced renal GSH depletion could interfere with intrarenal detoxification of APAP or its toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) and may be the mechanism responsible for the potentiation of APAP nephrotoxicity. Renal-specific GSH depletion has been demonstrated in mice and rats following administration of amino acid gamma-glutamyl acceptor substrates for gamma-glutamyl transpeptidase (gamma-GT). The present study sought to determine if APAP-CYS-induced renal glutathione depletion is the result of disruption of the gamma-glutamyl cycle through interaction with gamma-GT. The results confirmed that APAP-CYS-induced renal GSH depletion was antagonized by the gamma-glutamyl transpeptidase (gamma-GT) inhibitor acivicin. In vitro analysis demonstrated that APAP-CYS is a gamma-glutamyl acceptor for both murine and bovine renal gamma-GT. Analysis of urine from mice pretreated with acivicin and then treated with APAP, APAP-CYS, or acetaminophen-glutathione identified a gamma-glutamyl-cysteinyl-acetaminophen metabolite. These findings are consistent with the hypothesis that APAP-CYS contributes to APAP nephrotoxicity by depletion of renal GSH stores through interaction with the gamma-glutamyl cycle.

  1. Alterations in left ventricular function during intermittent hypoxia: Possible involvement of O-GlcNAc protein and MAPK signaling.

    PubMed

    Guo, Xueling; Shang, Jin; Deng, Yan; Yuan, Xiao; Zhu, Die; Liu, Huiguo

    2015-07-01

    Obstructive sleep apnea, characterized by recurrent episodes of hypoxia [intermittent hypoxia (IH)], has been identified as a risk factor for cardiovascular diseases. The O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) of proteins has important regulatory implications on the pathophysiology of cardiovascular disorders. In this study, we examined the role of O-GlcNAcylation in cardiac architecture and left ventricular function following IH. Rats were randomly assigned to a normoxia and IH group (2 min 21% O2; 2 min 6-8% O2). Left ventricular function, myocardial morphology and the levels of signaling molecules were then measured. IH induced a significant increase in blood pressure, associated with a gradually abnormal myocardial architecture. The rats exposed to 2 or 3 weeks of IH presented with augmented left ventricular systolic and diastolic function, which declined at week 4. Consistently, the O-GlcNAc protein and O-GlcNAcase (OGA) levels in the left ventricular tissues steadily increased following IH, reaching peak levels at week 3. The O-GlcNAc transferase (OGT), extracellular signal-regulated kinase 1/2 (ERK1/2) and the p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation levels were affected in an opposite manner. The phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) remained unaltered. In parallel, compared with exposure to normoxia, 4 weeks of IH augmented the O-GlcNAc protein, OGT, phosphorylated ERK1/2 and p38 MAPK levels, accompanied by a decrease in OGA levels and an increase in the levels of myocardial nuclear factor-κB (NF-κB), inflammatory cytokines, caspase-3 and cardiomyocyte apoptosis. Taken together, our suggest a possible involvement of O-GlcNAc protein and MAPK signaling in the alterations of left ventricular function and cardiac injury following IH.

  2. The Impaired Viability of Prostate Cancer Cell Lines by the Recombinant Plant Kallikrein Inhibitor*

    PubMed Central

    Ferreira, Joana Gasperazzo; Diniz, Paula Malloy Motta; de Paula, Cláudia Alessandra Andrade; Lobo, Yara Aparecida; Paredes-Gamero, Edgar Julian; Paschoalin, Thaysa; Nogueira-Pedro, Amanda; Maza, Paloma Korehisa; Toledo, Marcos Sergio; Suzuki, Erika; Oliva, Maria Luiza Vilela

    2013-01-01

    Prostate cancer is the most common type of cancer, and kallikreins play an important role in the establishment of this disease. rBbKIm is the recombinant Bauhinia bauhinioides kallikreins inhibitor that was modified to include the RGD/RGE motifs of the inhibitor BrTI from Bauhinia rufa. This work reports the effects of rBbKIm on DU145 and PC3 prostate cancer cell lines. rBbKIm inhibited the cell viability of DU145 and PC3 cells but did not affect the viability of fibroblasts. rBbKIm caused an arrest of the PC3 cell cycle at the G0/G1 and G2/M phases but did not affect the DU145 cell cycle, although rBbKIm triggers apoptosis and cytochrome c release into the cytosol of both cell types. The differences in caspase activation were observed because rBbKIm treatment promoted activation of caspase-3 in DU145 cells, whereas caspase-9 but not caspase-3 was activated in PC3 cells. Because angiogenesis is important to the development of a tumor, the effect of rBbKIm in this process was also analyzed, and an inhibition of 49% was observed in in vitro endothelial cell capillary-like tube network formation. In summary, we demonstrated that different properties of the protease inhibitor rBbKIm may be explored for investigating the androgen-independent prostate cancer cell lines PC3 and DU145. PMID:23511635

  3. A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal vesicle protein.

    PubMed Central

    Lilja, H

    1985-01-01

    A 33-kD glycoprotein, known as the "prostate-specific antigen," was purified to homogeneity from human seminal plasma. The prostatic protein was identified as a serine protease, and its NH2-terminal sequence strongly suggests that it belongs to the family of glandular kallikreins. The structural protein of human seminal coagulum, the predominant protein in seminal vesicle secretion, was rapidly cleaved by the prostatic enzyme, which suggests that this seminal vesicle protein may serve as the physiological substrate for the protease. The prostatic enzyme hydrolyzed arginine- and lysine-containing substrates with a distinct preference for the former. All synthetic substrates tested were poor substrates for the enzyme. Synthetic Factor XIa substrate (pyro-glutamyl-prolyl-arginine-p-nitroanilide), and the synthetic kallikrein substrate (H-D-prolyl-phenylalanyl-arginine-p-nitroanilide) were hydrolyzed with maximum specific activities at 23 degrees C of 79 and 34 nmol/min per mg and Km values of 1.0 and 0.45 mM, respectively. Synthetic substrates for plasmin, chymotrypsin, and elastase were either not hydrolyzed by the enzyme at all, or only hydrolyzed very slowly. Images PMID:3902893

  4. Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance.

    PubMed

    Avgeris, Margaritis; Mavridis, Konstantinos; Scorilas, Andreas

    2012-04-01

    Tissue kallikrein (KLK1) and kallikrein-related peptidases (KLK2-15) comprise a family of 15 highly conserved secreted serine proteases with similar structural characteristics and a wide spectrum of functional properties. Both gene expression and protein activity of KLKs are rigorously controlled at various levels via diverse mechanisms, including extensive steroid hormone regulation, to exert their broad physiological role. Nevertheless, deregulated expression, secretion, and function of KLK family members has been observed in several pathological conditions and, particularly, in endocrine-related human malignancies, including those of the prostate, breast, and ovary. The cancer-related abnormal activity of KLKs upon substrates such as growth factors, cell adhesion molecules, cell surface receptors, and extracellular matrix proteins facilitate both tumorigenesis and disease progression to the advanced stages. The well-documented relationship between KLK status and the clinical outcome of cancer patients has led to their identification as promising diagnostic, prognostic, and treatment response monitoring biomarkers for these complex disease entities. The main objective of this review is to summarize the existing knowledge concerning the role of KLKs in prostate, breast, and ovarian cancers and to highlight their continually evolving biomarker capabilities that can provide significant benefits for the management of cancer patients.

  5. Evaluation of human tissue kallikrein-related peptidases 6 and 10 expression in early gastroesophageal adenocarcinoma.

    PubMed

    Grin, Andrea; Samaan, Sara; Tripathi, Monika; Rotondo, Fabio; Kovacs, Kalman; Bassily, Mena N; Yousef, George M

    2015-04-01

    Kallikreins are a family of serine proteases that are linked to malignancy of different body organs with potential clinical utility as tumor markers. In this study, we investigated kallikrein-related peptidase 6 (KLK6) and KLK10 expression in early gastroesophageal junction adenocarcinoma and Barrett esophagus (BE) with and without dysplasia. Immunohistochemistry revealed significantly increased KLK6 expression in early invasive cancer compared with dysplastic (P = .009) and nondysplastic BE (P = .0002). There was a stepwise expression increase from metaplasia to dysplasia and invasive tumors. Significantly higher KLK10 was seen in dysplastic lesions compared with metaplasia but not between dysplastic lesions and invasive cancers. KLK6 staining intensity was increased at the invasive front (P = .006), suggesting its role in tumor invasiveness. Neither KLK6 nor KLK10 was significantly associated with other prognostic markers, including depth of invasion, indicating their potential as independent biomarkers. Our results should be interpreted with caution due to limited sample size. There was a significant correlation between KLK6 and KLK10 expression both at the invasive front and within the main tumor, indicating a collaborative effect. We then compared KLK6 and KLK10 messenger RNA expression between metaplastic and cancerous tissues in an independent data set of esophageal carcinoma from The Cancer Genome Atlas. KLK6 and KLK10 may be useful markers and potential therapeutic targets in gastroesophageal junction tumors.

  6. A genetically engineered human Kunitz protease inhibitor with increased kallikrein inhibition in an ovine model of cardiopulmonary bypass.

    PubMed

    Ohri, S K; Parratt, R; White, T; Becket, J; Brannan, J J; Hunt, B J; Taylor, K M

    2001-05-01

    A recombinant human serine protease inhibitor known as Kunitz protease inhibitor (KPI) wild type has functional similarities to the bovine Kunitz inhibitor, aprotinin, and had shown a potential to reduce bleeding in an ovine model of cardiopulmonary bypass (CPB). The aim of this study was to assess KPI-185, a modification of KPI-wild type that differs from KPI-wild type in two amino acid residues and which enhances anti-kallikrein activity in a further double-blind, randomized study in an ovine model of CPB, and to compare with our previous study of KPI-wild type and aprotinin in the same ovine model. Post-operative drain losses and subjective assessment of wound 'dryness' showed no significant differences between KPI-185 and KPI-wild type, despite the significant enhancement of kallikrein inhibition using KPI-185 seen in serial kallikrein inhibition assays. These preliminary findings support the hypothesis that kallikrein inhibition is not the major mechanism by which Kunitz inhibitors such as aprotinin reduce perioperative bleeding.

  7. Nicotine improves ethanol-induced impairment of memory: possible involvement of nitric oxide in the dorsal hippocampus of mice.

    PubMed

    Raoufi, N; Piri, M; Moshfegh, A; Shahin, M-S

    2012-09-06

    In the present study, the possible involvement of nitric oxide (NO) systems in the dorsal hippocampus in nicotine's effect on ethanol-induced amnesia and ethanol state-dependent memory was investigated. Adult male mice were cannulated in the CA1 regions of the dorsal hippocampus and trained on a passive avoidance learning task for memory assessment. We found that pre-training intraperitoneal (i.p.) administration of ethanol (1 g/kg) decreased inhibitory avoidance memory when tested 24 h later. The response induced by pre-training ethanol was significantly reversed by pre-test administration of the drug. Similar to ethanol, pre-test administration of nicotine (0.4 and 0.8 μg/mouse, intra-CA1) alone and nicotine (0.2, 0.4 and 0.8 μg/mouse) plus an ineffective dose of ethanol also significantly reversed the amnesia induced by ethanol. Ethanol amnesia was also prevented by pre-test administration of L-arginine (1.2 μg/mouse, intra-CA1), a NO precursor. Interestingly, an ineffective dose of nicotine (0.2 μg/mouse) in combination with a low dose of L-arginine (0.8 μg/mouse) synergistically improved memory performance impaired by ethanol given before training. In contrast, pre-test intra-CA1 microinjection of L-NAME (NG-nitro-L-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor (0.4 and 0.8 μg/mouse), which reduced memory retrieval in inhibitory avoidance task by itself, in combination with an effective dose of nicotine (0.4 μg/mouse) prevented the improving effect of nicotine on memory impaired by pre-training ethanol. Moreover, intra-CA1 microinjection of L-NAME reversed the L-arginine-induced potentiation of the nicotine response. The results suggest the importance of NO system(s) in the CA1 regions of the dorsal hippocampus for improving the effect of nicotine on the ethanol-induced amnesia.

  8. Netherton syndrome: defective kallikrein inhibition in the skin leads to skin inflammation and allergy.

    PubMed

    Furio, Laetitia; Hovnanian, Alain

    2014-09-01

    Netherton syndrome (NS) is an orphan genetic skin disease with a profound skin barrier defect and severe allergic manifestations. NS is caused by loss of function mutations in SPINK5 encoding lympho-epithelial Kazal-type inhibitor (LEKTI), a secreted multi-domain serine protease inhibitor expressed in stratified epithelia. Studies in mouse models and in NS patients have established that unopposed kallikrein 5 activity triggers stratum corneum detachment and activates PAR-2 signaling, leading to the autonomous production of pro-allergic and pro-inflammatory mediators. This emerging knowledge on NS pathogenesis has highlighted a central role for protease regulation in skin homeostasis but also in the complexity of the disease, and holds the promise of new specific treatments.

  9. Differential expression of a human kallikrein 5 (KLK5) splice variant in ovarian and prostate cancer.

    PubMed

    Kurlender, Lisa; Yousef, George M; Memari, Nader; Robb, John-Desmond; Michael, Iacovos P; Borgoño, Carla; Katsaros, Dionyssios; Stephan, Carsten; Jung, Klaus; Diamandis, Eleftherios P

    2004-01-01

    The presence of more than one mRNA form is common among kallikrein genes. We identified an mRNA transcript of the human kallikrein gene 5 (KLK5), denoted KLK5 splice variant 1 (KLK5-SV1). This variant has a different 5'-splice site, but encodes the same protein as the classical KLK5 transcript. RT-PCR analysis of this variant transcript expression in 29 human tissues indicated highest expression in the cervix, salivary gland, kidney, mammary gland, and skin. Comparative analysis of the expression levels of KLK5-SV1, another splice variant named KLK5 splice variant 2 (KLK5-SV2), and the classical KLK5 form showed that out of all three mRNA transcripts, the classical form is predominantly expressed (found in more tissues and at higher expression levels) followed by KLK5-SV1. KLK5-SV1 is expressed at high levels in ovarian, pancreatic, breast and prostate cancer cell lines. KLK5-SV1 was also found to be expressed in 9/10 ovarian cancer tissues, but it was not found in one normal ovarian tissue tested. Hormonal regulation experiments suggest that KLK5-SV1 is regulated by steroid hormones in the BT-474 breast cancer cell line. Furthermore, this variant had significantly higher expression in normal prostate tissues compared to their matched cancer tissue counterparts. KLK5-SV1 may have clinical utility in various malignancies and should be further explored as a potential new biomarker for prostate and ovarian cancer.

  10. Tissue kallikrein deficiency, insulin resistance, and diabetes in mouse and man.

    PubMed

    Potier, Louis; Waeckel, Ludovic; Fumeron, Fréderic; Bodin, Sophie; Fysekidis, Marinos; Chollet, Catherine; Bellili, Naima; Bonnet, Fabrice; Gusto, Gaëlle; Velho, Gilberto; Marre, Michel; Alhenc-Gelas, François; Roussel, Ronan; Bouby, Nadine

    2014-05-01

    The kallikrein-kinin system has been suggested to participate in the control of glucose metabolism. Its role and the role of angiotensin-I-converting enzyme, a major kinin-inactivating enzyme, are however the subject of debate. We have evaluated the consequence of deficiency in tissue kallikrein (TK), the main kinin-forming enzyme, on the development of insulin resistance and diabetes in mice and man. Mice with inactivation of the TK gene were fed a high-fat diet (HFD) for 3 months, or crossed with obese, leptin-deficient (ob/ob) mice to generate double ob/ob-TK-deficient mutants. In man, a loss-of-function polymorphism of the TK gene (R53H) was studied in a large general population cohort tested for insulin resistance, the DESIR study (4843 participants, 9 year follow-up). Mice deficient in TK gained less weight on the HFD than their WT littermates. Fasting glucose level was increased and responses to glucose (GTT) and insulin (ITT) tolerance tests were altered at 10 and 16 weeks on the HFD compared with standard on the diet, but TK deficiency had no influence on these parameters. Likewise, ob-TK⁻/⁻ mice had similar GTT and ITT responses to those of ob-TK⁺/⁺ mice. TK deficiency had no effect on blood pressure in either model. In humans, changes over time in BMI, fasting plasma glucose, insulinemia, and blood pressure were not influenced by the defective 53H-coding TK allele. The incidence of diabetes was not influenced by this allele. These data do not support a role for the TK-kinin system, protective or deleterious, in the development of insulin resistance and diabetes.

  11. Possible stakeholder concerns regarding volatile organic compound in arid soils integrated demonstration technologies not evaluated in the stakeholder involvement program

    SciTech Connect

    Peterson, T.

    1995-12-01

    The Volatile Organic Compounds in Arid Soils Integrated Demonstration (VOC-Arid ID) supported the demonstration of a number of innovative technologies, not all of which were evaluated in the integrated demonstration`s stakeholder involvement program. These technologies have been organized into two categories and the first category ranked in order of priority according to interest in the evaluation of the technology. The purpose of this report is to present issues stakeholders would likely raise concerning each of the technologies in light of commentary, insights, data requirements, concerns, and recommendations offered during the VOC-Arid ID`s three-year stakeholder involvement, technology evaluation program. A secondary purpose is to provide a closeout status for each of the technologies associated with the VOC-Arid ID. This report concludes with a summary of concerns and requirements that stakeholders have for all innovative technologies.

  12. Possible involvement of 15-deoxy-Δ(12,14) -prostaglandin J2 in the development of leptin resistance.

    PubMed

    Hosoi, Toru; Matsuzaki, Syu; Miyahara, Tsuyoshi; Shimizu, Kaori; Hasegawa, Yuki; Ozawa, Koichiro

    2015-05-01

    Obesity is a worldwide health problem that urgently needs to be solved. Leptin is an anti-obesity hormone that activates satiety signals to the brain. Evidence to suggest that leptin resistance is involved in the development of obesity is increasing; however, the molecular mechanisms involved remain unclear. We herein demonstrated that 15-deoxy-Δ(12,14) -prostaglandin J2 (15d-PGJ2 ) was involved in the development of leptin resistance. A treatment with 15d-PGJ2 inhibited the leptin-induced activation of signal transducer and activator of transcription 3 (STAT3) in neuronal cells (SH-SY5Y-Ob-Rb cells). Furthermore, the intracerebroventricular administration of 15d-PGJ2 reversed the inhibitory effects of leptin on food intake in rats. The peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist, GW9662, slightly reversed the inhibitory effects of 15d-PGJ2 on the leptin-induced activation of STAT3 in neuronal cells. The PPAR-γ agonist, rosiglitazone, also inhibited leptin-induced STAT3 phosphorylation. Therefore, the inhibitory effects of 15d-PGJ2 may be mediated through PPAR-γ. On the other hand, 15d-PGJ2 -induced leptin resistance may not be mediated by endoplasmic reticulum stress or suppressor of cytokine signaling 3. The results of the present study suggest that 15d-PGJ2 is a novel factor for the development of leptin resistance in obesity. Leptin resistance, an insensitivity to the actions of leptin, is involved in the development of obesity. Here, we found 15-deoxy-Δ(12,14) -prostaglandin J2 (15d-PGJ2 ) may be involved in the development of leptin resistance. The present results suggest that the 15d-PGJ2 may be a novel factor for the development of leptin resistance in obesity. 15d-PGJ2 , 15-Deoxy-Δ(12,14) -prostaglandin J2; STAT3, signal tranducer and activator of transcription 3.

  13. Rat epileptic seizures evoked by BmK {alpha}IV and its possible mechanisms involved in sodium channels

    SciTech Connect

    Chai Zhifang; Bai Zhantao; Zhang Xuying; Liu Tong; Pang Xueyan; Ji Yonghua . E-mail: yhji@server.shcnc.ac.cn

    2007-05-01

    This study showed that rat unilateral intracerebroventricular injection of BmK {alpha}IV, a sodium channel modulator derived from scorpion Buthus martensi Karsch, induced clusters of spikes, epileptic discharges and convulsion-related behavioral changes. BmK {alpha}IV potently promoted the release of endogenous glutamate from rat cerebrocortical synaptosomes. In vitro examination of the effect of BmK {alpha}IV on intrasynaptosomal free calcium concentration [Ca{sup 2+}]{sub i} and sodium concentration [Na{sup +}]{sub i} revealed that BmK {alpha}IV-evoked glutamate release from synaptosomes was associated with an increase in Ca{sup 2+} and Na{sup +} influx. Moreover, BmK {alpha}IV-mediated glutamate release and ion influx was completely blocked by tetrodotoxin, a blocker of sodium channel. Together, these results suggest that the induction of BmK {alpha}IV-evoked epileptic seizures may be involved in the modulation of BmK {alpha}IV on tetrodotoxin-sensitive sodium channels located on the nerve terminal, which subsequently enhances the Ca{sup 2+} influx to cause an increase of glutamate release. These findings may provide some insight regarding the mechanism of neuronal action of BmK {alpha}IV in the central nervous system for understanding epileptogenesis involved in sodium channels.

  14. Synthesis, biological evaluation, and docking studies of PAR2-AP-derived pseudopeptides as inhibitors of kallikrein 5 and 6.

    PubMed

    Severino, Beatrice; Fiorino, Ferdinando; Corvino, Angela; Caliendo, Giuseppe; Santagada, Vincenzo; Assis, Diego Magno; Oliveira, Juliana R; Juliano, Luiz; Manganelli, Serena; Benfenati, Emilio; Frecentese, Francesco; Perissutti, Elisa; Juliano, Maria Aparecida

    2015-01-01

    A series of protease activated receptor 2 activating peptide (PAR2-AP) derivatives (1-15) were designed and synthesized. The obtained compounds were tested on a panel of human kallikreins (hKLK1, hKLK2, hKLK5, hKLK6, and hKLK7) and were found completely inactive toward hKLK1, hKLK2, and hKLK7. Aiming to investigate the mode of interaction between the most interesting compounds and the selected hKLKs, docking studies were performed. The described compounds distinguish the different human tissue kallikreins with compounds 1 and 5 as the best hKLK5 and hKLK6 inhibitors, respectively.

  15. Polymorphisms in the interleukin-10 gene cluster are possibly involved in the increased risk for major depressive disorder

    PubMed Central

    Traks, Tanel; Koido, Kati; Eller, Triin; Maron, Eduard; Kingo, Külli; Vasar, Veiko; Vasar, Eero; Kõks, Sulev

    2008-01-01

    Background Innate immune inflammatory response is suggested to have a role in the pathogenesis of major depressive disorder (MDD). Interleukin (IL)-10 family cytokines IL-10, IL-19, IL-20, and IL-24 are all implicated in the inflammatory processes and polymorphisms in respective genes have been associated with various immunopathological conditions. This study was carried out to investigate whether single-nucleotide polymorphisms (SNPs) in these genes are also associated with MDD. Methods Case-control association study was performed with seven SNPs from the IL10 gene cluster. 153 patients with MDD and 277 healthy control individuals were recruited. Results None of the selected SNPs were individually associated with MDD. The linkage disequilibrium (LD) analysis indicated the existence of two recombination sites in the IL10 gene cluster, thus confirming the formerly established LD pattern of this genomic region. This also created two haplotype blocks, both consisting of three SNPs. Additionally, the haplotype analysis detected a significantly higher frequency of block 2 (IL20 and IL24 genes) haplotype TGC in the patients group compared to healthy control individuals (P = 0.0097). Conclusion Our study established increased risk for MDD related to the IL20 and IL24 haplotype and suggests that cytokines may contribute to the pathogenesis of MDD. Since none of the block 2 SNPs were individually associated with MDD, it is possible that other polymorphisms linked to them contribute to the disease susceptibility. Future studies are needed to confirm the results and to find the possible functional explanation. PMID:19087313

  16. Adrenergic regulation of gluconeogenesis: possible involvement of two mechanisms of signal transduction in alpha 1-adrenergic action.

    PubMed Central

    García-Sáinz, J A; Hernández-Sotomayor, S M

    1985-01-01

    We have previously suggested that the effects of alpha 1-adrenergic agents on hepatocyte metabolism involve two mechanisms: (i) a calcium-independent insulin-sensitive process that is modulated by glucocorticoids and (ii) a calcium-dependent insulin-insensitive process that is modulated by thyroid hormones. We have studied the effect of epinephrine (plus propranolol) on gluconeogenesis from lactate and dihydroxyacetone. It was observed that the adrenergic stimulation of gluconeogenesis from lactate seemed to occur through both mechanisms, whereas when the substrate was dihydroxyacetone the action took place exclusively through the calcium-independent insulin-sensitive process. This effect was absent in hepatocytes from adrenalectomized rats, suggesting that it is modulated by glucocorticoids. PMID:2995981

  17. Structure of lpg0406, a carboxymuconolactone decarboxylase family protein possibly involved in antioxidative response from Legionella pneumophila.

    PubMed

    Chen, Xiaofang; Hu, Yanjin; Yang, Bo; Gong, Xiaojian; Zhang, Nannan; Niu, Liwen; Wu, Yun; Ge, Honghua

    2015-12-01

    Lpg0406, a hypothetical protein from Legionella pneumophila, belongs to carboxymuconolactone decarboxylase (CMD) family. We determined the crystal structure of lpg0406 both in its apo and reduced form. The structures reveal that lpg0406 forms a hexamer and have disulfide exchange properties. The protein has an all-helical fold with a conserved thioredoxin-like active site CXXC motif and a proton relay system similar to that of alkylhydroperoxidase from Mycobacterium tuberculosis (MtAhpD), suggesting that lpg0406 might function as an enzyme with peroxidase activity and involved in antioxidant defense. A comparison of the size and the surface topology of the putative substrate-binding region between lpg0406 and MtAhpD indicates that the two enzymes accommodate the different substrate preferences. The structural findings will enhance understanding of the CMD family protein structure and its various functions.

  18. Possible involvement of ERK 1/2 in UVA-induced melanogenesis in cultured normal human epidermal melanocytes.

    PubMed

    Yanase, H; Ando, H; Horikawa, M; Watanabe, M; Mori, T; Matsuda, N

    2001-04-01

    UV-induced melanogenesis is a well known physiological response of human skin exposed to solar radiation; however, the signaling molecules involved in the stimulation of melanogenesis in melanocytes following UV exposure remain unclear. In this study we induced melanogenesis in vitro in normal human epidermal melanocytes using a single irradiation with UVA at 1 kJ/m2 and examined the potential involvement of mitogen-activated protein kinases (MAPK) as UVA-responsive signaling molecules in those cells. UVA irradiation did not affect the proliferation of melanocytes, but it did increase tyrosinase mRNA expression, which reached a maximum level 4 hr after UVA irradiation. The amount of tyrosinase protein, as quantitated by immunoblotting, was also increased at 24 hr following UVA irradiation. Among the MAPK examined, extracellular signal-related kinase (ERK) 1/2 was phosphorylated within 15 min of UVA irradiation, but no such phosphorylation was observed for c-Jun N-terminal kinases (JNK) or p38. Accordingly, the activity of ERK1/2 was also increased shortly after UVA irradiation. These responses of ERK1/2 to UVA irradiation were markedly inhibited when cells were pre-treated with N-acetyl-L-cysteine, an antioxidant, or with suramin, a tyrosine kinase receptor inhibitor. The formation of (6-4)photoproducts or cyclobutane pyrimidine dimers was not detected in cellular DNA after UVA irradiation. These findings suggest that a single UVA irradiation-induced melanogenesis is associated with the activation of ERK1/2 by upstream signals that originate from reactive oxygen species or from activated tyrosine kinase receptors, but not from damaged DNA.

  19. Establishment and optimization of a wheat germ cell-free protein synthesis system and its application in venom kallikrein.

    PubMed

    Wang, Yunpeng; Xu, Wentao; Kou, Xiaohong; Luo, Yunbo; Zhang, Yanan; Ma, Biao; Wang, Mengsha; Huang, Kunlun

    2012-08-01

    Wheat germ cell-free protein synthesis systems have the potential to synthesize functional proteins safely and with high accuracy, but the poor energy supply and the instability of mRNA templates reduce the productivity of this system, which restricts its applications. In this report, phosphocreatine and pyruvate were added to the system to supply ATP as a secondary energy source. After comparing the protein yield, we found that phosphocreatine is more suitable for use in the wheat germ cell-free protein synthesis system. To stabilize the mRNA template, the plasmid vector, SP6 RNA polymerase, and Cu(2+) were optimized, and a wheat germ cell-free protein synthesis system with high yield and speed was established. When plasmid vector (30 ng/μl), SP6 RNA polymerase (15 U), phosphocreatine (25 mM), and Cu(2+) (5 mM) were added to the system and incubated at 26°C for 16 h, the yield of venom kallikrein increased from 0.13 to 0.74 mg/ml. The specific activity of the recombinant protein was 1.3 U/mg, which is only slightly lower than the crude venom kallikrein (1.74 U/mg) due to the lack of the sugar chain. In this study, the yield of venom kallikrein was improved by optimizing the system, and a good foundation has been laid for industrial applications and for further studies.

  20. Establishment of an ovarian metastasis model and possible involvement of E-cadherin down-regulation in the metastasis.

    PubMed

    Kuwabara, Yoshiko; Yamada, Taketo; Yamazaki, Ken; Du, Wen-Lin; Banno, Kouji; Aoki, Daisuke; Sakamoto, Michiie

    2008-10-01

    Clinical observations of cases of ovarian metastasis suggest that there may be a unique mechanism underlying ovarian-specific metastasis. This study was undertaken to establish an in vivo model of metastasis to the ovary, and to investigate the mechanism of ovarian-specific metastasis. We examined the capacity for ovarian metastasis in eight different human carcinoma cell lines by implantation in female NOD/SCID mice transvenously and intraperitoneally. By transvenous inoculation, only RERF-LC-AI, a poorly differentiated carcinoma cell line, frequently demonstrated ovarian metastasis. By intraperitoneal inoculation, four of the eight cell lines (HGC27, MKN-45, KATO-III, and RERF-LC-AI) metastasized to the ovary. We compared E-cadherin expression among ovarian metastatic cell lines and others. All of these four ovarian metastatic cell lines and HSKTC, a Krukenberg tumor cell line, showed E-cadherin down-regulation and others did not. E-cadherin was then forcibly expressed in RERF-LC-AI, and inhibited ovarian metastasis completely. The capacity for metastasizing to the other organs was not affected by E-cadherin expression. We also performed histological investigation of clinical ovarian-metastatic tumor cases. About half of all ovarian-metastatic tumor cases showed loss or reduction of E-cadherin expression. These data suggest that E-cadherin down-regulation may be involved in ovarian-specific metastasis.

  1. The antidepressant-like effect of bacopaside I: possible involvement of the oxidative stress system and the noradrenergic system.

    PubMed

    Liu, Xiaojun; Liu, Fang; Yue, Rongcai; Li, Yuanyuan; Zhang, Jigang; Wang, Shuping; Zhang, Shoude; Wang, Rui; Shan, Lei; Zhang, Weidong

    2013-09-01

    In the present study, the antidepressant-like effect of bacopaside I, a saponin compound present in the Bacopa monniera plant, was evaluated by behavioral and neurochemical methods. Bacopaside I (50, 15 and 5 mg/kg) was given to mice via oral gavage for 7 successive days. The treatment significantly decreased the immobility time in mouse models of despair tests, but it did not influence locomotor activity. Neurochemical assays suggested that treatment by bacopaside I (50, 15 and 5 mg/kg) improved brain antioxidant activity to varying degrees after the behavioral despair test. Bacopaside I (15 and 5 mg/kg) significantly reversed reserpine-induced depressive-like behaviors, including low temperature and ptosis. Conversely, bacopaside I did not affect either brain MAO-A or MAO-B activity after the behavioral despair test in mice. Additionally, 5-hydroxytryptophan (a precursor of 5-serotonin) was not involved in the antidepressant-like effect of bacopaside I. These findings indicated that the antidepressant-like effect of bacopaside I might be related to both antioxidant activation and noradrenergic activation, although the exact mechanism remains to be further elucidated.

  2. Increased non-rapid eye movement sleep by cocaine withdrawal: possible involvement of A2A receptors.

    PubMed

    Yang, Shu-Long; Han, Jin-Yi; Kim, Yun-Bae; Nam, Sang-Yoon; Song, Sukgil; Hong, Jin Tae; Oh, Ki-Wan

    2011-02-01

    This study attempted to clarify whether cocaine withdrawal altered sleep architecture and the role of adenosine receptors in this process. Cocaine (20 mg/kg) was administered subcutaneously once per day for 7 days to rat implanted with sleep/wake recording electrode. Polygraphic signs of undisturbed sleep/wake activities were recorded for 24 h before cocaine administration (basal recording as control); withdrawal-day 1 (after 1 day of repeated cocaine administration), withdrawal-day 8 (after 8 days of repeated cocaine administration), and withdrawal-day 14 (after 14 days of repeated cocaine administration), respectively. On cocaine withdrawal-day 1, wakefulness was significantly increased, total sleep was decreased, non-rapid eye movement sleep was markedly reduced, and rapid eye movement sleep was enhanced. Sleep/wake cycles were also increased on cocaine withdrawal day 1. However, non-rapid eye movement sleep was increased on withdrawal-day 8 and 14, whereas rapid eye movement sleep was decreased and no significant changes were observed in the total sleep and sleep/wake cycles during these periods. Adenosine A(2A) receptors expression was increased on withdrawal-day 8 and 14, whereas A(1) receptors levels were reduced after 14 days of withdrawal and the A(2B) receptors remained unchanged. Our findings suggest that alterations of sleep and sleep architecture during cocaine subacute and subchronic withdrawals after repeated cocaine administration may be partially involved in A(2A) receptors over-expression in the rat hypothalamus.

  3. Sucrose transport and phloem unloading in stem of Vicia faba: possible involvement of a sucrose carrier and osmotic regulation

    SciTech Connect

    Aloni, B.; Wyse, R.E.; Griffith, S.

    1986-06-01

    After pulse labeling of a source leaf with /sup 14/CO/sub 2/, stem sections of Vicia faba plants were cut and the efflux characteristics of /sup 14/C-labeled sugars into various buffered solutions were determined. Radiolabeled sucrose was shown to remain localized in the phloem and adjacent phloem parenchyma tissues after a 2-hour chase. Therefore, sucrose leakage from stem segments prepared following a 75-minute chase period was assumed to be characteristic of phloem unloading. The efflux of /sup 14/C assimilates from the phloem was enhanced by 1 millimolar p-chloromercuribenzene sulfonic acid (PCMBS) and by 5 micromolar carbonyl cyanide m-chlorophenly hydrazone (CCCP). However, PCMBS inhibited and CCCP enhanced general leakage of nonradioactive sugars from the stem segments. Sucrose at concentrations of 50 millimolar in the free space increased efflux of (/sup 14/C)sucrose, presumably through an exchange mechanism. This exchange was inhibited by PCMBS and abolished by 0.2 molar mannitol. Increasing the osmotic concentration of the efflux medium with mannitol reduced (/sup 14/C)sucrose efflux. However, this inhibition seems not to be specific to sucrose unloading since leakage of total sugars, nonlabeled sucrose, glucose, and amino acids from the bulk of the tissue was reduced in a similar manner. The data suggest that phloem unloading in cut stem segments is consistent with passive efflux of sucrose from the phloem to the apoplast and that sucrose exchange via a membrane carrier may be involved.

  4. Possible Involvement of TLRs and Hemichannels in Stress-Induced CNS Dysfunction via Mastocytes, and Glia Activation

    PubMed Central

    Aguirre, Adam; Maturana, Carola J.; Harcha, Paloma A.; Sáez, Juan C.

    2013-01-01

    In the central nervous system (CNS), mastocytes and glial cells (microglia, astrocytes and oligodendrocytes) function as sensors of neuroinflammatory conditions, responding to stress triggers or becoming sensitized to subsequent proinflammatory challenges. The corticotropin-releasing hormone and glucocorticoids are critical players in stress-induced mastocyte degranulation and potentiation of glial inflammatory responses, respectively. Mastocytes and glial cells express different toll-like receptor (TLR) family members, and their activation via proinflammatory molecules can increase the expression of connexin hemichannels and pannexin channels in glial cells. These membrane pores are oligohexamers of the corresponding protein subunits located in the cell surface. They allow ATP release and Ca2+ influx, which are two important elements of inflammation. Consequently, activated microglia and astrocytes release ATP and glutamate, affecting myelinization, neuronal development, and survival. Binding of ligands to TLRs induces a cascade of intracellular events leading to activation of several transcription factors that regulate the expression of many genes involved in inflammation. During pregnancy, the previous responses promoted by viral infections and other proinflammatory conditions are common and might predispose the offspring to develop psychiatric disorders and neurological diseases. Such disorders could eventually be potentiated by stress and might be part of the etiopathogenesis of CNS dysfunctions including autism spectrum disorders and schizophrenia. PMID:23935250

  5. Functional heterogeneity of osteocytes in FGF23 production: the possible involvement of DMP1 as a direct negative regulator

    PubMed Central

    Lee, Ji-Won; Yamaguchi, Akira; Iimura, Tadahiro

    2014-01-01

    Fibroblast growth factor 23 (FGF23) and dentin matrix protein (DMP1) are hallmarks of osteocytes in bone. However, the mechanisms underlying the actions of DMP1 as a local factor regulating FGF23 and bone mineralization are not well understood. We first observed spatially distinct distributions of FGF23- and DMP1-positive osteocytic lacunae in rat femurs using immunohistochemistry. Three-dimensional immunofluorescence morphometry further demonstrated that the distribution and relative expression levels of these two proteins exhibited reciprocally reversed patterns especially in midshaft cortical bone. These in vivo findings suggest a direct role of DMP1 in FGF23 expression in osteocytes. We next observed that the inoculation of recombinant DMP1 in UMR-106 osteoblast/osteocyte-like cells and long-cultured MC3T3-E1 osteoblastic cells showed significant downregulation of FGF23 production. This effect was rescued by incubation with an focal adhesion kinase (FAK) inhibitor or MEK (mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK)) inhibitor but not inhibitors of phosphoinositide 3-kinase or Rho kinase. Consistently, the levels of phosphorylated FAK, ERK and p38 were significantly elevated, indicating that exogenous DMP1 is capable of activating FAK-mediated MAPK signaling. These findings suggest that DMP1 is a local, direct and negative regulator of FGF23 production in osteocytes involved in the FAK-mediated MAPK pathway, proposing a relevant pathway that coordinates the extracellular environment of osteocytic lacunae and bone metabolism. PMID:24991406

  6. 5-HT7 receptor-mediated fear conditioning and possible involvement of extracellular signal-regulated kinase.

    PubMed

    Takeda, Kotaro; Tsuji, Minoru; Miyagawa, Kazuya; Takeda, Hiroshi

    2017-01-18

    Fear conditioning is a valuable behavioral paradigm for studying the neural basis of emotional learning and memory. The present study examined the involvement of extracellular signal-regulated kinase 1/2 (ERK) signaling on the serotonin (5-HT)7 receptor-mediated fear conditioning. Conditioning was performed in a trial in which a tone was followed by an electrical foot-shock. Context- and tone-dependent fear were examined in tests conducted 24 and 48h after conditioning, respectively. The selective 5-HT7 receptor antagonist 2a-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-2a,3,4,-tetrahydrobenzo(c,d)indol-2-(1H)-one (DR4004) (5mg/kg), when administered intraperitoneally (i.p.) immediately after conditioning, caused a significant decrease in both context- and tone-dependent fear responses (freezing behavior). A significant increase in ERK activity was observed in the amygdala of mice that displayed context- or tone-dependent fear responses, and these changes were also inhibited by the administration of DR4004 (5mg/kg, i.p.) immediately after conditioning. In contrast, the increase in hippocampal ERK activity in mice that displayed context-dependent fear responses was further enhanced by the administration of DR4004 (5mg/kg, i.p.). These results suggest that 5-HT7 receptor-mediated ERK signaling may play a significant role in the processes of emotional learning and memory.

  7. Brain iron accumulation in unexplained fetal and infant death victims with smoker mothers-The possible involvement of maternal methemoglobinemia

    PubMed Central

    2011-01-01

    Background Iron is involved in important vital functions as an essential component of the oxygen-transporting heme mechanism. In this study we aimed to evaluate whether oxidative metabolites from maternal cigarette smoke could affect iron homeostasis in the brain of victims of sudden unexplained fetal and infant death, maybe through the induction of maternal hemoglobin damage, such as in case of methemoglobinemia. Methods Histochemical investigations by Prussian blue reaction were made on brain nonheme ferric iron deposits, gaining detailed data on their localization in the brainstem and cerebellum of victims of sudden death and controls. The Gless and Marsland's modification of Bielschowsky's was used to identify neuronal cell bodies and neurofilaments. Results Our approach highlighted accumulations of blue granulations, indicative of iron positive reactions, in the brainstem and cerebellum of 33% of victims of sudden death and in none of the control group. The modified Bielschowsky's method confirmed that the cells with iron accumulations were neuronal cells. Conclusions We propose that the free iron deposition in the brain of sudden fetal and infant death victims could be a catabolic product of maternal methemoglobinemia, a biomarker of oxidative stress likely due to nicotine absorption. PMID:21733167

  8. Libidibia ferrea Mature Seeds Promote Antinociceptive Effect by Peripheral and Central Pathway: Possible Involvement of Opioid and Cholinergic Receptors

    PubMed Central

    Sawada, Luis Armando; Monteiro, Vanessa Sâmia da Conçeição; Rabelo, Guilherme Rodrigues; Dias, Germana Bueno; Da Cunha, Maura; do Nascimento, José Luiz Martins; Bastos, Gilmara de Nazareth Tavares

    2014-01-01

    Libidibia ferrea (LF) is a medicinal plant that holds many pharmacological properties. We evaluated the antinociceptive effect in the LF aqueous seed extract and Lipidic Portion of Libidibia ferrea (LPLF), partially elucidating their mechanisms. Histochemical tests and Gas chromatography of the LPLF were performed to characterize its fatty acids. Acetic acid-induced abdominal constriction, formalin-induced pain, and hot-plate test in mice were employed in the study. In all experiments, aqueous extract or LPLF was administered systemically at the doses of 1, 5, and 10 mg/kg. LF aqueous seed extract and LPLF demonstrated a dose-dependent antinociceptive effect in all tests indicating both peripheral anti-inflammatory and central analgesia properties. Also, the use of atropine (5 mg/kg), naloxone (5 mg/kg) in the abdominal writhing test was able to reverse the antinociceptive effect of the LPLF, indicating that at least one of LF lipids components is responsible for the dose related antinociceptive action in chemical and thermal models of nociception in mice. Together, the present results suggested that Libidibia ferrea induced antinociceptive activity is possibly related to its ability to inhibit opioid, cholinergic receptors, and cyclooxygenase-2 pathway, since its main component, linoleic acid, has been demonstrated to produce such effect in previous studies. PMID:24860820

  9. Hydroalcoholic extract of needles of Pinus eldarica enhances pentobarbital-induced sleep: possible involvement of GABAergic system

    PubMed Central

    Forouzanfar, Fatemeh; Ghorbani, Ahmad; Hosseini, Mahmoud; Rakhshandeh, Hassan

    2016-01-01

    Objective: Insomnia is accompanied by several health complications and the currently used soporific drugs can induce several side effects such as psychomotor impairment, amnesia, and tolerance. The present study was planned to investigate the sleep prolonging effect of Pinus eldarica. Materials and Methods: Hydroalcoholic extract (HAE) of P. eldarica, its water fraction (WF), ethyl acetate fraction (EAF) and n-butanol fraction (NBF) were injected (intraperitoneally) to mice 30 min before administration of pentobarbital. Then, the latent period and continuous sleeping time were recorded. Also, LD50 of P. eldarica extract was determined and the possible neurotoxicity of the extract was tested on neural PC12 cells. Results: The HAE and NBF decreased the latency of sleep (p<0.05) and significantly increased duration of sleep (p<0.05) induced by pentobarbital. These effects of P. eldarica were reversed by flumazenil. The LD50 value for HAE was found to be 4.8 g/Kg. HAE and its fractions did not show neurotoxic effects in cultured PC12-cell line. Conclusion: The present data indicate that P. eldarica potentiated pentobarbital hypnosis without major toxic effect. Most probably, the main components responsible for this effect are non-polar agents which are found in NBF of this plant. PMID:27516986

  10. Possible Involvement of Avoidant Attachment Style in the Relations Between Adult IBS and Reported Separation Anxiety in Childhood.

    PubMed

    Ben-Israel, Yuval; Shadach, Eran; Levy, Sigal; Sperber, Ami; Aizenberg, Dov; Niv, Yaron; Dickman, Ram

    2016-12-01

    Irritable bowel syndrome (IBS) in adults as well as separation anxiety disorder (SAD) and recurrent abdominal pain (RAP) in childhood are associated with anxiety and somatization. Our aim was to examine possible associations between IBS in adulthood and SAD in childhood. Patients with IBS and healthy subjects completed a demographic questionnaire, the Separation Anxiety Symptom Inventory (SASI), the Somatization Subscale of Symptom Checklist-90-R (SCL-90-R), the Attachment Style Questionnaire, and a retrospective self-report questionnaire regarding RAP. Compared with controls, patients with IBS were characterized by an avoidant attachment style and scored higher on the SCL-90-R scale regarding the tendency to somatization (25.35 ± 7.47 versus16.50 ± 4.40, p < 0.001). More patients with IBS (25% versus 7.5%) reported RAP in childhood, but contrary to prediction, also had significantly lower SASI scores. Adults with IBS were characterized by somatization, insecure attachment style and recalled higher rates of RAP and surprisingly less symptoms of SAD in childhood. Based on these results, an etiological model for IBS is suggested, in which an avoidant attachment style and a tendency to somatization play an important role in the development of IBS. Copyright © 2015 John Wiley & Sons, Ltd.

  11. Possible involvement of β₁ receptors in various emetogen-induced increases in salivary amylase activity in rats.

    PubMed

    Fukui, Hideo; Suyama, Yoshimi; Iwachido, Takako; Miwa, Eri

    2011-01-01

    We investigated the inhibitory effects of β₁- or β₂-adrenoceptor (AR) antagonists on salivary amylase secretion produced by various emetic agents, such as cisplatin, apomorphine, and lithium chloride (LiCl), or the non-emetic agent β(½)-AR agonist isoprenaline in rats. We also determined the inhibitory effect of metoclopramide, a dopamine D₂-receptor antagonist, on increases in the salivary amylase activity induced by apomorphine or granisetron, a 5-HT(3)-receptor antagonist, on LiCl-induced increased salivary amylase activity. Isoprenaline (0.01 mg/kg, s.c.) produced an increase in salivary amylase and the increase was inhibited by the β(½)-AR antagonist propranolol (5 mg/kg, s.c.) and β₁-AR antagonist atenolol (2 mg/kg, s.c.) but not by the β₂-AR antagonist butoxamine (8 mg/kg, s.c.). The increased amylase activity induced by cisplatin (15 mg/kg, i.v.), apomorphine (3 mg/kg, s.c.), or LiCl (120 mg/kg, i.p.) was inhibited significantly by atenolol (2 mg/kg, s.c.) but not by butoxamine (8 mg/kg, s.c.). In addition, increases in amylase activities induced by apomorphine and LiCl were inhibited significantly by metoclopramide (10 mg/kg, i.v.) and granisetron (3 mg/kg, i.v.), respectively. These results suggest that salivary amylase secretion induced by various emetogens is involved in β₁-adrenoceptor activity and that salivary amylase activity is useful to detect emetogens with no direct β₁-AR activation in rats, a species that does not exhibit vomiting.

  12. 50-Hz extremely low frequency electromagnetic fields enhance cell proliferation and DNA damage: possible involvement of a redox mechanism.

    PubMed

    Wolf, Federica I; Torsello, Angela; Tedesco, Beatrice; Fasanella, Silvia; Boninsegna, Alma; D'Ascenzo, Marcello; Grassi, Claudio; Azzena, Gian Battista; Cittadini, Achille

    2005-03-22

    HL-60 leukemia cells, Rat-1 fibroblasts and WI-38 diploid fibroblasts were exposed for 24-72 h to 0.5-1.0-mT 50-Hz extremely low frequency electromagnetic field (ELF-EMF). This treatment induced a dose-dependent increase in the proliferation rate of all cell types, namely about 30% increase of cell proliferation after 72-h exposure to 1.0 mT. This was accompanied by increased percentage of cells in the S-phase after 12- and 48-h exposure. The ability of ELF-EMF to induce DNA damage was also investigated by measuring DNA strand breaks. A dose-dependent increase in DNA damage was observed in all cell lines, with two peaks occurring at 24 and 72 h. A similar pattern of DNA damage was observed by measuring formation of 8-OHdG adducts. The effects of ELF-EMF on cell proliferation and DNA damage were prevented by pretreatment of cells with an antioxidant like alpha-tocopherol, suggesting that redox reactions were involved. Accordingly, Rat-1 fibroblasts that had been exposed to ELF-EMF for 3 or 24 h exhibited a significant increase in dichlorofluorescein-detectable reactive oxygen species, which was blunted by alpha-tocopherol pretreatment. Cells exposed to ELF-EMF and examined as early as 6 h after treatment initiation also exhibited modifications of NF kappa B-related proteins (p65-p50 and I kappa B alpha), which were suggestive of increased formation of p65-p50 or p65-p65 active forms, a process usually attributed to redox reactions. These results suggest that ELF-EMF influence proliferation and DNA damage in both normal and tumor cells through the action of free radical species. This information may be of value for appraising the pathophysiologic consequences of an exposure to ELF-EMF.

  13. Possible involvement of Helios in controlling the immature B cell functions via transcriptional regulation of protein kinase Cs.

    PubMed

    Kikuchi, Hidehiko; Nakayama, Masami; Takami, Yasunari; Kuribayashi, Futoshi; Nakayama, Tatsuo

    2011-01-01

    The transcription factor Ikaros family consists of five zinc-finger proteins: Ikaros, Aiolos, Helios, Eos and Pegasus; these proteins except Pegasus are essential for development and differentiation of lymphocytes. However, in B lymphocytes, the physiological role of Helios remains to be elucidated yet, because its expression level is very low. Here, we generated the Helios-deficient DT40 cells, Helios (-/-), and showed that the Helios-deficiency caused significant increases in transcriptions of four protein kinase Cs (PKCs); PKC-δ, PKC-ε, PKC-η and PKC-ζ, whereas their expressions were drastically down-regulated in the Aiolos-deficient DT40 cells, Aiolos (-/-). In addition, Helios (-/-) was remarkably resistant against phorbol 12-myristate 13-acetate (PMA)/ionomycin treatment, which mimics the B cell receptor (BCR)-mediated stimulation. In the presence of PMA/ionomycin, their viability was remarkably higher than that of DT40, and their DNA fragmentation was less severe than that of DT40 in the opposite manner for the Aiolos-deficiency. The resistance against the PMA/ionomycin-induced apoptosis of Helios (-/-) was sensitive to Rottlerin but not to Go6976. In addition, the Helios-deficiency caused remarkable up-regulation of the Rottlerin-sensitive superoxide (O2 (-))-generating activity. These data suggest that Helios may contribute to the regulation of the BCR-mediated apoptosis and O2 (-)-generating activity, via transcriptional regulation of these four PKCs (especially PKC-δ) in immature B lymphocytes. Together with previous data, our findings may significantly help in the understanding of the B lymphocyte-specific expressions of PKC genes and molecular mechanisms of both the BCR-mediated apoptosis involved in negative selection and the O2 (-)-generating system in immature B lymphocytes.

  14. Production of Macrophage Inhibitory Factor (MIF) by Primary Sertoli Cells; its Possible Involvement in Migration of Spermatogonial Cells.

    PubMed

    Huleihel, M; Abofoul-Azab, M; Abarbanel, Y; Einav, I; Levitas, E; Lunenfeld, E

    2016-12-07

    Macrophage migration inhibitory factor (MIF) is a multifunctional molecule. MIF was originally identified as a T-cell-derived factor responsible for the inhibition of macrophage migration. In testicular tissue of adult rats, MIF is constitutively expressed by Leydig cells under physiological conditions. The aim of this study was to examine MIF levels in testicular homogenates from different aged mice, and the capacity of Sertoli cells to produce it. We also examined MIF involvement in spermatogonial cell migration. Similar levels of MIF protein were detected in testicular homogenates of mice of different ages (1-8 weeks-old). However, the RNA expression levels of MIF were high in 1-week-old mice and significantly decreased with age compared to 1-week-old mice. MIF was stained in Sertoli, Leydig cells and developed germ cells in the seminiferous tubules. Isolated Sertoli cells from 1 week-old mice stained to MIF. Cultures of Sertoli cells from 1-week-old mice produced and expressed high levels of MIF which significantly decreased with age. MIF was localized in the cytoplasm and nucleus of Sertoli cell cultures isolated from 1-weeks-old mice; however it was localized only in the cytoplasm and branches of cultures isolated from 8-week-old mice. MIFR was detected in GFRα1 and Sertoli cells. MIF could induce migration of spermatogonial cells, and this effect was synergistic with glial cell-line neurotrophic factor. Our results show, for the first time, the capacity of Sertoli cells to produce MIF under normal conditions and that MIFR expressed in GFRα1 and Sertoli cells. We also showed that MIF induced spermatogonial cell migration. This article is protected by copyright. All rights reserved.

  15. Sexually mature European eels (Anguilla anguilla L.) stimulate gonadal development of neighbouring males: possible involvement of chemical communication.

    PubMed

    Huertas, Mar; Scott, Alexander P; Hubbard, Peter C; Canário, Adelino V M; Cerdà, Joan

    2006-07-01

    This study was aimed to investigate whether sexual maturation of immature male eels could be stimulated indirectly by placing them in contact with either male (Minj) or female (Finj) eels in which sexual maturation had been stimulated directly by weekly injections of human chorionic gonadotropin (hCG) or salmon pituitary extract (SPE), respectively. Untreated males were placed either in the same tank or in a separate tank that was linked to the injected fish via a recirculation system. The hormonal treatments stimulated spermatogenesis and spermiation in Minj, and ovulation in Finj as well as an increase of the ocular (Io) and gonadosomatic (GSI) indices in both sexes. Plasma levels of testosterone (T) and 11-ketotestosterone (11-KT) increased in Minj and T and 17beta-estradiol (E2) in Finj. A small peak of plasma 17,20beta-dihydroxypregn-4-en-3-one (17,20betaP) occurred during ovulation, while the plasma levels of 17alpha-hydroxypregn-4-ene-3,20-dione (17P) were undetectable in both males and females. The water conditioned by Minj and Finj induced significant, though relatively minor, increases in Io and GSI in uninjected males. In addition, uninjected fish showed small changes in plasma T and 11-KT levels, apparently related to the timing of spermiation and ovulation of Minj and Finj, respectively, as well as an activation of spermatogenesis (but not spermiation). Injected fish released free and conjugated T, 11-KT and E2 into the water, although immature eels were unable to smell (by electro-olfactogram) any of these steroids or prostaglandin F2alpha. However, immature males were highly sensitive to water extracts conditioned by spermiating Minj and pre-ovulatory and ovulated Finj. These preliminary results suggest the existence of chemical communication between maturing eels and immature males that stimulates gonad development, although the putative pheromone(s) involved has/have not yet been identified.

  16. The Apparent Involvement of ANMEs in Mineral Dependent Methane Oxidation, as an Analog for Possible Martian Methanotrophy

    PubMed Central

    House, Christopher H.; Beal, Emily J.; Orphan, Victoria J.

    2011-01-01

    On Earth, marine anaerobic methane oxidation (AOM) can be driven by the microbial reduction of sulfate, iron, and manganese. Here, we have further characterized marine sediment incubations to determine if the mineral dependent methane oxidation involves similar microorganisms to those found for sulfate-dependent methane oxidation. Through FISH and FISH-SIMS analyses using 13C and 15N labeled substrates, we find that the most active cells during manganese dependent AOM are primarily mixed and mixed-cluster aggregates of archaea and bacteria. Overall, our control experiment using sulfate showed two active bacterial clusters, two active shell aggregates, one active mixed aggregate, and an active archaeal sarcina, the last of which appeared to take up methane in the absence of a closely-associated bacterial partner. A single example of a shell aggregate appeared to be active in the manganese incubation, along with three mixed aggregates and an archaeal sarcina. These results suggest that the microorganisms (e.g., ANME-2) found active in the manganese-dependent incubations are likely capable of sulfate-dependent AOM. Similar metabolic flexibility for Martian methanotrophs would mean that the same microbial groups could inhabit a diverse set of Martian mineralogical crustal environments. The recently discovered seasonal Martian plumes of methane outgassing could be coupled to the reduction of abundant surface sulfates and extensive metal oxides, providing a feasible metabolism for present and past Mars. In an optimistic scenario Martian methanotrophy consumes much of the periodic methane released supporting on the order of 10,000 microbial cells per cm2 of Martian surface. Alternatively, most of the methane released each year could be oxidized through an abiotic process requiring biological methane oxidation to be more limited. If under this scenario, 1% of this methane flux were oxidized by biology in surface soils or in subsurface aquifers (prior to release), a total

  17. Possible involvement of TRPV1 and TRPV4 in nociceptive stimulation- induced nocifensive behavior and neuroendocrine response in mice.

    PubMed

    Ishikura, Toru; Suzuki, Hitoshi; Shoguchi, Kanako; Koreeda, Yuki; Aritomi, Takafumi; Matsuura, Takanori; Yoshimura, Mitsuhiro; Ohkubo, Jun-ichi; Maruyama, Takashi; Kawasaki, Makoto; Ohnishi, Hideo; Sakai, Akinori; Mizuno, Atsuko; Suzuki, Makoto; Ueta, Yoichi

    2015-09-01

    Members of the transient receptor potential (TRP) family of ion channels play important roles in inflammation and pain. Here, we showed that both TRPV1 and TRPV4 might contribute to biphasic nocifensive behavior and neuroendocrine response following a formalin test. We subcutaneously injected saline, formalin, or the TRPV4 agonist, 4α-phorbol 12,13-didecanoate (4α-PDD) into one hindpaw of wild-type (WT), TRPV1-deficient (Trpv1(-/-)), and TRPV4-deficient (Trpv4(-/-)) mice to investigate nocifensive behaviors (phase I [0-10 min] and phase II [10-60 min]) and Fos expression in the dorsal horn of the spinal cord and other brain regions related to pain, in the paraventricular nucleus (PVN), paraventricular nucleus of the thalamus, the medial habenular nucleus, the medial nucleus of the amygdala and capsular part of the central amygdala. Subcutaneous (s.c.) injection of formalin caused less nocifensive behavior in Trpv1(-/-) and Trpv4(-/-) mice than in WT mice during phase I. In phase II, however, formalin induced less nocifensive behavior only in the Trpv1(-/-) mice, but not in the Trpv4(-/-) mice, relative to WT mice. The number of Fos-like immunoreactive (LI) neurons in laminae I-II of the dorsal horn increased in all types of mice 90 min after s.c. injection of formalin; however, there was no difference in the other regions between saline- and formalin-treated mice. Furthermore, s.c. injection of 4α-PDD did not induce nociceptive behavior nor influence the number of Fos-LI neurons in the all above mentioned regions in any of the mice. These results suggest that TRPV4-mediated nociceptive information from the peripheral tissue excluding the spinal pathway might be involved the formalin behavioral response during phase I. Only TRPV1 might regulate the formalin behavioral response in peripheral neuron.

  18. Hydroxy-α sanshool induces colonic motor activity in rat proximal colon: a possible involvement of KCNK9

    PubMed Central

    Kubota, Kunitsugu; Ohtake, Nobuhiro; Ohbuchi, Katsuya; Mase, Akihito; Imamura, Sachiko; Sudo, Yuka; Miyano, Kanako; Yamamoto, Masahiro; Kono, Toru

    2015-01-01

    Various colonic motor activities are thought to mediate propulsion and mixing/absorption of colonic content. The Japanese traditional medicine daikenchuto (TU-100), which is widely used for postoperative ileus in Japan, accelerates colonic emptying in healthy humans. Hydroxy-α sanshool (HAS), a readily absorbable active ingredient of TU-100 and a KCNK3/KCNK9/KCNK18 blocker as well as TRPV1/TRPA1 agonist, has been investigated for its effects on colonic motility. Motility was evaluated by intraluminal pressure and video imaging of rat proximal colons in an organ bath. Distribution of KCNKs was investigated by RT-PCR, in situ hybridization, and immunohistochemistry. Current and membrane potential were evaluated with use of recombinant KCNK3- or KCNK9-expressing Xenopus oocytes and Chinese hamster ovary cells. Defecation frequency in rats was measured. HAS dose dependently induced strong propulsive “squeezing” motility, presumably as long-distance contraction (LDC). TRPV1/TRPA1 agonists induced different motility patterns. The effect of HAS was unaltered by TRPV1/TRPA1 antagonists and desensitization. Lidocaine (a nonselective KCNK blocker) and hydroxy-β sanshool (a geometrical isomer of HAS and KCNK3 blocker) also induced colonic motility as a rhythmic propagating ripple (RPR) and a LDC-like motion, respectively. HAS-induced “LDC,” but not lidocaine-induced “RPR,” was abrogated by a neuroleptic agent tetrodotoxin. KCNK3 and KCNK9 were located mainly in longitudinal smooth muscle cells and in neural cells in the myenteric plexus, respectively. Administration of HAS or TU-100 increased defecation frequency in normal and laparotomy rats. HAS may evoke strong LDC possibly via blockage of the neural KCNK9 channel in the colonic myenteric plexus. PMID:25634809

  19. Hydroxy-α sanshool induces colonic motor activity in rat proximal colon: a possible involvement of KCNK9.

    PubMed

    Kubota, Kunitsugu; Ohtake, Nobuhiro; Ohbuchi, Katsuya; Mase, Akihito; Imamura, Sachiko; Sudo, Yuka; Miyano, Kanako; Yamamoto, Masahiro; Kono, Toru; Uezono, Yasuhito

    2015-04-01

    Various colonic motor activities are thought to mediate propulsion and mixing/absorption of colonic content. The Japanese traditional medicine daikenchuto (TU-100), which is widely used for postoperative ileus in Japan, accelerates colonic emptying in healthy humans. Hydroxy-α sanshool (HAS), a readily absorbable active ingredient of TU-100 and a KCNK3/KCNK9/KCNK18 blocker as well as TRPV1/TRPA1 agonist, has been investigated for its effects on colonic motility. Motility was evaluated by intraluminal pressure and video imaging of rat proximal colons in an organ bath. Distribution of KCNKs was investigated by RT-PCR, in situ hybridization, and immunohistochemistry. Current and membrane potential were evaluated with use of recombinant KCNK3- or KCNK9-expressing Xenopus oocytes and Chinese hamster ovary cells. Defecation frequency in rats was measured. HAS dose dependently induced strong propulsive "squeezing" motility, presumably as long-distance contraction (LDC). TRPV1/TRPA1 agonists induced different motility patterns. The effect of HAS was unaltered by TRPV1/TRPA1 antagonists and desensitization. Lidocaine (a nonselective KCNK blocker) and hydroxy-β sanshool (a geometrical isomer of HAS and KCNK3 blocker) also induced colonic motility as a rhythmic propagating ripple (RPR) and a LDC-like motion, respectively. HAS-induced "LDC," but not lidocaine-induced "RPR," was abrogated by a neuroleptic agent tetrodotoxin. KCNK3 and KCNK9 were located mainly in longitudinal smooth muscle cells and in neural cells in the myenteric plexus, respectively. Administration of HAS or TU-100 increased defecation frequency in normal and laparotomy rats. HAS may evoke strong LDC possibly via blockage of the neural KCNK9 channel in the colonic myenteric plexus.

  20. Wavelength dependence of ultraviolet-induced DNA damage distribution: involvement of direct or indirect mechanisms and possible artefacts.

    PubMed

    Kuluncsics, Z; Perdiz, D; Brulay, E; Muel, B; Sage, E

    1999-03-01

    DNA damage profiles have been established in plasmid DNA using purified DNA repair enzymes and a plasmid relaxation assay, following exposure to UVC, UVB, UVA or simulated sunlight (SSL). Cyclobutane pyrimidine dimers (CPDs) are revealed as T4 endonuclease V-sensitive sites, oxidation products at purine and pyrimidine as Fpg- and Nth-sensitive sites, and abasic sites are detected by Nfo protein from Escherichia coli. CPDs are readily detected after UVA exposure, though produced 10(3) and 10(5) times less efficiently than by UVB or UVC, respectively. We demonstrate that CPDs are induced by UVA radiation and not by contaminating UVB wavelengths. Furthermore, they are produced at doses compatible with human exposure and are likely to contribute to the mutagenic specificity of UVA [E. Sage et al., Proc. Natl. Acad. Sci. USA 93 (1996) 176-180]. Oxidative damage is induced with a linear dose dependence, for each region of the solar spectrum, with the exception of oxidized pyrimidine and abasic sites, which are not detectable after UVB irradiation. The distribution of the different classes of photolesions varies markedly, depending on wavelengths. However, the unexpectedly high yield of oxidative lesions, as compared to CPDs, by UVA and SSL led us to investigate their production mechanism. An artificial formation of hydroxyl radicals is observed, which depends on the material of the sample holder used for UVA irradiation and is specific for long UV wavelengths. Our study sheds light on a possible artefact in the production of oxidative damage by UVA radiation. Meanwhile, after eliminating some potential sources of the artefact ratios of CPDs to oxidized purine of three and five upon irradiation with UVA and SSL, respectively, are still observed, whereas these ratios are about 140 and 200 after UVC and UVB irradiation.

  1. Possible involvement of self-defense mechanisms in the preferential vulnerability of the striatum in Huntington's disease

    PubMed Central

    Francelle, Laetitia; Galvan, Laurie; Brouillet, Emmanuel

    2014-01-01

    HD is caused by a mutation in the huntingtin gene that consists in a CAG repeat expansion translated into an abnormal poly-glutamine (polyQ) tract in the huntingtin (Htt) protein. The most striking neuropathological finding in HD is the atrophy of the striatum. The regional expression of mutant Htt (mHtt) is ubiquitous in the brain and cannot explain by itself the preferential vulnerability of the striatum in HD. mHtt has been shown to produce an early defect in transcription, through direct alteration of the function of key regulators of transcription and in addition, more indirectly, as a result of compensatory responses to cellular stress. In this review, we focus on gene products that are preferentially expressed in the striatum and have down- or up-regulated expression in HD and, as such, may play a crucial role in the susceptibility of the striatum to mHtt. Many of these striatal gene products are for a vast majority down-regulated and more rarely increased in HD. Recent research shows that some of these striatal markers have a pro-survival/neuroprotective role in neurons (e.g., MSK1, A2A, and CB1 receptors) whereas others enhance the susceptibility of striatal neurons to mHtt (e.g., Rhes, RGS2, D2 receptors). The down-regulation of these latter proteins may be considered as a potential self-defense mechanism to slow degeneration. For a majority of the striatal gene products that have been identified so far, their function in the striatum is unknown and their modifying effects on mHtt toxicity remain to be experimentally addressed. Focusing on these striatal markers may contribute to a better understanding of HD pathogenesis, and possibly the identification of novel therapeutic targets. PMID:25309327

  2. Glioblastoma-mesenchymal stem cell communication modulates expression patterns of kinin receptors: Possible involvement of bradykinin in information flow.

    PubMed

    Pillat, Micheli M; Oliveira, Mona N; Motaln, Helena; Breznik, Barbara; Glaser, Talita; Lah, Tamara T; Ulrich, Henning

    2016-04-01

    The most aggressive subtype of brain tumors is glioma WHO grade IV, the glioblastoma (GBM). The present work aims to elucidate the role of kinin receptors in interactions between GBM cells and mesenchymal stem cells (MSC). The GBM cell line U87-MG was stably transfected to express dsRed protein, single cell cloned, expanded, and cultured with MSC, both in the direct co-cultures (DC) and indirect co-cultures (IC) at equal cell number ratio for 72 h. Up- and down-regulation of matrix metalloproteases (MMP)-9 expression in U87-MG and MSC cells, respectively, in direct co-culture points to possible MSC participation in tumor invasion. MMP9 expression is in line with significantly increased expression of kinin B1 (B1R) and B2 receptor (B2R) in U87-MG cells and their decreased levels in MSC, as confirmed by quantitative assessment using flow cytometric analysis. Similarly, in indirect cultures (IC), lacking the contact between GBM and MSC cells, an increase of B1 and B2 receptor expression was again noted in U87-MG cells, and no significant changes in kinin receptors in MSC was observed. Functionality of kinin-B1 and B2 receptors was evidenced by stimulation of intracellular calcium fluxes by their respective agonists, des-Arg9-bradykinin (DBK) and bradykinin (BK). Moreover, BK showed a feedback control on kinin receptor expression in mono-cultures, direct and indirect co-cultures. The treatment with BK resulted in down-regulation of B1 and B2 receptors in MSC, with simultaneous up-regulation of these receptors in U87-MG cells, suggesting that functions of BK in information flow between these cells is important for tumor progression and invasion. © 2015 International Society for Advancement of Cytometry.

  3. DNase I and II present in avian oocytes: a possible involvement in sperm degradation at polyspermic fertilisation.

    PubMed

    Stepińska, Urszula; Olszańska, Bozenna

    2003-02-01

    During polyspermic fertilisation in birds numerous spermatozoa enter the eggs, in contrast to the situation in mammals where fertilisation is monospermic. However, in birds only one of the spermatozoa which have entered an egg participates in zygote nucleus formation, while the supernumerary spermatozoa degenerate at early embryogenesis. Our previous work has demonstrated the presence in preovulatory quail oocytes of DNase I and II activities able to digest naked lambdaDNA/HindIII substrate in vitro. In the present studies, the activities of both DNases in quail oocytes at different stages of oogenesis and in ovulated mouse oocytes were assayed in vitro using the same substrate. Degradation of quail spermatozoa by quail oocyte extracts was also checked. Digestion of the DNA substrate was evaluated by electrophoresis on agarose gels. The activities of DNase I and II in quail oocytes increased during oogenesis and were the highest in mature oocytes. The activities were present not only in germinal discs but also in a thin layer of cytoplasm adhering to the perivitelline layer surrounding the yolk. At all stages of oogenesis the activity of DNase II was much higher than that of DNase I. DNA contained in spermatozoa was also degraded by the quail oocyte extracts under conditions optimal for both DNases. In contrast to what is observed in quail oocytes, no DNase activities were detected in ovulated mouse eggs; this is logical as they would be useless or even harmful in monospermic fertilisation. The possible role of DNase activities in avian oocytes, in degradation of accessory spermatozoa during polyspermic fertilisation, is discussed.

  4. Disruption of social cognition in the sub-chronic PCP rat model of schizophrenia: Possible involvement of the endocannabinoid system.

    PubMed

    Seillier, Alexandre; Giuffrida, Andrea

    2016-02-01

    Previous studies have shown that social withdrawal in the phencyclidine (PCP) rat model of schizophrenia results from deficient endocannabinoid-induced activation of CB1 receptors. To understand the underlying cognitive mechanisms of the social deficit in PCP-treated rats, we examined the impact of pharmacological manipulation of the endocannabinoid system on sociability (i.e. social approach) and social novelty preference (which relies on social recognition). Control rats showed a clear preference for a "social" cage (i.e. unfamiliar stimulus rat placed under a wire mesh cage) versus an "empty" cage, and spent more time exploring a "novel" cage (i.e. new stimulus rat) versus a "familiar" cage. In contrast, rats receiving PCP (5 mg/kg, b.i.d. for 7 days, followed by a 7 day-washout period) showed intact sociability, but lacked social novelty preference. This PCP-induced deficit was due to increased activity at CB1 receptors as it was reversed by systemic administration of the CB1 antagonist AM251 (1 mg/kg). In agreement with this hypothesis, the cannabinoid agonist CP55,940 (0.003-0.03 mg/kg) dose-dependently suppressed social novelty preference in control animals without affecting sociability. Taken together, these data suggest that PCP-treated rats have a deficit in social cognition, possibly induced by increased stimulation of CB1 receptors. This deficit, however, is distinct from the social withdrawal previously observed in these animals, as the latter is due to deficient, rather than increased, CB1 stimulation.

  5. Disruption of social cognition in the sub-chronic PCP rat model of schizophrenia: possible involvement of the endocannabinoid system

    PubMed Central

    Seillier, Alexandre; Giuffrida, Andrea

    2015-01-01

    Previous studies have shown that social withdrawal in the phencyclidine (PCP) rat model of schizophrenia results from deficient endocannabinoid-induced activation of CB1 receptors. To understand the underlying cognitive mechanisms of the social deficit in PCP-treated rats, we examined the impact of pharmacological manipulation of the endocannabinoid system on sociability (i.e. social approach) and social novelty preference (which relies on social recognition). Control rats showed a clear preference for a “social” cage (i.e. unfamiliar stimulus rat placed under a wire mesh cage) versus an “empty” cage, and spent more time exploring a “novel” cage (i.e. new stimulus rat) versus a “familiar” cage. In contrast, rats receiving PCP (5 mg/kg, b.i.d. for 7 days, followed by a 7 day-washout period) showed intact sociability, but lacked social novelty preference. This PCP-induced deficit was due to increased activity at CB1 receptors as it was reversed by systemic administration of the CB1 antagonist AM251 (1 mg/kg). In agreement with this hypothesis, the cannabinoid agonist CP55,940 (0.003 – 0.03 mg/kg) dose-dependently suppressed social novelty preference in control animals without affecting sociability. Taken together, these data suggest that PCP-treated rats have a deficit in social cognition, possibly induced by increased stimulation of CB1 receptors. This deficit, however, is distinct from the social withdrawal previously observed in these animals, as the latter is due to deficient, rather than increased, CB1 stimulation. PMID:26706691

  6. Human kallikrein 14: a new potential biomarker for ovarian and breast cancer.

    PubMed

    Borgoño, Carla A; Grass, Linda; Soosaipillai, Antoninus; Yousef, George M; Petraki, Constantina D; Howarth, David H C; Fracchioli, Stefano; Katsaros, Dionyssios; Diamandis, Eleftherios P

    2003-12-15

    Human kallikrein gene 14 (KLK14) is a recently discovered member of the tissue kallikrein family of secreted serine proteases, which includes hK3/prostate-specific antigen, the best cancer biomarker to date. Given that KLK14 is hormonally regulated, differentially expressed in endocrine-related cancers, and a prognostic marker for breast and ovarian cancer at the mRNA level, we hypothesize that its encoded protein, hK14, like hK3/prostate-specific antigen, may constitute a new biomarker for endocrine-related malignancies. The objective of this study was to generate immunological reagents for hK14, to develop an ELISA and immunohistochemical techniques to study its expression in normal and cancerous tissues and biological fluids. Recombinant hK14 was produced in Pichia pastoris, purified by affinity chromatography, and injected into mice and rabbits for polyclonal antibody generation. Using the mouse and rabbit antisera, a sandwich-type immunofluorometric ELISA and immunohistochemical methodologies were developed for hK14. The ELISA was sensitive (detection limit of 0.1 micro g/liter), specific for hK14, linear from 0 to 20 micro g/liter with between-run and within-run coefficients of variation of <10%. hK14 was quantified in human tissue extracts and biological fluids. Highest levels were observed in the breast, skin, prostate, seminal plasma, and amniotic fluid, with almost undetectable levels in normal serum. hK14 concentration was higher in 40% of ovarian cancer tissues compared with normal ovarian tissues. Serum hK14 levels were elevated in a proportion of patients with ovarian (65%) and breast (40%) cancers. Immunohistochemical analyses indicated strong cytoplasmic staining of hK14 by the epithelial cells of normal and malignant skin, ovary, breast, and testis. In conclusion, we report the first ELISA and immunohistochemical assays for hK14 and describe its distribution in tissues and biological fluids. Our preliminary data indicate that hK14 is a potential

  7. Thrombin, kallikrein and complement C5b-9 adsorption on hydrophilic and hydrophobic titanium and glass after short time exposure to whole blood.

    PubMed

    Yahyapour, Noushin; Eriksson, Cecilia; Malmberg, Per; Nygren, Håkan

    2004-07-01

    Hydrophilic and hydrophobic titanium and glass were exposed to capillary whole blood between 5s and 24h. The time-sequence for adsorption of thrombin, kallikrein and complement C5b-9, and their relationship with adherent platelets and polymorphonuclear granulocyte (PMN) activation were investigated. Adsorbed thrombin and kallikrein were measured by cleavage of specific chromogenic substances, S-2238 and S-2303, respectively. Complement C5b-9 and expression of CD11b, CD66b, CD62P and Pan-platelets were measured by immunofluorescence. Thrombin and kallikrein were present on the surfaces during the whole investigated periods. Platelet adhesion and PMN cell adhesion and activation on all surfaces and activation of platelets on hydrophobic surfaces showed a similar pattern to thrombin adsorption. Kallikrein adsorption had a different pattern on each surface. C5b-9 was detected between 32min and 24h of blood exposure and a varying pattern of C5b-9 coverage was observed on each surface. In conclusion, our results indicate that the interaction between material and blood coagulation and kinin-activating proteins regulate the adhesion and activation of blood cells, whereas after longer time the coagulation and kallikrein-kinin system play minor roles and the complement system is decisive for mediating and elongating the inflammatory process.

  8. Human kallikrein 10 expression in surgically removed human pituitary corticotroph adenomas: an immunohistochemical study.

    PubMed

    Di Meo, Ashley; Rotondo, Fabio; Kovacs, Kalman; Cusimano, Michael D; Syro, Luis V; Di Ieva, Antonio; Diamandis, Eleftheros P; Yousef, George M

    2015-07-01

    Human kallikrein 10 (hk10), a secreted serine protease, was reported to function as a tumor suppressor. hK10 immunoexpression has been demonstrated in lactrotrophs and corticotrophs of the nontumorous human adenohypophysis. In the present study, for the first time we report hK10 immunoexpression in various surgically removed corticotroph adenoma subtypes. Specimens were fixed in formalin and embedded in paraffin. Immunostaining was performed using the streptavidin-biotin-peroxidase complex method with an hK10-specific rabbit polyclonal antibody. Results showed that the endocrinologically active adrenocorticotropic hormone (ACTH)-producing pituitary tumors and the silent subtypes were immunopositve for hK10. Intensity of staining varied between the different subtypes. Intensity was lowest in the silent subtypes (silent corticotroph subtypes 1 and 2) compared with nontumorous human adenohypophysial corticotrophs, whereas the endocrinologically active subtypes (ACTH-secreting adenomas, corticotroph carcinomas, Crooke cell adenomas, Crooke cell carcinomas), showed the highest hK10 immunoexpression. Immunopositivity in the nuclei of the ACTH-secreting adenomas and carcinomas, as well as dual cytoplasmic and nuclear localization of hK10 in some of the secreting tumor types was an intriguing finding. Immunoexpression of hK10 in the ACTH-secreting tumors as well as in the Crooke cell tumors was significantly increased when compared with the nonfunctioning tumors and in the corticotrophs of nontumorous pituitaries.

  9. Expression and bioregulation of the kallikrein-related peptidases family in the human neutrophil.

    PubMed

    Lizama, Alejandro J; Andrade, Yessica; Colivoro, Patricio; Sarmiento, Jose; Matus, Carola E; Gonzalez, Carlos B; Bhoola, Kanti D; Ehrenfeld, Pamela; Figueroa, Carlos D

    2015-08-01

    The family of kallikrein-related peptidases (KLKs) has been identified in a variety of immunolabeled human tissue sections, but no previous study has experimentally confirmed their presence in the human neutrophil. We have investigated the expression and bioregulation of particular KLKs in the human neutrophil and, in addition, examined whether stimulation by a kinin B(1) receptor (B1R) agonist or fMet-Leu-Phe (fMLP) induces their secretion. Western blot analysis of neutrophil homogenates indicated that the MM of the KLKs ranged from 27 to 50 kDa. RT-PCR showed that blood neutrophils expressed only KLK1, KLK4, KLK10, KLK13, KLK14 and KLK15 mRNAs, whereas the non-differentiated HL-60 cells expressed most of them, with exception of KLK3 and KLK7. Nevertheless, mRNAs for KLK2, KLK5, KLK6 and KLK9 that were previously undetectable appeared after challenging with a mixture of cytokines. Both kinin B(1)R agonist and fMLP induced secretion of KLK1, KLK6, KLK10, KLK13 and KLK14 into the culture medium in similar amounts, whereas the B(1)R agonist caused the release of lower amounts of KLK2, KLK4 and KLK5. When secreted, the differing proteolytic activity of KLKs provides the human neutrophil with a multifunctional enzymatic capacity supporting a new dimension for its role in human disorders of diverse etiology.

  10. Tissue kallikrein-modified human endothelial progenitor cell implantation improves cardiac function via enhanced activation of akt and increased angiogenesis.

    PubMed

    Yao, Yuyu; Sheng, Zulong; Li, YeFei; Fu, Cong; Ma, Genshan; Liu, Naifeng; Chao, Julie; Chao, Lee

    2013-05-01

    Endothelial progenitor cells (EPCs) have been shown to enhance angiogenesis not only by incorporating into the vasculature but also by secreting cytokines, thereby serving as an ideal vehicle for gene transfer. As tissue kallikrein (TK) has pleiotropic effects in inhibiting apoptosis and oxidative stress, and promoting angiogenesis, we evaluated the salutary potential of kallikrein-modified human EPCs (hEPCs; Ad.hTK-hEPCs) after acute myocardial infarction (MI). We genetically modified hEPCs with a TK gene and evaluated cell survival, engraftment, revascularization, and functional improvement in a nude mouse left anterior descending ligation model. hEPCs were manipulated to overexpress the TK gene. In vitro, the antiapoptotic and paracrine effects were assessed under oxidative stress. TK protects hEPCs from oxidative stress-induced apoptosis via inhibition of activation of caspase-3 and -9, induction of Akt phosphorylation, and secretion of vascular endothelial growth factor. In vivo, the Ad.hTK-hEPCs were transplanted after MI via intracardiac injection. The surviving cells were tracked after transplantation using near-infrared optical imaging. Left ventricular (LV) function was evaluated by transthoracic echocardiography. Capillary density was quantified using immunohistochemical staining. Engrafted Ad.hTK-hEPCs exhibited advanced protection against ischemia by increasing LV ejection fraction. Compared with Ad.Null-hEPCs, transplantation with Ad.hTK-hEPCs significantly decreased cardiomyocyte apoptosis in association with increased retention of transplanted EPCs in the myocardium. Capillary density and arteriolar density in the infarct border zone was significantly higher in Ad.hTK-hEPC-transplanted mice than in Ad.Null-hEPC-treated mice. Transplanted hEPCs were clearly incorporated into CD31(+) capillaries. These results indicate that implantation of kallikrein-modified EPCs in the heart provides advanced benefits in protection against ischemia-induced MI by

  11. Cardiac function and remodeling is attenuated in transgenic rats expressing the human kallikrein-1 gene after myocardial infarction.

    PubMed

    Koch, Matthias; Spillmann, Frank; Dendorfer, Andreas; Westermann, Dirk; Altmann, Christine; Sahabi, Merdad; Linthout, Sophie Van; Bader, Michael; Walther, Thomas; Schultheiss, Heinz-Peter; Tschöpe, Carsten

    2006-11-21

    Bradykinin coronary outflow, left ventricular performance and left ventricular dimensions of transgenic rats harboring the human tissue kallikrein-1 gene TGR(hKLK1) were investigated under basal and ischemic conditions. Bradykinin content in the coronary outflow of buffer-perfused, isolated hearts of controls and TGR(hKLK1) was measured by specific radioimmunoassay before and after global ischemia. Left ventricular function and left ventricular dimensions were determined in vivo using a tip catheter and echocardiography 6 days and 3 weeks after induction of myocardial infarction. Left ventricular type I collagen mRNA expression was analyzed by RNase protection assay. Compared to controls, basal bradykinin outflow was 3.5 fold increased in TGR(hKLK1). Ischemia induced an increase of bradykinin coronary outflow in controls but did not induce a further increase in TGR(hKLK1). However, despite similar unchanged infarction sizes, left ventricular function and remodeling improved in TGR(hKLK1) after myocardial infarction, indicated by an increase in left ventricular pressure (+34%; P<0.05), contractility (dp/dt max. +25%; P<0.05), and in ejection fraction (+20%; P<0.05) as well as by a reduction in left ventricular enddiastolic pressure (-49%, P<0.05), left ventricular enddiastolic diameter (-20%, P<0.05), and collagen mRNA expression (-15%, P<0.05) compared to controls. A chronically activated transgenic kallikrein kinin system with expression of human kallikrein-1 gene counteracts the progression of left ventricular contractile dysfunction after experimental myocardial infarction. Further studies have to show whether these results can be caused by other therapeutically options. Long acting bradykinin receptor agonists might be an alternative option to improve ischemic heart disease.

  12. Structures of the first representatives of Pfam family PF06938 (DUF1285) reveal a new fold with repeated structural motifs and possible involvement in signal transduction

    PubMed Central

    Han, Gye Won; Bakolitsa, Constantina; Miller, Mitchell D.; Kumar, Abhinav; Carlton, Dennis; Najmanovich, Rafael J.; Abdubek, Polat; Astakhova, Tamara; Axelrod, Herbert L.; Chen, Connie; Chiu, Hsiu-Ju; Clayton, Thomas; Das, Debanu; Deller, Marc C.; Duan, Lian; Ernst, Dustin; Feuerhelm, Julie; Grant, Joanna C.; Grzechnik, Anna; Jaroszewski, Lukasz; Jin, Kevin K.; Johnson, Hope A.; Klock, Heath E.; Knuth, Mark W.; Kozbial, Piotr; Krishna, S. Sri; Marciano, David; McMullan, Daniel; Morse, Andrew T.; Nigoghossian, Edward; Okach, Linda; Reyes, Ron; Rife, Christopher L.; Sefcovic, Natasha; Tien, Henry J.; Trame, Christine B.; van den Bedem, Henry; Weekes, Dana; Xu, Qingping; Hodgson, Keith O.; Wooley, John; Elsliger, Marc-André; Deacon, Ashley M.; Godzik, Adam; Lesley, Scott A.; Wilson, Ian A.

    2010-01-01

    The crystal structures of SPO0140 and Sbal_2486 were determined using the semiautomated high-throughput pipeline of the Joint Center for Structural Genomics (JCSG) as part of the NIGMS Protein Structure Initiative (PSI). The structures revealed a conserved core with domain duplication and a superficial similarity of the C-terminal domain to pleckstrin homology-like folds. The conservation of the domain interface indicates a potential binding site that is likely to involve a nucleotide-based ligand, with genome-context and gene-fusion analyses additionally supporting a role for this family in signal transduction, possibly during oxidative stress. PMID:20944214

  13. [Study of possible involvement of MEK mitogen-activated protein kinase and TGF-β receptor in planarian regeneration processes using pharmacological inhibition analysis].

    PubMed

    Ermakov, A M; Ermakova, O N; Ermolaeva, S A

    2014-01-01

    Possible involvement of MEK mitogen-activated protein kinase and TGF-β receptor in the processes of regeneration and morphogenesis in freshwater planarian flatworms Schmidtea mediterranea was studied using a pharmacological inhibitor analysis. It was found that pharmacological inhibitors of these kinases significantly inhibit the regeneration of the head end of the animals and that this effect is realized due to inhibition of proliferative activity of neoblasts, planarian stem cells. It is shown that that the inhibition of the studied protein kinases in regenerating planarians markedly disturbs stem cell differentiation and morphogenesis.

  14. Discovery of a new isomannide-based peptidomimetic synthetized by Ugi multicomponent reaction as human tissue kallikrein 1 inhibitor.

    PubMed

    Barros, Thalita G; Santos, Jorge A N; de Souza, Bruno E G; Sodero, Ana Carolina R; de Souza, Alessandra M T; da Silva, Dayane P; Rodrigues, Carlos Rangel; Pinheiro, Sergio; Dias, Luiza R S; Abrahim-Vieira, Bárbara; Puzer, Luciano; Muri, Estela M F

    2017-01-15

    Human kallikrein 1 (KLK1) is the most extensively studied member of this family and plays a major role in inflammation processes. From Ugi multicomponent reactions, isomannide-based peptidomimetic 10 and 13 where synthesized and showed low micromolar values of IC50 for KLK1 The most active compound (10) presented competitive mechanism, with three structural modifications important to interact with active site residues which corroborates its KLK1 inhibition. Finally, the most active compound also showed good ADMET profile, which indicates compound 10 as a potential hit in the search for new KLK1 inhibitors with low side effects.

  15. Kallikrein-kinin system in the plasma of the snake Bothrops jararaca.

    PubMed Central

    Abdalla, F. M.; Hiraichi, E.; Picarelli, Z. P.; Prezoto, B. C.

    1989-01-01

    1. Bothrops jararaca venom (BJV) caused a fall in the carotid artery blood pressure of the anaesthetized snake. This effect was tachyphylactic and was potentiated by captopril, a kininase II inhibitor; it was partially antagonized by promethazine plus cimetidine and was not affected by atropine. 2. Similar hypotensive effects were obtained by administration of trypsin or a partially purified BJV kininogenase to the snake. 3. Incubation of Bothrops jararaca plasma (BJP) with trypsin released a substance (or substances) that produced hypotension in the snake but not in the rat; this hypotensive effect was also potentiated by captopril. 4. The trypsinised plasma contracted Bothrops jararaca isolated uterus, a pharmacological preparation weakly sensitive to bradykinin. Trypsinised plasma was inactive on pigeon oviduct and rat uterus and displayed a weak action on the guinea-pig ileum. Similar effects were observed with incubates of a fraction of BJP, containing globulins, with a partially purified BJV kininogenase. 5. Like mammalian kinins, the substance(s) was(were) dialysable, thermostable in acid but not in alkaline pH, and inactivated by chymotrypsin but not by trypsin. Its(their) inactivation by BJP or BJP kininase II was inhibited by captopril. 6. These findings strongly suggest that, besides releasing histamine, BJV or trypsin release a kininlike substance (or substances) from the snake plasma. 7. Since BJV and other kininogenases active on mammalian plasma were shown to be unable to release kinins from BJP, in experiments conducted on pharmacological preparations suitable for the assay of mammalian kinins, these data also suggest that the snake Bothrops jararaca, like birds, may have developed its own kallikrein-kinin system. PMID:2804549

  16. Human Tissue Kallikrein Activity in Angiographically Documented Chronic Stable Coronary Artery Disease

    PubMed Central

    Figueiredo, Estêvão Lanna; Magalhães, Carolina Antunes; Belli, Karlyse Claudino; Mandil, Ari; Garcia, José Carlos Faria; Araújo, Rosanã Aparecida; Figueiredo, Amintas Fabiano de Souza; Pellanda, Lucia Campos

    2015-01-01

    Background Human tissue kallikrein (hK1) is a key enzyme in the kallikrein–kinin system (KKS). hK1-specific amidase activity is reduced in urine samples from hypertensive and heart failure (HF) patients. The pathophysiologic role of hK1 in coronary artery disease (CAD) remains unclear. Objective To evaluate hK1-specific amidase activity in the urine of CAD patients Methods Sixty-five individuals (18–75 years) who underwent cardiac catheterism (CATH) were included. Random midstream urine samples were collected immediately before CATH. Patients were classified in two groups according to the presence of coronary lesions: CAD (43 patients) and non-CAD (22 patients). hK1 amidase activity was estimated using the chromogenic substrate D-Val-Leu-Arg-Nan. Creatinine was determined using Jaffé’s method. Urinary hK1-specific amidase activity was expressed as µM/(min · mg creatinine) to correct for differences in urine flow rates. Results Urinary hK1-specific amidase activity levels were similar between CAD [0.146 µM/(min ·mg creatinine)] and non-CAD [0.189 µM/(min . mg creatinine)] patients (p = 0.803) and remained similar to values previously reported for hypertensive patients [0.210 µM/(min . mg creatinine)] and HF patients [0.104 µM/(min . mg creatinine)]. CAD severity and hypertension were not observed to significantly affect urinary hK1-specific amidase activity. Conclusion CAD patients had low levels of urinary hK1-specific amidase activity, suggesting that renal KKS activity may be reduced in patients with this disease. PMID:26351984

  17. Kallikrein 4 and matrix metalloproteinase-20 immunoexpression in malignant, benign and infiltrative odontogenic tumors

    PubMed Central

    Crivelini, Marcelo Macedo; Oliveira, Denise Tostes; de Mesquita, Ricardo Alves; de Sousa, Suzana Cantanhede Orsini Machado; Loyola, Adriano Motta

    2016-01-01

    Context: Matrix metalloproteinase-20 (MMP20) (enamelysin) and kallikrein 4 (KLK4) are enzymes secreted by ameloblasts that play an important role in enamel matrix degradation during amelogenesis. However, studies have shown that neoplastic cells can produce such enzymes, which may affect the tumor infiltrative and metastatic behaviors. Aims: The aim of this study is to assess the biological role of MMP20 and KLK4 in odontogenic tumors. Materials and Methods: The enzymes were analyzed immunohistochemically in ameloblastoma, adenomatoid odontogenic tumor (AOT), calcifying epithelial odontogenic tumor, keratocystic odontogenic tumor with or without recurrence and odontogenic carcinoma. Statistical Analysis Used: Clinicopathological parameters were statistically correlated with protein expression using the Fisher's exact test. Kruskal–Wallis and Wilcoxon-independent methods were used to evaluate the differences in median values. Results: Positive Immunoexpression was detected in all benign lesions, with a prevalence of 75–100% immunolabeled cells. Patients were predominantly young, Caucasian, female, with slow-growing tumors located in the mandible causing asymptomatic swelling. No KLK4 expression was seen in carcinomas, and the amount of MMP20-positive cells varied between 20% and 80%. Rapid evolution, recurrence and age >60 years characterized the malignant nature of these lesions. Conclusions: Data showed that KLK4 and MMP20 enzymes may not be crucial to tumoral infiltrative capacity, especially in malignant tumors, considering the diversity and peculiarity of these lesions. The significant immunoexpression in benign lesions, remarkably in AOT, is likely associated with differentiated tumor cells that can produce and degrade enamel matrix-like substances. This would be expected since the histogenesis of odontogenic tumors commonly comes from epithelium that recently performed a secretory activity in tooth formation. PMID:27601817

  18. Skin barrier homeostasis in atopic dermatitis: feedback regulation of kallikrein activity.

    PubMed

    Tanaka, Reiko J; Ono, Masahiro; Harrington, Heather A

    2011-01-01

    Atopic dermatitis (AD) is a widely spread cutaneous chronic disease characterised by sensitive reactions (eg. eczema) to normally innocuous elements. Although relatively little is understood about its underlying mechanisms due to its complexity, skin barrier dysfunction has been recognised as a key factor in the development of AD. Skin barrier homeostasis requires tight control of the activity of proteases, called kallikreins (KLKs), whose activity is regulated by a complex network of protein interactions that remains poorly understood despite its pathological importance. Characteristic symptoms of AD include the outbreak of inflammation triggered by external (eg. mechanical and chemical) stimulus and the persistence and aggravation of inflammation even if the initial stimulus disappears. These characteristic symptoms, together with some experimental data, suggest the presence of positive feedback regulation for KLK activity by inflammatory signals. We developed simple mathematical models for the KLK activation system to study the effects of feedback loops and carried out bifurcation analysis to investigate the model behaviours corresponding to inflammation caused by external stimulus. The model analysis confirmed that the hypothesised core model mechanisms capture the essence of inflammation outbreak by a defective skin barrier. Our models predicted the outbreaks of inflammation at weaker stimulus and its longer persistence in AD patients compared to healthy control. We also proposed a novel quantitative indicator for inflammation level by applying principal component analysis to microarray data. The model analysis reproduced qualitative AD characteristics revealed by this indicator. Our results strongly implicate the presence and importance of feedback mechanisms in KLK activity regulation. We further proposed future experiments that may provide informative data to enhance the system-level understanding on the regulatory mechanisms of skin barrier in AD and

  19. Possible involvement of phosphorylated heat-shock factor-1 in changes in heat shock protein 72 induction in the failing rat heart following myocardial infarction.

    PubMed

    Marunouchi, Tetsuro; Murata, Mao; Takagi, Norio; Tanonaka, Kouichi

    2013-01-01

    It is supposed that an increase in the level of heat shock protein 72 (HSP72) in the failing heart would be beneficial for reducing the myocardial damage. However, the induction of HSP72 after an exposure to heat shock is blunted in the failing rat heart following myocardial infarction. In this study, to clarify the possible mechanisms underlying this reduction in the ability for HSP72 induction in the failing heart, the possible involvement of heat-shock factor-1 (HSF1), an HSP transcription factor, in this reduction was examined. When hemodynamic parameters of rats with myocardial infarction 8 weeks after coronary artery ligation were measured, the animals showed the signs of chronic heart failure. The HSF1 content was increased in the viable myocardium in the failing heart. The ability to induce cardiac HSP72 was reduced after an exposure to hyperthermia. The level of HSF1 in the cytosolic fraction from the failing heart with or without exposure to hyperthermia was increased, whereas that of HSF1 in the nuclear fraction was reduced. In the failing heart, the level of HSF1 on its serine 303 (Ser303) residue, which phosphorylation represses HSF1, was increased. These findings suggest that HSF1 translocation from the cytosol into the nucleus was attenuated after an exposure to hyperthermia and that an increase in the phosphorylation of HSF1 Ser303 was involved in the impairment of heat shock-induced HSP72 induction in the failing heart following myocardial infarction.

  20. Human kallikrein 4 signal peptide induces cytotoxic T cell responses in healthy donors and prostate cancer patients.

    PubMed

    Wilkinson, Ray; Woods, Katherine; D'Rozario, Rachael; Prue, Rebecca; Vari, Frank; Hardy, Melinda Y; Dong, Ying; Clements, Judith A; Hart, Derek N J; Radford, Kristen J

    2012-02-01

    Immunotherapy is a promising new treatment for patients with advanced prostate and ovarian cancer, but its application is limited by the lack of suitable target antigens that are recognized by CD8+ cytotoxic T lymphocytes (CTL). Human kallikrein 4 (KLK4) is a member of the kallikrein family of serine proteases that is significantly overexpressed in malignant versus healthy prostate and ovarian tissue, making it an attractive target for immunotherapy. We identified a naturally processed, HLA-A*0201-restricted peptide epitope within the signal sequence region of KLK4 that induced CTL responses in vitro in most healthy donors and prostate cancer patients tested. These CTL lysed HLA-A*0201+ KLK4 + cell lines and KLK4 mRNA-transfected monocyte-derived dendritic cells. CTL specific for the HLA-A*0201-restricted KLK4 peptide were more readily expanded to a higher frequency in vitro compared to the known HLA-A*0201-restricted epitopes from prostate cancer antigens; prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA) and prostatic acid phosphatase (PAP). These data demonstrate that KLK4 is an immunogenic molecule capable of inducing CTL responses and identify it as an attractive target for prostate and ovarian cancer immunotherapy.

  1. Kallikrein 1 is overexpressed by astrocytes in the hippocampus of patients with refractory temporal lobe epilepsy, associated with hippocampal sclerosis.

    PubMed

    Simões, Priscila Santos Rodrigues; Perosa, Sandra Regina; Arganãraz, Gustavo Adolfo; Yacubian, Elza Márcia; Carrete, Henrique; Centeno, Ricardo Silva; Varella, Pedro Paulo Vasconcellos; Santiago, Joselita Ferreira Carvalho; Canzian, Mauro; Silva, Jose Antonio; Mortara, Renato Arruda; Amado, Débora; Cavalheiro, Esper Abrão; Mazzacoratti, Maria da Graça Naffah

    2011-03-01

    Kallikrein 1 (hK1) is a tissue enzyme responsible for kinin release in inflammatory cascade. This study was delineated to study the distribution and the co-localization of hK1 and kinin B1 and B2 receptors with glial and/or neuronal proteins markers, in the hippocampus of patients with refractory temporal lobe epilepsy, associated with hippocampal sclerosis (TLE-HS), comparing with control tissues. Hippocampal levels of KLK1 mRNA were also measured. hK1, kinin B1 and B2 receptors, NeuN and GFAP were analyzed using immunohistochemistry and confocal microscopy and KLK1 mRNA was quantified with real time PCR. Increased expression of hK1 by astrocytes co-localized with GFAP was found, contrasting with kinin B1 and B2 receptors, which were co-localized with NeuN in the sclerotic hippocampus. In addition, KLK1 mRNA was also up-regulated in same tissues. These data suggest an overexpression of kallikrein-kinin system and a neuron-glia interaction in the inflammatory process present in refractory TLE-HS.

  2. Tissue Kallikrein Inhibitors Based on the Sunflower Trypsin Inhibitor Scaffold – A Potential Therapeutic Intervention for Skin Diseases

    PubMed Central

    Chen, Wenjie; Kinsler, Veronica A.

    2016-01-01

    Tissue kallikreins (KLKs), in particular KLK5, 7 and 14 are the major serine proteases in the skin responsible for skin shedding and activation of inflammatory cell signaling. In the normal skin, their activities are controlled by an endogenous protein protease inhibitor encoded by the SPINK5 gene. Loss-of-function mutations in SPINK5 leads to enhanced skin kallikrein activities and cause the skin disease Netherton Syndrome (NS). We have been developing inhibitors based on the Sunflower Trypsin Inhibitor 1 (SFTI-1) scaffold, a 14 amino acids head-to-tail bicyclic peptide with a disulfide bond. To optimize a previously reported SFTI-1 analogue (I10H), we made five analogues with additional substitutions, two of which showed improved inhibition. We then combined those substitutions and discovered a variant (Analogue 6) that displayed dual inhibition of KLK5 (tryptic) and KLK7 (chymotryptic). Analogue 6 attained a tenfold increase in KLK5 inhibition potency with an Isothermal Titration Calorimetry (ITC) Kd of 20nM. Furthermore, it selectively inhibits KLK5 and KLK14 over seven other serine proteases. Its biological function was ascertained by full suppression of KLK5-induced Protease-Activated Receptor 2 (PAR-2) dependent intracellular calcium mobilization and postponement of Interleukin-8 (IL-8) secretion in cell model. Moreover, Analogue 6 permeates through the cornified layer of in vitro organotypic skin equivalent culture and inhibits protease activities therein, providing a potential drug lead for the treatment of NS. PMID:27824929

  3. The role of glandular kallikrein in the formation of a salivary proline-rich protein A by cleavage of a single bond in salivary protein C.

    PubMed Central

    Wong, R S; Madapallimattam, G; Bennick, A

    1983-01-01

    An enzyme was purified from human parotid saliva that can cleave a single arginine-glycine peptide bond between residues 106 and 107 in human salivary proline-rich protein C, hereby giving rise to another proline-rich protein A, which is also found in saliva. The enzyme was purified 2400-fold. It cleaved salivary protein C at the rate of 59 micrograms of protein/h per microgram of enzyme and had amino acid composition, molecular weight and inhibition characteristics similar to those reported for human salivary kallikrein. Confirmation that the enzyme was kallikrein was demonstrated by its kinin-generating ability. Histochemical evidence indicates that a post-synthetic cleavage of protein C by kallikrein would have to take place during passage of saliva through the secretory ducts. In secreted saliva, cleavage of salivary protein C can only be observed after 72 h incubation. In addition, there is no effect of salivary flow rate on the relative amounts of proteins A and C in saliva. On the basis of the experimental observations, it is proposed that in vivo it is unlikely that kallikrein secreted from ductal cells plays a significant role in converting protein C into protein A. PMID:6553499

  4. Synthetic peptides and fluorogenic substrates related to the reactive site sequence of Kunitz-type inhibitors isolated from Bauhinia: interaction with human plasma kallikrein.

    PubMed

    Oliva, M L; Santomauro-Vaz, E M; Andrade, S A; Juliano, M A; Pott, V J; Sampaio, M U; Sampaio, C A

    2001-01-01

    We have previously described Kunitz-type serine proteinase inhibitors purified from Bauhinia seeds. Human plasma kallikrein shows different susceptibility to those inhibitors. In this communication, we describe the interaction of human plasma kallikrein with fluorogenic and non-fluorogenic peptides based on the Bauhinia inhibitors' reactive site. The hydrolysis of the substrate based on the B. variegata inhibitor reactive site sequence, Abz-VVISALPRSVFIQ-EDDnp (Km 1.42 microM, kcat 0.06 s(-1), and kcat/Km 4.23 x 10(4) M(-1) s(-1)), is more favorable than that of Abz-VMIAALPRTMFIQ-EDDnp, related to the B. ungulata sequence (Km 0.43 microM, kcat 0.00017 s(-1), and kcat/Km 3.9 x 10(2) M(-1) s(-1)). Human plasma kallikrein does not hydrolyze the substrates Abz-RPGLPVRFESPL-EDDnp and Abz-FESPLRINIIKE-EDDnp based on the B. bauhinioides inhibitor reactive site sequence, the most effective inhibitor of the enzyme. These peptides are competitive inhibitors with Ki values in the nM range. The synthetic peptide containing 19 amino acids based on the B. bauhinioides inhibitor reactive site (RPGLPVRFESPL) is poorly cleaved by kallikrein. The given substrates are highly specific for trypsin and chymotrypsin hydrolysis. Other serine proteinases such as factor Xa, factor XII, thrombin and plasmin do not hydrolyze B. bauhinioides inhibitor related substrates.

  5. Study the Antinociceptive Effect of Intracerebroventricular Injection of Aqueous Extract of Origanum Vulgare Leaves in Rat: Possible Involvement of Opioid System

    PubMed Central

    Pahlavan, Yasaman; Sepehri, Gholamreza; Sheibani, Vahid; Afarinesh khaki, Mohammadreza; Gojazadeh, Morteza; Pahlavan, Bahare; Pahlavan, Fereshteh

    2013-01-01

    Objective(s): The aim of study was to investigate the antinociceptive effect of intracerebroventricular (ICV) microinjection of Origanum vulgare (ORG) extract and possible involvement of opioid receptors. Materials and Methods: Cannula was inserted into left ventricle of male rats. Five days after surgery Tail Flick Latency (TFL) was measured after ICV microinjection of, ORG (1, 3 and 6 µg / rat). Effective dose of ORG was injected ICV in concomitant with morphine (2 mg/kg, IP), naloxone (2 mg / kg, IP) and saline (0.5 µl/rat) and TFL was recorded. Results: The co- administration of ORG extract with morphine showed a significant increase in TFL and naloxone, pretreatment significantly inhibited the antinociceptive activity of ORG and morphine. Conclusion: The aqueous extract of ORG possesses antinociceptive activities in the tail-flick test in a dose dependent manner. ORG - induced antinociception may have been mediated by opioid systems. PMID:24379969

  6. The structure of the first representative of Pfam family PF06475 reveals a new fold with possible involvement in glycolipid metabolism

    PubMed Central

    Bakolitsa, Constantina; Kumar, Abhinav; McMullan, Daniel; Krishna, S. Sri; Miller, Mitchell D.; Carlton, Dennis; Najmanovich, Rafael; Abdubek, Polat; Astakhova, Tamara; Chiu, Hsiu-Ju; Clayton, Thomas; Deller, Marc C.; Duan, Lian; Elias, Ylva; Feuerhelm, Julie; Grant, Joanna C.; Grzechnik, Slawomir K.; Han, Gye Won; Jaroszewski, Lukasz; Jin, Kevin K.; Klock, Heath E.; Knuth, Mark W.; Kozbial, Piotr; Marciano, David; Morse, Andrew T.; Nigoghossian, Edward; Okach, Linda; Oommachen, Silvya; Paulsen, Jessica; Reyes, Ron; Rife, Christopher L.; Trout, Christina V.; van den Bedem, Henry; Weekes, Dana; White, Aprilfawn; Xu, Qingping; Hodgson, Keith O.; Wooley, John; Elsliger, Marc-André; Deacon, Ashley M.; Godzik, Adam; Lesley, Scott A.; Wilson, Ian A.

    2010-01-01

    The crystal structure of PA1994 from Pseudomonas aeruginosa, a member of the Pfam PF06475 family classified as a domain of unknown function (DUF1089), reveals a novel fold comprising a 15-stranded β-sheet wrapped around a single α-helix that assembles into a tight dimeric arrangement. The remote structural similarity to lipoprotein localization factors, in addition to the presence of an acidic pocket that is conserved in DUF1089 homologs, phospholipid-binding and sugar-binding proteins, indicate a role for PA1994 and the DUF1089 family in glycolipid metabolism. Genome-context analysis lends further support to the involvement of this family of proteins in glycolipid metabolism and indicates possible activation of DUF1089 homologs under conditions of bacterial cell-wall stress or host–pathogen interactions. PMID:20944213

  7. Reduced corporal fibrosis to protect erectile function by inhibiting the Rho-kinase/LIM-kinase/cofilin pathway in the aged transgenic rat harboring human tissue kallikrein 1

    PubMed Central

    Cui, Kai; Luan, Yang; Wang, Tao; Zhuan, Li; Rao, Ke; Wang, Shao-Gang; Ye, Zhang-Qun; Liu, Ji-Hong; Wang, Dao-Wen

    2017-01-01

    Our previous studies have demonstrated that erectile function was preserved in aged transgenic rats (TGR) harboring the human tissue kallikrein 1 (hKLK1), while the molecular level of hKLK1 on corporal fibrosis to inhibit age-related erectile dysfunction (ED) is poorly understood. Male wild-type Sprague-Dawley rats (WTR) and TGR harboring the hKLK1 gene were fed to 4- or 18-month-old and divided into three groups: young WTR (yWTR) as the control, aged WTR (aWTR), and aged TGR (aTGR). Erectile function of all rats was assessed by cavernous nerve electrostimulation method. Masson's trichrome staining was used to evaluate corporal fibrosis in the corpus cavernosum. We found that the erectile function of rats in the aWTR group was significantly lower than that of other two groups. Masson's trichrome staining revealed that compared with those of the yWTR and aTGR groups, the ratio of smooth muscle cell (SMC)/collagen (C) was significantly lower in the aWTR group. Immunohistochemistry and Western blotting analysis were performed, and results demonstrated that expression of α-SMA was lower, while expressions of transforming growth factor-β 1 (TGF-β1), RhoA, ROCK1, p-MYPT1, p-LIMK2, and p-cofilin were higher in the aWTR group compared with those in other two groups. However, LIMK2 and cofilin expressions did not differ among three groups. Taken together, these results indicated that the RhoA/ROCK1/LIMK/cofilin pathway may be involved in the corporal fibrosis caused by advanced age, and hKLK1 may reduce this corporal fibrosis by inhibiting the activation of this pathway to ameliorate age-related ED. PMID:27678468

  8. A Highly Sensitive Porous Silicon (P-Si)-Based Human Kallikrein 2 (hK2) Immunoassay Platform toward Accurate Diagnosis of Prostate Cancer.

    PubMed

    Lee, Sang Wook; Hosokawa, Kazuo; Kim, Soyoun; Jeong, Ok Chan; Lilja, Hans; Laurell, Thomas; Maeda, Mizuo

    2015-05-22

    Levels of total human kallikrein 2 (hK2), a protein involved the pathology of prostate cancer (PCa), could be used as a biomarker to aid in the diagnosis of this disease. In this study, we report on a porous silicon antibody immunoassay platform for the detection of serum levels of total hK2. The surface of porous silicon has a 3-dimensional macro- and nanoporous structure, which offers a large binding capacity for capturing probe molecules. The tailored pore size of the porous silicon also allows efficient immobilization of antibodies by surface adsorption, and does not require chemical immobilization. Monoclonal hK2 capture antibody (6B7) was dispensed onto P-Si chip using a piezoelectric dispenser. In total 13 × 13 arrays (169 spots) were spotted on the chip with its single spot volume of 300 pL. For an optimization of capture antibody condition, we firstly performed an immunoassay of the P-Si microarray under a titration series of hK2 in pure buffer (PBS) at three different antibody densities (75, 100 and 145 µg/mL). The best performance of the microarray platform was seen at 100 µg/mL of the capture antibody concentration (LOD was 100 fg/mL). The platform then was subsequently evaluated for a titration series of serum-spiked hK2 samples. The developed platform utilizes only 15 µL of serum per test and the total assay time is about 3 h, including immobilization of the capture antibody. The detection limit of the hK2 assay was 100 fg/mL in PBS buffer and 1 pg/mL in serum with a dynamic range of 106 (10(-4) to 10(2) ng/mL).

  9. A Highly Sensitive Porous Silicon (P-Si)-Based Human Kallikrein 2 (hK2) Immunoassay Platform toward Accurate Diagnosis of Prostate Cancer

    PubMed Central

    Lee, Sang Wook; Hosokawa, Kazuo; Kim, Soyoun; Jeong, Ok Chan; Lilja, Hans; Laurell, Thomas; Maeda, Mizuo

    2015-01-01

    Levels of total human kallikrein 2 (hK2), a protein involved the pathology of prostate cancer (PCa), could be used as a biomarker to aid in the diagnosis of this disease. In this study, we report on a porous silicon antibody immunoassay platform for the detection of serum levels of total hK2. The surface of porous silicon has a 3-dimensional macro- and nanoporous structure, which offers a large binding capacity for capturing probe molecules. The tailored pore size of the porous silicon also allows efficient immobilization of antibodies by surface adsorption, and does not require chemical immobilization. Monoclonal hK2 capture antibody (6B7) was dispensed onto P-Si chip using a piezoelectric dispenser. In total 13 × 13 arrays (169 spots) were spotted on the chip with its single spot volume of 300 pL. For an optimization of capture antibody condition, we firstly performed an immunoassay of the P-Si microarray under a titration series of hK2 in pure buffer (PBS) at three different antibody densities (75, 100 and 145 µg/mL). The best performance of the microarray platform was seen at 100 µg/mL of the capture antibody concentration (LOD was 100 fg/mL). The platform then was subsequently evaluated for a titration series of serum-spiked hK2 samples. The developed platform utilizes only 15 µL of serum per test and the total assay time is about 3 h, including immobilization of the capture antibody. The detection limit of the hK2 assay was 100 fg/mL in PBS buffer and 1 pg/mL in serum with a dynamic range of 106 (10−4 to 102 ng/mL). PMID:26007739

  10. PF-04886847 (an inhibitor of plasma kallikrein) attenuates inflammatory mediators and activation of blood coagulation in rat model of lipopolysaccharide (LPS)-induced sepsis.

    PubMed

    Kolte, D; Bryant, J W; Gibson, G W; Wang, J; Shariat-Madar, Z

    2012-06-01

    The plasma kallikrein-mediated proteolysis regulates both thrombosis and inflammation. Previous study has shown that PF-04886847 is a potent and competitive inhibitor of kallikrein, suggesting that it might be useful for the treatment of kallikrein-kinin mediated inflammatory and thrombotic disorders. In the rat model of lipopolysaccharide (LPS) -induced sepsis used in this study, pretreatment of rats with PF-04886847 (1 mg/kg) prior to LPS (10 mg/kg) prevented endotoxin-induced increase in granulocyte count in the systemic circulation. PF-04886847 significantly reduced the elevated plasma 6-keto PGF1α levels in LPS treated rats, suggesting that PF-04886847 could be useful in preventing hypotensive shock during sepsis. PF-04886847 did not inhibit LPS-induced increase in plasma TNF-α level. Pretreatment of rats with PF-04886847 prior to LPS did not attenuate endotoxin-induced decrease in platelet count and plasma fibrinogen levels as well as increase in plasma D-dimer levels. PF-04886847 did not protect the animals against LPS-mediated acute hepatic and renal injury and disseminated intravascular coagulation (DIC). Since prekallikrein (the zymogen form of plasma kallikrein) deficient patients have prolonged activated partial thromboplastin time (aPTT) without having any bleeding disorder, the anti-thrombotic property and mechanism of action of PF-04886847 was assessed. In a rabbit balloon injury model designed to mimic clinical conditions of acute thrombotic events, PF-04886847 reduced thrombus mass dose-dependently. PF-04886847 (1 mg/kg) prolonged both aPTT and prothrombin time (PT) in a dose-dependent manner. Although the findings of this study indicate that PF-04886847 possesses limited anti-thrombotic and anti-inflammatory effects, PF-04886847 may have therapeutic potential in other kallikrein-kinin mediated diseases.

  11. Differences in substrate and inhibitor sequence specificity of human, mouse and rat tissue kallikreins.

    PubMed Central

    Fogaça, Sandro E; Melo, Robson L; Pimenta, Daniel C; Hosoi, Kazuo; Juliano, Luiz; Juliano, Maria A

    2004-01-01

    The kininogenase activities of mouse (mK1), rat (rK1) and human (hK1) tissue kallikreins were assayed with the bradykinin-containing synthetic peptides Abz-MTEMARRPPGFSPFRSVTVQNH2 (where Abz stands for o-aminobenzoyl) and Abz-MTSVIRRPPGFSPFRAPRV-NH2, which correspond to fragments Met374-Gln393 and Met375-Val393 of mouse and rat LMWKs (low-molecular-mass kininogens) with the addition of Abz. Bradykinin was released from these peptides by the mK1- and rK1-mediated hydrolysis of Arg-Arg and Arg-Ser (or Arg-Ala) peptide bonds. However, owing to preferential hydrolysis of Phe-Arg compared with the Arg-Ala bond in the peptide derived from rat LMWK, hK1 released bradykinin only from the mouse LMWK fragment and preferentially released des-[Arg9]bradykinin from the rat LMWK fragment (Abz-MTSVIRRPPGFSPFRAPRV-NH2). The formation of these hydrolysis products was examined in more detail by determining the kinetic parameters for the hydrolysis of synthetic, internally quenched fluorescent peptides containing six N- or C-terminal amino acids of bradykinin added to the five downstream or upstream residues of mouse and rat kininogens respectively. One of these peptides, Abz-GFSPFRAPRVQ-EDDnp (where EDDnp stands for ethylenediamine 2,4-dinitrophenyl), was preferentially hydrolysed at the Phe-Arg bond, confirming the potential des-[Arg9]bradykinin-releasing activity of hK1 on rat kininogen. The proline residue that is two residues upstream of bradykinin in rat kininogen is, in part, responsible for this pattern of hydrolysis, since the peptide Abz-GFSPFRASRVQ-EDDnp was preferentially cleaved at the Arg-Ala bond by hK1. Since this peptidase accepts the arginine or phenylalanine residue at its S1 subsite, this preference seems to be determined by the prime site of the substrates. These findings also suggested that the effects observed in rats overexpressing hK1 should consider the activation of B1 receptors by des-[Arg9]bradykinin. For further comparison, two short internally quenched

  12. Gene expression of transforming growth factor-beta 1 and its type II receptor in giant cell tumors of bone. Possible involvement in osteoclast-like cell migration.

    PubMed Central

    Zheng, M. H.; Fan, Y.; Wysocki, S. J.; Lau, A. T.; Robertson, T.; Beilharz, M.; Wood, D. J.; Papadimitriou, J. M.

    1994-01-01

    Giant cell tumor of bone (GCT) is a relatively rare skeletal neoplasm characterized by multinuclear giant cells (osteoclast-like cells) scattered in a mass of mononuclear cells. The currently favored hypothesis for the origin of cells within GCT is that the multinuclear giant cells are reactive osteoclasts, whereas the truly neoplastic cells are the major component of the mononuclear population. However, the pathological significance and the precise relationship of tumor cells and osteoclast-like cells in GCT have not been fully established. In this study, we evaluated two GCTs for the presence of transforming growth factor-beta 1 (TGF-beta 1) and TGF-beta type II receptor gene transcripts and attempted to establish a possible role for TGF-beta 1 in the interaction between tumor cells and osteoclast-like cells. By using in situ hybridization and Northern blot analysis, we have demonstrated that TGF-beta 1 mRNA transcript is consistently detected in both tumor mononuclear cells and osteoclast-like cells, whereas TGF-beta type II receptor gene transcript is only present in osteoclast-like cells. Moreover, isolated rat osteoclasts were tested for their ability to migrate in response to GCT-conditioned medium (GCTCM) in an in vitro chemotactic assay. Our results showed that GCTCM stimulates the migration of osteoclasts in a dose-dependent manner. Interestingly, only osteoclasts containing less than three nuclei can migrate through 12-mu pore filters. Addition of monoclonal antibody against TGF-beta significantly reduced but did not abolish the chemotactic activity of GCTCM. Moreover, TGF-beta type II receptor mRNA has been demonstrated in the normal rat osteoclasts and may be involved in the chemotactic action of TGF-beta 1. We concluded that TGF-beta 1, possibly in concert with other cytokines, is involved in the recruitment of osteoclast-like cells in GCT by acting in an autocrine or paracrine fashion. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

  13. Cell cycle alterations induced by urban PM2.5 in bronchial epithelial cells: characterization of the process and possible mechanisms involved

    PubMed Central

    2013-01-01

    Background This study explores and characterizes cell cycle alterations induced by urban PM2.5 in the human epithelial cell line BEAS-2B, and elucidates possible mechanisms involved. Methods The cells were exposed to a low dose (7.5 μg/cm2) of Milan winter PM2.5 for different time points, and the cell cycle progression was analyzed by fluorescent microscopy and flow cytometry. Activation of proteins involved in cell cycle control was investigated by Western blotting and DNA damage by 32P-postlabelling, immunostaining and comet assay. The formation of reactive oxygen species (ROS) was quantified by flow cytometry. The role of PM organic fraction versus washed PM on the cell cycle alterations was also examined. Finally, the molecular pathways activated were further examined using specific inhibitors. Results Winter PM2.5 induced marked cell cycle alteration already after 3 h of exposure, represented by an increased number of cells (transient arrest) in G2. This effect was associated with an increased phosphorylation of Chk2, while no changes in p53 phosphorylation were observed at this time point. The increase in G2 was followed by a transient arrest in the metaphase/anaphase transition point (10 h), which was associated with the presence of severe mitotic spindle aberrations. The metaphase/anaphase delay was apparently followed by mitotic slippage at 24 h, resulting in an increased number of tetraploid G1 cells and cells with micronuclei (MN), and by apoptosis at 40 h. Winter PM2.5 increased the level of ROS at 2 h and DNA damage (8-oxodG, single- and double stand breaks) was detected after 3 h of exposure. The PM organic fraction caused a similar G2/M arrest and augmented ROS formation, while washed PM had no such effects. DNA adducts were detected after 24 h. Both PM-induced DNA damage and G2 arrest were inhibited by the addition of antioxidants and α-naphthoflavone, suggesting the involvement of ROS and reactive electrophilic metabolites formed via a P

  14. Anatomy of the antennal dorsal organ in female of Neodryinus typhlocybae (Hymenoptera: Dryinidae): A peculiar sensory structure possibly involved in perception of host vibration.

    PubMed

    Riolo, Paola; Isidoro, Nunzio; Ruschioni, Sara; Minuz, Roxana L; Bin, Ferdinando; Romani, Roberto

    2016-01-01

    Neodryinus typhlocybae (Hymenoptera: Dryinidae) is a natural enemy of the planthopper Metcalfa pruinosa, which was introduced from North America into Europe and has become established in various regions as a pest species. Vibrational signals play a crucial role in the communication of M. pruinosa, which appears to be exploited by N. typhlocybae. Scanning and transmission electron microscopy have shown that the antennae of N. typhlocybae females have peculiar and complex sensory structures: deep longitudinal grooves that house long sensilla trichodea, termed here "Antennal Dorsal Organs." Such structures were not present on male antennae. These sensilla extend for the length of the grooves, without contact with the groove cuticle. Their hair shaft is empty and aporous, and inserted into a specialized socket, underneath which there is a cuticular ampulla-like chamber. Each sensillum is associated with two sensory neurons: one terminates at the proximal end of the dendritic sheath; the other continues into the sensillum sinus and is enclosed in the dendritic sheath. This second sensory neuron then enters the ampulla-like chamber through the circular opening, and then terminates with a conspicuous tubular body at the shaft base. The possible involvement of this peculiar structure in the context of host recognition mechanism is discussed.

  15. Transcriptional profiling analysis of Spodoptera litura larvae challenged with Vip3Aa toxin and possible involvement of trypsin in the toxin activation

    PubMed Central

    Song, Feifei; Chen, Chen; Wu, Songqing; Shao, Ensi; Li, Mengnan; Guan, Xiong; Huang, Zhipeng

    2016-01-01

    Vip proteins, a new group of insecticidal toxins produced by Bacillus thuringiensis, are effective against specific pests including Spodoptera litura. Here, we report construction of a transcriptome database of S. litura by de novo assembly along with detection of the transcriptional response of S. litura larvae to Vip3Aa toxin. In total, 56,498 unigenes with an N50 value of 1,853 bp were obtained. Results of transcriptome abundance showed that Vip3Aa toxin provoked a wide transcriptional response of the S. litura midgut. The differentially expressed genes were enriched for immunity-related, metabolic-related and Bt-related genes. Twenty-nine immunity-related genes, 102 metabolic-related genes and 62 Bt-related genes with differential expression were found. On the basis of transcriptional profiling analysis, we focus on the functional validation of trypsin which potentially participated in the activation of Vip3Aa protoxin. Zymogram analysis indicated that the presence of many proteases, including trypsin, in S. litura larvae midgut. Results of enzymolysis in vitro of Vip3Aa by trypsin, and bioassay and histopathology of the trypsin-digested Vip3Aa toxin showed that trypsin was possibly involved in the Vip3Aa activation. This study provides a transcriptome foundation for the identification and functional validation of the differentially expressed genes in an agricultural important pest, S. litura. PMID:27025647

  16. Transcriptional profiling analysis of Spodoptera litura larvae challenged with Vip3Aa toxin and possible involvement of trypsin in the toxin activation.

    PubMed

    Song, Feifei; Chen, Chen; Wu, Songqing; Shao, Ensi; Li, Mengnan; Guan, Xiong; Huang, Zhipeng

    2016-03-30

    Vip proteins, a new group of insecticidal toxins produced by Bacillus thuringiensis, are effective against specific pests including Spodoptera litura. Here, we report construction of a transcriptome database of S. litura by de novo assembly along with detection of the transcriptional response of S. litura larvae to Vip3Aa toxin. In total, 56,498 unigenes with an N50 value of 1,853 bp were obtained. Results of transcriptome abundance showed that Vip3Aa toxin provoked a wide transcriptional response of the S. litura midgut. The differentially expressed genes were enriched for immunity-related, metabolic-related and Bt-related genes. Twenty-nine immunity-related genes, 102 metabolic-related genes and 62 Bt-related genes with differential expression were found. On the basis of transcriptional profiling analysis, we focus on the functional validation of trypsin which potentially participated in the activation of Vip3Aa protoxin. Zymogram analysis indicated that the presence of many proteases, including trypsin, in S. litura larvae midgut. Results of enzymolysis in vitro of Vip3Aa by trypsin, and bioassay and histopathology of the trypsin-digested Vip3Aa toxin showed that trypsin was possibly involved in the Vip3Aa activation. This study provides a transcriptome foundation for the identification and functional validation of the differentially expressed genes in an agricultural important pest, S. litura.

  17. A Single Glycan at the 99-Loop of Human Kallikrein-related Peptidase 2 Regulates Activation and Enzymatic Activity.

    PubMed

    Guo, Shihui; Skala, Wolfgang; Magdolen, Viktor; Briza, Peter; Biniossek, Martin L; Schilling, Oliver; Kellermann, Josef; Brandstetter, Hans; Goettig, Peter

    2016-01-08

    Human kallikrein-related peptidase 2 (KLK2) is a key serine protease in semen liquefaction and prostate cancer together with KLK3/prostate-specific antigen. In order to decipher the function of its potential N-glycosylation site, we produced pro-KLK2 in Leishmania tarentolae cells and compared it with its non-glycosylated counterpart from Escherichia coli expression. Mass spectrometry revealed that Asn-95 carries a core glycan, consisting of two GlcNAc and three hexoses. Autocatalytic activation was retarded in glyco-pro-KLK2, whereas the activated glyco-form exhibited an increased proteolytic resistance. The specificity patterns obtained by the PICS (proteomic identification of protease cleavage sites) method are similar for both KLK2 variants, with a major preference for P1-Arg. However, glycosylation changes the enzymatic activity of KLK2 in a drastically substrate-dependent manner. Although glyco-KLK2 has a considerably lower catalytic efficiency than glycan-free KLK2 toward peptidic substrates with P2-Phe, the situation was reverted toward protein substrates, such as glyco-pro-KLK2 itself. These findings can be rationalized by the glycan-carrying 99-loop that prefers to cover the active site like a lid. By contrast, the non-glycosylated 99-loop seems to favor a wide open conformation, which mostly increases the apparent affinity for the substrates (i.e. by a reduction of Km). Also, the cleavage pattern and kinetics in autolytic inactivation of both KLK2 variants can be explained by a shift of the target sites due to the presence of the glycan. These striking effects of glycosylation pave the way to a deeper understanding of kallikrein-related peptidase biology and pathology.

  18. Possible involvement of GABAergic mechanism in protective effect of melatonin against sleep deprivation-induced behaviour modification and oxidative damage in mice.

    PubMed

    Kumar, Anil; Singh, Anant

    2009-08-01

    Sleep is an important physiological process responsible for the maintenance of physical, mental and emotional health of a living being. Sleep deprivation is considered risky for several pathological diseases such as anxiety and motor and cognitive dysfunctions. Sleep deprivation has recently been reported to cause oxidative damage. This study has been designed to explore the possible involvement of the GABAergic mechanism in protective effects of melatonin against 72-h sleep deprivation-induced behaviour modification and oxidative damage in mice. Mice were sleep-deprived for a period of 72 h using the grid over water suspended method. Animals were divided into groups of 6-8 animals each. Melatonin (5 and 10 mg/kg), flumazenil (0.5 mg/kg), picrotoxin (0.5 mg/kg) and muscimol (0.05 mg/kg) were administered for 5 days starting 2 days before 72-h sleep deprivation. Various behavioural tests (plus maze, zero maze, mirror chamber, actophotometer) and body weight assessment followed by oxidative stress parameters (malondialdehyde level, glutathione, catalase, nitrite and protein) were carried out. The 72-h sleep deprivation caused significant anxiety-like behaviour, weight loss, impaired locomotor activity and oxidative damage as compared with naïve (without sleep deprivation). Treatment with melatonin (5 mg/kg and 10 mg/kg, ip) significantly improved locomotor activity, weight loss and antianxiety effect as compared with control (sleep-deprived). Biochemically, melatonin treatment significantly restored reduced glutathione, catalase activity, attenuated lipid peroxidation and nitrite level as compared with control animals (72-h sleep-deprived). Flumazenil (0.5 mg/kg) and picrotoxin (0.5 mg/kg) pretreatments with a lower dose of melatonin (5 mg/kg) significantly antagonized the protective effect of melatonin. However, muscimol (0.05 mg/kg) pretreatment with melatonin (5 mg/kg, ip) potentiated the protective effect of melatonin which was significant as compared with their

  19. Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: Possible involvement of angiotensin-converting enzyme-2

    SciTech Connect

    Han Suxia; He Guangming; Wang Tao; Chen Lei; Ning Yunye; Luo Feng; An Jin; Yang Ting; Dong Jiajia; Liao Zenglin; Xu Dan; Wen Fuqiang

    2010-05-15

    Chronic cigarette smoking induces pulmonary arterial hypertension (PAH) by largely unknown mechanisms. Renin-angiotensin system (RAS) is known to function in the development of PAH. Losartan, a specific angiotensin II receptor antagonist, is a well-known antihypertensive drug with a potential role in regulating angiotensin-converting enzyme-2 (ACE2), a recently found regulator of RAS. To determine the effect of losartan on smoke-induced PAH and its possible mechanism, rats were daily exposed to cigarette smoke for 6 months in the absence and in the presence of losartan. Elevated right ventricular systolic pressure (RVSP), thickened wall of pulmonary arteries with apparent medial hypertrophy along with increased angiotensin II (Ang II) and decreased ACE2 levels were observed in smoke-exposed-only rats. Losartan administration ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs. In cultured primary pulmonary artery smooth muscle cells (PASMCs) from 3- and 6-month smoke-exposed rats, ACE2 levels were significantly lower than in those from the control rats. Moreover, PASMCs from 6-month exposed rats proliferated more rapidly than those from 3-month exposed or control rats, and cells grew even more rapidly in the presence of DX600, an ACE2 inhibitor. Consistent with the in vivo study, in vitro losartan pretreatment also inhibited cigarette smoke extract (CSE)-induced cell proliferation and ACE2 reduction in rat PASMCs. The results suggest that losartan may be therapeutically useful in the chronic smoking-induced pulmonary vascular remodeling and PAH and ACE2 may be involved as part of its mechanism. Our study might provide insight into the development of new therapeutic interventions for PAH smokers.

  20. Profiling of MicroRNAs under Wound Treatment in Aquilaria sinensis to Identify Possible MicroRNAs Involved in Agarwood Formation

    PubMed Central

    Gao, Zhi-Hui; Yang, Yun; Zhang, Zheng; Zhao, Wen-Ting; Meng, Hui; Jin, Yue; Huang, Jun-Qing; Xu, Yan-Hong; Zhao, Li-Zi; Liu, Juan; Wei, Jian-He

    2014-01-01

    Agarwood, a kind of highly valued non-timber product across Asia, is formed only when its resource trees -- the endangered genus Aquilaria are wounded or infected by some microbes. To promote the efficiency of agarwood production and protect the wild resource of Aquilaria species, we urgently need to reveal the regulation mechanism of agarwood formation. MicroRNAs (miRNAs) are a group of gene expression regulators with overwhelming effects on a large spectrum of biological processes. However, their roles in agarwood formation remain unknown. This work aimed at identifying possible miRNAs involved in the wound induced agarwood formation. In this study, the high-throughput sequencing was adopted to identify miRNAs and monitor their expression under wound treatment in the stems of A. sinensis. The miR171, miR390, miR394, miR2111, and miR3954 families remained at the reduced level two days after the treatment. 131 homologous miRNAs in the 0.5 h library showed over three-fold variation of read number compared with the control library, of which 12 exhibiting strong expression alterations were further confirmed by real-time quantitative PCR. Target prediction and annotation of the miRNAs demonstrated that the binding, metabolic process, catalytic activity, and cellular process are the most common functions of the predicted targets of these newly identified miRNAs in A.sinensis. The cleaveage sites of three newly predicted targets were verified by 5'RACE. PMID:24795531

  1. Profiling of microRNAs under wound treatment in Aquilaria sinensis to identify possible microRNAs involved in agarwood formation.

    PubMed

    Gao, Zhi-Hui; Yang, Yun; Zhang, Zheng; Zhao, Wen-Ting; Meng, Hui; Jin, Yue; Huang, Jun-Qing; Xu, Yan-Hong; Zhao, Li-Zi; Liu, Juan; Wei, Jian-He

    2014-01-01

    Agarwood, a kind of highly valued non-timber product across Asia, is formed only when its resource trees--the endangered genus Aquilaria are wounded or infected by some microbes. To promote the efficiency of agarwood production and protect the wild resource of Aquilaria species, we urgently need to reveal the regulation mechanism of agarwood formation. MicroRNAs (miRNAs) are a group of gene expression regulators with overwhelming effects on a large spectrum of biological processes. However, their roles in agarwood formation remain unknown. This work aimed at identifying possible miRNAs involved in the wound induced agarwood formation. In this study, the high-throughput sequencing was adopted to identify miRNAs and monitor their expression under wound treatment in the stems of A. sinensis. The miR171, miR390, miR394, miR2111, and miR3954 families remained at the reduced level two days after the treatment. 131 homologous miRNAs in the 0.5 h library showed over three-fold variation of read number compared with the control library, of which 12 exhibiting strong expression alterations were further confirmed by real-time quantitative PCR. Target prediction and annotation of the miRNAs demonstrated that the binding, metabolic process, catalytic activity, and cellular process are the most common functions of the predicted targets of these newly identified miRNAs in A.sinensis. The cleaveage sites of three newly predicted targets were verified by 5'RACE.

  2. Possible involvement of brain prostaglandin E2 and prostanoid EP3 receptors in prostaglandin E2 glycerol ester-induced activation of central sympathetic outflow in the rat.

    PubMed

    Shimizu, Takahiro; Tanaka, Kenjiro; Nakamura, Kumiko; Taniuchi, Keisuke; Yawata, Toshio; Higashi, Youichirou; Ueba, Tetsuya; Dimitriadis, Fotios; Shimizu, Shogo; Yokotani, Kunihiko; Saito, Motoaki

    2014-07-01

    We recently reported that intracerebroventricularly administered 2-arachidonoylglycerol elevated plasma noradrenaline and adrenaline by brain monoacylglycerol lipase- (MGL) and cyclooxygenase-mediated mechanisms in the rat. These results suggest that 2-arachidonoylglycerol is hydrolyzed by MGL to free arachidonic acid, which is further metabolized to prostaglandins (PGs) by cyclooxygenase in the brain, thereby elevating plasma noradrenaline and adrenaline. On the other hand, 2-arachidonoylglycerol can be also metabolized by cyclooxygenase to PG glycerol esters (PG-Gs), which seems to be hydrolyzed by MGL to free PGs. Here, we examined the involvement of brain PG-Gs in the elevation of plasma noradrenaline and adrenaline regarding PGE2-G and prostanoid EP receptors using anesthetized male Wistar rats. Intracerebroventricularly administered PGE2-G (1.5 and 3 nmol/animal) dose-dependently elevated plasma noradrenaline but not adrenaline. PGE2-G also elevated systolic, mean and diastolic blood pressure and heart rate. The PGE2-G-induced elevation of plasma noradrenaline was attenuated by JZL184 (MGL inhibitor). Intracerebroventricularly administered PGE2 (0.3 and 1.5 nmol/animal) and sulprostone (0.1 and 0.3 nmol/animal) (EP1/EP3 agonist) also elevated plasma noradrenaline but not adrenaline in a dose-dependent manner. The sulprostone-induced elevation was attenuated by L-798,106 (EP3 antagonist), but not by SC-51322 (EP1 antagonist). L-798,106 also attenuated the PGE2-G- and PGE2-induced elevation of plasma noradrenaline, while PF-04418948 (EP2 antagonist) and L-161,982 (EP4 antagonist) had no effect on the PGE2-G-induced response. These results suggest a possibility that brain PGE2-G produced from 2-arachidonoylglycerol can be hydrolyzed to free PGE2, thereby activating central sympathetic outflow by brain prostanoid EP3 receptor-mediated mechanisms in the rat.

  3. In vitro screening of major neurotransmitter systems possibly involved in the mechanism of action of antibodies to S100 protein in released-active form

    PubMed Central

    Gorbunov, Evgeniy A; Ertuzun, Irina A; Kachaeva, Evgeniya V; Tarasov, Sergey A; Epstein, Oleg I

    2015-01-01

    Experimentally and clinically, it was shown that released-active form of antibodies to S100 protein (RAF of Abs to S100) exerts a wide range of pharmacological activities: anxiolytic, antiasthenic, antiaggressive, stress-protective, antihypoxic, antiischemic, neuroprotective, and nootropic. The purpose of this study was to determine the influence of RAF of Abs to S100 on major neurotransmitter systems (serotoninergic, GABAergic, dopaminergic, and on sigma receptors as well) which are possibly involved in its mechanism of pharmacological activity. Radioligand binding assays were used for assessment of the drug influence on ligand–receptor interaction. [35S]GTPγS binding assay, cyclic adenosine monophosphate HTRF™, cellular dielectric spectroscopy assays, and assays based on measurement of intracellular concentration of Ca2+ ions were used for assessment of agonist or antagonist properties of the drug toward receptors. RAF of Abs to S100 increased radioligand binding to 5-HT1F, 5-HT2B, 5-HT2Cedited, 5-HT3, and to D3 receptors by 142.0%, 131.9%, 149.3%, 120.7%, and 126.3%, respectively. Also, the drug significantly inhibited specific binding of radioligands to GABAB1A/B2 receptors by 25.8%, and to both native and recombinant human sigma1 receptors by 75.3% and 40.32%, respectively. In the functional assays, it was shown that the drug exerted antagonism at 5-HT1B, D3, and GABAB1A/B2 receptors inhibiting agonist-induced responses by 23.24%, 32.76%, and 30.2%, respectively. On the contrary, the drug exerted an agonist effect at 5-HT1A receptors enhancing receptor functional activity by 28.0%. The pharmacological profiling of RAF of Abs to S100 among 27 receptor provides evidence for drug-related modification of major neurotransmitter systems. PMID:26604768

  4. Screening of UV-B-induced genes from apple peels by SSH: possible involvement of MdCOP1-mediated signaling cascade genes in anthocyanin accumulation.

    PubMed

    Peng, Ting; Saito, Takanori; Honda, Chikako; Ban, Yusuke; Kondo, Satoru; Liu, Ji-Hong; Hatsuyama, Yoshimichi; Moriguchi, Takaya

    2013-07-01

    Suppression subtractive hybridization (SSH) was employed to identify candidate genes involved in red coloration in apple peel with the ultraviolet (UV)-B-treated 'Mutsu'. After reverse Northern blotting verification, nearly 80 clones were successfully sequenced. Large portions of the expressed sequence tags (ESTs) are well characterized anthocyanin biosynthesis-related genes, such as chalcone synthase (11A5), flavonol synthase (12F3), anthocyanidin synthase (11H5) and UDP-glycosyl transferase (14A12) whose presence proved the success of SSH. Eight ESTs were selected for quantitative real-time polymerase chain reaction analysis and their expressions were all elevated in 'Induction', further confirming the reliability of the SSH library. One EST, 11F4 (CONSTITUTIVE PHOTOMORPHOGENIC 1: COP1) with putative function in light signal relay was further analyzed in 'Mutsu' and 'Tsugaru', along with MdHY5 (ELONGATED HYPOCOTYL 5: the downstream target of COP1), MdMYB22 (a possible flavonol-specific activator under the regulation of HY5, belonging to the SG7/PRODUCTION OF FLAVONOL GLYCOSIDES family) and MdMYBA. Results showed that MdCOP1, MdHY5, MdMYB22 and MdMYBA were all UV-B inducible genes and anthocyanin accumulation occurred after their increased expressions. Moreover, their expressions and anthocyanin content were enhanced under UV-B plus 17°C treatment. The presence of G box, a known consensus binding site of HY5, in the MdMYBA promoter region implicated that it could be regulated by MdHY5, which was verified by the result of the yeast one-hybrid analysis. Our data suggested that UV-B irradiation would induce the utmost upstream light signaling factor, MdCOP1, which activates MdHY5 signaling by binding to the promoter regions of MdMYBs, and finally leads to the red coloration of apple peels.

  5. Androgens act synergistically to enhance estrogen-induced upregulation of human tissue kallikreins 10, 11, and 14 in breast cancer cells via a membrane bound androgen receptor.

    PubMed

    Paliouras, Miltiadis; Diamandis, Eleftherios P

    2008-04-01

    The regulation of gene expression by steroid hormones plays an important role in the normal development and function of many organs, as well as in the pathogenesis of endocrine-related cancers, especially breast cancer. However, clinical data suggest that combined testosterone and estrogen treatments on post-menopausal women increase the risk of breast cancer. Experiments have shown that many, if not all kallikreins are under steroid hormone regulation in breast cancer cell lines. Their implication as prognostic and diagnostic markers has also been well-documented. Thus, we investigated the effect of combined hormone stimulation with androgens and 17beta-estradiol on the ductal caricinoma cell line BT474. This cell line has been shown to be sensitive to both, androgens (secreting PSA) and estrogens (secreting a number of kallikreins including KLK10, 11, and KLK14). We found that PSA expression was downregulated upon combined hormone stimulation, confirming reports that estrogen can antagonize and block the activity of the androgen receptor. Upon analysis of estrogen-sensitive kallikreins 10, 11, and 14, all showed to be synergistically enhanced in their expression three- to fourfold, upon joint hormone treatment versus individual hormone stimulation. The enhancement is dependent upon the action of androgens as treatment with the androgen receptor antagonist cyproterone actetate normalized the expression of KLK10, 11, and KLK14 to estrogen-stimulation levels. The synergistic effects between estrogens and androgens on estrogen-sensitive genes may have implications on the role of the kallikreins in associated risk of breast cancer and progression.

  6. Transcriptome reveals the overexpression of a kallikrein gene cluster (KLK1/3/7/8/12) in the Tibetans with high altitude-associated polycythemia

    PubMed Central

    Li, Kang; Gesang, Luobu; Dan, Zeng; Gusang, Lamu

    2017-01-01

    High altitude-associated polycythemia (HAPC) is a very common disease. However, it the disease is still unmanageable and the related molecular mechanisms remain largely unclear. In the present study, we aimed to explore the molecular mechanisms responsible for the development of HAPC using transcriptome analysis. Transcriptome analysis was conducted in 3 pairs of gastric mucosa tissues from patients with HAPC and healthy residents at a similar altitude. Endoscopy and histopathological analyses were used to examine the injury to gastric tissues. Molecular remodeling was performed for the interaction between different KLK members and cholesterol. HAPC was found to lead to morphological changes and pathological damage to the gastric mucosa of patients. A total of 10,304 differentially expressed genes (DEGs) were identified. Among these genes, 4,941 DEGs were upregulated, while 5,363 DEGs were downregulated in the patients with HAPC (fold change ≥2, P<0.01 and FDR <0.01). In particular, the kallikrein gene cluster (KLK1/3/7/8/12) was upregulated >17-fold. All the members had high-score binding cholesterol, particularly for the polymers of KLK7. The kallikrein gene cluster (KLK1/3/7/8/12) is on chromosome 19q13.3–13.4. The elevated levels of KLK1, KLK3, KLK7, KLK8 and KLK12 may be closely associated with the hypertension, inflammation, obesity and other gastric injuries associated with polycythemia. The interaction of KLKs and cholesterol maybe play an important role in the development of hypertension. The findings of the present study revealed that HAPC induces gastric injury by upregulating the kallikrein gene cluster (KLK1/3/7/8/12), which can bind cholesterol and result in kallikrein hypertension. These findings provide some basic information for understanding the molecular mechanisms responsible for HAPC and HAPC-related diseases. PMID:28000848

  7. Skin pH Is the Master Switch of Kallikrein 5-Mediated Skin Barrier Destruction in a Murine Atopic Dermatitis Model.

    PubMed

    Jang, Hyosun; Matsuda, Akira; Jung, Kyungsook; Karasawa, Kaoru; Matsuda, Kenshiro; Oida, Kumiko; Ishizaka, Saori; Ahn, Ginnae; Amagai, Yosuke; Moon, Changjong; Kim, Sung-Ho; Arkwright, Peter D; Takamori, Kenji; Matsuda, Hiroshi; Tanaka, Akane

    2016-01-01

    Elevated skin surface pH has been reported in patients with atopic dermatitis. In this study, we explored the role of skin pH in the pathogenesis of atopic dermatitis using the NC/Tnd murine atopic dermatitis model. Alkalinization of the skin of asymptomatic NC/Tnd mice housed in specific pathogen-free conditions induced kallikrein 5 and activated protease-activated receptor 2, resulting in thymic stromal lymphopoietin secretion and a cutaneous T-helper 2 allergic response. This was associated with increased transepidermal water loss and development of eczematous lesions in these specific pathogen-free NC/Tnd mice, which normally do not suffer from atopic dermatitis. Injection of recombinant thymic stromal lymphopoietin also induced scratching behavior in the specific pathogen-free NC/Tnd mice. Thymic stromal lymphopoietin production and dermatitis induced by alkalinization of the skin could be blocked by the protease-activated receptor 2 antagonist ENMD-1068. In contrast, weak acidification of eczematous skin in conventionally housed NC/Tnd mice reduced kallikrein 5 activity and ameliorated the dermatitis. Onset of the dermatitis was associated with increased epidermal filaggrin expression and impaired activity of the sodium/hydrogen exchanger 1, a known regulator of skin pH. We conclude that alterations in skin pH directly modulate kallikrein 5 activity leading to skin barrier dysfunction, itch, and dermatitis via the protease-activated receptor 2-thymic stromal lymphopoietin pathway.

  8. Cellular transport of microcystin-LR in rainbow trout (Oncorhynchus mykiss) across the intestinal wall: possible involvement of multidrug resistance-associated proteins.

    PubMed

    Bieczynski, Flavia; De Anna, Julieta S; Pirez, Macarena; Brena, Beatríz M; Villanueva, Silvina S M; Luquet, Carlos M

    2014-09-01

    We studied Abcc mediated-transport in middle and posterior intestine of the rainbow trout, Oncorhynchus mykiss. Luminal and serosal transport were evaluated in everted and non-everted intestinal sacs, respectively, incubated with 1-chloro-2,4-dinitrobenzene (CDNB; 200 μM). CDNB enters the cells and is conjugated with glutathione via glutathione S-transferase (GST) to form 2,4-dinitrophenyl-S-glutathione (DNP-SG), a known Abcc substrate. DNP-SG concentration in the bath was recorded every 10 min, in order to calculate the mass-specific transport rate. For evaluating the possible involvement of Abcc proteins in microcystin-LR (MCLR) transport, 1.135 μM MCLR was added to the bath or inside the sacs, in everted or non-everted preparations, respectively. Both luminal and serosal DNP-SG efflux were significantly inhibited by MCLR. A concentration-response curve obtained using strips from middle intestine yielded an IC50 value of 1.33 μM MCLR. The Abcc inhibitor, MK571 produced concentration-dependent inhibition of DNP-SG similar to that produced by MCLR. Since competition of MCLR and CDNB as GST substrates could bias the DNP-SG transport results, we evaluated the effects of MCLR on calcein efflux, which does not depend on GST activity. We applied the non-fluorescent, cell-permeant compound calcein-AM (0.25 μM) to middle intestinal strips and recorded the efflux of its hydrolysis product, the fluorescent Abcc substrate calcein. 2.27 μM MCLR and 3 μM MK571 inhibited calcein efflux (17.39 and 20.2%, respectively). Finally, MCLR interaction with Abcc transporters was evaluated by measuring its toxic intracellular effects. Middle intestinal segments were incubated in saline solution with 1.135 μM MCLR (MC1), 2.27 μM MCLR (MC2), 3 μM MK571 (MK) or 1.135 μM MCLR+3 μM MK571 (MC1/MK). After 1h, GSH concentration, protein phosphatase 1 and 2A (PP1, PP2A) and GST activities were measured in each segment. MC1did not produce significant effect while MC1/MK and MC2

  9. Systems analysis of immune responses in Marek's disease virus-infected chickens identifies a gene involved in susceptibility and highlights a possible novel pathogenicity mechanism.

    PubMed

    Smith, Jacqueline; Sadeyen, Jean-Remy; Paton, Ian R; Hocking, Paul M; Salmon, Nigel; Fife, Mark; Nair, Venugopal; Burt, David W; Kaiser, Pete

    2011-11-01

    Marek's disease virus (MDV) is a highly contagious oncogenic alphaherpesvirus that causes disease that is both a cancer model and a continuing threat to the world's poultry industry. This comprehensive gene expression study analyzes the host response to infection in both resistant and susceptible lines of chickens and inherent expression differences between the two lines following the infection of the host. A novel pathogenicity mechanism, involving the downregulation of genes containing HIC1 transcription factor binding sites as early as 4 days postinfection, was suggested from this analysis. HIC1 drives antitumor mechanisms, suggesting that MDV infection switches off genes involved in antitumor regulation several days before the expression of the MDV oncogene meq. The comparison of the gene expression data to previous QTL data identified several genes as candidates for involvement in resistance to MD. One of these genes, IRG1, was confirmed by single nucleotide polymorphism analysis to be involved in susceptibility. Its precise mechanism remains to be elucidated, although the analysis of gene expression data suggests it has a role in apoptosis. Understanding which genes are involved in susceptibility/resistance to MD and defining the pathological mechanisms of the disease gives us a much greater ability to try to reduce the incidence of this virus, which is costly to the poultry industry in terms of both animal welfare and economics.

  10. IgG4-related epididymo-orchitis associated with bladder cancer: possible involvement of BAFF/BAFF-R interaction in IgG4-related urogenital disease.

    PubMed

    Migita, Kiyoshi; Miyashita, Taiichiro; Mizuno, Aya; Jiuchi, Yuka; Ito, Masahiro; Matsuo, Manabu; Izumi, Yasumori; Takeoka, Atsushi; Nishino, Ayako; Hayashi, Mikio

    2014-01-01

    We describe herein a patient who presented with immunoglobulin G4-related disease (IgG4-RD) involving the testis and prostate as well as the submandibular glands. Massive infiltration of IgG4-expressing plasma cells was observed in testis and prostate tissues. Serum concentrations of B cell activating factor belonging to the tumor necrosis factor family (BAFF) were elevated in parallel with serum IgG4 concentrations, and infiltration of BAFF-receptor (BAFF-R)-expressing B cells and BAFF-expressing lymphoid cells was observed around the ectopic lymphoid foci in the affected urogenital tissues. To date, testicular involvement in a patient diagnosed with IgG4-RD had not been reported, making this the first reported case of IgG4-related epididymo-orchitis. These findings suggest that the immune mechanism underlying ectopic lymphoneogenesis in IgG4-RD may involve enhanced BAFF/BAFF-R interactions among lymphoid cells.

  11. The Plant-Derived Bauhinia bauhinioides Kallikrein Proteinase Inhibitor (rBbKI) Attenuates Elastase-Induced Emphysema in Mice

    PubMed Central

    Martins-Olivera, Bruno Tadeu; Theodoro-Júnior, Osmar Aparecido; Oliva, Leandro Vilela; Neto dos Santos Nunes, Natalia; Olivo, Clarice Rosa; Vilela de Brito, Marlon; Prado, Carla Máximo; Leick, Edna Aparecida; Martins, Mílton de Arruda

    2016-01-01

    Background. Elastase mediates important oxidative actions during the development of chronic obstructive pulmonary disease (COPD). However, few resources for the inhibition of elastase have been investigated. Our study evaluated the ability of the recombinant plant derived Bauhinia bauhinioides Kallikrein proteinase Inhibitor (rBbKI) to modulate elastase-induced pulmonary inflammation. Methods. C57Bl/6 mice were given intratracheal elastase (ELA group) or saline (SAL group) and were treated intraperitoneally with rBbKI (ELA-rBbKI and SAL-rBbKI groups). At day 28, the following analyses were performed: (I) lung mechanics, (II) exhaled nitric oxide (ENO), (III) bronchoalveolar lavage fluid (BALF), and (IV) lung immunohistochemical staining. Results. In addition to decreasing mechanical alterations and alveolar septum disruption, rBbKI reduced the number of cells in the BALF and decreased the cellular expression of TNF-α, MMP-9, MMP-12, TIMP-1, eNOS, and iNOS in airways and alveolar walls compared with the ELA group. rBbKI decreased the volume proportion of 8-iso-PGF2α, collagen, and elastic fibers in the airways and alveolar walls compared with the ELA group. A reduction in the number of MUC-5-positive cells in the airway walls was also observed. Conclusion. rBbKI reduced elastase-induced pulmonary inflammation and extracellular matrix remodeling. rBbKI may be a potential pharmacological tool for COPD treatment. PMID:27528793

  12. Kallikrein 6 Signals through PAR1 and PAR2 to Promote Neuron Injury and Exacerbate Glutamate Neurotoxicity

    PubMed Central

    Yoon, Hyesook; Radulovic, Maja; Wu, Jianmin; Blaber, Sachiko I.; Blaber, Michael; Fehlings, Michael G.; Scarisbrick, Isobel A.

    2014-01-01

    CNS trauma generates a proteolytic imbalance contributing to secondary injury, including axonopathy and neuron degeneration. Kallikrein 6 (Klk6) is a serine protease implicated in neurodegeneration and here we investigate the role of protease activated receptors 1 (PAR1) and PAR2 in mediating these effects. First we demonstrate Klk6 and the prototypical activator of PAR1, thrombin, as well as PAR1 and PAR2, are each elevated in murine experimental traumatic spinal cord injury (SCI) at acute or subacute time points. Recombinant Klk6 triggered ERK1/2 signaling in cerebellar granule neurons and in the NSC34 spinal cord motoneuron cell line, in a PI3K and MEK-dependent fashion. Importantly, lipopeptide inhibitors of PAR1 or PAR2, and PAR1 genetic deletion, each reduced Klk6-ERK1/2 activation. In addition, Klk6 and thrombin promoted degeneration of cerebellar neurons and exacerbated glutamate neurotoxicity. Moreover, genetic deletion of PAR1 blocked thrombin-mediated cerebellar neurotoxicity and reduced the neurotoxic effects of Klk6. Klk6 also increased glutamate-mediated Bim signaling, PARP cleavage and lactate dehydrogenase (LDH) release in NSC34 motoneurons and these effects were blocked by PAR1 and PAR2 lipopeptide inhibitors. Taken together these data point to a novel Klk6-signaling axis in CNS neurons that is mediated by PAR1 and PAR2 and is positioned to contribute to neurodegeneration. PMID:23647384

  13. A Novel Antithrombotic Mechanism Mediated by the Receptors of the Kallikrein/Kinin and Renin–Angiotensin Systems

    PubMed Central

    Schmaier, Alvin H.

    2016-01-01

    The contact activation (CAS) and kallikrein/kinin (KKS) systems regulate thrombosis risk in two ways. First, the CAS influences contact activation-induced factor XI activation and thrombin formation through the hemostatic cascade. Second, prekallikrein (PK) and bradykinin of the KKS regulate expression of three vessel wall G-protein-coupled receptors, the bradykinin B2 receptor (B2R), angiotensin receptor 2, and Mas to influence prostacyclin formation. The degree of intravascular prostacyclin formation inversely regulates intravascular thrombosis risk. A 1.5- to 2-fold increase in prostacyclin, as seen in PK deficiency, increases vessel wall Sirt1 and KLF4 to downregulate vessel wall tissue factor which alone is sufficient to lengthen induced thrombosis times. A twofold to threefold increase in prostacyclin, as seen the B2R-deficient mouse, delays thrombosis and produces a selective platelet function defect of reduced GPVI activation and platelet spreading. Regulation of CAS and KKS protein expression has a profound influence on thrombosis-generating mechanisms in the intravascular compartment. PMID:27965959

  14. Possible involvement of nitric oxide (NO) signaling pathway in the antidepressant-like effect of MK-801(dizocilpine), a NMDA receptor antagonist in mouse forced swim test.

    PubMed

    Dhir, Ashish; Kulkarni, S K

    2008-03-01

    L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) is an important signaling pathway involved in depression. With this information, the present study aimed to study the involvement of this signaling pathway in the antidepressant-like action of MK-801 (dizocilpine; N-methyl-d-aspartate receptor antagonist) in the mouse forced-swim test. Total immobility period was recorded in mouse forced swim test for 6 min. MK-801 (5-25 microg/kg., ip) produced a U-shaped curve in reducing the immobility period. The antidepressant-like effect of MK-801 (10 microg/kg, ip) was prevented by pretreatment with L-arginine (750 mg/kg, ip) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (7-NI) (25 mg/kg, ip) [a specific neuronal nitric oxide synthase inhibitor] produced potentiation of the action of subeffective dose of MK-801 (5 microg/kg, ip). In addition, treatment of mice with methylene blue (10 mg/kg, ip) [direct inhibitor of both nitric oxide synthase and soluble guanylate cyclase] potentiated the effect of MK-801 (5 microg/kg, ip) in the forced-swim test. Further, the reduction in the immobility period elicited by MK-801 (10 microg/kg, ip) was also inhibited by pretreatment with sildenafil (5 mg/kg, ip) [phosphodiesterase 5 inhibitor]. The various modulators used in the study and their combination did not produce any changes in locomotor activity per se and in combination with MK-801. MK-801 however, at higher doses (25 microg/kg, ip) produced hyperlocomotion. The results demonstrated the involvement of nitric oxide signaling pathway in the antidepressant-like effect of MK-801 in mouse forced-swim test.

  15. Identification and functional analysis of the BIM interactome; new clues on its possible involvement in Epstein-Barr Virus-associated diseases.

    PubMed

    Rouka, Erasmia; Kyriakou, Despoina

    2015-12-01

    Epigenetic deregulation is a common feature in the pathogenesis of Epstein-Barr Virus (EBV)-related lymphomas and carcinomas. Previous studies have demonstrated a strong association between EBV latency in B-cells and epigenetic silencing of the tumor suppressor gene BIM. This study aimed to the construction and functional analysis of the BIM interactome in order to identify novel host genes that may be targeted by EBV. Fifty-nine unique interactors were found to compose the BIM gene network. Ontological analysis at the pathway level highlighted infectious diseases along with neuropathologies. These results underline the possible interplay between the BIM interactome and EBV-associated disorders.

  16. Possible involvement of HSP90-HSF1 multichaperone complex in impairment of HSP72 induction in the failing heart following myocardial infarction in rats.

    PubMed

    Marunouchi, Tetsuro; Araki, Masato; Murata, Mao; Takagi, Norio; Tanonaka, Kouichi

    2013-01-01

    It is generally accepted that an increase in the myocardial level of heat-shock protein 72 (HSP72) protects viable cardiac tissue against myocardial infarction (MI)-induced stress. However, the induction of HSP72 after exposure to heat shock (HS) is blunted in the failing rat heart following MI. The mechanisms underlying this impairment in the HSP72 induction ability of the failing heart are not yet clearly defined. In the present study, we examined the involvement in heat-shock factor 1 (HSF1), a transcription factor of HSPs, in decreased ability for HSP72 induction in the failing rat heart following MI. In the failing heart, nuclear translocation of the HSF1 after exposure to hyperthermia was markedly reduced, whereas HSF1 in the cytosolic fraction and the HSP90 chaperone complex containing HSF1, a repressor of HSF1, were increased. Treatment with an HSP90 inhibitor, 17-allylamino-17-demethoxygel-danamycin, appeared to dissociate the interaction of HSF1 with HSP90, and then induced HSP72 in the failing heart after exposure to hyperthermia. These results suggest that an increase in the multichaperone complex, especially the HSF1-HSP90 interaction, associated with attenuation of HSF1 translocation into the nucleus, was involved in the impairment of HS-induced HSP72 induction in the failing heart following MI.

  17. Possible involvement of nuclear factor erythroid 2-related factor 2 in the gene expression of Cyp2b10 and Cyp2a5.

    PubMed

    Ashino, Takashi; Ohkubo-Morita, Haruyo; Yamamoto, Masayuki; Yoshida, Takemi; Numazawa, Satoshi

    2014-01-01

    Cytochrome P450 gene expression is altered by various chemical compounds. In this study, we used nuclear factor erythroid 2-related factor 2 (Nrf2)-deficient (Nrf2(-⧸-)) mice to investigate the involvement of Nrf2 in Cyp2b10 and Cyp2a5 gene expression. Phorone, an Nrf2 activator, strongly increased Cyp2b10 and Cyp2a5 mRNA as well as Nrf2 target genes, including NAD(P)H-quinone oxidoreductase-1 and heme oxygenase-1, in wild-type mouse livers 8 h after treatment. The phorone-induced mRNA levels in Nrf2(-⧸-) mouse livers were lower than that in wild-type mouse livers. Nrf2(-⧸-) mice showed attenuated Cyp2b10 and Cyp2a5 induction by phenobarbital, a classical Cyp2b inducer. These findings suggest that the Nrf2 pathway is involved in Cyp2b10 and Cyp2a5 gene expression.

  18. Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer's disease: possible involvement of HRD1, a novel molecule related to endoplasmic reticulum stress, in Alzheimer's disease.

    PubMed

    Kaneko, Masayuki; Okuma, Yasunobu; Nomura, Yasuyuki

    2012-01-01

    Endoplasmic reticulum (ER)-associated degradation (ERAD) is a protective mechanism against ER stress in which unfolded proteins accumulated in the ER are selectively transported to the cytosol for degradation by the ubiquitin-proteasome system. We cloned the novel ubiquitin ligase HRD1, which is involved in ERAD, and showed that HRD1 promoted amyloid precursor protein (APP) ubiquitination and degradation, resulting in decreased generation of amyloid β (Aβ). In addition, suppression of HRD1 expression caused APP accumulation and promoted Aβ generation associated with ER stress and apoptosis. Interestingly, HRD1 levels were significantly decreased in the cerebral cortex of patients with Alzheimer's disease (AD), and the brains of these patients experienced ER stress. Our recent study revealed that this decrease in HRD1 was due to its insolubilization; however, controversy persists about whether the decrease in HRD1 protein promotes Aβ generation or whether Aβ neurotoxicity causes the decrease in HRD1 protein levels. Here, we review current findings on the mechanism of HRD1 protein loss in the AD brain and the involvement of HRD1 in the pathogenesis of AD. Furthermore, we propose that HRD1 may be a target for novel AD therapeutics.

  19. Hydrogen sulfide alleviates toxic effects of arsenate in pea seedlings through up-regulation of the ascorbate-glutathione cycle: Possible involvement of nitric oxide.

    PubMed

    Singh, Vijay Pratap; Singh, Samiksha; Kumar, Jitendra; Prasad, Sheo Mohan

    2015-06-01

    In plants, hydrogen sulfide (H2S) is an emerging novel signaling molecule that is involved in growth regulation and abiotic stress responses. However, little is known about its role in the regulation of arsenate (As(V)) toxicity. Therefore, hydroponic experiments were conducted to investigate whether sodium hydrosulfide (NaHS; a source of H2S) is involved in the regulation of As(V) toxicity in pea seedlings. Results showed that As(V) caused decreases in growth, photosynthesis (measured as chlorophyll fluorescence) and nitrogen content, which was accompanied by the accumulation of As. As(V) treatment also reduced the activities of cysteine desulfhydrase and nitrate reductase, and contents of H2S and nitric oxide (NO). However, addition of NaHS ameliorated As(V) toxicity in pea seedlings, which coincided with the increased contents of H2S and NO. The cysteine level was higher under As(V) treatment in comparison to all other treatments (As-free; NaHS; As(V)+NaHS). The content of reactive oxygen species (ROS) and damage to lipids, proteins and membranes increased by As(V) while NaHS alleviated these effects. Enzymes of the ascorbate-glutathione cycle (AsA-GSH cycle) showed inhibition of their activities following As(V) treatment while their activities were increased by application of NaHS. The redox status of ascorbate and glutathione was disturbed by As(V) as indicated by a steep decline in their reduced/oxidized ratios. However, simultaneous NaHS application restored the redox status of the ascorbate and glutathione pools. The results of this study demonstrated that H2S and NO might both be involved in reducing the accumulation of As and triggering up-regulation of the AsA-GSH cycle to counterbalance ROS-mediated damage to macromolecules. Furthermore, the results suggest a crucial role of H2S in plant priming, and in particular for pea seedlings in mitigating As(V) stress.

  20. Involvement of endothelial progenitor cells in the formation of plexiform lesions in broiler chickens: possible role of local immune/inflammatory response*

    PubMed Central

    Tan, Xun; Juan, Fan-guo; Shah, Ali Q.

    2017-01-01

    Plexiform lesions (PLs), which are often accompanied by perivascular infiltrates of mononuclear cells, represent the hallmark lesions of pulmonary arteries in humans suffering from severe pulmonary arterial hypertension (PAH). Endothelial progenitor cells (EPCs) have been recently implicated in the formation of PLs in human patients. PLs rarely develop in rodent animal models of PAH but can develop spontaneously in broiler chickens. The aim of the present study was to confirm the presence of EPCs in the PLs in broilers. The immune mechanisms involved in EPC dysfunction were also evaluated. Lungs were collected from commercial broilers at 1 to 4 weeks of age. The right/total ventricle ratios indicated normal pulmonary arterial pressures for all sampled birds. Immunohistochemistry was performed to determine the expressions of EPC markers (CD133 and VEGFR-2) and proangiogenic molecule hepatocyte growth factor (HGF) in the lung samples. An EPC/lymphocyte co-culture system was used to investigate the functional changes of EPCs under the challenge of immune cells. PLs with different cellular composition were detected in the lungs of broilers regardless of age, and they were commonly surrounded by moderate to dense perivascular mononuclear cell infiltrates. Immunohistochemical analyses revealed the presence of CD133+ and VEGFR-2+ cells in PLs. These structures also exhibited a strong expression of HGF. Lymphocyte co-culture enhanced EPC apoptosis and completely blocked HGF-stimulated EPC survival and in vitro tube formation. Taken together, this work provides evidence for the involvement of EPCs in the development of PLs in broilers. It is suggested that the local immune cell infiltrate might serve as a contributor to EPC dysfunction by inducing EPC death and limiting their response to angiogenic stimuli. Broiler chickens may be valuable for investigating reversibility of plexogenic arteriopathy using gene-modified inflammation-resistant EPCs. PMID:28070997

  1. Possible involvement of the long terminal repeat of transposable element 17.6 in regulating expression of an insecticide resistance-associated P450 gene in Drosophila.

    PubMed Central

    Waters, L C; Zelhof, A C; Shaw, B J; Ch'ang, L Y

    1992-01-01

    P450-A and P450-B are electrophoretically defined subsets of cytochrome P450 enzymes in Drosophila melanogaster. P450-A is present among all strains tested, whereas expression of P450-B is associated with resistance to insecticides. Monoclonal antibodies were used to obtain cDNA clones for an enzyme from each P450 subset (i.e., P450-A1 and P450-B1). The P450-B1 cDNA was sequenced and shown to code for a P450 of 507 amino acids. Its gene has been named CYP6A2. Comparative molecular analyses of a pair of susceptible, 91-C, and resistant, 91-R, Drosophila strains were made. There was 20-30 times more P450-B1 mRNA in 91-R than in 91-C, and the small amount of P450-B1 mRNA in 91-C was significantly larger in size than that in 91-R. The P450-B1 gene in 91-R was structurally different from that in 91-C but was not amplified. The P450-B1 gene in 91-C contained a solitary long terminal repeat of transposable element 17.6 in its 3' untranslated region. It was absent in the P450-B1 gene of 91-R. On the basis of features of the long terminal repeat and its location in the gene of the susceptible fly, we propose that a posttranscriptional mechanism involving mRNA stability could be involved in regulating P450-B1 gene expression. Images PMID:1317576

  2. Involvement of endothelial progenitor cells in the formation of plexiform lesions in broiler chickens: possible role of local immune/inflammatory response.

    PubMed

    Tan, Xun; Juan, Fan-Guo; Shah, Ali Q

    Plexiform lesions (PLs), which are often accompanied by perivascular infiltrates of mononuclear cells, represent the hallmark lesions of pulmonary arteries in humans suffering from severe pulmonary arterial hypertension (PAH). Endothelial progenitor cells (EPCs) have been recently implicated in the formation of PLs in human patients. PLs rarely develop in rodent animal models of PAH but can develop spontaneously in broiler chickens. The aim of the present study was to confirm the presence of EPCs in the PLs in broilers. The immune mechanisms involved in EPC dysfunction were also evaluated. Lungs were collected from commercial broilers at 1 to 4 weeks of age. The right/total ventricle ratios indicated normal pulmonary arterial pressures for all sampled birds. Immunohistochemistry was performed to determine the expressions of EPC markers (CD133 and VEGFR-2) and proangiogenic molecule hepatocyte growth factor (HGF) in the lung samples. An EPC/lymphocyte co-culture system was used to investigate the functional changes of EPCs under the challenge of immune cells. PLs with different cellular composition were detected in the lungs of broilers regardless of age, and they were commonly surrounded by moderate to dense perivascular mononuclear cell infiltrates. Immunohistochemical analyses revealed the presence of CD133(+) and VEGFR-2(+) cells in PLs. These structures also exhibited a strong expression of HGF. Lymphocyte co-culture enhanced EPC apoptosis and completely blocked HGF-stimulated EPC survival and in vitro tube formation. Taken together, this work provides evidence for the involvement of EPCs in the development of PLs in broilers. It is suggested that the local immune cell infiltrate might serve as a contributor to EPC dysfunction by inducing EPC death and limiting their response to angiogenic stimuli. Broiler chickens may be valuable for investigating reversibility of plexogenic arteriopathy using gene-modified inflammation-resistant EPCs.

  3. An investigation into possible xenobiotic-endobiotic inter-relationships involving the amino acid analogue drug, S-carboxymethyl-L-cysteine and plasma amino acids in humans.

    PubMed

    Steventon, Glyn B; Mitchell, Stephen C; Angulo, Santigo; Barbas, Coral

    2012-05-01

    The amino acid derivative, S-carboxymethyl-L-cysteine, is an anti-oxidant agent extensively employed as adjunctive therapy in the treatment of human pulmonary conditions. A major biotransformation route of this drug, which displays considerable variation in capacity in man, involves the oxidation of the sulfide moiety to the inactive S-oxide metabolite. Previous observations have indicated that fasted plasma L-cysteine concentrations and fasted plasma L-cysteine/free inorganic sulfate ratios were correlated with the degree of sulfoxidation of this drug and that these particular parameters may be used as endobiotic biomarkers for this xenobiotic metabolism. It has been proposed also that the enzyme, cysteine dioxygenase, was responsible for the drug sulfoxidation. Further in this theme, the degree of S-oxidation of S-carboxymethyl-L-cysteine in 100 human volunteers was investigated with respect to it potential correlation with fasted plasma amino acid concentrations. Extensive statistical analyses showed no significant associations or relationships between the degree of drug S-oxidation and fasted plasma amino acid concentrations, especially with respect to the sulfur-containing compounds, methionine, L-cysteine, L-cysteine sulfinic acid, taurine and free inorganic sulfate, also the derived ratios of L-cysteine/L-cysteine sulfinic acid and L-cysteine/free inorganic sulfate. It was concluded that plasma amino acid levels or derived ratios cannot be employed to predict the degree of S-oxidation of S-carboxymethyl-L-cysteine (or vice versa) and that it is doubtful if the enzyme, cysteine dioxygenase, has any involvement in the metabolism of this drug.

  4. Possible involvement of nitric oxide mechanism in the neuroprotective effect of rutin against immobilization stress induced anxiety like behaviour, oxidative damage in mice.

    PubMed

    Machawal, Lalit; Kumar, Anil

    2014-02-01

    Dietary supplements are widely used to manage stress and related consequences. However, the exact pathological mechanism and cellular cascades involved in the action of these supplements are not properly understood so far. Therefore, the present study has been designed to explore the neuroprotective mechanism of rutin against immobilization stress-induced anxiety-like behavioural and oxidative damage in mice. Laboratory Animal Centre A-strain (laca) mice were used in the present study. Rutin (20, 40, and 80 mg/kg), l-arginine (100 mg/kg), l-nitroarginine methyl ester (l-NAME) (5 mg/kg) and vitamin-E (50 mg/kg) were administered for 5 days before 6h immobilization stress on 6th day. Various behavioural parameters (mirror chamber test, locomotor activity) followed by biochemical parameters (lipid peroxidation, nitrite concentration, reduced glutathione and catalase) in brain and then serum corticosterone level were assessed. 6 h immobilization stress produced anxiety-like behavioural in mirror chamber test, raised corticosterone level and oxidative stress (as evidenced by rise in lipid peroxidation, nitrite concentration, depletion of reduced glutathione and catalase activity) significantly as compared to naive group. 5 days pre-treatment with rutin (40 and 80 mg/kg) causes a significant attenuation of locomotor activity, corticosterone level, oxidative stress as compared to control. Further, l-arginine (100 mg/kg) pre-treatment significantly reversed the protective effect of rutin (40 mg/kg) in 6 h immobilized animals. However, l-NAME (5 mg/kg) pre-treatment with rutin (40 mg/kg) potentiated their protective effect which was significant as compared to their effect per se. The present study suggests the involvement of nitric oxide mechanism in the neuroprotective effect of rutin against immobilization stress-induced anxiety-like behaviour and oxidative damage in mice.

  5. Transcriptome reveals the overexpression of a kallikrein gene cluster (KLK1/3/7/8/12) in the Tibetans with high altitude-associated polycythemia.

    PubMed

    Li, Kang; Gesang, Luobu; Dan, Zeng; Gusang, Lamu

    2017-02-01

    High altitude-associated polycythemia (HAPC) is a very common disease. However, it the disease is still unmanageable and the related molecular mechanisms remain largely unclear. In the present study, we aimed to explore the molecular mechanisms responsible for the development of HAPC using transcriptome analysis. Transcriptome analysis was conducted in 3 pairs of gastric mucosa tissues from patients with HAPC and healthy residents at a similar altitude. Endoscopy and histopathological analyses were used to examine the injury to gastric tissues. Molecular remodeling was performed for the interaction between different KLK members and cholesterol. HAPC was found to lead to morphological changes and pathological damage to the gastric mucosa of patients. A total of 10,304 differentially expressed genes (DEGs) were identified. Among these genes, 4,941 DEGs were upregulated, while 5,363 DEGs were downregulated in the patients with HAPC (fold change ≥2, P<0.01 and FDR <0.01). In particular, the kallikrein gene cluster (KLK1/3/7/8/12) was upregulated >17-fold. All the members had high-score binding cholesterol, particularly for the polymers of KLK7. The kallikrein gene cluster (KLK1/3/7/8/12) is on chromosome 19q13.3-13.4. The elevated levels of KLK1, KLK3, KLK7, KLK8 and KLK12 may be closely associated with the hypertension, inflammation, obesity and other gastric injuries associated with polycythemia. The interaction of KLKs and cholesterol maybe play an important role in the development of hypertension. The findings of the present study revealed that HAPC induces gastric injury by upregulating the kallikrein gene cluster (KLK1/3/7/8/12), which can bind cholesterol and result in kallikrein hypertension. These findings provide some basic information for understanding the molecular mechanisms responsible for HAPC and HAPC-related diseases.

  6. Possible involvement of CD10 in the development of endometriosis due to its inhibitory effects on CD44-dependent cell adhesion.

    PubMed

    Iwase, Akira; Kotani, Tomomi; Goto, Maki; Kobayashi, Hiroharu; Takikawa, Sachiko; Nakahara, Tatsuo; Nakamura, Tomoko; Kondo, Mika; Bayasula; Nagatomo, Yoshinari; Kikkawa, Fumitaka

    2014-01-01

    A reduced response to progesterone in the eutopic endometrium with endometriosis and in endometriotic tissues is considered to be the underlying factor for endometriosis. CD10 is known to be expressed by endometrial and endometriotic stromal cells and may be induced by progestins, although the function of CD10 is not fully revealed in endometrial or endometriotic tissues. In the current study, the expression of CD10 was significantly increased by treatment of the cells with progesterone, 17β-estradiol, and dibutyryl cyclic adenosine monophosphate (cAMP) in the endometrial stromal cells. On the other hand, the expression of CD10 following treatment with progesterone, 17β-estradiol, and dibutyryl cAMP was not significantly increased in endometriotic stromal cells. The adhesion assay for endometrial and endometriotic stromal cells to hyaluronan using 5- or 6-(N-succinimidyloxycarbonyl)-fluorescein 3', 6'-diacetate-labeled cells demonstrated that the CD44-dependent adhesion of stromal cells was inhibited by CD10. As far as the induction of CD10 is concerned, the effect of progesterone was different between endometrial stromal cells and endometriotic stromal cells. CD10 might be involved in the development of endometriosis due to its influence on CD44-dependent cell adhesion.

  7. Endo-β-N-acetylglucosamidases (ENGases) in the fungus Trichoderma atroviride: possible involvement of the filamentous fungi-specific cytosolic ENGase in the ERAD process.

    PubMed

    Tzelepis, Georgios; Hosomi, Akira; Hossain, Tanim Jabid; Hirayama, Hiroto; Dubey, Mukesh; Jensen, Dan Funck; Suzuki, Tadashi; Karlsson, Magnus

    2014-06-27

    N-Glycosylation is an important post-translational modification of proteins, which mainly occurs in the endoplasmic reticulum (ER). Glycoproteins that are unable to fold properly are exported to the cytosol for degradation by a cellular system called ER-associated degradation (ERAD). Once misfolded glycoproteins are exported to the cytosol, they are subjected to deglycosylation by peptide:N-glycanase (PNGase) to facilitate the efficient degradation of misfolded proteins by the proteasome. Interestingly, the ortholog of PNGase in some filamentous fungi was found to be an inactive deglycosylating enzyme. On the other hand, it has been shown that in filamentous fungi genomes, usually two different fungi-specific endo-β-N-acetylglucosamidases (ENGases) can be found; one is predicted to be localized in the cytosol and the other to have a signal sequence, while the functional importance of these enzymes remains to be clarified. In this study the ENGases of the filamentous fungus Trichoderma atroviride was characterized. By heterologous expression of the ENGases Eng18A and Eng18B in Saccharomyces cerevisiae, it was found that both ENGases are active deglycosylating enzymes. Interestingly, only Eng18B was able to enhance the efficient degradation of the RTL protein, a PNGase-dependent ERAD substrate, implying the involvement of this enzyme in the ERAD process. These results indicate that T. atroviride Eng18B may deglycosylate misfolded glycoproteins, substituting the function of the cytoplasmic PNGase in the ERAD process.

  8. Possible involvement of NO/NOS signaling in hippocampal amyloid-beta production induced by transient focal cerebral ischemia in aged rats.

    PubMed

    Li, Song; Wang, Wei; Wang, Che; Tang, Yi-Yuan

    2010-02-12

    In the present study, to define the roles of nitric oxide (NO) signaling in amyloid-beta (A beta) production after transient cerebral ischemia, extracellular levels of NO and A beta were monitored by intracerebral microdialysis in the hippocampus of aged rats exposed to transient middle cerebral artery occlusion and reperfusion (MCAO/R). The results indicated that 1-h MCAO significantly upregulated hippocampal NO and A beta levels. In addition, the NO elevation preceded the A beta changes. The Western blotting suggested that acute hypoperfusion could increase the expression of beta-secretase 1 (BACE1) but not BACE2. The enhanced NO concentration in acute stage of MCAO/R was coincident with increased eNOS expression, while in subacute stage was coincident with increased iNOS and nNOS. Our results also indicated that pretreatment of L-NAME, one non-selective NOS inhibitor could decrease the BACE1 expression, reverse both NO and A beta changes and rescue the delayed neuronal death. These preliminary findings indicated that activation of NOS/NO signaling system could trigger A beta production through BACE1 pathway during acute ischemic episode. The present data may be important in understanding, at least in part, the pathological role of NO/NOS system involved in hippocampal A beta production and neuronal damage induced by transient cerebral ischemia.

  9. The accumulation mechanism of the hypoxia imaging probe “FMISO” by imaging mass spectrometry: possible involvement of low-molecular metabolites

    PubMed Central

    Masaki, Yukiko; Shimizu, Yoichi; Yoshioka, Takeshi; Tanaka, Yukari; Nishijima, Ken-ichi; Zhao, Songji; Higashino, Kenichi; Sakamoto, Shingo; Numata, Yoshito; Yamaguchi, Yoshitaka; Tamaki, Nagara; Kuge, Yuji

    2015-01-01

    18F-fluoromisonidazole (FMISO) has been widely used as a hypoxia imaging probe for diagnostic positron emission tomography (PET). FMISO is believed to accumulate in hypoxic cells via covalent binding with macromolecules after reduction of its nitro group. However, its detailed accumulation mechanism remains unknown. Therefore, we investigated the chemical forms of FMISO and their distributions in tumours using imaging mass spectrometry (IMS), which visualises spatial distribution of chemical compositions based on molecular masses in tissue sections. Our radiochemical analysis revealed that most of the radioactivity in tumours existed as low-molecular-weight compounds with unknown chemical formulas, unlike observations made with conventional views, suggesting that the radioactivity distribution primarily reflected that of these unknown substances. The IMS analysis indicated that FMISO and its reductive metabolites were nonspecifically distributed in the tumour in patterns not corresponding to the radioactivity distribution. Our IMS search found an unknown low-molecular-weight metabolite whose distribution pattern corresponded to that of both the radioactivity and the hypoxia marker pimonidazole. This metabolite was identified as the glutathione conjugate of amino-FMISO. We showed that the glutathione conjugate of amino-FMISO is involved in FMISO accumulation in hypoxic tumour tissues, in addition to the conventional mechanism of FMISO covalent binding to macromolecules. PMID:26582591

  10. Possible Involvement of µ Opioid Receptor in the Antidepressant-Like Effect of Shuyu Formula in Restraint Stress-Induced Depression-Like Rats

    PubMed Central

    Wang, Fu-rong; Qiao, Ming-qi; Xue, Ling; Wei, Sheng

    2015-01-01

    Recently μ opioid receptor (MOR) has been shown to be closely associated with depression. Here we investigated the action of Shuyu, a Chinese herbal prescription, on repeated restraint stress induced depression-like rats, with specific attention to the role of MOR and the related signal cascade. Our results showed that repeated restraint stress caused significant depressive-like behaviors, as evidenced by reduced body weight gain, prolonged duration of immobility in forced swimming test, and decreased number of square-crossings and rearings in open field test. The stress-induced depression-like behaviors were relieved by Shuyu, which was accompanied by decreased expression of MOR in hippocampus. Furthermore, Shuyu upregulated BDNF protein expression, restored the activity of CREB, and stimulated MEK and ERK phosphorylation in hippocampus of stressed rats. More importantly, MOR is involved in the effects of Shuyu on these depression-related signals, as they can be strengthened by MOR antagonist CTAP. Collectively, these data indicated that the antidepressant-like properties of Shuyu are associated with MOR and the corresponding CREB, BDNF, MEK, and ERK signal pathway. Our study supports clinical use of Shuyu as an effective treatment of depression and also suggests that MOR might be a target for treatment of depression and developing novel antidepressants. PMID:25821488

  11. The anxiogenic-like effects of dehydration in a semi-desert rodent Meriones shawi indicating the possible involvement of the serotoninergic system.

    PubMed

    Elgot, Abdeljalil; El hiba, Omar; Gamrani, Halima

    2012-10-01

    Dehydration is a powerful stimulus causing disequilibrium in homeostasis of water and electrolytes resulting from depletion in total body water. Most studies have focused on domestic and laboratory animals; however, the study of desert animals allows improved understanding about water balance and resistance to dehydration and associated behavioral changes, including those related to mood disorders. Meriones shawi (Shaw's Jird) is a desert rodent characterized by its resistance to long periods of thirst that can extend for several months. In the present study, M. shawi were subjected to water deprivation for 1 and 3 months. We used 5-HT immunohistochemistry to evaluate the effects of prolonged dehydration on the serotoninergic system in both dorsal and median raphe nuclei (DRN, MRN), which are the main sources of 5-HT input to several brain areas. In addition, a dark/light box was used to evaluate the anxiolytic-like or anxiogenic-like effects of dehydration on M. shawi. The results showed a reduction in the 5-HT immunolabelling in both DRN and MRN following 1 and 3 months of dehydration. This diminution of serotonin immunoreactivity was accompanied by noticeable changes in anxiety behavior of Meriones, with animals spending more time in the light box, suggesting anxiogenic-like effects caused by dehydration. Overall, the results indicate that dehydration is able to reduce serotoninergic neurotransmission, which might be involved in generating anxiety behavior in this desert animal.

  12. Aging decreases collagen IV expression in vivo in the dermo-epidermal junction and in vitro in dermal fibroblasts: possible involvement of TGF-β1.

    PubMed

    Feru, Jezabel; Delobbe, Etienne; Ramont, Laurent; Brassart, Bertrand; Terryn, Christine; Dupont-Deshorgue, Aurelie; Garbar, Christian; Monboisse, Jean-Claude; Maquart, Francois-Xavier; Brassart-Pasco, Sylvie

    2016-08-01

    Collagen IV is a major component of the dermo-epidermal junction (DEJ). To study expression of collagen IV upon aging in the DEJ and dermal fibroblasts isolated from the same patients. A model of senescent fibroblasts was developed in order to identify biological compounds that might restore the level of collagen IV. Skin fragments of women (30 to 70 years old) were collected. Localisation of collagen IV expression in the DEJ was studied by immunofluorescence. Fibroblast collagen IV expression was studied by real-time PCR, ELISA, and western blotting. Premature senescence was simulated by exposing fibroblasts to subcytotoxic H2O2 concentrations. Collagen IV decreased in the DEJ and fibroblasts relative to age. TGF-β1 treatment significantly increased collagen IV gene and protein expression in fibroblasts and restored expression in the model of senescence. Addition of TGF-β1-neutralizing antibody to fibroblast cultures decreased collagen IV expression. Taken together, the results suggest that the decrease in collagen IV in the DEJ, relative to age, could be due to a decrease in collagen IV expression by senescent dermal fibroblasts and may involve TGF-β1 signalling.

  13. Metabolic response in liver and Brockmann bodies of rainbow trout to inhibition of lipolysis; possible involvement of the hypothalamus-pituitary-interrenal (HPI) axis.

    PubMed

    Librán-Pérez, Marta; Velasco, Cristina; Otero-Rodiño, Cristina; López-Patiño, Marcos A; Míguez, Jesús M; Soengas, José L

    2015-05-01

    We previously demonstrated in rainbow trout that the decrease in circulating levels of fatty acid (FA) induced by treating fish with SDZ WAG 994 (SDZ) induced a counter-regulatory response in which the activation of the hypothalamus-pituitary-interrenal (HPI, equivalent to mammalian hypothalamus-pituitary-adrenal) axis was likely involved. This activation, probably not related to the control of food intake through FA sensor systems but to the modulation of lipolysis in peripheral tissues, liver and Brockmann bodies (BB, the main site of pancreatic endocrine cells in fish), would target the restoration of FA levels in plasma. To assess this hypothesis, we lowered circulating FA levels by treating fish with SDZ alone, or SDZ in the presence of metyrapone (an inhibitor of cortisol synthesis). In liver, the changes observed were not compatible with a direct FA-sensing response but with a stress response, which allows us to suggest that the detection of a FA decrease in the hypothalamus elicits a counter-regulatory response in liver, resulting in an activation of lipolysis to restore FA levels in plasma. The activation of these metabolic changes in liver could be attributable to the activation of the HPI axis and/or to the action of sympathetic pathways. In contrast, in BB, changes in circulating FA levels induce changes in several parameters compatible with the function of FA-sensing systems informing about the decrease in circulating FA levels.

  14. Mitofusin 2 expression dominates over mitofusin 1 exclusively in mouse dorsal root ganglia - a possible explanation for peripheral nervous system involvement in Charcot-Marie-Tooth 2A.

    PubMed

    Kawalec, Maria; Zabłocka, Barbara; Kabzińska, Dagmara; Neska, Jacek; Beręsewicz, Małgorzata

    2014-01-01

    Mitofusin 2 (Mfn2), a protein of the mitochondrial outer membrane, is essential for mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. Mutations in the mitofusin 2 gene cause axonal Charcot-Marie-Tooth type 2A (CMT2A), an inherited disease affecting peripheral nerve axons. The precise mechanism by which mutations in MFN2 selectively cause the degeneration of long peripheral axons is not known. There is a hypothesis suggesting the involvement of reduced expression of a homologous protein, mitofusin 1 (Mfn1), in the peripheral nervous system, and less effective compensation of defective mitofusin 2 by mitofusin 1. We therefore aimed to perform an analysis of the mitofusin 1 and mitofusin 2 mRNA and protein expression profiles in different mouse tissues, with special attention paid to dorsal root ganglia (DRGs), as parts of the peripheral nervous system. Quantitative measurement relating to mRNA revealed that expression of the Mfn2 gene dominates over Mfn1 mainly in mouse DRG, as opposed to other nervous system samples and other tissues studied. This result was further supported by Western blot evaluation. Both these sets of data confirm the hypothesis that the cellular consequences of mutations in the mitofusin 2 gene can mostly be manifested in the peripheral nervous system.

  15. Cell cycle arrest induced by inhibitors of epigenetic modifications in maize (Zea mays) seedling leaves: characterization of the process and possible mechanisms involved.

    PubMed

    Wang, Pu; Zhang, Hao; Hou, Haoli; Wang, Qing; Li, Yingnan; Huang, Yan; Xie, Liangfu; Gao, Fei; He, Shibin; Li, Lijia

    2016-07-01

    Epigenetic modifications play crucial roles in the regulation of chromatin architecture and are involved in cell cycle progression, including mitosis and meiosis. To explore the relationship between epigenetic modifications and the cell cycle, we treated maize (Zea mays) seedlings with six different epigenetic modification-related inhibitors and identified the postsynthetic phase (G2 ) arrest via flow cytometry analysis. Total H4K5ac levels were significantly increased and the distribution of H3S10ph signalling was obviously changed in mitosis under various treatments. Further statistics of the cells in different periods of mitosis confirmed that the cell cycle was arrested at preprophase. Concentrations of hydrogen peroxide were relatively higher in the treated plants and the antioxidant thiourea could negate the influence of the inhibitors. Moreover, all of the treated plants displayed negative results in the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) and γ-H2AX immunostaining assays after exposure for 3 d. Additionally, the expression level of topoisomerase genes in the treated plants was relatively lower than that in the untreated plants. These results suggest that these inhibitors of epigenetic modifications could cause preprophase arrest via reactive oxygen species formation inhibiting the expression of DNA topoisomerase genes, accompanied by changes in the H4K5ac and H3S10ph histone modifications.

  16. Inhibitory Effects of Scolopendra Pharmacopuncture on the Development and Maintenance of Neuropathic Pain in Rats: Possible Involvement of Spinal Glial Cells.

    PubMed

    Li, Chengjin; Ji, Byeong Uk; Lee, Ji Eun; Park, Min Young; Kim, Sungchul; Kim, Seung Tae; Koo, Sungtae

    2015-10-01

    Scolopendra extracts were used for pharmacopuncture at the Kidney 1 acupoint to investigate the role of Scolopendra pharmacopuncture (SPP) in both the development and maintenance of neuropathic pain induced by L5 spinal nerve ligation in rats and the contribution of spinal glial cells. A single treatment and five once-daily treatments with SPP were given to evaluate its effects on the development and maintenance stages of neuropathic pain, respectively, which was followed by behavioral tests. Immunohistochemistry and Western blotting tests were also carried out. A single treatment of SPP delayed spinal nerve ligation-induced mechanical allodynia and thermal hyperalgesia and induced a profound decrease in the expression of ionized calcium binding adaptor protein in the lumbar spinal cord. Repeated SPP treatments reliably suppressed mechanical allodynia and thermal hyperalgesia at later time points, and these results correlated mainly with decreases in glial fibrillary acidic protein. Intriguingly, ionized calcium binding adaptor protein expression was also reduced after repeated SPP. These results illustrate that neuropathic pain in the development and maintenance stages is alleviated by SPP treatment, which may be ascribed principally to deactivations of microglia and astroglia, respectively. Additionally, microglial inactivation seems to be partially involved in preventing neuropathic pain in the maintenance stage.

  17. Possible involvement of GABAergic mechanism in protective effect of melatonin against sleep deprivation-induced behavior modification and oxidative damage in mice.

    PubMed

    Kumar, Anil; Singh, Anant; Kumar, Puneet

    2011-03-01

    Sleep deprivation for 72 h caused anxiety like behavior, weight loss, impaired locomotor activity and oxidative damage as indicated by increase in lipid peroxidation, nitrite level and depletion of reduced glutathione and catalase activity in sleep deprived mice brain. Treatment with melatonin (5 and 10 mg/kg, ip) significantly improved locomotor activity, weight loss and antianxiety effect as compared to control (sleep deprived). Biochemically, melatonin treatment significantly restored depleted reduced glutathione, catalase activity, attenuated lipid peroxidation and nitrite level as compared to control (72 h sleep-deprived) animals. A combination of flumazenil (0.5 mg/kg, ip) and picrotoxin (0.5 mg/kg, ip) with lower dose of melatonin (5 mg/kg, ip) significantly antagonized the protective effect of melatonin. However, combination of muscimol (0.05 mg/kg, ip) with melatonin (5 mg/kg, ip) potentiated protective effect of melatonin as compared to their effect per se. The results suggest that melatonin may produce its protective effect by involving GABAergic system against sleep deprivation-induced anxiety like behavior and related oxidative damage.

  18. Similar chemokine receptor profiles in lymphomas with central nervous system involvement - possible biomarkers for patient selection for central nervous system prophylaxis, a retrospective study.

    PubMed

    Lemma, Siria A; Pasanen, Anna Kaisa; Haapasaari, Kirsi-Maria; Sippola, Antti; Sormunen, Raija; Soini, Ylermi; Jantunen, Esa; Koivunen, Petri; Salokorpi, Niina; Bloigu, Risto; Turpeenniemi-Hujanen, Taina; Kuittinen, Outi

    2016-05-01

    Central nervous system (CNS) relapse occurs in around 5% of diffuse large B-cell lymphoma (DLBCL) cases. No biomarkers to identify high-risk patients have been discovered. We evaluated the expression of lymphocyte-guiding chemokine receptors in systemic and CNS lymphomas. Immunohistochemical staining for CXCR4, CXCR5, CCR7, CXCL12, and CXCL13 was performed on 89 tissue samples, including cases of primary central nervous system lymphoma (PCNSL), secondary CNS lymphoma (sCNSL), and systemic DLBCL. Also, 10 reactive lymph node samples were included. Immunoelectron microscopy was performed on two PCNSLs, one sCNSL, one systemic DLBCL, and one reactive lymph node samples, and staining was performed for CXCR4, CXCR5, CXCL12, and CXCL13. Chi-square test was used to determine correlations between clinical parameters, diagnostic groups, and chemokine receptor expression. Strong nuclear CXCR4 positivity correlated with systemic DLBCL, whereas strong cytoplasmic CXCR5 positivity correlated with CNS involvement (P = 0.003 and P = 0.039). Immunoelectron microscopy revealed a nuclear CXCR4 staining in reactive lymph node, compared with cytoplasmic and membranous localization seen in CNS lymphomas. We found that CNS lymphoma presented a chemokine receptor profile different from systemic disease. Our findings give new information on the CNS tropism of DLBCL and, if confirmed, may contribute to more effective targeting of CNS prophylaxis among patients with DLBCL.

  19. Possible Involvement of F1F0-ATP synthase and Intracellular ATP in Keratinocyte Differentiation in normal skin and skin lesions

    PubMed Central

    Xiaoyun, Xie; Chaofei, Han; Weiqi, Zeng; Chen, Chen; Lixia, Lu; Queping, Liu; Cong, Peng; Shuang, Zhao; Juan, Su; Xiang, Chen

    2017-01-01

    The F1F0-ATP synthase, an enzyme complex, is mainly located on the mitochondrial inner membrane or sometimes cytomembrane to generate or hydrolyze ATP, play a role in cell proliferation. This study focused on the role of F1F0-ATP synthase in keratinocyte differentiation, and its relationship with intracellular and extracellular ATP (InATP and ExATP). The F1F0-ATP synthase β subunit (ATP5B) expression in various skin tissues and confluence-dependent HaCaT differentiation models was detected. ATP5B expression increased with keratinocyte and HaCaT cell differentiation in normal skin, some epidermis hyper-proliferative diseases, squamous cell carcinoma, and the HaCaT cell differentiation model. The impact of InATP and ExATP content on HaCaT differentiation was reflected by the expression of the differentiation marker involucrin. Inhibition of F1F0-ATP synthase blocked HaCaT cell differentiation, which was associated with a decrease of InATP content, but not with changes of ExATP. Our results revealed that F1F0-ATP synthase expression is associated with the process of keratinocyte differentiation which may possibly be related to InATP synthesis. PMID:28209970

  20. Troxerutin exerts neuroprotection in 6-hydroxydopamine lesion rat model of Parkinson's disease: Possible involvement of PI3K/ERβ signaling.

    PubMed

    Baluchnejadmojarad, Tourandokht; Jamali-Raeufy, Nida; Zabihnejad, Sedigheh; Rabiee, Nafiseh; Roghani, Mehrdad

    2017-04-15

    Parkinson's disease (PD) is a neurodegenerative disease with progressive loss of mesencephalic dopaminergic neurons of the substantia nigra and with multiple incapacitating motor and non-motor symptoms. Troxerutin is a natural bioflavonoid with nephro- and hepato-protective, antioxidant, and anti-inflammatory properties. In this study, we evaluated its possible neuroprotective effect in 6-hydroxydopamine (6-OHDA) rat model of PD. Intrastriatal 6-OHDA-lesioned rats were pretreated with troxerutin at a dose of 150mg/kg/day for 1 week. Results showed that troxerutin mitigates apomorphine-induced motor asymmetry and lowered the latency to initiate and the total time in the narrow beam task and this beneficial effect was lost following central application of estrogen receptor β (ERβ) antagonist or phosphatidylinositol 3-kinase (PI3K) inhibitor. In addition, troxerutin reduced striatal malondialdehyde (MDA) as an index of lipid peroxidation, reactive oxygen species, glial fibrillary acid protein (GFAP) as a marker of astrogliosis, and DNA fragmentation as an apoptotic marker with no significant alteration of catalase activity and nitrite level. Meanwhile, troxerutin was capable to prevent loss of nigral tyrosine hydroxylase (TH)-positive neurons. These findings indicate neuroprotective potential of troxerutin in 6-OHDA rat model of PD through mitigation of apoptosis, astrogliosis, and oxidative stress and part of its effect is dependent on PI3K/ERβ signaling.

  1. Increase in telencephalic dopamine and cerebellar norepinephrine contents by hydrostatic pressure in goldfish: the possible involvement in hydrostatic pressure-related locomotion.

    PubMed

    Ikegami, Taro; Takemura, Akihiro; Choi, Eunjung; Suda, Atsushi; Tomonaga, Shozo; Badruzzaman, Muhammad; Furuse, Mitsuhiro

    2015-10-01

    Fish are faced with a wide range of hydrostatic pressure (HP) in their natural habitats. Additionally, freshwater fish are occasionally exposed to rapid changes in HP due to heavy rainfall, flood and/or dam release. Accordingly, variations in HP are one of the most important environmental cues for fish. However, little information is available on how HP information is perceived and transmitted in the central nervous system of fish. The present study examined the effect of HP (water depth of 1.3 m) on the quantities of monoamines and their metabolites in the telencephalon, optic tectum, diencephalon, cerebellum (including partial mesencephalon) and vagal lobe (including medulla oblongata) of the goldfish, Carassius auratus, using high-performance liquid chromatography. HP affected monoamine and metabolite contents in restricted brain regions, including the telencephalon, cerebellum and vagal lobe. In particular, HP significantly increased the levels of dopamine (DA) in the telencephalon at 15 min and that of norepinephrine (NE) in the cerebellum at 30 min. In addition, HP also significantly increased locomotor activity at 15 and 30 min after HP treatment. It is possible that HP indirectly induces locomotion in goldfish via telencephalic DA and cerebellar NE neuronal activity.

  2. Possible Involvement of the Double-Stranded RNA-Binding Core Protein ςA in the Resistance of Avian Reovirus to Interferon

    PubMed Central

    Martínez-Costas, José; González-López, Claudia; Vakharia, Vikram N.; Benavente, Javier

    2000-01-01

    Treatment of primary cultures of chicken embryo fibroblasts with a recombinant chicken alpha/beta interferon (rcIFN) induces an antiviral state that causes a strong inhibition of vaccinia virus and vesicular stomatitis virus replication but has no effect on avian reovirus S1133 replication. The fact that avian reovirus polypeptides are synthesized normally in rcIFN-treated cells prompted us to investigate whether this virus expresses factors that interfere with the activation and/or the activity of the IFN-induced, double-stranded RNA (dsRNA)-dependent enzymes. Our results demonstrate that extracts of avian-reovirus-infected cells, but not those of uninfected cells, are able to relieve the translation-inhibitory activity of dsRNA in reticulocyte lysates, by blocking the activation of the dsRNA-dependent enzymes. In addition, our results show that protein ςA, an S1133 core polypeptide, binds to dsRNA in an irreversible manner and that clearing this protein from extracts of infected cells abolishes their protranslational capacity. Taken together, our results raise the interesting possibility that protein ςA antagonizes the IFN-induced cellular response against avian reovirus by blocking the intracellular activation of enzyme pathways dependent on dsRNA, as has been suggested for several other viral dsRNA-binding proteins. PMID:10627522

  3. Neurotrophin-3 promotes cell death induced in cerebral ischemia, oxygen-glucose deprivation, and oxidative stress: possible involvement of oxygen free radicals.

    PubMed

    Bates, Brian; Hirt, Lorenz; Thomas, Sunu S; Akbarian, Schahram; Le, Dean; Amin-Hanjani, Sepideh; Whalen, Michael; Jaenisch, Rudolf; Moskowitz, Michael A

    2002-02-01

    To explore the role of neurotrophin-3 (NT-3) during cerebral ischemia, NT-3-deficient brains were subjected to transient focal ischemia. Conditional mutant brains produced undetectable amounts of NT-3 mRNA, whereas the expression of the neurotrophin, BDNF, the NT-3 receptor, TrkC, and the nonselective, low-affinity neurotrophin receptor p75NTR, were comparable to wild-type. Baseline absolute blood flow, vascular and neuroanatomical features, as well as physiological measurements were also indistinguishable from wild-type. Interestingly, the absence of NT-3 led to a significantly decreased infarct volume 23 h after middle cerebral artery occlusion. Consistent with this, the addition of NT-3 to primary cortical cell cultures exacerbated neuronal death caused by oxygen-glucose deprivation. Coincubation with the oxygen free radical chelator, trolox, diminished potentiation of neuronal death. NT-3 also enhanced neuronal cell death and the production of reactive oxygen species caused by oxidative damage inducing agents. We conclude that endogenous NT-3 enhanced neuronal injury during acute stroke, possible by increasing oxygen-radical mediated cell death.

  4. Ellagic acid exerts protective effect in intrastriatal 6-hydroxydopamine rat model of Parkinson's disease: Possible involvement of ERβ/Nrf2/HO-1 signaling.

    PubMed

    Baluchnejadmojarad, Tourandokht; Rabiee, Nafiseh; Zabihnejad, Sedigheh; Roghani, Mehrdad

    2017-02-23

    Parkinson's disease (PD) is a prevalent movement disorder in the elderly with progressive loss of mesencephalic dopaminergic neurons and incapacitating motor and non-motor complications. Ellagic acid is a natural phenolic compound with potent antioxidant and anti-inflammatory properties. In this study, we investigated its possible neuroprotective effect in 6-hydroxydopamine (6-OHDA) rat model of PD. Intrastriatal 6-OHDA-lesioned rats were pretreated with ellagic acid at a dose of 50 mg/kg/day for 1 week. Results showed that ellagic acid attenuates apomorphine-induced rotational bias and lowers the latency to initiate and the total time in the narrow beam task and this beneficial effect was partially abrogated following intracerebroventricular microinjection of estrogen receptor β (ERβ) antagonist. Furthermore, ellagic acid reduced striatal malondialdehyde (MDA), reactive oxygen species (ROS), and DNA fragmentation, and improved monoamine oxidase B (MAO-B), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and heme oxygenase 1 (HO-1). Meanwhile, ellagic acid prevented loss of tyrosine hydroxylase (TH)-positive neurons within substantia nigra pars compacta (SNC). These findings indicate neuroprotective potential of ellagic acid in 6-OHDA rat model of PD via amelioration of apoptosis and oxidative stress, suppression of MAO-B, and its favorable influence is partly reliant on ERβ/Nrf2/HO-1 signaling cascade.

  5. Increased production of 4 kDa amyloid beta peptide in serum deprived human primary neuron cultures: possible involvement of apoptosis.

    PubMed

    LeBlanc, A

    1995-12-01

    The etiology of the amyloid beta peptide in sporadic Alzheimer's disease (AD) is not known. Amyloid beta peptide (A beta), a proteolytic product of the amyloid precursor protein (APP), is deposited in the senile plaques and cerebrovascular tissues of individuals with either sporadic or familial AD (FAD). Increased A beta production from mutant APPs in FAD fosters the hypothesis that overexpression of A beta plays a primary role in the pathogenesis of AD. The absence of APP mutations in sporadic AD which displays identical pathological features than FAD such as synapse and neuronal loss, senile plaques and neurofibrillary tangles, suggests other causes for overexpression and/or deposition of A beta. To investigate the effect of neuronal death on APP metabolism and A beta secretion, human primary neuron cultures were induced to undergo apoptosis by serum deprivation. Serum deprived neurons display shrunken and rounded morphology, contain condensed chromatine and fragmented DNA, which are characteristic of apoptosis. In serum deprived neurons, metabolism of APP through the nonamyloidogenic secretory pathway is decreased to 20% from 40% in control cultures whereas 4kDa A beta is increased three- to fourfold. The results suggest that human neurons undergoing apoptosis generate excess A beta and indicates a possible mechanism for increased A beta in the absence of APP mutations.

  6. Molecular composition of drusen and possible involvement of anti-retinal autoimmunity in two different forms of macular degeneration in cynomolgus monkey (Macaca fascicularis).

    PubMed

    Umeda, Shinsuke; Suzuki, Michihiro T; Okamoto, Haru; Ono, Fumiko; Mizota, Atsushi; Terao, Keiji; Yoshikawa, Yasuhiro; Tanaka, Yasuhiko; Iwata, Takeshi

    2005-10-01

    We have previously reported a cynomolgus monkey (Macaca fascicularis) pedigree with early onset macular degeneration that develops drusen at 2 yr after birth. In this study, the molecular composition of drusen in monkeys affected with late onset and early onset macular degeneration was both characterized. Involvement of anti-retinalautoimmunity in the deposition of drusen and the pathogenesis of the disease was also evaluated. Funduscopic and histological examinations were performed on 278 adult monkeys (mean age=16.94 yr) for late onset macular degeneration. The molecular composition of drusen was analyzed by immunohistochemistry and/or direct proteome analysis using liquid chromatography tandem mass spectroscopy (LC-MS/MS). Anti-retinal autoantibodies in sera were screened in 20 affected and 10 age-matched control monkeys by Western blot techniques. Immunogenic molecules were identified by 2D electrophoresis and LC-MS/MS. Relative antibody titer against each antigen was determined by ELISA in sera from 42 affected (late onset) and 41 normal monkeys. Yellowish-white spots in the macular region were observed in 90 (32%) of the late onset monkeys that were examined. Histological examination demonstrated that drusen or degenerative retinal pigment epithelium (RPE) cells were associated with the pigmentary abnormalities. Drusen in both late and early onset monkeys showed immunoreactivities for apolipoprotein E, amyloid P component, complement component C5, the terminal C5b-9 complement complex, vitronectin, and membrane cofactor protein. LC-MS/MS analyses identified 60 proteins as constituents of drusen, including a number of common components in drusen of human age-related macular degeneration (AMD), such as annexins, crystallins, immunoglobulins, and complement components. Half of the affected monkeys had single or multiple autoantibodies against 38, 40, 50, and 60 kDa retinal proteins. The reacting antigens of 38 and 40 kDa were identified as annexin II and mu

  7. The Ca(2+) -binding protein PCaP2 located on the plasma membrane is involved in root hair development as a possible signal transducer.

    PubMed

    Kato, Mariko; Aoyama, Takashi; Maeshima, Masayoshi

    2013-05-01

    Plasma membrane-associated Ca(2+) -binding protein-2 (PCaP2) of Arabidopsis thaliana is a novel-type protein that binds to the Ca(2+) /calmodulin complex and phosphatidylinositol phosphates (PtdInsPs) as well as free Ca(2+) . Although the PCaP2 gene is predominantly expressed in root hair cells, it remains unknown how PCaP2 functions in root hair cells via binding to ligands. From biochemical analyses using purified PCaP2 and its variants, we found that the N-terminal basic domain with 23 amino acids (N23) is necessary and sufficient for binding to PtdInsPs and the Ca(2+) /calmodulin complex, and that the residual domain of PCaP2 binds to free Ca(2+) . In mutant analysis, a pcap2 knockdown line displayed longer root hairs than the wild-type. To examine the function of each domain in root hair cells, we over-expressed PCaP2 and its variants using the root hair cell-specific EXPANSIN A7 promoter. Transgenic lines over-expressing PCaP2, PCaP2(G2A) (second glycine substituted by alanine) and ∆23PCaP2 (lacking the N23 domain) exhibited abnormal branched and bulbous root hair cells, while over-expression of the N23 domain suppressed root hair emergence and elongation. The N23 domain was necessary and sufficient for the plasma membrane localization of GFP-tagged PCaP2. These results suggest that the N23 domain of PCaP2 negatively regulates root hair tip growth via processing Ca(2+) and PtdInsP signals on the plasma membrane, while the residual domain is involved in the polarization of cell expansion.

  8. Possible involvement of suppression of Th2 differentiation in the anti-allergic effect of Sho-seiryu-to in mice.

    PubMed

    Ikeda, Yoshiki; Kaneko, Atsushi; Yamamoto, Masahiro; Ishige, Atsushi; Sasaki, Hiroshi

    2002-12-01

    The clinical effectiveness of the Kampo medicine Sho-seiryu-to (SST) has recently been demonstrated in a double-blind randomized study of allergic asthma and rhinitis. We investigated the effect of SST on a type 1 allergic model in mice. Ovalbumin (OVA)-induced sneezing and the total and OVA-specific IgE levels were significantly suppressed with SST at 1.0 g/kg, but that of OVA-specific IgG(2a) was not. In the splenocytes isolated from SST-administered mice, OVA-induced interleukin (IL)-4 production decreased while interferon (IFN)-gamma production was not. The co-culture experiments using purified CD4(+)T cells and antigen-presenting cells (APCs) suggested that SST influenced both cell types. Flow-cytometric analysis showed that SST suppressed the number of IL-4 producing CD4(+)T cells but not the number of IFN-gamma producing CD4(+)T cells. The CD86(+) major histocompatibility complex class II(+) (MHC II)(+) cells and CD28(+)CD4(+)T cells were decreased by SST treatment, while CD80(+)MHC II(+) cells, CD40(+)MHC II(+) cells and CD154(+)CD4(+)T cells showed no change. These data suggested that SST may suppress IL-4 production in CD4(+)T cells via influencing CD28-CD86 interaction. In addition to the previously reported inhibitory activity on histamine release, suppression of Th2 differentiation at the stage of APC-CD4(+)T cell interaction may be involved in the anti-allergic effects of SST.

  9. Reduction in traumatic brain injury-induced oxidative stress, apoptosis, and calcium entry in rat hippocampus by melatonin: Possible involvement of TRPM2 channels.

    PubMed

    Yürüker, Vehbi; Nazıroğlu, Mustafa; Şenol, Nilgün

    2015-02-01

    Melatonin, which is a very effective reactive oxygen species (ROS) scavenger, acts through a direct reaction with free radicals. Ca(2+) entry induced by traumatic brain injury (TBI) has deleterious effects on human hippocampal function. TRPM2 is a Ca(2+) permeable non-selective channel in hippocampal neurons, and its activation of during oxidative stress has been linked to cell death. Despite the importance of oxidative stress in TBI, its role in apoptosis and Ca(2+) entry in TBI is poorly understood. Therefore, we tested the effects of melatonin on apoptosis, oxidative stress, and Ca(2+) entry through the TRPM2 channel in the hippocampal neurons of TBI-induced rats. Thirty-two rats were divided into the following four groups: control, melatonin, TBI, and TBI + melatonin groups. Melatonin (5 mg/kg body weight) was intraperitoneally given to animals in the melatonin group and the TBI + melatonin group after 1 h of brain trauma. Hippocampal neurons were freshly isolated from the four groups, incubated with a nonspecific TRPM2 blocker (2-aminoethyl diphenylborinate, 2-APB), and then stimulated with cumene hydroperoxide. Apoptosis, caspase-3, caspase-9, intracellular ROS production, mitochondrial membrane depolarization and intracellular free Ca(2+) ([Ca(2+)]i) values were high in the TBI group, and low in the TBI + melatonin group. The [Ca(2+)]i concentration was decreased in the four groups by 2-APB. In our TBI experimental model, TRPM2 channels were involved in Ca(2+) entry-induced neuronal death, and the negative modulation of the activity of this channel by melatonin pretreatment may account for the neuroprotective activity of TRPM2 channels against oxidative stress, apoptosis, and Ca(2+) entry.

  10. Tickling stimulation causes the up-regulation of the kallikrein family in the submandibular gland of the rat.

    PubMed

    Yamamuro, Takuya; Hori, Miyo; Nakagawa, Yoshimi; Hayashi, Takashi; Sakamoto, Shigeko; Ohnishi, Junji; Takeuchi, Shino; Mihara, Yuko; Shiga, Takashi; Murakami, Kazuo; Urayama, Osamu

    2013-01-01

    We recently showed that tactile stimulation (tickling) accompanied by positive emotion altered the expression of many genes in the rat hypothalamus (Hori et al., 2009 [15]). In this study, the effect of repeated tickling on gene expressions of the rat salivary gland was examined. After 4-week stimulation, several genes of the kallikrein (Klk) family were remarkably up-regulated and the alpha-amylase (amylase) gene was down-regulated in DNA microarray analysis. In quantitative analysis using real-time PCR of the submandibular gland of the rats tickled for 2 weeks, mRNAs of Klk1, Klk2 (Klk1c2, Tonin), Klk7 (Klk1l), Klk1b3 (Nerve growth factor, gamma), Klk1c10, Klks3 (Klk1c9) and GK11 were significantly 2-5-fold increased among 18 members of the Klk gene family examined and the submandibular amylase was decreased compared with the lightly touched and untouched control rats. In immunoblot analysis the increase in Klk7 protein was observed in the whole cell lysate fraction of the submandibular gland. In immunohistochemical analysis with anti-Klk7 polyclonal antibody, the immunostain was increased in duct cells of the submandibular gland of the tickled rat when compared with the lightly touched and untouched control rats. These results suggest that tactile sensory processing in the central nervous system affects the gene expression in the peripheral tissue probably via hormonal and/or autonomic neural activities. Submandibular Klks may be biochemical markers indicating positive emotional states.

  11. The Kallikrein-Kinin System: A Novel Mediator of IL-17-Driven Anti-Candida Immunity in the Kidney

    PubMed Central

    Ramani, Kritika; Garg, Abhishek V.; Jawale, Chetan V.; Jackson, Edwin K.; Shiva, Sruti S.; Horne, William; Kolls, Jay K.; Gaffen, Sarah L.; Biswas, Partha S.

    2016-01-01

    The incidence of life-threatening disseminated Candida albicans infections is increasing in hospitalized patients, with fatalities as high as 60%. Death from disseminated candidiasis in a significant percentage of cases is due to fungal invasion of the kidney, leading to renal failure. Treatment of candidiasis is hampered by drug toxicity, the emergence of antifungal drug resistance and lack of vaccines against fungal pathogens. IL-17 is a key mediator of defense against candidiasis. The underlying mechanisms of IL-17-mediated renal immunity have so far been assumed to occur solely through the regulation of antimicrobial mechanisms, particularly activation of neutrophils. Here, we identify an unexpected role for IL-17 in inducing the Kallikrein (Klk)-Kinin System (KKS) in C. albicans-infected kidney, and we show that the KKS provides significant renal protection in candidiasis. Microarray data indicated that Klk1 was upregulated in infected kidney in an IL-17-dependent manner. Overexpression of Klk1 or treatment with bradykinin rescued IL-17RA-/- mice from candidiasis. Therapeutic manipulation of IL-17-KKS pathways restored renal function and prolonged survival by preventing apoptosis of renal cells following C. albicans infection. Furthermore, combining a minimally effective dose of fluconazole with bradykinin markedly improved survival compared to either drug alone. These results indicate that IL-17 not only limits fungal growth in the kidney, but also prevents renal tissue damage and preserves kidney function during disseminated candidiasis through the KKS. Since drugs targeting the KKS are approved clinically, these findings offer potential avenues for the treatment of this fatal nosocomial infection. PMID:27814401

  12. Asynchronous reformation of individual kallikrein-related secretory proteinases in rat submandibular glands following degranulation by cyclocytidine.

    PubMed

    Proctor, G B; Shori, D K; Chan, K M; Garrett, J R

    1993-10-01

    Time scales for the reformation of the secretory granules in granular tubules and their constituent proteinases were assessed after inducing a massive degranulation by intraperitoneal injection of cyclocytidine in conscious animals. The minimum working dose of cyclocytidine to produce the maximum degranulation and depletion of proteinase activity, at 3 h after injection, was 75 mg/kg. Histologically, although most granular tubule cells then appeared to be extensively degranulated, isolated individual cells showing little or no degranulation always persisted. Acinar cells also showed some depletion of secretory material. At 15 h after injecting cyclocytidine the formation of new granules had begun in the granular tubule cells, but it was not extensive or uniform in adjacent cells; however, the acinar cells already appeared to be regranulated. The pattern of granule reformation in granular tubule cells progressed gradually, so that 7-10 days after cyclocytidine-induced degranulation the cells were mostly packed with granules and showed similar appearances to those of normal resting control glands. Individual proteinases in extracts of the glands were assayed specifically using fluorogenic oligopeptide amidase substrates, with and without appropriate inhibitors. This revealed a 95% reduction in total proteinase activity 3 h after cyclocytidine (75 mg/kg). In the same extracts, acinar peroxidase was reduced by 28%. Peroxidase levels recovered to control values within 15 h after cyclocytidine but recovery of proteinases progressed more gradually and did not occur uniformly for the different constituent proteinases. Tissue kallikrein (rK1) showed the most rapid recovery and had reached levels approaching normal within 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Genomic Instability and Copy-Number Heterogeneity of Chromosome 19q, Including the Kallikrein Locus, in Ovarian Carcinomas

    PubMed Central

    Bayani, Jane; Marrano, Paula; Graham, Cassandra; Zheng, Yingye; Li, Lin; Katsaros, Dionyssios; Lassus, Heini; Butzow, Ralf; Squire, Jeremy A.; Diamandis, Eleftherios P.

    2011-01-01

    Many tissue kallikrein (KLK) genes and proteins are candidate diagnostic, prognostic and predictive biomarkers for ovarian cancer (OCa). We previously demonstrated that the KLK locus (19q13.3/4) is subject to copy-number gains and structural rearrangements in a pilot study of cell lines and ovarian cancer primary tissues, shown to overexpress KLK gene family members. To determine the overall frequency of genomic instability and copy-number changes, a retrospective study was conducted using formalin-fixed paraffin embedded (FFPE) tissues. Eighty-one chemotherapy naïve serous OCas were examined using 3-colour fluorescence in situ hybridization (FISH) to identify structural and numerical changes on 19q, including the KLK locus; in addition to immunohistochemistry (IHC) for KLK6, which has been shown to be overexpressed in OCa. The KLK locus was subject to copy-number changes in ~83% of cases: net gain in 51%, net loss in 30% and amplified in 2%; and found to be chromosomally unstable (p<0.001). All cases showed a wide range of immuoreactivity for KLK6 by IHC. Although no strong correlation could be found with copy number, the latter was contributing factor to the observed KLK6 protein overexpression. Moreover, univariate and multivariate analyses showed an association between the net loss of the KLK locus with longer disease-free survival. Interestingly, FISH analyses indicated that chromosome 19q was subject to structural rearrangement in 62% of cases and was significantly correlated to tumor grade (p<0.001). We conclude that numerical and structural aberrations of chromosome 19q, affect genes including the KLK gene members, may contributing to ovarian carcinoma progression and aggressiveness. PMID:20800559

  14. Resetting of renal tissular renin-angiotensin and bradykinin-kallikrein systems after unilateral kidney denervation in rats.

    PubMed

    Bohlender, Jürgen M; Nussberger, Jürg; Birkhäuser, Frédéric; Grouzmann, Eric; Thalmann, George N; Imboden, Hans

    2017-02-20

    The renal tissular renin-angiotensin and bradykinin-kallikrein systems control kidney function together with the renal sympathetic innervation but their interaction is still unclear. To further elucidate this relationship, we investigated these systems in rats 6 days after left kidney denervation (DNX, n = 8) compared to sham-operated controls (CTR, n = 8). Plasma renin concentration was unchanged in DNX vs. CTR (p = NS). Kidney bradykinin (BK) and angiotensin (Ang) I and II concentrations decreased bilaterally in DNX vs. CTR rats (~20 to 40%, p < 0.05) together with Ang IV and V concentrations that were extremely low (p = NS). Renin, Ang III and dopamine concentrations decreased by ~25 to 50% and norepinephrine concentrations by 99% in DNX kidneys (p < 0.05) but were unaltered in opposite kidneys. Ang II/I and KA were comparable in DNX, contralateral and CTR kidneys. Ang III/II increased in right vs. DNX or CTR kidneys (40-50%, p < 0.05). Ang II was mainly located in tubular epithelium by immunocytological staining and its cellular distribution was unaffected by DNX. Moreover, the angiotensinergic and catecholaminergic innervation of right kidneys was unchanged vs. CTR. We found an important dependency of tissular Ang and BK levels on the renal innervation that may contribute to the resetting of kidney function after DNX. The DNX-induced peptide changes were not readily explained by kidney KA, renin or plasma Ang I generation. However, tissular peptide metabolism and compartmentalization may have played a central role. The mechanisms behind the concentration changes remain unclear and deserve further clarification.

  15. Histamine H3-receptor signaling in the heart: possible involvement of Gi/Go proteins and N-type Ca++ channels.

    PubMed

    Endou, M; Poli, E; Levi, R

    1994-04-01

    Discovered as inhibitory autoreceptors in central histaminergic pathways, histamine H3-receptors may also modulate peripheral cholinergic and central adrenergic function. Recently, H3-receptors were reported to inhibit adrenergic inotropic responses in guinea pig atria, possibly at prejunctional sites. We have assessed whether the H3-mediated modulation of cardiac adrenergic activities results from a reduction in norepinephrine release. We have found that (R) alpha-methylhistamine, the selective histamine H3-receptor agonist, attenuates the inotropic and chronotropic response of isolated guinea pig atria to transmural stimulation of adrenergic nerve endings. This attenuation was associated with a marked reduction in endogenous norepinephrine release. In contrast (R) alpha-methylhistamine did not modify the chronotropic effect of exogenous norepinephrine. The attenuation of adrenergic responses by (R) alpha-methylhistamine was 1) prevented by thioperamide, the selective H3-receptor antagonist; 2) attenuated by pertussis-toxin pretreatment and 3) potentiated by the N-type Ca(++)-channel blocker omega-conotoxin, which also potentiated the sympathetic modulatory effects of adrenergic-alpha 2 and adenosine-A1 receptor agonists. Our findings indicate that prejunctional histamine H3-receptors modulate the depolarization-dependent norepinephrine release from sympathetic nerve endings in the guinea pig myocardium. These receptors are probably coupled to a pertussis-toxin-sensitive Gi/Go protein and probably effect a reduction in Ca++ current. We have previously reported that sympathetic stimulation elicits a frequency-dependent release of cardiac histamine, whereas others had found that adrenergic activity regulates histamine's rapid turnover pool. Accordingly, presynaptic H3-receptors are likely to serve a modulatory role in cardiac adrenergic function.

  16. Possible involvement of iNOS and TNF-α in nutritional intervention against nicotine-induced pancreatic islet cell damage.

    PubMed

    Bhattacharjee, Ankita; Prasad, Shilpi Kumari; Pal, Swagata; Maji, Bithin; Banerjee, Arnab; Das, Debasmita; Bose, Ananya; Chatterjee, Nabanita; Mukherjee, Sandip

    2016-12-01

    Nicotine is the more abundant and most significant components of cigarette smoke. Epidemiological evidence strongly suggests an association between cigarette smoking and pancreatic injury. Although effects of smoking on endocrine pancreas are still controversial Here, we examined the impact and underlying mechanisms of action of folic acid and vitamin B12 on nicotine induced damage in pancreatic islets of rats. Male Wistar rats were treated with nicotine (3mg/kg body weight/day, intraperitonealy) with or without folic acid (36μg/kg body weight/day, orally) and vitamin B12 (0.63μg/kg body weight/day, orally) for 21days. Supplementation with folic acid and vitamin B12 suppressed the nicotine induced changes in HbA1c, insulin, TNF-α, IL-6, generation of reactive oxygen species, and attenuated the changes in markers of oxidative stress. Moreover, folic acid and vitamin B12 also counteracted the increased expression of protein and mRNA contents of TNF-α and iNOS produced by nicotine. Further, folic acid and vitamin B12 in combination limits the nicotine induced changes in cell cycle and excessive apoptosis of the pancreatic β-cells and also successfully blunted the nicotine induced alteration in loss of mitochondrial membrane potential. In conclusion, data demonstrate that folic acid and vitamin B12 may be possible nutritional intervention against cellular oxidative stress, which is a critical step in nicotine-mediated islet injury, and improves islet cell functional status by scavenging free radicals and by inhibiting the generation of pro-inflammatory mediators.

  17. Homocysteine stimulates the expression of monocyte chemoattractant protein-1 receptor (CCR2) in human monocytes: possible involvement of oxygen free radicals.

    PubMed Central

    Wang, G; O, K

    2001-01-01

    Homocysteinaemia is an independent risk factor for atherosclerosis. The development of atherosclerosis involves monocyte chemoattractant protein 1 (MCP-1)-mediated monocyte recruitment to the lesion site. The action of MCP-1 is mostly via its interaction with MCP-1 receptor (CCR2), which is the major receptor for MCP-1 on the surface of monocytes. The objective of the present study was to investigate the effect of homocysteine on CCR2 expression in human THP-1 monocytes. Cells were incubated with various concentrations of homocysteine for 6, 12, 24 and 48 h. The expression of CCR2 mRNA was determined by nuclease protection assay and the CCR2 protein was measured by Western immunoblotting analysis. The binding of MCP-1 to CCR2 as a functional receptor on the monocyte surface was determined by flow cytometry. Homocysteine (0.05-0.2 mM) significantly enhanced the expression of CCR2 mRNA (129-209% of the control) and CCR2 protein (up to 183% of control) in these cells after 24 h of incubation. Stimulation of CCR2 expression was associated with a parallel increase in the binding activity of CCR2 (129-191% of control) as well as an enhanced chemotactic response of homocysteine-treated monocytes. Further investigation revealed that the levels of superoxide were significantly elevated in cells incubated with homocysteine for 12-48 h. The addition of superoxide dismutase, a scavenger of superoxide, to the culture medium abolished the stimulatory effect of homocysteine on CCR2 expression as well as the binding activity of the receptor. The stimulatory effect of homocysteine on the expression of CCR2 mRNA and the levels of CCR2 protein was also observed in human peripheral blood monocytes. In conclusion, the present study has clearly demonstrated that homocysteine stimulates CCR2 expression in monocytes, leading to an enhanced binding activity and chemotatic response. Homocysteine-induced superoxide formation might serve as one of the underlying mechanisms for this effect

  18. Beetroot juice reduces infarct size and improves cardiac function following ischemia-reperfusion injury: Possible involvement of endogenous H2S.

    PubMed

    Salloum, Fadi N; Sturz, Gregory R; Yin, Chang; Rehman, Shabina; Hoke, Nicholas N; Kukreja, Rakesh C; Xi, Lei

    2015-05-01

    Ingestion of high dietary nitrate in the form of beetroot juice (BRJ) has been shown to exert antihypertensive effects in humans through increasing cyclic guanosine monophosphate (cGMP) levels. Since enhanced cGMP protects against myocardial ischemia-reperfusion (I/R) injury through upregulation of hydrogen sulfide (H2S), we tested the hypothesis that BRJ protects against I/R injury via H2S. Adult male CD-1 mice received either regular drinking water or those dissolved with BRJ powder (10 g/L, containing ∼ 0.7 mM nitrate). Seven days later, the hearts were explanted for molecular analyses. Subsets of mice were subjected to I/R injury by occlusion of the left coronary artery for 30 min and reperfusion for 24 h. A specific inhibitor of H2S producing enzyme--cystathionine-γ-lyase (CSE), DL-propargylglycine (PAG, 50 mg/kg) was given i.p. 30 min before ischemia. Myocardial infarct size was significantly reduced in BRJ-fed mice (15.8 ± 3.2%) versus controls (46.5 ± 3.5%, mean ± standard error [SE], n = 6/group, P < .05). PAG completely blocked the infarct-limiting effect of BRJ. Moreover, BRJ significantly preserved ventricular function following I/R. Myocardial levels of H2S and its putative protein target--vascular endothelial growth factor receptor 2 (VEGFR2) were significantly increased by BRJ intake, whereas CSE mRNA and protein content did not change. Interestingly, the BRJ-induced cardioprotection was not associated with elevated blood nitrate-nitrite levels following I/R nor induction of cardiac peroxiredoxin 5, a mitochondrial antioxidant enzyme previously linked to nitrate-induced cardioprotection. We conclude that BRJ ingestion protects against post-I/R myocardial infarction and ventricular dysfunction possibly through CSE-mediated endogenous H2S generation. BRJ could be a promising natural and inexpensive nutraceutical supplement to reduce cardiac I/R injury in patients.

  19. Ethanol Extract of Peanut Sprout Lowers Blood Triglyceride Levels, Possibly Through a Pathway Involving SREBP-1c in Rats Fed a High-Fat Diet.

    PubMed

    Ha, Ae Wha; Kang, Nam E; Kim, Woo Kyoung

    2015-08-01

    The hypothesis of this study was that peanut sprout extracts (PSE) could reduce fat accumulation through activating the transcription of SREBP-1c genes. Sprague-Dawley (SD) were randomly assigned into two groups and fed the following diet for 4 weeks; 10 normal fat (NF, 7 g of fat/100 g diet) and 30 high fat (HF, 20 g of fat/100 g diet). After 4 weeks, the HF group was divided into three groups; HF, HF with 15 mg of PSE/kg diet (HF+low PSE, 0.025% resveratrol), and HF with 30 mg of PSE/kg diet (HF+high PSE, 0.05% resveratrol) and fed for an additional 5 weeks. The HF+high PSE group had significantly lower weight gain than the HF group. Plasma triglyceride (TG) level and the hepatic total lipid level were significantly lower in the HF+high PSE group compared to the HF group. Fecal excretions of total lipids, cholesterol, and TG in the HF+high PSE group tended to be higher than in the HF group, but these differences were not significant. The mRNA expressions of fatty acid synthase, glucose-6-phosphate dehydrogenase, and sterol regulatory element binding protein-c (SREBP-1c) were significantly lower in the HF+high PSE group than in the HF group. The mRNA expressions of hydroxy-3-methylglutaryl coenzyme A reductase and acyl-CoA cholesterol acyltransferase were significantly lower in the HF+high PSE groups compared to the HF group. The mRNA expression of cholesterol 7α-hydroxylase1 was significantly higher than the HF group in both the HF+low PSE and HF+high PSE groups, with much greater increase observed in the HF+high PSE group. In conclusion, consumption of PSE was effective for improving blood lipid levels, possibly by suppressing the expression of SREBP-1c, in rats fed a high-fat diet.

  20. β-D-Glucoside utilization by Mycoplasma mycoides subsp. mycoides SC: possible involvement in the control of cytotoxicity towards bovine lung cells

    PubMed Central

    Vilei, Edy M; Correia, Ivone; Ferronha, M Helena; Bischof, Daniela F; Frey, Joachim

    2007-01-01

    Background Contagious bovine pleuropneumonia (CBPP) caused by Mycoplasma mycoides subsp. mycoides small-colony type (SC) is among the most serious threats for livestock producers in Africa. Glycerol metabolism-associated H2O2 production seems to play a crucial role in virulence of this mycoplasma. A wide number of attenuated strains of M. mycoides subsp. mycoides SC are currently used in Africa as live vaccines. Glycerol metabolism is not affected in these vaccine strains and therefore it does not seem to be the determinant of their attenuation. A non-synonymous single nucleotide polymorphism (SNP) in the bgl gene coding for the 6-phospho-β-glucosidase (Bgl) has been described recently. The SNP differentiates virulent African strains isolated from outbreaks with severe CBPP, which express the Bgl isoform Val204, from strains to be considered less virulent isolated from CBPP outbreaks with low mortality and vaccine strains, which express the Bgl isoform Ala204. Results Strains of M. mycoides subsp. mycoides SC considered virulent and possessing the Bgl isoform Val204, but not strains with the Bgl isoform Ala204, do trigger elevated levels of damage to embryonic bovine lung (EBL) cells upon incubation with the disaccharides (i.e., β-D-glucosides) sucrose and lactose. However, strains expressing the Bgl isoform Val204 show a lower hydrolysing activity on the chromogenic substrate p-nitrophenyl-β-D-glucopyranoside (pNPbG) when compared to strains that possess the Bgl isoform Ala204. Defective activity of Bgl in M. mycoides subsp. mycoides SC does not lead to H2O2 production. Rather, the viability during addition of β-D-glucosides in medium-free buffers is higher for strains harbouring the Bgl isoform Val204 than for those with the isoform Ala204. Conclusion Our results indicate that the studied SNP in the bgl gene is one possible cause of the difference in bacterial virulence among strains of M. mycoides subsp. mycoides SC. Bgl does not act as a direct virulence

  1. β-cyclodextrin complex containing Lippia grata leaf essential oil reduces orofacial nociception in mice - evidence of possible involvement of descending inhibitory pain modulation pathway.

    PubMed

    Siqueira-Lima, Pollyana S; Araújo, Adriano A S; Lucchese, Angélica M; Quintans, Jullyana S S; Menezes, Paula P; Alves, Péricles B; de Lucca Júnior, Waldecy; Santos, Marcio R V; Bonjardim, Leonardo R; Quintans-Júnior, Lucindo J

    2014-02-01

    The treatment of orofacial pain remains a major challenge for modern medicine. Thus, we prepared and physicochemically characterized a new β-cyclodextrin complex containing Lippia grata leaf essential oil (β-CD/EO) to investigate their possible antinociceptive activity in animal models of orofacial pain. The results of Differential scanning calorimeter (DSC) and Thermogravimetry/derivative thermogravimetry (TG/DTG) showed that the products prepared by Slurry complexation (SC) method were able to incorporate greater amounts of EO. In the X-ray diffractogram, it was shown that complex between EO and β-CD was formed. Male Swiss mice were pre-treated with β-CD/EO (6, 12 or 24 mg/kg, per os, gavage, p.o.), morphine (5 mg/kg, i.p.) or vehicle (distilled water, p.o.) 1 hr before treatment with formalin (20 μL, 2%), capsaicin (20 μL, 2.5 μg) or glutamate (40 μL, 25 μM) into the right upper lip. Our results demonstrated that p.o. treatment with β-CD/EO was significantly (p < 0.05 or p < 0.001) capable of reducing the nociceptive face-rubbing behaviour in both phases of the formalin test. β-CD/EO-treated mice were also significantly (p < 0.05 or p < 0.001) protected against nociception induced by capsaicin and glutamate. For the action in the central nervous system (CNS), ninety minutes after the treatment, the mice were perfused, the brains collected, crioprotected, cut in a criostate and submitted to an immunofluorescence protocol for Fos protein. The immunofluorescence protocol demonstrated that the β-CD/EO significantly activated (p < 0.05; p < 0.01 or p < 0.001) the motor cortex, the Locus ceruleus, the nucleus raphe magnus and the periaqueductal gray of the CNS. These effects apparently did not alter, in tested doses, the motor coordination of mice in the rota-rod test. Our results proposed that β-CD/EO might present an important draft of drug to the study of new compounds for the treatment of orofacial pain.

  2. Somatosensory Psychophysical Losses in Inhabitants of Riverside Communities of the Tapajós River Basin, Amazon, Brazil: Exposure to Methylmercury Is Possibly Involved

    PubMed Central

    Khoury, Eliana Dirce Torres; Souza, Givago da Silva; da Costa, Carlos Araújo; de Araújo, Amélia Ayako Kamogari; de Oliveira, Cláudia Simone Baltazar; Silveira, Luiz Carlos de Lima; Pinheiro, Maria da Conceição Nascimento

    2015-01-01

    . There was a weak linear correlation between tactile sensation threshold and mercury concentration in the head hair samples. No correlation was found for the other two measurements. Mercury-exposed subjects had impaired somatosensory function compared with non-exposed control subjects. Long-term mercury exposure of riverside communities in the Tapajós river basin is a possible but not a definitely proven cause for psychophysical somatosensory losses observed in their population. Additionally, the relatively simple psychophysical measures used in this work should be followed by more rigorous measures of the same population. PMID:26658153

  3. Resveratrol Ameliorates the Anxiety- and Depression-Like Behavior of Subclinical Hypothyroidism Rat: Possible Involvement of the HPT Axis, HPA Axis, and Wnt/β-Catenin Pathway

    PubMed Central

    Ge, Jin-Fang; Xu, Ya-Yun; Qin, Gan; Cheng, Jiang-Qun; Chen, Fei-Hu

    2016-01-01

    Metabolic disease subclinical hypothyroidism (SCH) is closely associated with depression-like behavior both in human and animal studies, and our previous studies have identified the antidepressant effect of resveratrol (RES) in stressed rat model. The aim of this study was to investigate whether RES would manifest an antidepressant effect in SCH rat model and explore the possible mechanism. A SCH rat model was induced by hemi-thyroid electrocauterization, after which the model rats in the RES and LT4 groups received a daily intragastric injection of RES at the dose of 15 mg/kg or LT4 at the dose of 60 μg/kg for 16 days. The rats’ plasma concentrations of thyroid hormones were measured. Behavioral performance and hypothalamic–pituitary–adrenal (HPA) activity were evaluated. The protein expression levels of the Wnt/β-catenin in the hippocampus were detected by western blot. The results showed that RES treatment downregulated the elevated plasma thyroid-stimulating hormone concentration and the hypothalamic mRNA expression of thyrotropin-releasing hormone in the SCH rats. RES-treated rats showed increased rearing frequency and distance in the open-field test, increased sucrose preference in the sucrose preference test, and decreased immobility in the forced swimming test compared with SCH rats. The ratio of the adrenal gland weight to body weight, the plasma corticosterone levels, and the hypothalamic corticotrophin-releasing hormone mRNA expression were reduced in the RES-treated rats. Moreover, RES treatment upregulated the relative ratio of phosphorylated-GSK3β (p-GSK3β)/GSK3β and protein levels of p-GSK3β, cyclin D1, and c-myc, while downregulating the relative ratio of phosphorylated-β-catenin (p-β-catenin)/β-catenin and expression of GSK3β in the hippocampus. These findings suggest that RES exerts anxiolytic- and antidepressant-like effect in SCH rats by downregulating hyperactivity of the HPA axis and regulating both the HPT axis and the

  4. Possible involvement of serotonin in extinction.

    PubMed

    Beninger, R J; Phillips, A G

    1979-01-01

    In Experiment 1, rats were trained to leverpress for continuous reinforcement with food; half were then intubated with the serotonin synthesis inhibitor parachlorophenylalanine (PCPA: 400 mg/kg) and half with water. In extinction the PCPA-treated rats responded at a higher rate. In Experiment 2, rats were trained on a random interval schedule and then assigned to two groups, treated as in Experiment 1, and tested in extinction. There was no significant difference in the resistance to extinction of the two groups. In Experiment 3, the responding of rats trained in a punished stepdown response paradigm and then given an intragastric injection of PCPA took longer to recover than the responding of water-injected controls. These observations suggest that serotonergic neurons might play a role in extinction processes.

  5. Acute effect of potassium canrenoate administration on renin-angiotensin, kallikrein-kinin and prostaglandin systems.

    PubMed

    Lahera, V; Cachofeiro, V; Duran, F; Cañizo, F J; Rodriguez, F J; Tresguerres, J A

    1988-01-01

    1. To investigate the possible effects of potassium canrenoate (PC) on plasma renin activity (PRA) and on renal prostaglandins (PGS) and kinins under elevated sodium and/or potassium intakes, a single dose of PC was administered to four groups of Wistar male rats. 2. They were fed a normal diet (C), a diet supplemented with 4% of NaCl, (Na), with 1% of KCl: (K) or both supplements (NaK). 3. PRA and urinary PGS excretion did not show changes after PC administration, but total urinary kinins showed higher values after the treatment in all groups. 4. A diuretic but not natriuretic effect was observed only in C animals. 5. In conclusion, the single dose of PC was able to stimulate urinary kinins and to spare potassium independently of dietary electrolyte supplements that were able to block the diuretic effect of the drug.

  6. Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels

    PubMed Central

    Portelli, Michael A.; Siedlinski, Mateusz; Stewart, Ceri E.; Postma, Dirkje S.; Nieuwenhuis, Maartje A.; Vonk, Judith M.; Nurnberg, Peter; Altmuller, Janine; Moffatt, Miriam F.; Wardlaw, Andrew J.; Parker, Stuart G.; Connolly, Martin J.; Koppelman, Gerard H.; Sayers, Ian

    2014-01-01

    The soluble cleaved urokinase plasminogen activator receptor (scuPAR) is a circulating protein detected in multiple diseases, including various cancers, cardiovascular disease, and kidney disease, where elevated levels of scuPAR have been associated with worsening prognosis and increased disease aggressiveness. We aimed to identify novel genetic and biomolecular mechanisms regulating scuPAR levels. Elevated serum scuPAR levels were identified in asthma (n=514) and chronic obstructive pulmonary disease (COPD; n=219) cohorts when compared to controls (n=96). In these cohorts, a genome-wide association study of serum scuPAR levels identified a human plasma kallikrein gene (KLKB1) promoter polymorphism (rs4253238) associated with serum scuPAR levels in a control/asthma population (P=1.17×10−7), which was also observed in a COPD population (combined P=5.04×10−12). Using a fluorescent assay, we demonstrated that serum KLKB1 enzymatic activity was driven by rs4253238 and is inverse to scuPAR levels. Biochemical analysis identified that KLKB1 cleaves scuPAR and negates scuPAR's effects on primary human bronchial epithelial cells (HBECs) in vitro. Chymotrypsin was used as a proproteolytic control, while basal HBECs were used as a control to define scuPAR-driven effects. In summary, we reveal a novel post-translational regulatory mechanism for scuPAR using a hypothesis-free approach with implications for multiple human diseases.—Portelli, M. A., Siedlinski, M., Stewart, C. E., Postma, D. S., Nieuwenhuis, M. A., Vonk, J. M., Nurnberg, P., Altmuller, J., Moffatt, M. F., Wardlaw, A. J., Parker, S. G., Connolly, M. J., Koppelman, G. H., Sayers, I. Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels. PMID:24249636

  7. Possible involvement of cationic-drug sensitive transport systems in the blood-to-brain influx and brain-to-blood efflux of amantadine across the blood-brain barrier.

    PubMed

    Suzuki, Toyofumi; Fukami, Toshiro; Tomono, Kazuo

    2015-03-01

    The purpose of this study was to characterize the brain-to-blood efflux transport of amantadine across the blood-brain barrier (BBB). The apparent in vivo efflux rate constant for [(3) H]amantadine from the rat brain (keff ) was found to be 1.53 × 10(-2) min(-1) after intracerebral microinjection using the brain efflux index method. The efflux of [(3) H]amantadine was inhibited by 1-methyl-4-phenylpyridinium (MPP(+) ), a cationic neurotoxin, suggesting that amantadine transport from the brain to the blood across the BBB potentially involves the rat plasma membrane monoamine transporter (rPMAT). On the other hand, other selected substrates for organic cation transporters (OCTs) and organic anion transporters (OATs), as well as inhibitors of P-glycoprotein (P-gp), did not affect the efflux transport of [(3) H]amantadine. In addition, in vitro studies using an immortalized rat brain endothelial cell line (GPNT) showed that the uptake and retention of [(3) H]amantadine by the cells was not changed by the addition of cyclosporin, which is an inhibitor of P-gp. However, cyclosporin affected the uptake and retention of rhodamine123. Finally, the initial brain uptake of [(3) H]amantadine was determined using an in situ mouse brain perfusion technique. Notably, the brain uptake clearance for [(3) H]amantadine was significantly decreased with the co-perfusion of quinidine or verapamil, which are cationic P-gp inhibitors, while MPP(+) did not have a significant effect. It is thus concluded that while P-gp is not involved, it is possible that rPMAT and the cationic drug-sensitive transport system participate in the brain-to-blood efflux and the blood-to-brain influx of amantadine across the BBB, respectively.

  8. Low-dose etoposide-treatment induces endoreplication and cell death accompanied by cytoskeletal alterations in A549 cells: Does the response involve senescence? The possible role of vimentin

    PubMed Central

    2013-01-01

    Background Senescence in the population of cells is often described as a program of restricted proliferative capacity, which is manifested by broad morphological and biochemical changes including a metabolic shift towards an autophagic-like response and a genotoxic-stress related induction of polyploidy. Concomitantly, the cell cycle progression of a senescent cell is believed to be irreversibly arrested. Recent reports suggest that this phenomenon may have an influence on the therapeutic outcome of anticancer treatment. The aim of this study was to verify the possible involvement of this program in the response to the treatment of the A549 cell population with low doses of etoposide, as well as to describe accompanying cytoskeletal alterations. Methods After treatment with etoposide, selected biochemical and morphological parameters were examined, including: the activity of senescence-associated ß-galactosidase, SAHF formation, cell cycle progression, the induction of p21Cip1/Waf1/Sdi1 and cyclin D1, DNA strand breaks, the disruption of cell membrane asymmetry/integrity and ultrastructural alterations. Vimentin and G-actin cytoskeleton was evaluated both cytometrically and microscopically. Results and conclusions Etoposide induced a senescence-like phenotype in the population of A549 cells. Morphological alterations were nevertheless not directly coupled with other senescence markers including a stable cell cycle arrest, SAHF formation or p21Cip1/Waf1/Sdi1 induction. Instead, a polyploid, TUNEL-positive fraction of cells visibly grew in number. Also upregulation of cyclin D1 was observed. Here we present preliminary evidence, based on microscopic analyses, that suggest a possible role of vimentin in nuclear alterations accompanying polyploidization-depolyploidization events following genotoxic insults. PMID:23383739

  9. Possible involvement of type 1 inositol 1,4,5-trisphosphate receptors up-regulated by dopamine D1 and D2 receptors in mouse nucleus accumbens neurons in the development of methamphetamine-induced place preference.

    PubMed

    Kurokawa, K; Mizuno, K; Ohkuma, S

    2012-12-27

    Little is known about regulatory mechanisms of type 1 inositol-1,4,5-triphosphate receptor (IP(3)R-1) expression in conditioned place preference by methamphetamine (METH), though significant enhancement of IP(3)R-1 expression in the mouse frontal cortex and limbic forebrain by intermittent administration of cocaine is reported. The present study investigated the role and regulation of IP(3)R-1 in mice with METH-induced place preference. Injection of IP(3)R antagonists with different chemical structures, 2-aminophenoxyethane-borate and xestospongin C, into the mouse nucleus accumbens (NAcc) dose-dependently inhibited METH-induced place preference. The levels of IP(3)R-1 protein in the NAcc of METH-conditioned mice significantly increased, which was completely abolished by microinjection of SCH23390 and raclopride, selective dopamine D1-like and D2-like receptor (D1 and D2DR) antagonists respectively, into the mouse NAcc. Immunohistochemical assessment revealed co-localization of immunoreactivity for IP(3)R-1 and those for D1 and D2DRs in the NAcc. These findings suggest that IP(3)R-1 could be involved in the development of METH-induced place preference and that D1 and D2DRs in the NAcc of mice showing METH-induced place preference play possible regulatory roles in IP(3)R-1 expression.

  10. Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels.

    PubMed

    Portelli, Michael A; Siedlinski, Mateusz; Stewart, Ceri E; Postma, Dirkje S; Nieuwenhuis, Maartje A; Vonk, Judith M; Nurnberg, Peter; Altmuller, Janine; Moffatt, Miriam F; Wardlaw, Andrew J; Parker, Stuart G; Connolly, Martin J; Koppelman, Gerard H; Sayers, Ian

    2014-02-01

    The soluble cleaved urokinase plasminogen activator receptor (scuPAR) is a circulating protein detected in multiple diseases, including various cancers, cardiovascular disease, and kidney disease, where elevated levels of scuPAR have been associated with worsening prognosis and increased disease aggressiveness. We aimed to identify novel genetic and biomolecular mechanisms regulating scuPAR levels. Elevated serum scuPAR levels were identified in asthma (n=514) and chronic obstructive pulmonary disease (COPD; n=219) cohorts when compared to controls (n=96). In these cohorts, a genome-wide association study of serum scuPAR levels identified a human plasma kallikrein gene (KLKB1) promoter polymorphism (rs4253238) associated with serum scuPAR levels in a control/asthma population (P=1.17 × 10(-7)), which was also observed in a COPD population (combined P=5.04 × 10(-12)). Using a fluorescent assay, we demonstrated that serum KLKB1 enzymatic activity was driven by rs4253238 and is inverse to scuPAR levels. Biochemical analysis identified that KLKB1 cleaves scuPAR and negates scuPAR's effects on primary human bronchial epithelial cells (HBECs) in vitro. Chymotrypsin was used as a proproteolytic control, while basal HBECs were used as a control to define scuPAR-driven effects. In summary, we reveal a novel post-translational regulatory mechanism for scuPAR using a hypothesis-free approach with implications for multiple human diseases.

  11. Tissue kallikrein induces SH-SY5Y cell proliferation via epidermal growth factor receptor and extracellular signal-regulated kinase1/2 pathway

    SciTech Connect

    Lu, Zhengyu; Yang, Qi; Cui, Mei; Liu, Yanping; Wang, Tao; Zhao, Hong; Dong, Qiang

    2014-03-28

    Highlights: • TK promotes EGFR phosphorylation in SH-SY5Y cells. • TK activates ERK1/2 and p38 phosphorylation in SH-SY5Y cells. • TK mediates SH-SY5Y cell proliferation via EGFR and ERK1/2 pathway. - Abstract: Tissue kallikrein (TK) is well known to take most of its biological functions through bradykinin receptors. In the present study, we found a novel signaling pathway mediated by TK through epidermal growth factor receptor (EGFR) in human SH-SY5Y cells. We discovered that TK facilitated the activation of EGFR, extracellular signal-regulated kinase (ERK) 1/2 and p38 cascade. Interestingly, not p38 but ERK1/2 phosphorylation was severely compromised in cells depleted of EGFR. Nevertheless, impairment of signaling of ERK1/2 seemed not to be restricted to EGFR phosphorylation. We also observed that TK stimulation could induce SH-SY5Y cell proliferation, which was reduced by EGFR down-regulation or ERK1/2 inhibitor. Overall, our findings provided convincing evidence that TK could mediate cell proliferation via EGFR and ERK1/2 pathway in vitro.

  12. Non-combinatorial library screening reveals subsite cooperativity and identifies new high-efficiency substrates for kallikrein-related peptidase 14.

    PubMed

    de Veer, Simon J; Swedberg, Joakim E; Parker, Edward A; Harris, Jonathan M

    2012-04-01

    An array of substrates link the tryptic serine protease, kallikrein-related peptidase 14 (KLK14), to physiological functions including desquamation and activation of signaling molecules associated with inflammation and cancer. Recognition of protease cleavage sequences is driven by complementarity between exposed substrate motifs and the physicochemical signature of an enzyme's active site cleft. However, conventional substrate screening methods have generated conflicting subsite profiles for KLK14. This study utilizes a recently developed screening technique, the sparse matrix library, to identify five novel high-efficiency sequences for KLK14. The optimal sequence, YASR, was cleaved with higher efficiency (k(cat)/K(m)=3.81 ± 0.4 × 10(6) M(-1) s(-1)) than favored substrates from positional scanning and phage display by 2- and 10-fold, respectively. Binding site cooperativity was prominent among preferred sequences, which enabled optimal interaction at all subsites as indicated by predictive modeling of KLK14/substrate complexes. These simulations constitute the first molecular dynamics analysis of KLK14 and offer a structural rationale for the divergent subsite preferences evident between KLK14 and closely related KLKs, KLK4 and KLK5. Collectively, these findings highlight the importance of binding site cooperativity in protease substrate recognition, which has implications for discovery of optimal substrates and engineering highly effective protease inhibitors.

  13. Spatio-temporal expression of MMP-2, MMP-9 and tissue kallikrein in uteroplacental units of the pregnant guinea-pig (Cavia porcellus)

    PubMed Central

    Corthorn, Jenny; Rey, Sergio; Chacón, Cecilia; Valdés, Gloria

    2007-01-01

    Background In humans trophoblast invasion and vascular remodeling are critical to determine the fate of pregnancy. Since guinea-pigs share with women an extensive migration of the trophoblasts through the decidua and uterine arteries, and a haemomonochorial placenta, this species was used to evaluate the spatio-temporal expression of three enzymes that have been associated to trophoblast invasion, MMP-2, MMP-9 and tissue kallikrein (K1). Methods Uteroplacental units were collected from early to term pregnancy. MMP-2, MMP-9 and K1 were analysed by immunohistochemistry and Western blot. The activities of MMP-2 and MMP-9 were assessed by gelatin zymography. Results Immunoreactive MMP-2, MMP-9 and K1 were detected in the subplacenta, interlobar and labyrinthine placenta, syncytial sprouts and syncytial streamers throughout pregnancy. In late pregnancy, perivascular or intramural trophoblasts expressed the three enzymes. The intensity of the signal in syncytial streamers was increased in mid and late pregnancy for MMP-2, decreased in late pregnancy for MMP-9, and remained stable for K1. Western blots of placental homogenates at days 20, 40 and 60 of pregnancy identified bands with the molecular weights of MMP-2, MMP-9 and K1. MMP-2 expression remained constant throughout gestation. In contrast, MMP-9 and K1 attained their highest expression during midgestation. Placental homogenates of 20, 40 and 60 days yielded bands of gelatinase activity that were compatible with MMP-2 and MMP-9 activities. ProMMP-2 and MMP-9 activities did not vary along pregnancy, while MMP-2 and MMP-9 increased at 40 and 40–60 days respectively. Conclusion The spatio-temporal expression of MMPs and K1 supports a relevant role of these proteins in trophoblast invasion, vascular remodeling and placental angiogenesis, and suggests a functional association between K1 and MMP-9 activation. PMID:17605824

  14. A novel signaling pathway of tissue kallikrein in promoting keratinocyte migration: Activation of proteinase-activated receptor 1 and epidermal growth factor receptor

    SciTech Connect

    Gao, Lin; Chao, Lee; Chao, Julie

    2010-02-01

    Biological functions of tissue kallikrein (TK, KLK1) are mainly mediated by kinin generation and subsequent kinin B2 receptor activation. In this study, we investigated the potential role of TK and its signaling pathways in cultured human keratinocyte migration and in a rat skin wound healing model. Herein, we show that TK promoted cell migration and proliferation in a concentration- and time-dependent manner. Inactive TK or kinin had no significant effect on cell migration. Interestingly, cell migration induced by active TK was not blocked by icatibant or L-NAME, indicating an event independent of kinin B2 receptor and nitric oxide formation. TK's stimulatory effect on cell migration was inhibited by small interfering RNA for proteinase-activated receptor 1 (PAR{sub 1}), and by PAR{sub 1} inhibitor. TK-induced migration was associated with increased phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK), which was blocked by inhibition of protein kinase C (PKC), Src, EGFR and ERK. TK-induced cell migration and EGFR phosphorylation were blocked by metalloproteinase (MMP) inhibitor, heparin, and antibodies against EGFR external domain, heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin (AR). Local application of TK promoted skin wound healing in rats, whereas icatibant and EGFR inhibitor blocked TK's effect. Skin wound healing was further delayed by aprotinin and neutralizing TK antibody. This study demonstrates a novel role of TK in skin wound healing and uncovers new signaling pathways mediated by TK in promoting keratinocyte migration through activation of the PAR{sub 1}-PKC-Src-MMP pathway and HB-EGF/AR shedding-dependent EGFR transactivation.

  15. On Involvement.

    ERIC Educational Resources Information Center

    Greene, Michael B.

    Involvement Ratings In Settings (IRIS), a multi-dimensional non-verbal scale of involvement adaptable to a time-sampling method of data collection, was constructed with the aid of the videotapes of second-grade Follow Through classrooms made by CCEP. Scales were defined through observations of involved and alienated behavior, and the IRIS was…

  16. Induction of GST-P-positive proliferative lesions facilitating lipid peroxidation with possible involvement of transferrin receptor up-regulation and ceruloplasmin down-regulation from the early stage of liver tumor promotion in rats.

    PubMed

    Mizukami, Sayaka; Ichimura, Ryohei; Kemmochi, Sayaka; Taniai, Eriko; Shimamoto, Keisuke; Ohishi, Takumi; Takahashi, Miwa; Mitsumori, Kunitoshi; Shibutani, Makoto

    2010-04-01

    To elucidate the role of metal-related molecules in hepatocarcinogenesis, we examined immunolocalization of transferrin receptor (Tfrc), ceruloplasmin (Cp) and metallothionein (MT)-1/2 in relation to liver cell foci positive for glutathione-S-transferase placental form (GST-P) in the early stage of tumor promotion by fenbendazole (FB), phenobarbital, piperonyl butoxide or thioacetamide in a rat two-stage hepatocarcinogenesis model. To estimate the involvement of oxidative stress responses to the promotion, immunolocalization of 4-hydroxy-2-nonenal, malondialdehyde and acrolein was similarly examined. Our findings showed that MT-1/2 immunoreactivity was not associated with the cellular distribution of GST-P and proliferating cell nuclear antigen, suggesting no role of MT-1/2 in hepatocarcinogenesis. We also found enhanced expression of Tfrc after treatment with strong tumor-promoting chemicals. With regard to Cp, the population showing down-regulation was increased in the GST-P-positive foci in relation to tumor promotion. Up-regulation of Tfrc and down-regulation of Cp was maintained in GST-P-positive neoplastic lesions induced after long-term promotion with FB, suggesting the expression changes occurring downstream of the signaling pathway involved in the formation of GST-P-positive lesions. Furthermore, enhanced accumulation of lipid peroxidation end products was observed in the GST-P-positive foci by promotion. Post-initiation treatment with peroxisome proliferator-activated receptor alpha agonists did not enhance any such distribution changes in GST-P-negative foci. The results thus suggest that facilitation of lipid peroxidation is involved in the induction of GST-P-positive lesions by tumor promotion from an early stage, and up-regulation of Tfrc and down-regulation of Cp may be a signature of enhanced oxidative cellular stress in these lesions.

  17. Possible involvement of membrane lipids peroxidation and oxidation of catalytically essential thiols of the cerebral transmembrane sodium pump as component mechanisms of iron-mediated oxidative stress-linked dysfunction of the pump's activity.

    PubMed

    Omotayo, T I; Akinyemi, G S; Omololu, P A; Ajayi, B O; Akindahunsi, A A; Rocha, J B T; Kade, I J

    2015-01-01

    The precise molecular events defining the complex role of oxidative stress in the inactivation of the cerebral sodium pump in radical-induced neurodegenerative diseases is yet to be fully clarified and thus still open. Herein we investigated the modulation of the activity of the cerebral transmembrane electrogenic enzyme in Fe(2+)-mediated in vitro oxidative stress model. The results show that Fe(2+) inhibited the transmembrane enzyme in a concentration dependent manner and this effect was accompanied by a biphasic generation of aldehydic product of lipid peroxidation. While dithiothreitol prevented both Fe(2+) inhibitory effect on the pump and lipid peroxidation, vitamin E prevented only lipid peroxidation but not inhibition of the pump. Besides, malondialdehyde (MDA) inhibited the pump by a mechanism not related to oxidation of its critical thiols. Apparently, the low activity of the pump in degenerative diseases mediated by Fe(2+) may involve complex multi-component mechanisms which may partly involve an initial oxidation of the critical thiols of the enzyme directly mediated by Fe(2+) and during severe progression of such diseases; aldehydic products of lipid peroxidation such as MDA may further exacerbate this inhibitory effect by a mechanism that is likely not related to the oxidation of the catalytically essential thiols of the ouabain-sensitive cerebral electrogenic pump.

  18. Stochastic and nonstochastic post-transcriptional silencing of chitinase and beta-1,3-glucanase genes involves increased RNA turnover-possible role for ribosome-independent RNA degradation.

    PubMed Central

    Holtorf, H; Schöb, H; Kunz, C; Waldvogel, R; Meins, F

    1999-01-01

    Stochastic and nonstochastic post-transcriptional gene silencing (PTGS) in Nicotiana sylvestris plants carrying tobacco class I chitinase (CHN) and beta-1,3-glucanase transgenes differs in incidence, stability, and pattern of expression. Measurements with inhibitors of RNA synthesis (cordycepin, actinomycin D, and alpha-amanitin) showed that both forms of PTGS are associated with increased sequence-specific degradation of transcripts, suggesting that increased RNA turnover may be a general feature of PTGS. The protein synthesis inhibitors cycloheximide and verrucarin A did not inhibit degradation of CHN RNA targeted for PTGS, confirming that PTGS-related RNA degradation does not depend on ongoing protein synthesis. Because verrucarin A, unlike cycloheximide, dissociates mRNA from ribosomes, our results also suggest that ribosome-associated RNA degradation pathways may not be involved in CHN PTGS. PMID:10072405

  19. Δ(9)-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells.

    PubMed

    Takeda, Shuso; Ikeda, Eriko; Su, Shengzhong; Harada, Mari; Okazaki, Hiroyuki; Yoshioka, Yasushi; Nishimura, Hajime; Ishii, Hiroyuki; Kakizoe, Kazuhiro; Taniguchi, Aya; Tokuyasu, Miki; Himeno, Taichi; Watanabe, Kazuhito; Omiecinski, Curtis J; Aramaki, Hironori

    2014-12-04

    We recently reported that Δ(9)-tetrahydrocannabinol (Δ(9)-THC), a major cannabinoid component in Cannabis Sativa (marijuana), significantly stimulated the expression of fatty acid 2-hydroxylase (FA2H) in human breast cancer MDA-MB-231 cells. Peroxisome proliferator-activated receptor α (PPARα) was previously implicated in this induction. However, the mechanisms mediating this induction have not been elucidated in detail. We performed a DNA microarray analysis of Δ(9)-THC-treated samples and showed the selective up-regulation of the PPARα isoform coupled with the induction of FA2H over the other isoforms (β and γ). Δ(9)-THC itself had no binding/activation potential to/on PPARα, and palmitic acid (PA), a PPARα ligand, exhibited no stimulatory effects on FA2H in MDA-MB-231 cells; thus, we hypothesized that the levels of PPARα induced were involved in the Δ(9)-THC-mediated increase in FA2H. In support of this hypothesis, we herein demonstrated that; (i) Δ(9)-THC activated the basal transcriptional activity of PPARα in a concentration-dependent manner, (ii) the concomitant up-regulation of PPARα/FA2H was caused by Δ(9)-THC, (iii) PA could activate PPARα after the PPARα expression plasmid was introduced, and (iv) the Δ(9)-THC-induced up-regulation of FA2H was further stimulated by the co-treatment with L-663,536 (a known PPARα inducer). Taken together, these results support the concept that the induced levels of PPARα may be involved in the Δ(9)-THC up-regulation of FA2H in MDA-MB-231 cells.

  20. Involvement of outer membrane protein TolC, a possible member of the mar-sox regulon, in maintenance and improvement of organic solvent tolerance of Escherichia coli K-12.

    PubMed

    Aono, R; Tsukagoshi, N; Yamamoto, M

    1998-02-01

    Escherichia coli mutants with improved organic solvent tolerance levels showed high levels of outer membrane protein TolC and inner membrane protein AcrA. The TolC level was regulated positively by MarA, Rob, or SoxS. A possible mar-rob-sox box sequence was found upstream of the tolC gene. These findings suggest that tolC is a member of the mar-sox regulon responsive to stress conditions. When a defective tolC gene was transferred to n-hexane- or cyclohexane-tolerant strains by P1 transduction, the organic solvent tolerance level was lowered dramatically to the decane-tolerant and nonane-sensitive level. The tolerance level was restored by transformation of the transductants with a wild-type tolC gene. Therefore, it is evident that TolC is essential for E. coli to maintain organic solvent tolerance.

  1. Family Involvement.

    ERIC Educational Resources Information Center

    Liontos, Lynn Balster

    1992-01-01

    Family involvement in schools will work only when perceived as an enlarged concept focusing on all children, including those from at-risk families. Each publication reviewed here is specifically concerned with family involvement strategies concerned with all children or targeted at primarily high risk students. Susan McAllister Swap looks at three…

  2. Acylated and unacylated ghrelin protect MC3T3-E1 cells against tert-butyl hydroperoxide-induced oxidative injury: pharmacological characterization of ghrelin receptor and possible epigenetic involvement.

    PubMed

    Dieci, Elisa; Casati, Lavinia; Pagani, Francesca; Celotti, Fabio; Sibilia, Valeria

    2014-07-01

    Increasing evidence suggests a role for oxidative stress in age-related decrease in osteoblast number and function leading to the development of osteoporosis. This study was undertaken to investigate whether ghrelin, previously reported to stimulate osteoblast proliferation, counteracts tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in MC3T3-E1 osteoblastic cells as well as to characterize the ghrelin receptor (GHS-R) involved in such activity. Pretreatment with ghrelin (10(-7)-10(-11)M) significantly increased viability and reduced apoptosis of MC3T3-E1 cells cultured with t-BHP (250 μM) for three hours at the low concentration of 10(-9)M as shown by MTT assay and Hoechst-33258 staining. Furthermore, ghrelin prevented t-BHP-induced osteoblastic dysfunction and changes in the cytoskeleton organization evidenced by the staining of the actin fibers with Phalloidin-FITC by reducing reactive oxygen species generation. The GHS-R type 1a agonist, EP1572 (10(-7)-10(-11)M), had no effect against t-BHP-induced cytotoxicity and pretreatment with the selective GHS-R1a antagonist, D-Lys(3)-GHRP-6 (10(-7)M), failed to remove ghrelin (10(-9) M)-protective effects against oxidative injury, indicating that GHS-R1a is not involved in such ghrelin activity. Accordingly, unacylated ghrelin (DAG), not binding GHS-R1a, displays the same protective actions of ghrelin against t-BHP-induced cytotoxicity. Preliminary observations indicate that ghrelin increased the trimethylation of lys4 on histones H3, a known epigenetic mark activator, which may regulate the expression of some genes limiting oxidative damage. In conclusion, our data demonstrate that ghrelin and DAG promote survival of MC3T3-E1 cell exposed to t-BHP-induced oxidative damage. Such effect is independent of GHS-R1a and is likely mediated by a common ghrelin/DAG binding site.

  3. Analysis of the surface proteins of Acidithiobacillus ferrooxidans strain SP5/1 and the new, pyrite-oxidizing Acidithiobacillus isolate HV2/2, and their possible involvement in pyrite oxidation.

    PubMed

    Klingl, Andreas; Moissl-Eichinger, Christine; Wanner, Gerhard; Zweck, Josef; Huber, Harald; Thomm, Michael; Rachel, Reinhard

    2011-12-01

    Two strains of rod-shaped, pyrite-oxidizing acidithiobacilli, their cell envelope structure and their interaction with pyrite were investigated in this study. Cells of both strains, Acidithiobacillus ferrooxidans strain SP5/1 and the moderately thermophilic Acidithiobacillus sp. strain HV2/2, were similar in size, with slight variations in length and diameter. Two kinds of cell appendages were observed: flagella and pili. Besides a typical Gram-negative cell architecture with inner and outer membrane, enclosing a periplasm, both strains were covered by a hitherto undescribed, regularly arranged 2-D protein crystal with p2-symmetry. In A. ferrooxidans, this protein forms a stripe-like structure on the surface. A similar surface pattern with almost identical lattice vectors was also seen on the cells of strain HV2/2. For the surface layer of both bacteria, a direct contact to pyrite crystals was observed in ultrathin sections, indicating that the S-layer is involved in maintaining this contact site. Observations on an S-layer-deficient strain show, however, that cell adhesion does not strictly depend on the presence of the S-layer and that this surface protein has an influence on cell shape. Furthermore, the presented data suggest the ability of the S-layer protein to complex Fe3+ ions, suggesting a role in the physiology of the microorganisms.

  4. Involvement of serotoninergic 5-HT1A/2A, alpha-adrenergic and dopaminergic D1 receptors in St. John's wort-induced prepulse inhibition deficit: a possible role of hyperforin.

    PubMed

    Tadros, Mariane G; Mohamed, Mohamed R; Youssef, Amal M; Sabry, Gilane M; Sabry, Nagwa A; Khalifa, Amani E

    2009-05-16

    Prepulse inhibition (PPI) of acoustic startle response is a valuable paradigm for sensorimotor gating processes. Previous research showed that acute administration of St. John's wort extract (500 mg/kg, p.o.) to rats caused significant disruption of PPI while elevating monoamines levels in some brain areas. The cause-effect relationship between extract-induced PPI disruption and augmented monoaminergic transmission was studied using different serotoninergic, adrenergic and dopaminergic antagonists. The effects of hypericin and hyperforin, as the main active constituents of the extract, on PPI response were also tested. PPI disruption was prevented after blocking the serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors. Results also demonstrated a significant PPI deficit after acute treatment of rats with hyperforin, and not hypericin. In some conditions manifesting disrupted PPI response, apoptosis coexists. Electrophoresis of DNA isolated from brains of hyperforin-treated animals revealed absence of any abnormal DNA fragmentation patterns. It is concluded that serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors are involved in the disruptive effect of St. John's wort extract on PPI response in rats. We can also conclude that hyperforin, and not hypericin, is one of the active ingredients responsible for St. John's wort-induced PPI disruption with no relation to apoptotic processes.

  5. Colitis elicits differential changes in the expression levels of receptor tyrosine kinase TrkA and TrkB in colonic afferent neurons: A possible involvement of axonal transport

    PubMed Central

    Qiao, Li-Ya; Grider, John R

    2010-01-01

    The role of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in colitis-induced hypersensitivity has been suggested. NGF and BDNF facilitate cellular physiology through binding to receptor tyrosine kinase TrkA and TrkB respectively. The present study by examining the mRNA and/or protein levels of TrkA and TrkB in the distal colon and in colonic primary afferent neurons in the dorsal root ganglia (DRG) during colitis demonstrated that colitis elicited location-specific changes in the mRNA and protein levels of TrkA and TrkB in colonic primary sensory pathways. In colitis both the TrkA and TrkB protein levels were increased in the L1 and S1 DRGs in a time-dependent manner; however, the level of TrkB mRNA but not TrkA mRNA was increased in these DRGs. Further experiments showed that colitis facilitated a retrograde transport of TrkA protein toward and an anterograde transport of TrkA mRNA away from the DRG, which may contribute to the increased TrkA mRNA level in the distal colon during colitis. Colitis also increased the level of NGF mRNA but not BDNF mRNA in the distal colon. Double staining showed that the expression of TrkA but not TrkB was increased in the specifically labeled colonic afferent neurons in the L1 and S1 DRGs during colitis; this increase in TrkA level was attenuated by pretreatment with resiniferatoxin. These results suggested that colitis-induced primary afferent activation involved retrograde transport of TrkA but not TrkB from the distal colon to primary afferent neurons in DRG. PMID:20638179

  6. Organization of a Clostridium thermocellum gene cluster encoding the cellulosomal scaffolding protein CipA and a protein possibly involved in attachment of the cellulosome to the cell surface.

    PubMed Central

    Fujino, T; Béguin, P; Aubert, J P

    1993-01-01

    The nucleotide sequence was determined for a 9.4-kb region of Clostridium thermocellum DNA extending from the 3' end of the gene (now termed cipA), encoding the S1/SL component of the cellulosome. Three open reading frames (ORFs) belonging to two operons were detected. They encoded polypeptides of 1,664, 688, and 447 residues, termed ORF1p, ORF2p, and ORF3p, respectively. The COOH-terminal regions of the three polypeptides were highly similar and contained three reiterated segments of 60 to 70 residues each. Similar segments have been found at the NH2 terminus of the S-layer proteins of Bacillus brevis and Acetogenium kivui, suggesting that ORF1p, ORF2p, and ORF3p might also be located on the cell surface. Otherwise, the sequence of ORF1p and ORF2p gave little clue concerning their potential function. However, the NH2-terminal region of ORF3p was similar to the reiterated domains previously identified in CipA as receptors involved in binding the duplicated segment of 22 amino acids present in catalytic subunits of the cellulosome. Indeed, it was found previously that ORF3p binds 125I-labeled endoglucanase CelD containing the duplicated segment (T. Fujino, P. Béguin, and J.-P. Aubert, FEMS Microbiol. Lett. 94:165-170, 1992). These findings suggest that ORF3p might serve as an anchoring factor for the cellulosome on the cell surface by binding the duplicated segment that is present at the COOH end of CipA. Images PMID:8458832

  7. Impairments in brain-derived neurotrophic factor-induced glutamate release in cultured cortical neurons derived from rats with intrauterine growth retardation: possible involvement of suppression of TrkB/phospholipase C-γ activation.

    PubMed

    Numakawa, Tadahiro; Matsumoto, Tomoya; Ooshima, Yoshiko; Chiba, Shuichi; Furuta, Miyako; Izumi, Aiko; Ninomiya-Baba, Midori; Odaka, Haruki; Hashido, Kazuo; Adachi, Naoki; Kunugi, Hiroshi

    2014-04-01

    Low birth weight due to intrauterine growth retardation (IUGR) is suggested to be a risk factor for various psychiatric disorders such as schizophrenia. It has been reported that developmental cortical dysfunction and neurocognitive deficits are observed in individuals with IUGR, however, the underlying molecular mechanisms have yet to be elucidated. Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are associated with schizophrenia and play a role in cortical development. We previously demonstrated that BDNF induced glutamate release through activation of the TrkB/phospholipase C-γ (PLC-γ) pathway in developing cultured cortical neurons, and that, using a rat model for IUGR caused by maternal administration of thromboxane A2, cortical levels of TrkB were significantly reduced in IUGR rats at birth. These studies prompted us to hypothesize that TrkB reduction in IUGR cortex led to impairment of BDNF-dependent glutamatergic neurotransmission. In the present study, we found that BDNF-induced glutamate release was strongly impaired in cultured IUGR cortical neurons where TrkB reduction was maintained. Impairment of BDNF-induced glutamate release in IUGR neurons was ameliorated by transfection of human TrkB (hTrkB). Although BDNF-stimulated phosphorylation of TrkB and of PLC-γ was decreased in IUGR neurons, the hTrkB transfection recovered the deficits in their phosphorylation. These results suggest that TrkB reduction causes impairment of BDNF-stimulated glutamatergic function via suppression of TrkB/PLC-γ activation in IUGR cortical neurons. Our findings provide molecular insights into how IUGR links to downregulation of BDNF function in the cortex, which might be involved in the development of IUGR-related diseases such as schizophrenia.

  8. A possible involvement of Nrf2-mediated heme oxygenase-1 up-regulation in protective effect of the proton pump inhibitor pantoprazole against indomethacin-induced gastric damage in rats

    PubMed Central

    2012-01-01

    Background Proton pump is an integral membrane protein that is ubiquitous ATP binding cassette (ABC) involved in many transport processes in all living organisms, among which a specialized form of pump, so called p-type proton pump, exists in the parietal cells of stomach. Though proton pump inhibitors (PPIs) are frequently prescribed to prevent nonsteroidal anti-inflammatory drugs (NSAIDs)-induced gastric damage, the acid suppressive actions do not suffice to explain. Methods In order to document the effects of pantoprazole, one of PPIs, on the NSAIDs-induced gastric damage, in vitro and in vivo studies were performed. Immunocytochemistry, Western blot analysis, electrophoretic mobility shift assay and RT-PCR were conducted to evaluate the induction of heme oxygenase-1 (HO-1) through Nrf2 activation in normal gastric mucosal RGM-1 cells or in vivo stomach tissues from rats treated with indomethacin and/or pantoprazole. Results Pantoprazole activated Nrf2 through inactivation of Keap1, after which the expression of HO-1 was significantly increased in a dose-dependent manner in RGM-1 cells. Increased ARE-DNA binding activity was observed maximally at 1 h with 300 μM of pantoprazole. The expression of HO-1 induced by pantoprazole was significantly associated with the increased in vitro tube formation (P < 0.05) and angiogenic factors including VEGF, bFGF, and HIF-1α. Indomethacin markedly increased the expressions of TNF-α, IL-1ß, IL-8, NOX-1, ICAM-1 and VCAM, whereas pantoprazole significantly decreased the expressions of indomethacin-induced these inflammatory mediators in accord with pantoprazole-induced HO-1 (P < 0.05) as documented with HO-1 inhibitor. In vivo model of indomethacin-induced gastric damage could validate in vitro-drawn results that pantoprazole remarkably protected against indomethacin-induced gastric damage, in which zinc protoporphyrin (5 mg/kg, ip) significantly abolished the protective efficacy of pantoprazole. Conclusion These results

  9. Conversion of 5(10)-oestrene-3 beta,17 beta-diol to 19-nor-4-ene-3-ketosteroids by luteal cells in vitro: possible involvement of the 3 beta-hydroxysteroid dehydrogenase/isomerase.

    PubMed

    Lee, C M; Tekpetey, F R; Armstrong, D T; Khalil, M W

    1991-05-01

    We have previously suggested that in porcine granulosa cells, a putative intermediate, 5(10)-oestrene-3,17-dione is involved in 4-oestrene-3,17-dione (19-norandrostenedione; 19-norA) and 4-oestren-17 beta-ol-3-one (19-nortestosterone: 19-norT) formation from C19 aromatizable androgens. In this study, luteal cells prepared from porcine, bovine and rat corpora lutea by centrifugal elutriation were used as a source of 3 beta-hydroxysteroid dehydrogenase/isomerase in order to investigate the role of this enzyme in the biosynthesis of 19-norsteroids. Small porcine luteal cells made mainly 19-norT and large porcine luteal cells 19-norA from 5(10)-oestrene-3 beta,17 beta-diol, the reduced product of the putative intermediate 5(10)-oestrene-3,17-dione. However, neither small nor large cells metabolized androstenedione to 19-norsteroids. Serum and serum plus LH significantly stimulated formation of both 19-norA and 19-norT from 5(10)-oestrene-3 beta,17 beta-diol, compared with controls. Inhibitors of the 3 beta-hydroxysteroid dehydrogenase/isomerase (trilostane and cyanoketone) significantly reduced formation of 19-norT in small porcine luteal cells and 19-norA in large porcine luteal cells, although they were effective at different concentrations in each cell type. In parallel incubations, formation of [4-14C]androstenedione from added [4-14C]dehydroepiandrosterone was also inhibited by cyanoketone in both small and large porcine luteal cells in a dose-dependent manner; however, trilostane (up to 100 mumol/l) did not inhibit androstenedione formation in large porcine luteal cells. In addition, the decrease in progesterone synthesis induced by trilostane and cyanoketone (100 mumol/l each) was accompanied by a parallel accumulation of pregnenolone in both cell types. These results suggest that 3 beta-hydroxysteroid dehydrogenase/isomerase, or a closely related enzyme, present in small and large porcine luteal cells can convert added 5(10)-3 beta-hydroxysteroids into 19-nor-4

  10. Spindle function in Xenopus oocytes involves possible nanodomain calcium signaling

    PubMed Central

    Li, Ruizhen; Leblanc, Julie; He, Kevin; Liu, X. Johné

    2016-01-01

    Intracellular calcium transients are a universal phenomenon at fertilization and are required for egg activation, but the exact role of Ca2+ in second-polar-body emission remains unknown. On the other hand, similar calcium transients have not been demonstrated during oocyte maturation, and yet, manipulating intracellular calcium levels interferes with first-polar-body emission in mice and frogs. To determine the precise role of calcium signaling in polar body formation, we used live-cell imaging coupled with temporally precise intracellular calcium buffering. We found that BAPTA-based calcium chelators cause immediate depolymerization of spindle microtubules in meiosis I and meiosis II. Surprisingly, EGTA at similar or higher intracellular concentrations had no effect on spindle function or polar body emission. Using two calcium probes containing permutated GFP and the calcium sensor calmodulin (Lck-GCaMP3 and GCaMP3), we demonstrated enrichment of the probes at the spindle but failed to detect calcium increase during oocyte maturation at the spindle or elsewhere. Finally, endogenous calmodulin was found to colocalize with spindle microtubules throughout all stages of meiosis. Our results—most important, the different sensitivities of the spindle to BAPTA and EGTA—suggest that meiotic spindle function in frog oocytes requires highly localized, or nanodomain, calcium signaling. PMID:27582389

  11. Space sickness predictors suggest fluid shift involvement and possible countermeasures

    NASA Technical Reports Server (NTRS)

    Simanonok, K. E.; Moseley, E. C.; Charles, J. B.

    1992-01-01

    Preflight data from 64 first time Shuttle crew members were examined retrospectively to predict space sickness severity (NONE, MILD, MODERATE, or SEVERE) by discriminant analysis. From 9 input variables relating to fluid, electrolyte, and cardiovascular status, 8 variables were chosen by discriminant analysis that correctly predicted space sickness severity with 59 pct. success by one method of cross validation on the original sample and 67 pct. by another method. The 8 variables in order of their importance for predicting space sickness severity are sitting systolic blood pressure, serum uric acid, calculated blood volume, serum phosphate, urine osmolality, environmental temperature at the launch site, red cell count, and serum chloride. These results suggest the presence of predisposing physiologic factors to space sickness that implicate a fluid shift etiology. Addition of a 10th input variable, hours spent in the Weightless Environment Training Facility (WETF), improved the prediction of space sickness severity to 66 pct. success by the first method of cross validation on the original sample and to 71 pct. by the second method. The data suggest that WETF training may reduce space sickness severity.

  12. On probability-possibility transformations

    NASA Technical Reports Server (NTRS)

    Klir, George J.; Parviz, Behzad

    1992-01-01

    Several probability-possibility transformations are compared in terms of the closeness of preserving second-order properties. The comparison is based on experimental results obtained by computer simulation. Two second-order properties are involved in this study: noninteraction of two distributions and projections of a joint distribution.

  13. Skin Barrier Function Is Not Impaired and Kallikrein 7 Gene Polymorphism Is Frequently Observed in Korean X-linked Ichthyosis Patients Diagnosed by Fluorescence in Situ Hybridization and Array Comparative Genomic Hybridization.

    PubMed

    Lee, Noo Ri; Yoon, Na Young; Jung, Minyoung; Kim, Ji-Yun; Seo, Seong Jun; Wang, Hye-Young; Lee, Hyeyoung; Sohn, Young Bae; Choi, Eung Ho

    2016-08-01

    X-linked ichthyosis (XLI) is a recessively inherited ichthyosis. Skin barrier function of XLI patients reported in Western countries presented minimally abnormal or normal. Here, we evaluated the skin barrier properties and a skin barrier-related gene mutation in 16 Korean XLI patients who were diagnosed by fluorescence in situ hybridization and array comparative genomic hybridization analysis. Skin barrier properties were measured, cytokine expression levels in the stratum corneum (SC) were evaluated with the tape stripped specimen from skin surface, and a genetic test was done on blood. XLI patients showed significantly lower SC hydration, but normal basal trans-epidermal water loss and skin surface pH as compared to a healthy control group. Histopathology of ichthyosis epidermis showed no acanthosis, and levels of the pro-inflammatory cytokines in the corneal layer did not differ between control and lesional/non-lesional skin of XLI patients. Among the mutations in filaggrin (FLG), kallikrein 7 (KLK7), and SPINK5 genes, the prevalence of KLK7 gene mutations was significantly higher in XLI patients (50%) than in controls (0%), whereas FLG and SPINK5 prevalence was comparable. Korean XLI patients exhibited unimpaired skin barrier function and frequent association with the KLK7 gene polymorphism, which may differentiate them from Western XLI patients.

  14. Skin Barrier Function Is Not Impaired and Kallikrein 7 Gene Polymorphism Is Frequently Observed in Korean X-linked Ichthyosis Patients Diagnosed by Fluorescence in Situ Hybridization and Array Comparative Genomic Hybridization

    PubMed Central

    2016-01-01

    X-linked ichthyosis (XLI) is a recessively inherited ichthyosis. Skin barrier function of XLI patients reported in Western countries presented minimally abnormal or normal. Here, we evaluated the skin barrier properties and a skin barrier-related gene mutation in 16 Korean XLI patients who were diagnosed by fluorescence in situ hybridization and array comparative genomic hybridization analysis. Skin barrier properties were measured, cytokine expression levels in the stratum corneum (SC) were evaluated with the tape stripped specimen from skin surface, and a genetic test was done on blood. XLI patients showed significantly lower SC hydration, but normal basal trans-epidermal water loss and skin surface pH as compared to a healthy control group. Histopathology of ichthyosis epidermis showed no acanthosis, and levels of the pro-inflammatory cytokines in the corneal layer did not differ between control and lesional/non-lesional skin of XLI patients. Among the mutations in filaggrin (FLG), kallikrein 7 (KLK7), and SPINK5 genes, the prevalence of KLK7 gene mutations was significantly higher in XLI patients (50%) than in controls (0%), whereas FLG and SPINK5 prevalence was comparable. Korean XLI patients exhibited unimpaired skin barrier function and frequent association with the KLK7 gene polymorphism, which may differentiate them from Western XLI patients. PMID:27478344

  15. Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

    PubMed Central

    2009-01-01

    Anthropometric data from three groups of adolescent girls - preoperative adolescent idiopathic scoliosis (AIS), screened for scoliosis and normals were analysed by comparing skeletal data between higher and lower body mass index subsets. Unexpected findings for each of skeletal maturation, asymmetries and overgrowth are not explained by prevailing theories of AIS pathogenesis. A speculative pathogenetic theory for girls is formulated after surveying evidence including: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone formation/resorption and bone growth; (3) white adipose tissue storing triglycerides and the adiposity hormone leptin which functions as satiety hormone and sentinel of energy balance to the hypothalamus for long-term adiposity; and (4) central leptin resistance in obesity and possibly in healthy females. The new theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept = LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal effects and contributes to curve progression, a concept with therapeutic implications. In the somatic

  16. Persistent Possible Science Selves

    ERIC Educational Resources Information Center

    Mills, Leila A.; Lin, Lin

    2014-01-01

    This paper examines literature on the development of self-knowledge for possible selves--how an individual thinks about oneself and one's potential future selves (Markus & Nurius, 1986). Future science selves research, a recent offshoot of possible selves theories, centers on the development and loss of future possible scientific selves and…

  17. A Systematic Review and Meta-analysis of the Diagnostic Accuracy of Prostate Health Index and 4-Kallikrein Panel Score in Predicting Overall and High-grade Prostate Cancer.

    PubMed

    Russo, Giorgio Ivan; Regis, Federica; Castelli, Tommaso; Favilla, Vincenzo; Privitera, Salvatore; Giardina, Raimondo; Cimino, Sebastiano; Morgia, Giuseppe

    2016-12-30

    Markers for prostate cancer (PCa) have progressed over recent years. In particular, the prostate health index (PHI) and the 4-kallikrein (4K) panel have been demonstrated to improve the diagnosis of PCa. We aimed to review the diagnostic accuracy of PHI and the 4K panel for PCa detection. We performed a systematic literature search of PubMed, EMBASE, Cochrane, and Academic One File databases until July 2016. We included diagnostic accuracy studies that used PHI or 4K panel for the diagnosis of PCa or high-grade PCa. The methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Twenty-eight studies including 16,762 patients have been included for the analysis. The pooled data showed a sensitivity of 0.89 and 0.74 for PHI and 4K panel, respectively, for PCa detection and a pooled specificity of 0.34 and 0.60 for PHI and 4K panel, respectively. The derived area under the curve (AUC) from the hierarchical summary receiver operating characteristic (HSROC) showed an accuracy of 0.76 and 0.72 for PHI and 4K panel respectively. For high-grade PCa detection, the pooled sensitivity was 0.93 and 0.87 for PHI and 4K panel, respectively, whereas the pooled specificity was 0.34 and 0.61 for PHI and 4K panel, respectively. The derived AUC from the HSROC showed an accuracy of 0.82 and 0.81 for PHI and 4K panel, respectively. Both PHI and the 4K panel provided good diagnostic accuracy in detecting overall and high-grade PCa.

  18. The kallikrein-kinin system in experimental Chagas disease: a paradigm to investigate the impact of inflammatory edema on GPCR-mediated pathways of host cell invasion by Trypanosoma cruzi

    PubMed Central

    Scharfstein, Julio; Andrade, Daniele; Svensjö, Erik; Oliveira, Ana Carolina; Nascimento, Clarissa R.

    2013-01-01

    Chronic chagasic myocarditis (CCM) depends on Trypanosoma cruzi persistence in the myocardium. Studies of the proteolytic mechanisms governing host/parasite balance in peripheral sites of T. cruzi infection revealed that tissue culture trypomastigotes (TCTs) elicit inflammatory edema and stimulate protective type-1 effector T cells through the activation of the kallikrein-kinin system. Molecular studies linked the proinflammatory phenotype of Dm28c TCTs to the synergistic activities of tGPI, a lipid anchor that functions as a Toll-like receptor 2 (TLR2) ligand, and cruzipain, a kinin-releasing cysteine protease. Analysis of the dynamics of inflammation revealed that TCTs activate innate sentinel cells via TLR2, releasing CXC chemokines, which in turn evoke neutrophil/CXCR2-dependent extravasation of plasma proteins, including high molecular weight kininogen (HK), in parasite-laden tissues. Further downstream, TCTs process surface bound HK, liberating lysyl-BK (LBK), which then propagates inflammatory edema via signaling of endothelial G-protein-coupled bradykinin B2 receptors (BK2R). Dm28 TCTs take advantage of the transient availability of infection-promoting peptides (e.g., bradykinin and endothelins) in inflamed tissues to invade cardiovascular cells via interdependent signaling of BKRs and endothelin receptors (ETRs). Herein we present a space-filling model whereby ceramide-enriched endocytic vesicles generated by the sphingomyelinase pathway might incorporate BK2R and ETRs, which then trigger Ca2+-driven responses that optimize the housekeeping mechanism of plasma membrane repair from cell wounding. The hypothesis predicts that the NF-κB-inducible BKR (BK1R) may integrate the multimolecular signaling platforms forged by ceramide rafts, as the chronic myocarditis progresses. Exploited as gateways for parasite invasion, BK2R, BK1R, ETAR, ETBR, and other G protein-coupled receptor partners may enable persistent myocardial parasitism in the edematous tissues at

  19. Malignant haemangioendothelioma involving the liver

    PubMed Central

    Pollard, Stella M.; Millward-Sadler, G. H.

    1974-01-01

    The features of four cases of malignant haemangioendothelioma involving the liver and other organs are described. Two cases were associated with a microangiopathic haemolytic anaemia. The nature of the tumours and possible pathogenesis for the anaemias are discussed. Images PMID:4832301

  20. Genome-wide association reveals that common genetic variation in the kallikrein-kinin system is associated with serum L-arginine levels.

    PubMed

    Zhang, Weihua; Jernerén, Fredrik; Lehne, Benjamin C; Chen, Ming-Huei; Luben, Robert N; Johnston, Carole; Elshorbagy, Amany; Eppinga, Ruben N; Scott, William R; Adeyeye, Elizabeth; Scott, James; Böger, Rainer H; Khaw, Kay-Tee; van der Harst, Pim; Wareham, Nicholas J; Vasan, Ramachandran S; Chambers, John C; Refsum, Helga; Kooner, Jaspal S

    2016-11-30

    L-arginine is the essential precursor of nitric oxide, and is involved in multiple key physiological processes, including vascular and immune function. The genetic regulation of blood L-arginine levels is largely unknown. We performed a genome-wide association study (GWAS) to identify genetic factors determining serum L-arginine levels, amongst 901 Europeans and 1,394 Indian Asians. We show that common genetic variations at the KLKB1 and F12 loci are strongly associated with serum L-arginine levels. The G allele of single nucleotide polymorphism (SNP) rs71640036 (T/G) in KLKB1 is associated with lower serum L-arginine concentrations (10 µmol/l per allele copy, p=1×10(-24)), while allele T of rs2545801 (T/C) near the F12 gene is associated with lower serum L-arginine levels (7 µmol/l per allele copy, p=7×10(-12)). Together these two loci explain 7 % of the total variance in serum L-arginine concentrations. The associations at both loci were replicated in independent cohorts with plasma L-arginine measurements (p<0.004). The two sentinel SNPs are in nearly complete LD with the nonsynonymous SNP rs3733402 at KLKB1 and the 5'-UTR SNP rs1801020 at F12, respectively. SNPs at both loci are associated with blood pressure. Our findings provide new insight into the genetic regulation of L-arginine and its potential relationship with cardiovascular risk.

  1. POLITICS OF UNIVERSITY INVOLVEMENT IN SOCIAL CHANGE.

    ERIC Educational Resources Information Center

    CAMPBELL, ALAN K.

    THE AUTHOR DISCUSSES THE UNIVERSITY'S ROLE IN SOCIAL CHANGE FROM THE POLITICAL VIEWPOINT. BY EXAMINING OUR POLITICAL SYSTEM AS IT RELATED TO UNIVERSITY INVOLVEMENT, HE INDICATES THE POLITICAL RAMIFICATIONS OF SUCH INVOLVEMENT AND SHOWS THE KIND OF INVOLVEMENT THAT IS POLITICALLY POSSIBLE. HE PINPOINTS THE DIFFICULTIES CIVIC ADMINISTRATORS AND…

  2. Possible markets for dirigibles

    NASA Technical Reports Server (NTRS)

    1979-01-01

    The use of mini, small, medium, and heavy dirigibles for the transportation of passengers and cargo, for aerial handling of materials, for the support of scientific platforms, and for use in agriculture and forest management is evaluated. The operational efficiency of one or more dirigibles in view of possible integration into the general transport system is described.

  3. A Small as Possible

    NASA Technical Reports Server (NTRS)

    Tibbitts, Scott

    2003-01-01

    This story begins with a bit of serendipity: I was on a trip to see a Shuttle launch and I happened to sit next to a guy who was in charge of batteries for Space Systems/Loral. He told me that they needed to create a new battery bypass switch, the device that takes a battery out of commission if it goes bad. After discussing the conversation back at my company, we decided that we could create the switch. We contacted the folks at Loral and they said, 'Okay, let s see what you can come up with. We need it as small as possible.' We asked, 'How small?' They said, 'We need it as small as you can possibly make it.'

  4. Eye Involvement in TSC

    MedlinePlus

    ... Privacy Policy Sitemap Learn Engage Donate About TSC Eyes Campbell (1905) first described the eye involvement in ... some form of eye involvement. Nonretinal and Retinal Eye Findings Facial angiofibromas may involve the eyelids of ...

  5. Possible number systems.

    PubMed

    Rips, Lance J; Thompson, Samantha

    2014-03-01

    Number systems-such as the natural numbers, integers, rationals, reals, or complex numbers-play a foundational role in mathematics, but these systems can present difficulties for students. In the studies reported here, we probed the boundaries of people's concept of a number system by asking them whether "number lines" of varying shapes qualify as possible number systems. In Experiment 1, participants rated each of a set of number lines as a possible number system, where the number lines differed in their structures (a single straight line, a step-shaped line, a double line, or two branching structures) and in their boundedness (unbounded, bounded below, bounded above, bounded above and below, or circular). Participants also rated each of a group of mathematical properties (e.g., associativity) for its importance to number systems. Relational properties, such as associativity, predicted whether participants believed that particular forms were number systems, as did the forms' ability to support arithmetic operations, such as addition. In Experiment 2, we asked participants to produce properties that were important for number systems. Relational, operation, and use-based properties from this set again predicted ratings of whether the number lines were possible number systems. In Experiment 3, we found similar results when the number lines indicated the positions of the individual numbers. The results suggest that people believe that number systems should be well-behaved with respect to basic arithmetic operations, and that they reject systems for which these operations produce ambiguous answers. People care much less about whether the systems have particular numbers (e.g., 0) or sets of numbers (e.g., the positives).

  6. Possible Selves, Possible Futures: The Dynamic Influence of Changes in the Possible Selves on Community College Returnees' Persistence Decisions

    ERIC Educational Resources Information Center

    Ozaki, C. Casey

    2016-01-01

    This qualitative study explored the external and internal reasons involved in students' decisions to return to college after an extended absence. Specifically, it sought to explore the role of students' concepts of who they might be (or want to avoid becoming) in the college and career domains of their lives, their possible selves. Analysis of…

  7. Possibility of hyperbolic tunneling

    SciTech Connect

    Lobo, Francisco S. N.; Mimoso, Jose P.

    2010-08-15

    Traversable wormholes are primarily useful as 'gedanken experiments' and as a theoretician's probe of the foundations of general relativity. In this work, we analyze the possibility of having tunnels in a hyperbolic spacetime. We obtain exact solutions of static and pseudo-spherically symmetric spacetime tunnels by adding exotic matter to a vacuum solution referred to as a degenerate solution of class A. The physical properties and characteristics of these intriguing solutions are explored, and through the mathematics of embedding it is shown that particular constraints are placed on the shape function, that differ significantly from the Morris-Thorne wormhole. In particular, it is shown that the energy density is always negative, and the radial pressure is positive, at the throat, contrary to the Morris-Thorne counterpart. Specific solutions are also presented by considering several equations of state, and by imposing restricted choices for the shape function or the redshift function.

  8. Two possible active supernovae in IC 2150

    NASA Astrophysics Data System (ADS)

    Parker, Stu; Bock, Greg; Marples, Peter; Drescher, Colin; Pearl, Patrick; BOSS Team; Contreras, Carlos; Phillips, Mark; Morrell, Nidia; Hsiao, Eric; Carnegie Supernova Project

    2016-03-01

    Stu Parker and the BOSS team report the discovery of a rare event involving two possible active supernovae in IC 2150 (z=0.010404; NED) which were recorded in images obtained by Stu Parker during the ongoing program by the Backyard Observatory Supernova Search (BOSS) team.

  9. Of possible cheminformatics futures.

    PubMed

    Oprea, Tudor I; Taboureau, Olivier; Bologa, Cristian G

    2012-01-01

    For over a decade, cheminformatics has contributed to a wide array of scientific tasks from analytical chemistry and biochemistry to pharmacology and drug discovery; and although its contributions to decision making are recognized, the challenge is how it would contribute to faster development of novel, better products. Here we address the future of cheminformatics with primary focus on innovation. Cheminformatics developers often need to choose between "mainstream" (i.e., accepted, expected) and novel, leading-edge tools, with an increasing trend for open science. Possible futures for cheminformatics include the worst case scenario (lack of funding, no creative usage), as well as the best case scenario (complete integration, from systems biology to virtual physiology). As "-omics" technologies advance, and computer hardware improves, compounds will no longer be profiled at the molecular level, but also in terms of genetic and clinical effects. Among potentially novel tools, we anticipate machine learning models based on free text processing, an increased performance in environmental cheminformatics, significant decision-making support, as well as the emergence of robot scientists conducting automated drug discovery research. Furthermore, cheminformatics is anticipated to expand the frontiers of knowledge and evolve in an open-ended, extensible manner, allowing us to explore multiple research scenarios in order to avoid epistemological "local information minimum trap".

  10. Of possible cheminformatics futures

    NASA Astrophysics Data System (ADS)

    Oprea, Tudor I.; Taboureau, Olivier; Bologa, Cristian G.

    2012-01-01

    For over a decade, cheminformatics has contributed to a wide array of scientific tasks from analytical chemistry and biochemistry to pharmacology and drug discovery; and although its contributions to decision making are recognized, the challenge is how it would contribute to faster development of novel, better products. Here we address the future of cheminformatics with primary focus on innovation. Cheminformatics developers often need to choose between "mainstream" (i.e., accepted, expected) and novel, leading-edge tools, with an increasing trend for open science. Possible futures for cheminformatics include the worst case scenario (lack of funding, no creative usage), as well as the best case scenario (complete integration, from systems biology to virtual physiology). As "-omics" technologies advance, and computer hardware improves, compounds will no longer be profiled at the molecular level, but also in terms of genetic and clinical effects. Among potentially novel tools, we anticipate machine learning models based on free text processing, an increased performance in environmental cheminformatics, significant decision-making support, as well as the emergence of robot scientists conducting automated drug discovery research. Furthermore, cheminformatics is anticipated to expand the frontiers of knowledge and evolve in an open-ended, extensible manner, allowing us to explore multiple research scenarios in order to avoid epistemological "local information minimum trap".

  11. Home Fires Involving Grills

    MedlinePlus

    ... fires were fueled by gas while 13% used charcoal or other solid fuel. Gas grills were involved ... structure fires and 4,300 outdoor fires annually. Charcoal or other solid-fueled grills were involved in ...

  12. Involving Parents at School

    ERIC Educational Resources Information Center

    Montgomery, Joel R.

    2008-01-01

    This working paper explores reasons to encourage parents of English language learners (ELLs) to be involved in the learning process at the middle school level. Barriers to parental involvement of language minority students will be identified and successful, research-based strategies to increase parental involvement will be introduced. Five…

  13. Involving Faculty in Planning.

    ERIC Educational Resources Information Center

    Andrew, Lloyd D.

    1979-01-01

    Firm planning objectives, clearly stated relationships to overall institutional objectives, faculty involvement, and active leadership are advocated for successful academic planning. Faculty involvement is dependent on the strength of the technical, marketing, and budgeting staffs, and involvement in the planning process may kindle faculty…

  14. Gubernatorial Involvement in Education.

    ERIC Educational Resources Information Center

    Hines, Edward R.

    This research on 12 States' gubernatorial involvement in State educational policy formation investigates four functional stages of that involvement--issue definition, proposal formulation, support mobilization, and decision enactment. Drawing on the Educational Governance Project information and interviews, a gubernatorial involvement index was…

  15. Involving LEP Parents.

    ERIC Educational Resources Information Center

    Garate, Dama; And Others

    Four community liaisons for public school programs for limited- English-proficient (LEP) populations discuss briefly aspects of parent involvement. Dama Garate describes the populations served by the Trinity-Arlington Project in the Arlington (Virginia) Public Schools and suggests issues to be considered in parent involvement efforts. Pirun Sen of…

  16. High Involvement Work Teams.

    ERIC Educational Resources Information Center

    1996

    These three papers were presented at a symposium on high-involvement work teams moderated by Michael Leimbach at the 1996 conference of the Academy of Human Resource Development. "Beyond Training to the New Learning Environment: Workers on the High-Involvement Frontline" (Joseph Anthony Ilacqua, Carol Ann Zulauf) shows the link between…

  17. [Families Involved in Learning.

    ERIC Educational Resources Information Center

    Ashby, Nicole, Ed.

    2001-01-01

    This issue of "Community Update" focuses on families involved in learning. The first article briefly discusses the "Ready to Read, Ready to Learn" White House summit that highlighted new research on early childhood learning. The center spread of this issue offers "Priming the Primary Educator: A Look at L. A. County's Parent Involvement Programs"…

  18. Categories of Parent Involvement.

    ERIC Educational Resources Information Center

    Bauch, Jerold P.

    1994-01-01

    The growing interest in effective parent involvement has produced several ways to classify or describe ways parents are or should be involved. This article reviews and evaluates Ira Gordon's systems approach, the California-based System Development Corporation's categories, Eugenia H. Berger's parental role categories, Chavkin and Williams' parent…

  19. Commericial Involvement in Intramurals.

    ERIC Educational Resources Information Center

    Maas, Gerry

    Sport in general has long had ties with commercial interests, the most popular and widespread involving publicity. Intramural sports programs, however, have not cultivated many commercial involvements in publicity. The approach in intramural sports advertising is simple. A commercial interest pays for space or time in a given communication media…

  20. Possible NASA Contributions to HEAT

    NASA Technical Reports Server (NTRS)

    Shepherd, J. M.

    2004-01-01

    A four-year experiment (HEAT) has been proposed (one summer in the field, 2005) to determine the sources and causes for the enhanced cloud-to-ground lightning over Houston, Texas, in association with simultaneous experiments by the Environmental Protection Agency (EPA) and the Texas Natural Resource Conservation Commission (TNRCC). Houston is the third most populous city in the United States and the region contains 50% of the petroleum refining capacity of the United States. Recent studies covering the period 1989-2000 document a 50% increase of cloud-to-ground lightning in the Houston area as compared to background values, which is second in flash density only to the Tampa Bay, Florida area. It is suggested that the elevated flash densities could result from several factors, including, 1) the convergence due to the urban heat island effect and complex sea breeze, and 2) the increasing levels of air pollution from anthropogenic sources producing numerous small droplets and thereby suppressing mean droplet size. The latter effect would enable more cloud water to reach the mixed phase region where it is involved in the formation of precipitation and the separation of electric charge, leading to an enhancement of lightning. The primary goals of HEAT are to examine the effects of (1) pollution, (2) the urban heat island, and (3) the complex coastline, on storms and lightning characteristics in the Houston area. The project is a multi- agency effort and will employ numerous observing capabilities and expertise. Dr. Shepherd has been asked to serve as a possible co- investigator to contribute expertise in areas related to urban impacts on precipitation variability. Dr. Shepherd is also a key NASA representative in the interagency effort. This presentation will provide an overview of recent NASA research focused on urban rainfall in Houston and offer potential NASA capabilities that could contribute to HEAT.

  1. Cognitive hearing aids? Insights and possibilities

    NASA Astrophysics Data System (ADS)

    Petersen, Eline Borch; Lunner, Thomas

    2015-12-01

    The working memory plays an important role in successfully overcoming adverse listening conditions and should consequently be considered when designing and testing hearing aids. A number of studies have established the relationship between hearing in noise and working memory involvement, but with the Sentence-final Word Identification and Recall (SWIRL) test, it is possible to show that working memory is also involved in listening under favorable conditions and that noise reduction has a positive influence in situation with very little noise. Although the capacity of the working memory is a finite individual size, its involvement can differ with fatigue and other factors and individualization of hearing aids should take this into account to obtain the best performance. A way of individually adapting hearing aids is based on changes in the electrical activity of the brain (EEG). Here we present the possibilities that arise from using EEG and show that ear-mounted electrodes is able to record useful EEG that can be explored for individualization of hearing aids. Such an adaptation could be done based on changes in the electrical activity of the brain (EEG). Here we present the possibilities that arise from using EEG and show that ear-mounted electrodes is able to record useful EEG that can be explored for individualization of hearing aids.

  2. [Heart involvement in sarcoglycanopathies].

    PubMed

    Fayssoil, A; Nardi, O; Orlikowski, D; Annane, D

    2012-11-01

    Sarcoglycanopathies (SG) are autosomic recessive muscular dystrophies, secondary to mutations of the sarcoglycan complex. Clinical pictures include muscle weakness affecting mainly the proximal limb girdle musculature. We review heart involvement in this group of disease.

  3. Consumer Involvement in Rehabilitation

    ERIC Educational Resources Information Center

    Daniels, Susan

    1976-01-01

    With the emphasis on consumer involvement in the Rehabilitation Act of 1973, changes in the counseling relationship must occur. This article discusses new interaction patterns for consumer and counselor. (Author)

  4. Vasculitis and gastrointestinal involvement.

    PubMed

    Casella, G; Bronzino, B; Cutrino, L; Montani, N; Somma, A; Baldini, V

    2006-06-01

    The incidence of gastrointestinal involvement is relatively observed in patients with vasculitis processes. Vasculitis can be primary (necrotising or hypersensitivity) or secondary to another primary disease. Gastrointestinal involvement is present in up to 50% of the various forms of systemic vasculitis. Primary or secondary vasculitic process, according to the classification in necrotizing and hypersensitivity vasculitis, are described in this paper. A review of the literature on the the subject is also presented.

  5. KLK11 — EDRN Public Portal

    Cancer.gov

    The glandular kallikreins are a distinct group of serine proteases with molecular masses of 25,000 to 40,000. Kallikreins are a subgroup of serine proteases having diverse physiological functions. hk11 is a possible multifunctional protease which efficiently cleaves 'bz-Phe-Arg-4-methylcoumaryl-7-amide', a kallikrein substrate, and weakly cleaves other substrates for kallikrein and trypsin. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. Several human kallikrein genes have been isolated. Expressed in brain, skin and prostate. Isoform 1 is expressed preferentially in brain. Isoform 2 is expressed in prostate.

  6. Musculoskeletal involvement in sarcoidosis*, **

    PubMed Central

    Nessrine, Akasbi; Zahra, Abourazzak Fatima; Taoufik, Harzy

    2014-01-01

    Sarcoidosis is a multisystem inflammatory disorder of unknown cause. It most commonly affects the pulmonary system but can also affect the musculoskeletal system, albeit less frequently. In patients with sarcoidosis, rheumatic involvement is polymorphic. It can be the presenting symptom of the disease or can appear during its progression. Articular involvement is dominated by nonspecific arthralgia, polyarthritis, and Löfgren's syndrome, which is defined as the presence of lung adenopathy, arthralgia (or arthritis), and erythema nodosum. Skeletal manifestations, especially dactylitis, appear mainly as complications of chronic, multiorgan sarcoidosis. Muscle involvement in sarcoidosis is rare and usually asymptomatic. The diagnosis of rheumatic sarcoidosis is based on X-ray findings and magnetic resonance imaging findings, although the definitive diagnosis is made by anatomopathological study of biopsy samples. Musculoskeletal involvement in sarcoidosis is generally relieved with nonsteroidal anti-inflammatory drugs or corticosteroids. In corticosteroid-resistant or -dependent forms of the disease, immunosuppressive therapy, such as treatment with methotrexate or anti-TNF-α, is employed. The aim of this review was to present an overview of the various types of osteoarticular and muscle involvement in sarcoidosis, focusing on their diagnosis and management. PMID:24831403

  7. Neuropsin--a possible modulator of synaptic plasticity.

    PubMed

    Shiosaka, Sadao; Ishikawa, Yasuyuki

    2011-09-01

    Accumulating evidence has suggested pivotal roles for neural proteases in development, maturation, aging, and cognitive functions. Among such proteases, neuropsin, a kallikrein gene-related (KLK) endoprotease, appears to have a significant plasticity function that has been analyzed primarily in the hippocampal Schaffer-collateral pathway. In this article, after reviewing the general features of neuropsin, its role in Schaffer-collateral synaptic plasticity is discussed in some detail. Enzymatically active neuropsin is necessary to establish the early phase of long-term potentiation (LTP). This type of LTP, which can be elicited by rather weak tetanic stimulation, is significant in synaptic late association between two independent hippocampal synapses. Neuropsin deficiency completely impaired the early phase of LTP, leading to the absence of late associativity. Associations between early and persistent-LTP synapses may be related to mammalian working memory and consequently integration in learning and memory.

  8. Possible form of vacuum deformation by heavy particles

    NASA Technical Reports Server (NTRS)

    Mackenzie, R.; Wilczek, F.; Zee, A.

    1984-01-01

    The possibility is discussed that the lowest-energy state for certain quantum numbers involves a Higgs field polarized into a skyrmion-type configuration. In some models a new type of vacuum instability arises. Phenomenological consequences are indicated schematically.

  9. Mechanisms Involved in the Nociception Triggered by the Venom of the Armed Spider Phoneutria nigriventer

    PubMed Central

    Gewehr, Camila; Oliveira, Sara Marchesan; Rossato, Mateus Fortes; Trevisan, Gabriela; Dalmolin, Gerusa Duarte; Rigo, Flávia Karine; de Castro Júnior, Célio José; Cordeiro, Marta Nascimento; Ferreira, Juliano; Gomez, Marcus V.

    2013-01-01

    Background The frequency of accidental spider bites in Brazil is growing, and poisoning due to bites from the spider genus Phoneutria nigriventer is the second most frequent source of such accidents. Intense local pain is the major symptom reported after bites of P. nigriventer, although the mechanisms involved are still poorly understood. Therefore, the aim of this study was to identify the mechanisms involved in nociception triggered by the venom of Phoneutria nigriventer (PNV). Methodology/Principal Findings Twenty microliters of PNV or PBS was injected into the mouse paw (intraplantar, i.pl.). The time spent licking the injected paw was considered indicative of the level of nociception. I.pl. injection of PNV produced spontaneous nociception, which was reduced by arachnid antivenin (ArAv), local anaesthetics, opioids, acetaminophen and dipyrone, but not indomethacin. Boiling or dialysing the venom reduced the nociception induced by the venom. PNV-induced nociception is not dependent on glutamate or histamine receptors or on mast cell degranulation, but it is mediated by the stimulation of sensory fibres that contain serotonin 4 (5-HT4) and vanilloid receptors (TRPV1). We detected a kallikrein-like kinin-generating enzyme activity in tissue treated with PNV, which also contributes to nociception. Inhibition of enzymatic activity or administration of a receptor antagonist for kinin B2 was able to inhibit the nociception induced by PNV. PNV nociception was also reduced by the blockade of tetrodotoxin-sensitive Na+ channels, acid-sensitive ion channels (ASIC) and TRPV1 receptors. Conclusion/Significance Results suggest that both low- and high-molecular-weight toxins of PNV produce spontaneous nociception through direct or indirect action of kinin B2, TRPV1, 5-HT4 or ASIC receptors and voltage-dependent sodium channels present in sensory neurons but not in mast cells. Understanding the mechanisms involved in nociception caused by PNV are of interest not only for

  10. Consumer Involvement in Rehabilitation.

    ERIC Educational Resources Information Center

    Thursz, Daniel

    A new approach to rehabilitation of the disabled and disadvantaged is necessary, but the problem of how to involve consumers and how to organize groups for community action is a big one. Moreover, citizen participation cannot be a substitute for basic improvement in the quality of service. Service agencies need to be decentralized and staff…

  11. Getting Parents Involved.

    ERIC Educational Resources Information Center

    Butts, Vickie; Finch, Patty A.

    1985-01-01

    Describes a parental involvement program in reading, writing, and human education. The project consists of caring for Clifford, a stuffed toy dog, on a rotated basis by first grade students. Books and pet care items accompany Clifford and provide an opportunity for parent and child to work together. (ML)

  12. Parent Involvement. Research Brief

    ERIC Educational Resources Information Center

    Walker, Karen

    2007-01-01

    What are some ways in which to get parents meaningfully involved in their child's high school? According to the research, the most successful programs are those that provide a variety of ways in which parents can be actively engaged in their child's academic life. Joyce Epstein, Director of the National Network of Partnership Schools, out of Johns…

  13. Rethinking Parent Involvement.

    ERIC Educational Resources Information Center

    Vandergrift, Judith A.; Greene, Andrea L.

    1992-01-01

    Arizona At-Risk Pilot Project results suggest most effective means to involve parents are those that establish personal rapport between someone from the school and a parent and do not initially require high levels of commitment or participation. The "ideal" parent may be hard to find, but getting to know parents individually and…

  14. Estimating Terrorist Risk with Possibility Theory

    SciTech Connect

    J.L. Darby

    2004-11-30

    This report summarizes techniques that use possibility theory to estimate the risk of terrorist acts. These techniques were developed under the sponsorship of the Department of Homeland Security (DHS) as part of the National Infrastructure Simulation Analysis Center (NISAC) project. The techniques have been used to estimate the risk of various terrorist scenarios to support NISAC analyses during 2004. The techniques are based on the Logic Evolved Decision (LED) methodology developed over the past few years by Terry Bott and Steve Eisenhawer at LANL. [LED] The LED methodology involves the use of fuzzy sets, possibility theory, and approximate reasoning. LED captures the uncertainty due to vagueness and imprecision that is inherent in the fidelity of the information available for terrorist acts; probability theory cannot capture these uncertainties. This report does not address the philosophy supporting the development of nonprobabilistic approaches, and it does not discuss possibility theory in detail. The references provide a detailed discussion of these subjects. [Shafer] [Klir and Yuan] [Dubois and Prade] Suffice to say that these approaches were developed to address types of uncertainty that cannot be addressed by a probability measure. An earlier report discussed in detail the problems with using a probability measure to evaluate terrorist risk. [Darby Methodology]. Two related techniques are discussed in this report: (1) a numerical technique, and (2) a linguistic technique. The numerical technique uses traditional possibility theory applied to crisp sets, while the linguistic technique applies possibility theory to fuzzy sets. Both of these techniques as applied to terrorist risk for NISAC applications are implemented in software called PossibleRisk. The techniques implemented in PossibleRisk were developed specifically for use in estimating terrorist risk for the NISAC program. The LEDTools code can be used to perform the same linguistic evaluation as

  15. Well posedness and physical possibility

    NASA Astrophysics Data System (ADS)

    Gyenis, Balazs

    There is a sentiment shared among physicists that well posedness is a necessary condition for physical possibility. The arguments usually offered for well posedness have an epistemic flavor and thus they fall short of establishing the metaphysical claim that lack of well posedness implies physical impossibility. In this work we analyze the relationship of well posedness to prediction and confirmation as well as the notion of physical possibility and we devise three novel and independent argumentative strategies that may succeed where the usual epistemic arguments fail. Keywords: determinism, laws of nature, metaphysics, philosophy of physics, physical possibility, prediction, well posed problem.

  16. Hypothalamic involvement in chronic migraine

    PubMed Central

    Peres, M; del Rio, M S.; Seabra, M; Tufik, S; Abucham, J; Cipolla-Neto, J; Silberstein, S; Zukerman, E

    2001-01-01

    OBJECTIVES—Chronic migraine (CM), previously called transformed migraine, is a frequent headache disorder that affects 2%-3% of the general population. Analgesic overuse, insomnia, depression, and anxiety are disorders that are often comorbid with CM. Hypothalamic dysfunction has been implicated in its pathogenesis, but it has never been studied in patients with CM. The aim was to analyze hypothalamic involvement in CM by measurement of melatonin, prolactin, growth hormone, and cortisol nocturnal secretion.
METHODS—A total of 338 blood samples (13/patient) from 17 patients with CM and nine age and sex matched healthy volunteers were taken. Melatonin, prolactin, growth hormone, and cortisol concentrations were determined every hour for 12 hours. The presence of comorbid disorders was also evaluated.
RESULTS—An abnormal pattern of hypothalamic hormonal secretion was found in CM. This included: (1) a decreased nocturnal prolactin peak, (2) increased cortisol concentrations, (3) a delayed nocturnal melatonin peak in patients with CM, and (4) lower melatonin concentrations in patients with CM with insomnia. Growth hormone secretion did not differ from controls.
CONCLUSION—These results support hypothalamic involvement in CM, shown by a chronobiologic dysregulation, and a possible hyperdopaminergic state in patients with CM. Insomnia might be an important variable in the study findings.

 PMID:11723194

  17. Chapter 5. Students' Involvement with the Internet

    ERIC Educational Resources Information Center

    Russian Education and Society, 2004

    2004-01-01

    In this article, the authors examine a number of questions that make it possible to characterize the different aspects of students' involvement with the Internet. They will analyse the regularity of students in using the Internet, the age at which they begin to use means of electronic communication, the place where they use it, the intensiveness…

  18. Asbestos exposure and upper lobe involvement

    SciTech Connect

    Hillerdal, G.

    1982-12-01

    In a study of 1,251 persons with asbestos-related pleural and parenchymal changes, 16 had slowly progressive changes of the upper lobes, involving both pleura and parenchyma, with shrinkage of the lobes. In addition there were 41 cases with less advanced apical changes. Tuberculosis and other possible causes were excluded. It is hypothesized that the changes rate due to asbestos disease.

  19. Possible improvements in gasoline engines

    NASA Technical Reports Server (NTRS)

    Ziembinski, S

    1923-01-01

    High-compression engines are investigated with the three main objects being elimination of vibration, increase of maximum efficiency, and conservation of this efficiency at the highest possible speeds.

  20. 49 CFR 225.18 - Alcohol or drug involvement.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Alcohol or drug involvement. 225.18 Section 225.18....18 Alcohol or drug involvement. (a) In preparing Form FRA F 6180.54, “Rail Equipment Accident... the circumstances into the possible involvement of alcohol or drug use or impairment in such...

  1. 49 CFR 225.18 - Alcohol or drug involvement.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Alcohol or drug involvement. 225.18 Section 225.18....18 Alcohol or drug involvement. (a) In preparing Form FRA F 6180.54, “Rail Equipment Accident... the circumstances into the possible involvement of alcohol or drug use or impairment in such...

  2. 49 CFR 225.18 - Alcohol or drug involvement.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Alcohol or drug involvement. 225.18 Section 225.18....18 Alcohol or drug involvement. (a) In preparing Form FRA F 6180.54, “Rail Equipment Accident... the circumstances into the possible involvement of alcohol or drug use or impairment in such...

  3. 49 CFR 225.18 - Alcohol or drug involvement.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Alcohol or drug involvement. 225.18 Section 225.18....18 Alcohol or drug involvement. (a) In preparing Form FRA F 6180.54, “Rail Equipment Accident... the circumstances into the possible involvement of alcohol or drug use or impairment in such...

  4. SLS-2 involvement

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1995-01-01

    The purpose of this study is to support Russian space flight experiments carried out on rats flown aboard Space Shuttle Mission SLS-2. The Russian experiments were designed to determine the effects of space flight on immunological parameters. The Russian experiment included the first in-flight dissection of rodents that allowed the determination of kinetics of when space flight affected immune responses. The support given the Russians by this laboratory was to carry out assays for immunologically important cytokines that could not readily be carried out in their home laboratories. These included essays of interleukin-1, interleukin-6, interferon-gamma and possibly other cytokines.

  5. Endocannabinoid involvement in endometriosis

    PubMed Central

    Dmitrieva, Natalia; Nagabukuro, Hiroshi; Resuehr, David; Zhang, Guohua; McAllister, Stacy L.; McGinty, Kristina A.; Mackie, Ken; Berkley, Karen J.

    2010-01-01

    Endometriosis is a disease common in women that is defined by abnormal extrauteral growths of uterine endometrial tissue and associated with severe pain. Partly because how the abnormal growths become associated with pain is poorly understood, the pain is difficult to alleviate without resorting to hormones or surgery, which often produce intolerable side effects or fail to help. Recent studies in a rat model and women showed that sensory and sympathetic nerve fibers sprout branches to innervate the abnormal growths. This situation, together with knowledge that the endocannabinoid system is involved in uterine function and dysfunction and that exogenous cannabinoids were once used to alleviate endometriosis-associated pain, suggests that the endocannabinoid system is involved in both endometriosis and its associated pain. Here, using a rat model, we found that CB1 cannabinoid receptors are expressed on both the somata and fibers of both the sensory and sympathetic neurons that innervate endometriosis’s abnormal growths. We further found that CB1 receptor agonists decrease, whereas CB1 receptor antagonists increase, endometriosis-associated hyperalgesia. Together these findings suggest that the endocannabinoid system contributes to mechanisms underlying both the peripheral innervation of the abnormal growths and the pain associated with endometriosis, thereby providing a novel approach for the development of badly-needed new treatments. PMID:20833475

  6. [Bone involvement in endocrinopathies].

    PubMed

    Ribot, C; Trémollières, F; Pouillès, J M

    1994-06-04

    Progress in bone densitometry, particularly biphotonic absoptiometry, has made it possible to better identify the effects of endocrinopathies on bone. Both cortical and trabecular bone structures can be evaluated quantitatively and topographically revealing important information on the pathophysiology of bone loss. Sex hormones play a major role in the regulation of bone mineralization and hypogonadism, whatever the origin, can lead to deleterious effects. Bone loss is known to be significative in high performance female athletes with amenorrhoea; long-term consequences are not yet determined, but stress fractures have been reported in up to 50%. Other hypogonadisms leading to bone demineralization include anorexia nervosa, chronic intake of gonadotrophin releasing hormone analogues and anti-oestrogens, and hyperprolactinism. Hyperthyroidism leads to a negative calcium balance and demineralization with remodelling, predominantly in cortical bone. In hypothyroid states a 10% bone loss is observed in vertebrae. In both cases, bone densitometry should be performed in order to evaluate the effect of treatment. The deleterious effect of spontaneous or iatrogenic hypercortisism is well known, leading to spontaneous wedge fractures of the vertebrae due to predominating trabecular bone loss. The mechanism of action of corticosteroids on bone metabolism is complex, but the major effect is an inhibition of osteoblast maturation. Recovery may be possible, but no large long-term series have yet been reported. Hyperparathyroidism and acromegaly also affect bone mineralization. The information provided by bone densitometry is essential to properly manage patients with endocrinopathies affecting bone mineralization.

  7. [Possible involvement of histone acetylation in the development of emotional resistance to stress stimuli].

    PubMed

    Miyagawa, Kazuya; Tsuji, Minoru; Takeda, Hiroshi

    2012-11-01

    Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene transcription without altering the DNA code, could play a critical role in the pathophysiology of psychiatric disorders. We previously reported that pretreatment of mice with 5-HT(1A) receptor agonists 24 hr before testing suppressed the decrease in emotional behaviors induced by exposure to acute restraint stress. In addition, DNA microarray analysis showed that such a pretreatment with 5-HT(1A) receptor agonist produces changes in several gene transcriptions in the hippocampus including the reduction of histone deacetylase 10. Based on these findings, we recently carried out studies focused on the relationship between the development of emotional resistance to stress and histone acetylation induced by a 5-HT(1A) receptor agonist as well as a histone deacetylase inhibitor. The findings suggest that 5-HT(1A) receptor agonists may be useful for preventing mental illnesses that arise due to a decreased resistance and adaptability to stress. Moreover, the notion that chromatin remodeling is an important mechanism in mediating emotionality under stressful situations is further supported.

  8. Kindling-induced learning deficiency and possible cellular and molecular involved mechanisms.

    PubMed

    Sherafat, Mohammad Amin; Ronaghi, Abdolaziz; Ahmad-Molaei, Leila; Nejadhoseynian, Mohammad; Ghasemi, Rasoul; Hosseini, Arman; Naderi, Nima; Motamedi, Fereshteh

    2013-06-01

    Hippocampus learning disturbance is a major symptom of patients with seizure, hence hippocampal dysfunction has essential role in worsening the disease. Hippocampal formation includes neurons and myelinated fibers that are necessary for acquisition and consolidation of memory, long-term potentiation and learning activity. The exact mechanism by which seizure can decrease memory and learning activity of hippocampus remains unknown. In the present study, electrical kindling-induced learning deficit in rats was evaluated by Morris water maze (MWM) test. The hippocampus was removed and changes in neurons and myelin sheaths around hippocampal fibers were investigated using histological and immunohistochemical methods. Demyelination was assessed by luxol fast blue staining, and immunohistological staining of myelin-binding protein (MBP). The TUNEL assay was used for evaluation of neuronal apoptosis and the glial fibriliary acetic protein (GFAP) was used for assessment of inflammatory reaction. The results indicated that electrical kindling of hippocampus could induce deficiency in spatial learning and memory as compared to control group. In addition, electrical kindling caused damage to the myelin sheath around hippocampal fibers and produced vast demyelination. Furthermore, an increase in the number of apoptotic cells in hippocampal slices was observed. In addition, inflammatory response was higher in kindled animals as compared to the control group. The results suggested that the decrease in learning and memory in kindled animals is likely due to demyelination and augmentation in apoptosis rate accompanied by inflammatory reaction in hippocampal neurons of kindled rats.

  9. The cerebellar serotoninergic system and its possible involvement in cerebellar ataxia.

    PubMed

    Trouillas, P

    1993-05-01

    A review concerning the characteristics of the cerebellar serotoninergic system is presented. In rat, cat and oppossum, the perikarya of origin are located in the brain stem raphe nuclei and in other brainstem structures. The projections to the cerebellar layers and deep nuclei include synaptic connections, but also non synaptic terminals, especially in a diffuse cortical plexus. Serotoninergic receptors have been described: 5-HT1B in the molecular layer and 5-HT2 in the inferior olive. Serotonin exerts neurophysiological effects on several target cells, directly or indirectly, presynaptically or postsynaptically. A modulatory effect on Purkinje cells is well documented. In thiamine deprived animals, a specific serotoninergic cerebellar syndrome includes a selective degeneration of the serotoninergic cerebellar system, an increase of the 5-HIAA cerebellar values and an exaggerated serotoninergic turnover. In human heredoataxias (Friedreich's ataxia and cerebellar cortical atrophy), serotoninergic disturbances have been observed in the CSF, including low 5-HIAA values and an increased serotoninergic turnover. Therapeutic results have been obtained with L-5-HTP, a precursor of serotonin, in several conditions presenting cerebellar ataxia. L-5-HTP resistance of olivopontocerebellar atrophies may be explained by the destruction of serotonin-sensitive target cells, especially Purkinje cells.

  10. Activation of Hepatic Lipase Expression by Oleic Acid: Possible Involvement of USF1

    PubMed Central

    van Deursen, Diederik; van Leeuwen, Marije; Akdogan, Deniz; Adams, Hadie; Jansen, Hans; Verhoeven, Adrie J.M.

    2009-01-01

    Polyunsaturated fatty acids affect gene expression mainly through peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element binding proteins (SREBPs), but how monounsaturated fatty acids affect gene expression is poorly understood. In HepG2 cells, oleate supplementation has been shown to increase secretion of hepatic lipase (HL). We hypothesized that oleate affects HL gene expression at the transcriptional level. To test this, we studied the effect of oleate on HL promoter activity using HepG2 cells and the proximal HL promoter region (700 bp). Oleate increased HL expression and promoter activity 1.3–2.1 fold and reduced SREBP activity by 50%. Downregulation of SREBP activity by incubation with cholesterol+25-hydroxycholesterol had no effect on HL promoter activity. Overexpression of SREBP2, but not SREBP1, reduced HL promoter activity, which was effected mainly through the USF1 binding site at -307/-312. Oleate increased the nuclear abundance of USF1 protein 2.7 ± 0.6 fold, while USF1 levels were reduced by SREBP2 overexpression. We conclude that oleate increases HL gene expression via USF1. USF1 may be an additional fatty acid sensor in liver cells. PMID:22253973

  11. Neuroprotective activity of stiripentol with a possible involvement of voltage-dependent calcium and sodium channels.

    PubMed

    Verleye, Marc; Buttigieg, Dorothée; Steinschneider, Rémy

    2016-02-01

    A growing body of data has shown that recurrent epileptic seizures may be caused by an excessive release of the excitatory neurotransmitter glutamate in the brain. Glutamatergic overstimulation results in massive neuronal influxes of calcium and sodium through N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainic acid glutamate subtype receptors and also through voltage-gated calcium and sodium channels. These persistent and abnormal sodium and calcium entry points have deleterious consequences (neurotoxicity) for neuronal function. The therapeutic value of an antiepileptic drug would include not only control of seizure activity but also protection of neuronal tissue. The present study examines the in vitro neuroprotective effects of stiripentol, an antiepileptic compound with γ-aminobutyric acidergic properties, on neuronal-astroglial cultures from rat cerebral cortex exposed to oxygen-glucose deprivation (OGD) or to glutamate (40 µM for 20 min), two in vitro models of brain injury. In addition, the affinity of stiripentol for the different glutamate receptor subtypes and the interaction with the cell influx of Na(+) and of Ca(2+) enhanced by veratridine and NMDA, respectively, are assessed. Stiripentol (10-100 µM) included in the culture medium during OGD or with glutamate significantly increased the number of surviving neurons relative to controls. Stiripentol displayed no binding affinity for different subtypes of glutamate receptors (IC50  >100 µM) but significantly blocked the entry of Na(+) and Ca(2+) activated by veratridine and NMDA, respectively. These results suggest that Na(+) and Ca(2+) channels could contribute to the neuroprotective properties of sitiripentol.

  12. Fryns syndrome with Hirschsprung disease: support for possible neural crest involvement.

    PubMed

    Alkuraya, Fowzan S; Lin, Angela E; Irons, Mira B; Kimonis, Virginia E

    2005-01-15

    Fryns syndrome is an autosomal recessive multiple congenital anomaly/mental retardation syndrome characterized by coarse face, distal limb hypoplasia, and diaphragmatic anomalies. We describe a newborn girl with Fryns syndrome and Hirschsprung disease, an association that has been reported in five previous cases. These patients support the hypothesis that the neural crest plays a role in the pathogenesis of Fryns syndrome. Clinically asymptomatic or subtle anomalies that are in the spectrum of neural crest maldevelopment should be sought in all patients with Fryns syndrome including stillbirths, neonatal deaths, as well as long-term survivors. We suspect that the clinical observation about Hirschsprung disease and Fryns syndrome may provide insight into its molecular mechanisms and candidate genes.

  13. Disintegration of lysosomes mediated by GTPgammaS-treated cytosol: possible involvement of phospholipases.

    PubMed

    Sai, Y; Matsuda, T; Arai, K; Ohkuma, S

    1998-04-01

    We showed previously that cytosol treated with guanosine 5'-O-(3-thiotriphosphate) (GTP-gammaS) disintegrated lysosomes in vitro [Sai, Y. et al. (1994) Biochem. Biophys. Res. Commun. 198, 869-877] in time-, temperature-, and dose-dependent manners. This also requires ATP, however, the latter can be substituted with deoxy-ATP, ADP, or ATPgammaS, suggesting no requirement of ATP hydrolysis. The lysis was inhibited by several chemical modifiers, including N-ethylmaleimide, 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole, and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, and by various phospholipase inhibitors (trifluoperazine, p-bromophenacyl bromide, nordihydroguaiaretic acid, W-7, primaquine, compound 48/80, neomycin, and gentamicin), but not by ONO-RS-082, an inhibitor of phospholipase A2. The reaction was also inhibited by phospholipids (phosphatidylinositol, phosphatidylserine, phosphatidic acid, and phosphatidylcholine) and diacylglycerol. Among the phospholipase A2 hydrolysis products of phospholipids, unsaturated fatty acids (oleate, linoleate, and arachidonate) and lysophospholipid (lysophosphatidylcholine) by themselves broke lysosomes down directly, whereas saturated fatty acids (palmitate and stearate) had little effect. We found that GTPgammaS-stimulated cytosolic phospholipase A2 activity was highly sensitive to ONO-RS-082. These results suggest the participation of phospholipase(s), though not cytosolic phospholipase A2, in the GTPgammaS-dependent lysis of lysosomes.

  14. Possible involvement of basic FGF in the upregulation of PDGFRβ in pericytes after ischemic stroke.

    PubMed

    Nakamura, Kuniyuki; Arimura, Koichi; Nishimura, Ataru; Tachibana, Masaki; Yoshikawa, Yoji; Makihara, Noriko; Wakisaka, Yoshinobu; Kuroda, Junya; Kamouchi, Masahiro; Ooboshi, Hiroaki; Kitazono, Takanari; Ago, Tetsuro

    2016-01-01

    Central nervous system (CNS) pericytes have been recognized as an indispensable component of the neurovascular unit. The expression of platelet-derived growth factor receptor β (PDGFRβ) is markedly increased in CNS pericytes after brain ischemia. It has been elucidated that PDGFRβ, expressed in pericytes and pericyte-derived fibroblast-like cells, plays important roles in the maintenance of the blood-brain barrier (BBB) and in the repair process in infarct areas. The aim of this study was to uncover how the PDGFRβ expression is regulated in pericytes after brain ischemia. We found that basic fibroblast growth factor (bFGF), but neither hypoxia at 1% O2 nor acidification at pH 6.5, significantly upregulated the PDGFRβ expression in human cultured CNS pericytes. SU5402, an inhibitor of FGF receptor (FGFR), and inhibitors of its downstream effectors Akt and Erk abolished the bFGF-induced upregulation of PDGFRβ. On the other hand, acidification significantly upregulated the expression of bFGF, while hypoxia upregulated the expression of FGFR1 in the pericytes. The expression of bFGF and FGFR1 was markedly induced in the ischemic hemisphere after ischemic insult in a middle cerebral artery occlusion stroke model. Immunofluorescent double labeling demonstrated that the expression of bFGF and FGFR1 was co-localized with PDGFRβ-positive cells in peri-infarct areas. Moreover, treatment with bFGF enhanced cell growth and the PDGF-BB-induced migratory activity of cultured pericytes, which were significantly suppressed by SU5402 or Sunitinib, an inhibitor of PDGFR. These data suggested that increased bFGF upregulates the expression of PDGFRβ and may enhance PDGFRβ-mediated pericyte functions after brain ischemia.

  15. Possible involvement of microRNAs in vascular damage in experimental chronic kidney disease.

    PubMed

    Taïbi, Fatiha; Metzinger-Le Meuth, Valérie; M'Baya-Moutoula, Eléonore; Djelouat, Mohamed seif el Islam; Louvet, Loïc; Bugnicourt, Jean-Marc; Poirot, Sabrina; Bengrine, Abderrahmane; Chillon, Jean-Marc; Massy, Ziad A; Metzinger, Laurent

    2014-01-01

    Chronic kidney disease (CKD) is associated with vascular calcifications and atherosclerosis. There is a need for novel predictors to allow earlier diagnosis of these disorders, predict disease progression, and improve assessment of treatment response. We focused on microRNAs since they are implicated in a variety of cellular functions in cardiovascular pathology. We examined changes of microRNA expression in aortas of CKD and non-CKD wild type mice and apolipoprotein E knock-out mice, respectively. Both vascular smooth muscle-specific miR-143 and miR-145 expressions were decreased in states of atherosclerosis and/or CKD or both, and the expression level of protein target Myocardin was increased. The inflammatory miR-223 was increased in more advanced stages of CKD, and specific protein targets NFI-A and GLUT-4 were dramatically decreased. Expression of miR-126 was markedly increased and expression of protein targets VCAM-1 and SDF-1 was altered during the course of CKD. The drug sevelamer, commonly used in CKD, corrected partially these changes in microRNA expression, suggesting a direct link between the observed microRNA alterations and uremic vascular toxicity. Finally, miR-126, -143 and -223 expression levels were deregulated in murine serum during the course of experimental CKD. In conclusion, these miRNAs could have role(s) in CKD vascular remodeling and may therefore represent useful targets to prevent or treat complications of CKD.

  16. Human breast areolae as scent organs: morphological data and possible involvement in maternal-neonatal coadaptation.

    PubMed

    Schaal, Benoist; Doucet, Sébastien; Sagot, Paul; Hertling, Elisabeth; Soussignan, Robert

    2006-03-01

    In humans, areolar skin glands (AG) enlarge during pregnancy and lactation. Their role in mother-infant interactions may pertain to protective, mechanical, and communicative functions. It was questioned here whether more profuse AG could be related to more optimal adaptation to breastfeeding. A morphological study of the areolae was undertaken between birth and day 3 to assess the number, secretory status, and spatial distribution of AG. These data were related to infants' weight variation, mothers' perception of their infant's behavior at breast, and time between delivery and onset of lactation. AG were seen in virtually all women but with great interindividual variations; their areolar distribution was nonrandom, and about 1/5 of the women had AG giving off a secretion. The AG number was positively related with neonatal weight gain between birth and day 3, and with the mother's perception of infant's latching speed and sucking activity. AG numbers were also positively related with the onset of lactation in first-time mothers. In conclusion, the maternal endowment in AG may contribute to the infants' breastfeeding performance, early growth, and the mother's lactation onset.

  17. Effect of paternal overweight or obesity on IVF treatment outcomes and the possible mechanisms involved

    PubMed Central

    Yang, Qingling; Zhao, Feifei; Hu, Linli; Bai, Rui; Zhang, Nan; Yao, Guidong; Sun, Yingpu

    2016-01-01

    Leukocyte telomere lengths (LTLs) are shorter in obese compared with normal weight people. However, it is not known whether sperm telomere length (STL) is related to obesity. The aim of the study was to evaluate the impact of men’s body mass index (BMI) on STL, embryo quality, and clinical outcomes in couples undergoing IVF. In total, 651 couples were recruited, including 345 men with a normal BMI and 306 men with an overweight BMI (normal BMI group: 20–25 kg/m2; overweight BMI group: >28 kg/m2). We found that couples with male’s BMI over 28 kg/m2 exhibited a significantly lower fertilization rate, good-quality embryo rate and clinical pregnancy rate compared to their normal BMI counterparts. The mean STL in the overweight BMI group was also significantly shorter than that of the normal BMI group. The results also showed that individuals with higher BMI had higher ROS (Reactive oxygen species) content and sperm DNA fragmentation rate when compared with normal BMI individuals. Mitochondrial activity was also lower in the overweight BMI group than in the normal BMI group. This is the first report to find that STL is shorter in overweight/obese men, which may account for their poorer treatment outcomes in IVF cycles. PMID:27412918

  18. Possible involvement of put A gene in Helicobacter pylori colonization in the stomach and motility.

    PubMed

    Nakajima, Kazuhiko; Inatsu, Sakiko; Mizote, Tomoko; Nagata, Yoko; Aoyama, Kazue; Fukuda, Yoshihiro; Nagata, Kumiko

    2008-02-01

    H. pylori is a gram-negative bacterium associated with gastric inflammation and peptic ulcer and considered a risk factor for gastric cancer in its natural habitat. However, the energy metabolism of H. pylori in the stomach remains to be clarified. H. pylori shows rather high respiratory activity with L-proline and significantly large amounts of L-proline are present in the gastric juice from H. pylori infected patients. We constructed a disrupted mutant of the put A gene, which encodes the proline utilization A (Put A) flavin-linked enzyme, in order to examine the role of put A in the gastric colonization of H. pylori. The put A disrupted mutant, DeltaputA, was constructed by inserting a chloramphenicol resistant gene into put A. DeltaputA did not show respiratory activity using L-proline and could not incorporate L-proline into cells. DeltaputA also did not show motility in response to amino acids and did not display the swarming activity observed with the wild-type. DeltaputA had lost its ability to colonize the stomach of nude mice, an ability possessed by the wild-type. These findings indicate that put A may play an important role in H. pylori colonization on the gastric mucus layer.

  19. Are immunological mechanisms involved in colon cancer and are they possible markers for biotherapy improvement?

    PubMed

    Berghella, Anna Maria; Contasta, Ida; Pellegrini, Patrizia; Del Beato, Tiziana; Adorno, Domenico

    2006-10-01

    This paper focuses on our data on colon cancer patients. Our overall results lead us to believe that the suppressive effect of specific cytokines in colon cancer patients alters the functionality of TH1 and TH2 subsets of CD4+ T-cells, with an expansion of TH2 cells and a malfunctioning of TH1 cells. This immunological disregulation appears to increase with stage progression, suggesting a direct role in the mechanisms that allow the tumour to locate and expand within the host. It is also clear that in order to identify disease markers and generate an in vivo immune response that corrects the imbalance between TH1 and TH2 cells, we need to understand how tumour mechanisms cause this imbalance to begin with.

  20. Possible involvement of programmed cell death pathways in the neuroprotective action of polyphenols.

    PubMed

    Bastianetto, S; Krantic, S; Chabot, J-G; Quirion, R

    2011-08-01

    One of the hallmarks of Alzheimer's disease is the accumulation of senile plaques composed of extra-cellular aggregates of beta-amyloid (Aβ) peptides. It is well established that at least in vitro, Aβ triggers apoptotic cell death via the activation of caspase-dependent and -independent cell death effectors, namely caspase-3 and apoptosis inducing factor (AIF), respectively. Epidemiological studies have reported that elderly people have a lower risk (up to 50%) of developing dementia if they regularly eat fruits and vegetables and drink tea and red wine (in moderation). Numerous studies indicate that polyphenols derived from these foods and beverages account for the observed neuroprotective effects. In particular, we have reported that polyphenols extracted from green tea (i.e. epigallocatechin gallate or EGCG) and red wine (i.e. resveratrol) block Aβ-induced hippocampal cell death, by at least partially inhibiting Aβ fibrillisation. It has been shown that polyphenols may also modulate caspase-dependent and -independent programmed cell death (PCD) pathways. Indeed, polyphenols including resveratrol, EGCG and luteolin significantly inhibit the activation of the key apoptotic executioner, caspase-3 and are able to modulate mitogen-activated protein kinases known to play an important role in neuronal apoptosis. Moreover, it has been reported that polyphenols may exert their anti-apoptotic action by inhibiting AIF release from mitochondria, thus providing new mechanism of action for polyphenols. This review aims to update the current knowledge regarding the differential effects of polyphenols on PCD pathways and discuss their putative neuroprotective action resulting from their capacity to modulate these pathways.

  1. Possible mechanism of psoralen phototoxicity not involving direct interaction with DNA

    SciTech Connect

    Laskin, J.D.; Lee, E.; Yurkow, E.J.; Laskin, D.L.; Gallo, M.A.

    1985-09-01

    Psoralens in combination with ultraviolet light (UVA; 320-400 nm) are used in the photochemical treatment of a variety of skin diseases including vitiligo, a skin depigmentational disorder, and psoriasis, a disease of accelerated epidermal cell proliferation. Although it is generally assumed that the major site of action of the psoralens is DNA, the authors have obtained evidence that another site may be the primary target for these compounds. They have identified specific, saturable, high-affinity binding sites for 8-methoxypsoralen on HeLa cells and have detected specific binding of 8-methoxypsoralen to four other human cell lines and five mouse cell lines. In HeLa cells, specific binding is reversible and independent of the ability of the compound to intercalate into DNA. In addition, binding sites become covalently modified by the psoralen after UVA exposure. Specific binding of 8-(methyoxy-/sup 3/H)methoxypsoralen constitutes 79% of the label bound to the cells. Scatchard analysis indicated two classes of psoralen binding sites. Based on these findings, the authors hypothesize that specific binding sites for psoralens on mammalian cells mediate, at least in part, psoralen-induced phototoxicity.

  2. Possible Involvement of α-Farnesene in the Development of Chilling Injury in Bananas

    PubMed Central

    Wills, Ron B. H.; Bailey, Wilf Mc.; Scott, Kevin J.

    1975-01-01

    The levels of the sesquiterpene hydrocarbon, α-farnesene were found to be higher in green bananas (Musa accuminata AAA) that were more susceptible to the development of chilling injury. The levels of α-farnesene were further increased by storage of the fruit at low temperature. PMID:16659343

  3. Mycobacterial contamination of metalworking fluids: involvement of a possible new taxon of rapidly growing mycobacteria.

    PubMed

    Moore, J S; Christensen, M; Wilson, R W; Wallace, R J; Zhang, Y; Nash, D R; Shelton, B

    2000-01-01

    Contamination of air and metalworking fluid (MWF) systems with a rapidly growing mycobacterium (RGM) was detected in 1995 in a single manufacturing plant with recent cases of hypersensitivity pneumonitis (HP). Extensive environmental sampling was performed to determine the extent of the contamination and its variability over time. RGM were present in multiple indoor air samples, 100% of the central MWF storage tanks, and 75% of the freestanding cutting, drilling, and grinding machines. With one exception, contamination was limited to a recently introduced formulation (brand) of semisynthetic MWF used in 95% of the facility's machining operations. In general, the mycobacterial counts were stable over time, with the degree of contamination ranging from 10(2)-10(7) colony forming units (CFU)/mL. A few systems were culture positive for the mycobacterium (> 10(1) CFU/mL), changed to culture negative (< 10(1) CFU/mL), then changed back to culture positive without explanation. Samples obtained from diluted (5%) but unused MWF, a replenishment line with 2% unused MWF, an MWF pasteurizer, city water, and deionized water were culture negative for this species of mycobacterium. Inoculation and growth studies demonstrated that this mycobacterium does not grow in liquid samples of 5% unused MWF. By molecular techniques, the mycobacterial isolates consisted of a single strain and represented a previously undescribed taxon closely related to Mycobacterium chelonae/abscessus. The relationship of this mycobacterium to the cases of HP is unknown.

  4. Biodeterioration Risk Threatens the 3100 Year Old Staircase of Hallstatt (Austria): Possible Involvement of Halophilic Microorganisms

    PubMed Central

    Piñar, Guadalupe; Dalnodar, Dennis; Voitl, Christian; Reschreiter, Hans; Sterflinger, Katja

    2016-01-01

    Background The prosperity of Hallstatt (Salzkammergut region, Austria) is based on the richness of salt in the surrounding mountains and salt mining, which is documented as far back as 1500 years B.C. Substantial archaeological evidence of Bronze and Iron Age salt mining has been discovered, with a wooden staircase (1108 B.C.) being one of the most impressive and well preserved finds. However, after its discovery, fungal mycelia have been observed on the surface of the staircase, most probably due to airborne contamination after its find. Objective As a basis for the further preservation of this valuable object, the active micro-flora was examined to investigate the presence of potentially biodegradative microorganisms. Results Most of the strains isolated from the staircase showed to be halotolerant and halophilic microorganisms, due to the saline environment of the mine. Results derived from culture-dependent assays revealed a high fungal diversity, including both halotolerant and halophilic fungi, the most dominant strains being members of the genus Phialosimplex (synonym: Aspergillus). Additionally, some typical cellulose degraders, namely Stachybotrys sp. and Cladosporium sp. were detected. Numerous bacterial strains were isolated and identified as members of 12 different genera, most of them being moderately halophilic species. The most dominant isolates affiliated with species of the genera Halovibrio and Marinococcus. Halophilic archaea were also isolated and identified as species of the genera Halococcus and Halorubrum. Molecular analyses complemented the cultivation assays, enabling the identification of some uncultivable archaea of the genera Halolamina, Haloplanus and Halobacterium. Results derived from fungi and bacteria supported those obtained by cultivation methods, exhibiting the same dominant members in the communities. Conclusion The results clearly showed the presence of some cellulose degraders that may become active if the requirements for growth and the environmental conditions turn suitable; therefore, these microorganisms must be regarded as a threat to the wood. PMID:26885815

  5. Possible Involvement of Al-Induced Electrical Signals in Al Tolerance in Wheat.

    PubMed Central

    Papernik, L. A.; Kochian, L. V.

    1997-01-01

    The relationship between Al-induced depolarization of root-cell transmembrane electrical potentials (Em) and Al tolerance in wheat (Triticum aestivum L.) was investigated. Al exposure induced depolarizations of Em in the Al-tolerant wheat cultivars Atlas and ET3, but not in the Al-sensitive wheat cultivars Scout and ES3. The depolarizations of Em occured in root cap cells and as far back as 10 mm from the root tip. The depolarization was specific to Al3+; no depolarization was observed when roots were exposed to the rhizotoxic trivalent cation La3+. The Al-induced depolarization occurred in the presence of anion-channel antagonists that blocked the release of malate, indicating that the depolarization is not due to the electrogenic efflux of malate2-. K+-induced depolarizations in the root cap were of the same magnitude as Al-induced depolarizations, but did not trigger malate release, indicating that Al-induced depolarization of root cap cell membrane potentials is probably linked to, but is not sufficient to trigger, malate release. PMID:12223834

  6. Possible involvement of the circadian pathway in alcohol use disorder in a South African adolescent cohort.

    PubMed

    Dalvie, Shareefa; King, Anthony; Fein, George; Ramesar, Raj; Stein, Dan J

    2016-02-01

    Alcoholism has an estimated heritability of between 40 and 60% and it is thought that several genes of small effect may contribute to the risk of developing this disorder. Studies of the genetics of alcohol use disorder (AUD) may, however, be confounded by issues of comorbidity. The aim of this investigation was to assess associations between variants in a range of candidate genes and AUD in a unique sample of adolescents without comorbidity. Our cohort consisted of 80 adolescents with an AUD diagnosis and 80 matched controls of mixed ancestry ethnicity. An Illumina Infinium iSelect custom 6000 bead chip was used to genotype 5348 SNPs in 378 candidate genes. Association analysis, gene-based analysis and polygenic scoring were performed. There was no statistical association between any of the investigated SNPs and AUD after correction for multiple testing. However, from the gene-based analysis it was found that the circadian rhythm genes NR1D1 and BHLHE41 are associated with AUD. While preliminary, these data provide some evidence that the circadian pathway may be relevant to the pathophysiology of AUD. Study of early onset non-comorbid populations with AUD may be useful in identifying target genes for study in larger more representative samples.

  7. Involvement of peripheral artemin signaling in tongue pain: possible mechanism in burning mouth syndrome.

    PubMed

    Shinoda, Masamichi; Takeda, Mamoru; Honda, Kuniya; Maruno, Mitsuru; Katagiri, Ayano; Satoh-Kuriwada, Shizuko; Shoji, Noriaki; Tsuchiya, Masahiro; Iwata, Koichi

    2015-12-01

    Burning mouth syndrome is characterized by altered sensory qualities, namely tongue pain hypersensitivity. We found that the mRNA expression of Artemin (Artn) in the tongue mucosa of patients with burning mouth syndrome was significantly higher than that of control subjects, and we developed a mouse model of burning mouth syndrome by application of 2,4,6-trinitrobenzene sulfonic acid (TNBS) diluted with 50% ethanol to the dorsum of the tongue. TNBS treatment to the tongue induced persistent, week-long, noninflammatory tongue pain and a significant increase in Artn expression in the tongue mucosa and marked tongue heat hyperalgesia. Following TNBS treatment, the successive administration of the transient receptor potential vanilloid 1 (TRPV1) antagonist SB366791 or neutralizing anti-Artn antibody completely inhibited the heat hyperalgesia. The number of glial cell line-derived neurotrophic factor family receptor α3 (GFRα3)-positive and TRPV1-positive trigeminal ganglion (TG) neurons innervating the tongue significantly increased following TNBS treatment and was significantly reduced by successive administration of neutralizing anti-Artn antibody. The capsaicin-induced current in TG neurons innervating the tongue was enhanced following TNBS treatment and was inhibited by local administration of neutralizing anti-Artn antibody to the tongue. These results suggest that the overexpression of Artn in the TNBS-treated tongue increases the membrane excitability of TG neurons innervating the tongue by increasing TRPV1 sensitivity, which causes heat hyperalgesia. This model may be useful for the study of tongue pain hypersensitivity associated with burning mouth syndrome.

  8. Evaluation of the analgesic effect of alkaloid extract of Peganum harmala L.: possible mechanisms involved.

    PubMed

    Farouk, Loubna; Laroubi, Amine; Aboufatima, Rachida; Benharref, Ahmed; Chait, Abderrahman

    2008-02-12

    The seeds of Peganum harmala L. (Pgh) (Zygophyllaceae) have been used in Moroccan traditional medicine for treatment of a various diseases and to relieve dolorous process. The major objective of this paper was to investigate the mechanism of the analgesia induced by alkaloid extract of Peganum harmala. In the present work, the antinociceptive action was assayed in several experimental models in mice: writhing, formalin, and hot plate tests. The alkaloid extract (12.5 and 25mg/kg) and in a dose-dependent manner significantly reduced the nociception by acetic acid intraperitoneal injection (p<0.001). In the formalin test, the extract also significantly reduced the painful stimulus in both phases of the test (p<0.001). Treatment with the extract when given by (i.p. or i.c.v.) or with morphine (10mg/kg, i.p.) produced a significant increase of the reaction time in hot plate test. These result showed that the alkaloid extract of Pgh contains active analgesic principles acting both centrally and peripherally. Furthermore, this antinociceptive effect has been avoided by naloxone at a dose of 1mg/kg in the first phase of formalin and hot plate tests indicating that this extract act partly through an opioid-mediated mechanism. In conclusion, the alkaloid extract of Peganum harmala seems to have both central and peripheral antinociceptive activities which may be mediated by opioid receptors.

  9. Penis Fracture: Is It Possible?

    MedlinePlus

    Healthy Lifestyle Sexual health Is it possible to fracture your penis? Answers from Landon Trost, M.D. Yes. Although rare, penis fracture ... Original article: http://www.mayoclinic.org/healthy-lifestyle/sexual-health/expert-answers/penis-fracture/faq-20058154 . Mayo Clinic ...

  10. Exploring the Possibilities of Technology

    ERIC Educational Resources Information Center

    Fanton, Jonathan F.

    2006-01-01

    Over the last few years, the Board and staff of the MacArthur Foundation have been exploring the implications of the digital age. They are engaged in a continuous and purposeful meditation on technological innovations and their possibilities for all the work they do. Their working hypothesis is that the digital revolution will rank with the…

  11. Possible Ice Lenses on Mars

    NASA Astrophysics Data System (ADS)

    Raitala, J.; Aittola, M.; Korteniemi, J.; Öhman, T.; Törmänen, T.; Kukkonen, S.

    2010-03-01

    In a crater on Noachis Terra there are domes within a narrow crater floor unit. The unit is connected to a channel that breaches the crater rim. In this study we discuss of a possible pingo-like characteristics of the domes.

  12. Environmental Education: Practice and Possibility.

    ERIC Educational Resources Information Center

    Robottom, Ian, Ed.

    This collection of essays describes practices in environmental education and points to possibilities in the field. The intention is to appraise selected practices in order to prepare the ground for a consideration of alternative images of environmental education that may shape future action. The following articles are included: (1) "A…

  13. Medical office design: new possibilities.

    PubMed

    Malkin, J

    1992-01-01

    In summary, I have presented some unique projects that boldly deviate from our expectations for healthcare facilities. Perhaps this will inspire design professionals to look for opportunities to challenge "formula design" and to envision new possibilities for the 21st century. Remember that design professionals are creating the future today with every project they design.

  14. Possible role of hemichannels in cancer

    PubMed Central

    Schalper, Kurt A.; Carvajal-Hausdorf, Daniel; Oyarzo, Mauricio P.

    2014-01-01

    In humans, connexins (Cxs) and pannexins (Panxs) are the building blocks of hemichannels. These proteins are frequently altered in neoplastic cells and have traditionally been considered as tumor suppressors. Alteration of Cxs and Panxs in cancer cells can be due to genetic, epigenetic and post-transcriptional/post-translational events. Activated hemichannels mediate the diffusional membrane transport of ions and small signaling molecules. In the last decade hemichannels have been shown to participate in diverse cell processes including the modulation of cell proliferation and survival. However, their possible role in tumor growth and expansion remains largely unexplored. Herein, we hypothesize about the possible role of hemichannels in carcinogenesis and tumor progression. To support this theory, we summarize the evidence regarding the involvement of hemichannels in cell proliferation and migration, as well as their possible role in the anti-tumor immune responses. In addition, we discuss the evidence linking hemichannels with cancer in diverse models and comment on the current technical limitations for their study. PMID:25018732

  15. Deep exploration possibilities along the Quachita trend

    SciTech Connect

    Keller, G.R. )

    1991-03-01

    The late Paleozoic Ouachita orogeny produced a sinuous deformed belt that extends from Alabama through Mississippi, Arkansas, Oklahoma, Texas, and finally southward into Mexico. Recent geophysical studies have provided important new data that make it possible to reevaluate exploration possibilities along the Ouachita trend. A deep seismic study alo profile extending from the Ouachita Mountains in southwestern Arkansas into northwestern Louisiana has provided a surprisingly clear image of the early Paleozoic continental margin in the area. This margin is largely undeformed and suggests that the Ouachita orogeny involved little if any shortening of continental crust. Along with gravity data, this result implies that Ouachita thrusts are thin-skinned structures that include features such as the Benton and Broken Bow uplifts. Using these results as a base from which to build, the author has been able to trace this margin southeastward into Mississippi and westward through Texas and into Mexico. Although some production has been established in Ouachita facies rocks, gravity anomalies and limited amounts of seismic data suggest that two subthrusts plays have potential. In addition, there are areas where completely new subthrusts basins are possible. The second play is the early Paleozoic continental margin and rift basins that formed during the early stages of its development. His results to data indicate that these features are not greatly deformed and are at economically drillable depths in many areas. However, the area south of the Paleozoic continental margin should be avoided because the thickness of Ouachita facies rocks exceeds 10 km.

  16. 20 CFR 655.208 - Temporary labor certification applications involving fraud or willful misrepresentation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... involving fraud or willful misrepresentation. 655.208 Section 655.208 Employees' Benefits EMPLOYMENT AND... Temporary labor certification applications involving fraud or willful misrepresentation. (a) If possible fraud or willful misrepresentation involving a temporary labor certification application is...

  17. 20 CFR 655.208 - Temporary labor certification applications involving fraud or willful misrepresentation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... involving fraud or willful misrepresentation. 655.208 Section 655.208 Employees' Benefits EMPLOYMENT AND... Temporary labor certification applications involving fraud or willful misrepresentation. (a) If possible fraud or willful misrepresentation involving a temporary labor certification application is...

  18. 20 CFR 655.208 - Temporary labor certification applications involving fraud or willful misrepresentation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... involving fraud or willful misrepresentation. 655.208 Section 655.208 Employees' Benefits EMPLOYMENT AND... Temporary labor certification applications involving fraud or willful misrepresentation. (a) If possible fraud or willful misrepresentation involving a temporary labor certification application is...

  19. Drug hypersensitivity reactions involving skin.

    PubMed

    Hausmann, Oliver; Schnyder, Benno; Pichler, Werner J

    2010-01-01

    Immune reactions to drugs can cause a variety of diseases involving the skin, liver, kidney, lungs, and other organs. Beside immediate, IgE-mediated reactions of varying degrees (urticaria to anaphylactic shock), many drug hypersensitivity reactions appear delayed, namely hours to days after starting drug treatment, showing a variety of clinical manifestations from solely skin involvement to fulminant systemic diseases which may be fatal. Immunohistochemical and functional studies of drug-specific T cells in patients with delayed reactions confirmed a predominant role for T cells in the onset and maintenance of immune-mediated delayed drug hypersensitivity reactions (type IV reactions). In these reactions, drug-specific CD4+ and CD8+ T cells are stimulated by drugs through their T cell receptors (TCR). Drugs can stimulate T cells in two ways: they can act as haptens and bind covalently to larger protein structures (hapten-carrier model), inducing a specific immune response. In addition, they may accidentally bind in a labile, noncovalent way to a particular TCR of the whole TCR repertoire and possibly also major histocompatibility complex (MHC)-molecules - similar to their pharmacologic action. This seems to be sufficient to reactivate certain, probably in vivo preactivated T cells, if an additional interaction of the drug-stimulated TCR with MHC molecules occurs. The mechanism was named pharmacological interaction of a drug with (immune) receptor and thus termed the p-i concept. This new concept may explain the frequent skin symptoms in drug hypersensitivity to oral or parenteral drugs. Furthermore, the various clinical manifestations of T cell-mediated drug hypersensitivity may be explained by distinct T cell functions leading to different clinical phenotypes. These data allowed a subclassification of the delayed hypersensitivity reactions (type IV) into T cell reactions which, by releasing certain cytokines and chemokines, preferentially activate and recruit

  20. Microstructural lines involving luminescence

    NASA Astrophysics Data System (ADS)

    Shimada, Kazuhiko

    2004-06-01

    Japanese National Printing Bureau has been focused upon the development of anti-copy lines for many years. The basic concept with regard to security measure lies in the merge of art and technology. On this basis, our originally developed anti-copy lines show flexibility to various security designs. Our newest anti-copy lines comprising from the Tri-Branched and Divided Lines shows clearer latent image effect compared to that of our other developed anti-copy lines. However, the anti-copy effect of security printing lines with microstructure is deteriorating due to the emergence of digital image techniques with higher resolution. In this situation, this paper introduces a new security measure comprising from luminescence and security printing lines with microstructure. It gives rise to a latent image effect under UV light due to the characteristic microstructure while visually same density. The principle advantage is that the combination of the anti-copy and luminescent feature strongly enhances its secure effect in documents. There is no necessity of two kinds of inks and any specially designed equipment to produce security documents with microstructural lines involving luminescence.

  1. Hand involvement in multiple hereditary exostosis.

    PubMed

    Wood, V E; Molitor, C; Mudge, M K

    1990-11-01

    In summary, patients with multiple hereditary exostosis often inherit hand involvement but rarely show hand deformity. The principal area of involvement appears to be around the MCP joint but the PIP joint is the most common area of deformity. Metacarpal shortening usually does not cause functional problems and need not be treated. Angular deformity, though rare, does cause problems and needs surgical treatment. Unfortunately, there is no evidence that prevention of deformity is possible by early excision of osteochondromas. Treatment, therefore, requires both osteochondroma excision and closing-wedge corrective osteotomy.

  2. Possible theophylline toxicity during anesthesia.

    PubMed Central

    Redden, R. J.

    1996-01-01

    Asthmatic patients who undergo outpatient anesthesia are typically prescribed one or more drugs for treatment. Some of these agents have narrow therapeutic ranges and are associated with potentially serious adverse reactions, toxic effects, or drug interactions. Various clinical signs of toxicity may be first uncovered during routine monitoring of an office anesthetic. The case reported here demonstrates the need for proper understanding of the asthmatic patient's medical history and an appreciation for the medications used to control the disease. A sudden cardiovascular event possibly related to drug toxicity is witnessed and treated in an asthmatic patient during intravenous sedation. A possible drug interaction with a non-asthmatic medication taken concomitantly by the patient is implicated and discussed. In addition to the case report, the broad classification of drugs employed for bronchial asthma and their effects is reviewed. PMID:10323129

  3. Possible theophylline toxicity during anesthesia.

    PubMed

    Redden, R J

    1996-01-01

    Asthmatic patients who undergo outpatient anesthesia are typically prescribed one or more drugs for treatment. Some of these agents have narrow therapeutic ranges and are associated with potentially serious adverse reactions, toxic effects, or drug interactions. Various clinical signs of toxicity may be first uncovered during routine monitoring of an office anesthetic. The case reported here demonstrates the need for proper understanding of the asthmatic patient's medical history and an appreciation for the medications used to control the disease. A sudden cardiovascular event possibly related to drug toxicity is witnessed and treated in an asthmatic patient during intravenous sedation. A possible drug interaction with a non-asthmatic medication taken concomitantly by the patient is implicated and discussed. In addition to the case report, the broad classification of drugs employed for bronchial asthma and their effects is reviewed.

  4. Applying Employee Involvement in Schools.

    ERIC Educational Resources Information Center

    Mohrman, Susan Albers; And Others

    1992-01-01

    The applicability of employee-involvement approaches to the management of schools is explored, describing three approaches (parallel-suggestion involvement, job involvement, and high involvement). Design issues (technology; organizational structure; leadership; organizational boundaries, customer definition, and relation to stakeholder; measures;…

  5. Possible high magnification microlensing event

    NASA Astrophysics Data System (ADS)

    Udalski, Andrzej; Szymanski, Michal

    1998-05-01

    The OGLE team informs about a microlensing event in progress - OGLE-1998-BUL-15 (18:07:20.83, -27:34:10.8, J2000) which is presently about 4 days before maximum and is rising rapidly (already more than 2 mag above the normal level). Preliminary fit to the light curve predicts possible maximum magnification as large as 10 mag and maximum on JD=2450945.2. Follow up observations, both photometric and spectroscopic, are strongly encouraged.

  6. Current possibilities for hip arthroplasty.

    PubMed

    Polesello, Giancarlo Cavalli; Pereira Guimarães, Rodrigo; Ricioli Júnior, Walter; Keiske Ono, Nelson; Kiyoshi Honda, Emerson; Cavalheiro de Queiroz, Marcelo

    2014-01-01

    Hip arthroscopy has been popularized over the last decade and, with technical advances regarding imaging diagnostics, understanding of the physiopathology or surgical techniques, several applications have been described. Both arthroscopy for intra-articular conditions and endoscopy for extra-articular procedures can be used in diagnosing or treating different conditions. This updated article has the objective of presenting the various current possibilities for hip arthroscopy.

  7. The Possibilities of Network Sociality

    NASA Astrophysics Data System (ADS)

    Willson, Michele

    Technologically networked social forms are broad, extensive and in demand. The rapid development and growth of web 2.0, or the social web, is evidence of the need and indeed hunger for social connectivity: people are searching for many and varied ways of enacting being-together. However, the ways in which we think of, research and write about network(ed) sociality are relatively recent and arguably restricted, warranting further critique and development. This article attempts to do several things: it raises questions about the types of sociality enacted in contemporary techno-society; critically explores the notion of the networked individual and the focus on the individual evident in much of the technology and sociality literature and asks questions about the place of the social in these discussions. It argues for a more well-balanced and multilevelled approach to questions of sociality in networked societies. The article starts from the position that possibilities enabled/afforded by the technologies we have in place have an effect upon the ways in which we understand being in the world together and our possible actions and futures. These possibilities are more than simply supplementary; in many ways they are transformative. The ways in which we grapple with these questions reveals as much about our understandings of sociality as it does about the technologies themselves.

  8. Multidrug toxicity involving sumatriptan.

    PubMed

    Knittel, Jessica L; Vorce, Shawn P; Levine, Barry; Hughes, Rhome L; Bosy, Thomas Z

    2015-01-01

    A multidrug fatality involving sumatriptan is reported. Sumatriptan is a tryptamine derivative that acts at 5-HT(1B/1D) receptors and is used for the treatment of migraines. The decedent was a 21-year-old white female found dead in bed by her spouse. No signs of physical trauma were observed and a large number of prescription medications were discovered at the scene. Toxicological analysis of the central blood revealed sumatriptan at a concentration of 1.03 mg/L. Following therapeutic dosing guidelines, sumatriptan concentrations do not exceed 0.095 mg/L. Sumatriptan was isolated by solid-phase extraction and analyzed using liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode. A tissue distribution study was completed with the following concentrations measured: 0.61 mg/L in femoral blood, 0.56 mg/L in iliac blood, 5.01 mg/L in urine, 0.51 mg/kg in liver, 3.66 mg/kg in kidney, 0.09 mg/kg in heart, 0.32 mg/kg in spleen, 0.01 mg/kg in brain, 15.99 mg/kg in lung and 78.54 mg/45 mL in the stomach contents. Carisoprodol, meprobamate, fluoxetine, doxylamine, orphenadrine, dextromethorphan and hydroxyzine were also present in the blood at the following concentrations: 3.35, 2.36, 0.63, 0.19, 0.06, 0.55 and 0.16 mg/L. The medical examiner ruled the cause of death as acute mixed drug toxicity and the manner of death as accident.

  9. KLK2 — EDRN Public Portal

    Cancer.gov

    The glandular kallikreins are a distinct group of serine proteases with molecular masses of 25,000 to 40,000. The glandular kallikrein gene family comprises 25 to 30 highly homologous genes that encode specific proteases involved in the processing of biologically active peptides (they cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin). Several human kallikrein genes have been isolated.

  10. The grief involved in change.

    PubMed

    Linney, B J

    1999-01-01

    In this era of rapid change, people need to be helped through the grieving process at work. "By acknowledging and articulating what is involved, you facilitate people's movement through it ... successful people in growing organizations need to learn to move through the process as quickly and efficiently as possible and help others do the same." Morris Shectman, in Working Without a Net says, "Contrary to the old paradigm--which held that others don't have a right to know about your personal life--the new paradigm says that it's a necessity that they know." If people are to move through the grief that is caused by undesired change, they will have to tell some of their personal feelings. "Each stage of the process--shock and denial, anger, bargaining, depression, and acceptance--is functional ... when people go through the process in a healthy manner, they'll recycle through it in a diluted fashion." Leaders in the organization can help people start the process or move through it if they get stuck at a particular stage.

  11. Possible Roles of Strigolactones during Leaf Senescence.

    PubMed

    Yamada, Yusuke; Umehara, Mikihisa

    2015-09-11

    Leaf senescence is a complicated developmental process that involves degenerative changes and nutrient recycling. The progress of leaf senescence is controlled by various environmental cues and plant hormones, including ethylene, jasmonic acid, salicylic acid, abscisic acid, cytokinins, and strigolactones. The production of strigolactones is induced in response to nitrogen and phosphorous deficiency. Strigolactones also accelerate leaf senescence and regulate shoot branching and root architecture. Leaf senescence is actively promoted in a nutrient-poor soil environment, and nutrients are transported from old leaves to young tissues and seeds. Strigolactones might act as important signals in response to nutrient levels in the rhizosphere. In this review, we discuss the possible roles of strigolactones during leaf senescence.

  12. [Suicidality and musical preferences: a possible link?].

    PubMed

    Mikolajczak, Gladys; Desseilles, Martin

    2012-01-01

    Music is an important part of young people's lives. In this article, we attempt to answer two questions on the links between music et suicide. First, we examine if certain types of music favor suicidal process (ideation and acting out); and, secondly, we examine if music can constitute a tool to reduce the risk of suicide. Several factors possibly involved in links between musical preferences and the suicidal process are developed: the Velten effect and the musical mood induction procedure, the identification and the learning by imitation, the media influence as well as the individual characteristics. A multifactor approach is necessary to understand the complex and birectional links that unite musical preferences and suicide risk.

  13. Exclusive Reactions Involving Pions and Nucleons

    NASA Technical Reports Server (NTRS)

    Norbury, John W.; Blattnig, Steve R.; Tripathi, R. K.

    2002-01-01

    The HZETRN code requires inclusive cross sections as input. One of the methods used to calculate these cross sections requires knowledge of all exclusive processes contributing to the inclusive reaction. Conservation laws are used to determine all possible exclusive reactions involving strong interactions between pions and nucleons. Inclusive particle masses are subsequently determined and are needed in cross-section calculations for inclusive pion production.

  14. Recent Experiments Involving Few-Nucleon Systems

    NASA Astrophysics Data System (ADS)

    Tornow, W.

    2014-08-01

    Recent experimental results are presented for reactions involving A = 3 to A = 6 nuclear systems. The emphasis is on unique data obtained at new experimental facilities. It is shown that the inertial confinement fusion facilities OMEGA and NIF provide a largely unexpected opportunity for experimental few-body physics to both obtain data of unprecedented quality and extend previous measurements to energies not accessible in the past. Whenever possible, data are compared to state-of-the-art theoretical calculations.

  15. Possible violations of spacetime symmetries

    NASA Astrophysics Data System (ADS)

    Urrutia, Luis

    2016-10-01

    The identification of symmetries has played a fundamental role in our understanding of physical phenomena. Nevertheless, in most cases such symmetries constitute only a zeroth-order approximation and they need to be broken so that the predictions of the theory are consistent with experimental observation. In particular, the almost sacred CPT and Lorentz symmetries, which are certainly part of the fundamental ideas of modern physics, need to be probed experimentally. Recently, such efforts have been intensified because different theoretical approaches aiming to understand the microstructure of space-time suggest the possibility that such symmetries could present minute violations. Up to now, and with increasing experimental sensitivities, no signs of violation have been found. Nevertheless, we observe that even the persistence of such negative results will have a profound impact. On one hand, they will provide those symmetries with a firm experimental basis. On the other, they will set stringent experimental bounds to be compared with the possible emergence of such violations in quantum gravity models based upon a discrete structure of space. We present a very general perspective of the research on Lorentz symmetry breaking, together with a review of a few specific topics.

  16. Pseudomonas biofilms: possibilities of their control.

    PubMed

    Masák, Jan; Čejková, Alena; Schreiberová, Olga; Rezanka, Tomáš

    2014-07-01

    Genus Pseudomonas includes a large number of species that can be encountered in biotechnological processes as well as in the role of serious human or plant pathogens. Pseudomonads easily form biofilms on various types of surfaces. The biofilm phenotype is characterized by an increased resistance to environmental influences including resistance to antibiotics and other disinfectants, causing a number of problems in health care, food industry, and other areas. Considerable attention is therefore paid to the possibilities of eradication/destruction of pseudomonads biofilms both in terms of understanding the mechanisms of biofilm formation and at the level of finding suitable antibiofilm tools applicable in practice. The first part of this review is devoted to an overview of the regulatory mechanisms that are directly or indirectly involved in the formation of biofilm. The most effective approaches to suppressing the formation of biofilm that do not cause the development of resistance are based on the application of substances that interfere with the regulatory molecules or block the appropriate regulatory mechanisms involved in biofilm development by the cells. Pseudomonads biofilm formation is, similar to other microorganisms, a sophisticated process with many regulatory elements. The suppression of this process therefore also requires multiple antibiofilm tools.

  17. [Prostate cancer: papillomaviruses as a possible cause].

    PubMed

    Volgareva, G M

    2015-01-01

    Prostate cancer (PC) incidence and mortality are steadily increasing. Causation of PC is not clearly understood; in particular, role of human papillomaviruses (HPV) is still disputable. The review contains analysis of literature data on possible participation of HPV powerful biological carcinogens, in PC genesis. PC incidence increase in persons with immunodeficiency indicates involvement of some infectious agent in the disease etiology. Several research groups communicated HPV DNA finding including that of oncogenic types in PC specimens (transrectal biopsies). There are limited data on the occurrence of oncogenic HPV 16 oncoprotein E7 in such specimens and on its unfavorable effect on disease prognosis. The successful attempt is known to transfect normal human prostate cells with oncogenic HPVDNA in vitro. Epidemiological data on associations of PC with HPV are controversial. It may result from the considered in the present review certain technical peculiarities of these studies. Controlfor serum antibodies to HPV E6 and E7 oncoproteins recognized to indicate HPV-positive tumor growth in an organism has not been performed yet in PC patients. DNA of oncogenic HPV is rather commonly found in organs adjacent to prostate--urethra, rectum, urinary bladder. In the study held in Russia on a group of healthy men examined for sexually transmitted diseases genitourinary HPVinfection was found in every second person; 42% of them harbored oncogenic HPV. Possible participation of oncogenic HPV in PC genesis deserves close attention and further study.

  18. Nail involvement in pemphigus vulgaris.

    PubMed

    Engineer, L; Norton, L A; Ahmed, A R

    2000-09-01

    Nail involvement in pemphigus vulgaris is relatively rare. We describe a case of severe pemphigus involving both the skin and oral mucosa in which an acute exacerbation was preceded by the onset of nail involvement of all 4 extremities. Nail involvement occurred in the form of hemorrhagic paronychia of multiple digits. Oral, cutaneous, and nail manifestations of the disease were all well controlled by systemic therapy. A review of the literature on nail involvement in pemphigus reveals that this involvement may be manifested in multiple ways, with chronic paronychia and onychomadesis being the most common. Involvement of the nail occurs most frequently either as part of the initial presentation, or just before or concurrent with a flare of pre-existing disease. Nail involvement, when it occurs, is usually present when the disease is severe. Topical therapy is insufficient, and systemic therapy is warranted. In the majority of cases, nail recovery is complete, with no residual damage.

  19. [Possibilities of psychoprophylaxis in epilepsy].

    PubMed

    Bilikiewicz, A

    1976-01-01

    The psychiatrist should be given also their share in the prevetion of epilepsy by means of raising the psychiatric culture of the society and teaching the population the principles of mental hygiene and psychoprophylaxia. The possibilities of psychiatry in prophylactic management of patients with developed epilepsy include: 1. Energetic measures for controlling attacks which has many psychoprophylactic aspects. 2. Prevention of psychotraumatizing situations leading to secondary neurotic, psychotic and other reactions and behaviour disorders of the type of homilopathy and sociopathy, 3. Counteracting the development of mental and social disability in epileptics. Treatment of epilepsy should be conducted from its very beginning in cooperation with psychiatrists and therapeutic psychologists. The probems of prophylaxis cannot be separated from prophylactic treatment, psychotherapy sociotherapy and rehabilitation.

  20. Possibilities for Relapsing Fever Reemergence

    PubMed Central

    2006-01-01

    Relapsing fever Borrelia infections have attracted little attention in recent years; however, where endemic, these infections still result in considerable illness and death. Despite the marked antimicrobial drug susceptibility of these organisms, therapy is often delayed through lack of clinical suspicion. With increasing travel, infections may be imported, through exotic relapsing fever infection or through resurgence of infected disease vectors. Although louseborne relapsing fever is now geographically limited, it was once of global importance. The possibility for reemergence was recently highlighted by the probable reemergence of louseborne relapsing fever in homeless persons from France. Host limitations enforced through louseborne transmission are less applicable for the tickborne forms of relapsing fever. Although the latter have reduced potential for epidemic spread, they have the ability to infect diverse hosts, thus establishing reservoirs of infection and presenting greater challenges for their control. PMID:16704771

  1. Possibility of ferromagnetic neutron matter

    NASA Astrophysics Data System (ADS)

    Hashimoto, Koji

    2015-04-01

    We study ferromagnetism at high density of neutrons in the QCD hadron phase, by using the simplest chiral effective model incorporating magnetic fields and the chiral anomaly. Under the assumption of spatial homogeneity, we calculate the energy density as a function of neutron density, with a magnetization and a neutral pion condensation in the style of Dautry and Neyman. We find that at a high density the energy of the ferromagnetic order is lower than that of the ordinary neutron matter, and the reduction effect is enhanced by the anomaly. Compared to the inhomogeneous phase with the alternating layer structure, our ferromagnetic phase turns out to be unfavored. However, once an axial vector meson condensation is taken into account in our simplest model, the ferromagnetic energy density is lowered significantly, which still leaves some room for a possible realization of a QCD ferromagnetic phase and ferromagnetic magnetars.

  2. Possible climates on terrestrial exoplanets.

    PubMed

    Forget, F; Leconte, J

    2014-04-28

    What kind of environment may exist on terrestrial planets around other stars? In spite of the lack of direct observations, it may not be premature to speculate on exoplanetary climates, for instance, to optimize future telescopic observations or to assess the probability of habitable worlds. To begin with, climate primarily depends on (i) the atmospheric composition and the volatile inventory; (ii) the incident stellar flux; and (iii) the tidal evolution of the planetary spin, which can notably lock a planet with a permanent night side. The atmospheric composition and mass depends on complex processes, which are difficult to model: origins of volatiles, atmospheric escape, geochemistry, photochemistry, etc. We discuss physical constraints, which can help us to speculate on the possible type of atmosphere, depending on the planet size, its final distance for its star and the star type. Assuming that the atmosphere is known, the possible climates can be explored using global climate models analogous to the ones developed to simulate the Earth as well as the other telluric atmospheres in the solar system. Our experience with Mars, Titan and Venus suggests that realistic climate simulators can be developed by combining components, such as a 'dynamical core', a radiative transfer solver, a parametrization of subgrid-scale turbulence and convection, a thermal ground model and a volatile phase change code. On this basis, we can aspire to build reliable climate predictors for exoplanets. However, whatever the accuracy of the models, predicting the actual climate regime on a specific planet will remain challenging because climate systems are affected by strong positive feedbacks. They can drive planets with very similar forcing and volatile inventory to completely different states. For instance, the coupling among temperature, volatile phase changes and radiative properties results in instabilities, such as runaway glaciations and runaway greenhouse effect.

  3. Measuring Parent Involvement Program Implementation.

    ERIC Educational Resources Information Center

    Abramson, Lisa S.

    1994-01-01

    Investigates implementation of the 1990-91 New York City Parent Involvement Program. The first section summarizes the research underlying development of methodology for measuring parent involvement program implementation across diverse program sites. The second section outlines a six-step data collection and measurement methodology involving site…

  4. Measuring Involvement with Social Issues.

    ERIC Educational Resources Information Center

    Nowak, Glen J.; Salmon, Charles T.

    A study applied research concepts from consumer product involvement to test a model for research on involvement with social issues. Issue involvement was defined as the state or level of perceived importance and/or interest evoked by a stimulus (issue) within a specific situation. Attitudes on four social issues--abortion, pornography, the…

  5. Parental Involvement in High Schools.

    ERIC Educational Resources Information Center

    Brian, Donna JG

    Although parental involvement is recommended at all levels of schooling, involvement of parents at the secondary level has not been well defined in the literature. This paper presents findings of a case study that examined three high schools with varying levels of parental involvement--the first, a large high school with a predominantly working…

  6. Families Get Involved! Learning Partners.

    ERIC Educational Resources Information Center

    Office of Educational Research and Improvement (ED), Washington, DC. Media and Information Services.

    Noting that families who are involved in their children's education make a difference in their child's performance, this two-page information sheet encourages families to get involved by listing the benefits of family involvement on one side and the ways adult family members can help in the school on the other. As a result of family participation:…

  7. Is Negotiated Arms Control Possible?

    NASA Astrophysics Data System (ADS)

    Panofsky, W. K. H.

    2014-11-01

    I had a very difficult time deciding on the topic of this talk, since Viki's interests cover such a broad range of activities with which I am also concerned. You can hear next week about the recent exciting work with the SLAC storage rings, a description of the design principles of such rings, and their future promise for new physics through Professor Richter's Loeb Lectures at Harvard. Talking about inelastic lepton scattering during an M.I.T. conference would be bringing coals to Newcastle, since the local M.I.T. physicists are primary agents in these experiments. Broad problems in high energy physics policy, for instance such questions as the relation between University users and the large laboratories, are matters of current concern to Viki and his friends in high energy physics, but I doubt whether many would sit still for a one-hour talk on that subject. I would therefore like to use the opportunity to express some personal views on certain current issues in arms control, since I know that there exists a wide spectrum of involvement and also opinion on this subject in the local community...

  8. Occupational Therapists' Beliefs and Involvement with Secondary Transition Planning

    ERIC Educational Resources Information Center

    Mankey, Tina A.

    2011-01-01

    The purpose of the study was to investigate the involvement and beliefs toward possible involvement of occupational therapy in one geographical area of the United States in regard to secondary transition planning for students with disabilities. Secondary transition planning is mandated by federal legislature and occurs while the student is…

  9. 5 CFR 351.701 - Assignment involving displacement.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 5 Administrative Personnel 1 2011-01-01 2011-01-01 false Assignment involving displacement. 351... REDUCTION IN FORCE Assignment Rights (Bump and Retreat) § 351.701 Assignment involving displacement. (a... lease possible reduction, in representative rate. The employee must be qualified for the...

  10. Democratic Involvement of Students in High School Governance in Lesotho

    ERIC Educational Resources Information Center

    Matsepe, Mokone W.

    2014-01-01

    This paper is premised on the thesis that there is importance and necessity of involving high school students in school governance in Lesotho as well as consideration of cultural values' impact on this issue. The possibilities and limits of involving the high school students in school governance in Lesotho are examined. There are two opposing…

  11. Possible Risk Factors for Increased Suicide Following Bariatric Surgery

    PubMed Central

    Mitchell, James E.; Crosby, Ross; de Zwaan, Martina; Engel, Scott; Roerig, James; Steffen, Kristine; Gordon, Kathryn H.; Karr, Trisha; Lavender, Jason; Wonderlich, Steve

    2015-01-01

    There is a growing research literature suggesting that there may be elevated risk of suicide following bariatric surgery. Most of the data reported thus far has been cross-sectional and observational, and very little is known about the possible specific causal variables involved. The purpose of this report is to review this literature and to review possible risk factors for increased suicidal risk following bariatric surgery, in order to delineate future research directions. First a variety of medical, biological, and genetic factors, including the persistence of recurrence of medical comorbidities after bariatric surgery, the disinhibition and impulsivity secondary to changes in the absorption of alcohol, hypoglycemia, as well as pharmacokinetic changes that may affect the absorption of various medications including antidepressant medications are reviewed. Also reviewed are possible mediating factors involving changes in various peptidergic systems such as GLP-1 and Ghrelin. A number of psychosocial issues that might be involved are discussed, including lack of improvement in quality of life after surgery, continued or recurrent physical mobility restrictions, persistence or recurrence of sexual dysfunction and relationship problems, low self-esteem, and a history of child maltreatment. Inadequate weight loss or weight regain are also discussed. Possible theoretical models involved and directions for research are suggested. PMID:23404774

  12. Possibilities of lasers within NOTES.

    PubMed

    Stepp, Herbert; Sroka, Ronald

    2010-10-01

    Lasers possess unique properties that render them versatile light sources particularly for NOTES. Depending on the laser light sources used, diagnostic as well as therapeutic purposes can be achieved. The diagnostic potential offered by innovative concepts such as new types of ultra-thin endoscopes and optical probes supports the physician with optical information of ultra-high resolution, tissue discrimination and manifold types of fluorescence detection. In addition, the potential 3-D capability promises enhanced recognition of tissue type and pathological status. These diagnostic techniques might enable or at least contribute to accurate and safe procedures within the spatial restrictions inherent with NOTES. The therapeutic potential ranges from induction of phototoxic effects over tissue welding, coagulation and tissue cutting to stone fragmentation. As proven in many therapeutic laser endoscopic treatment concepts, laser surgery is potentially bloodless and transmits the energy without mechanical forces. Specialized NOTES endoscopes will likely incorporate suitable probes for improving diagnostic procedures, laser fibres with advantageous light delivery possibility or innovative laser beam manipulation systems. NOTES training centres may support the propagation of the complex handling and the safety aspects for clinical use to the benefit of the patient.

  13. Possibilities of Engineering Ethics Education

    NASA Astrophysics Data System (ADS)

    Matsuki, Junya

    This paper discusses the possibilities of teaching engineering ethics in universities. This is based on the teaching experience of a newly developed course that has been introduced to the Department of Electrical and Electronic Engineering at the University of Fukui, since April 2004. Entitled “ethics for engineers”, the course targeted senior-level students and makes use of a newly written textbook that emphasizes social aspects of science and technology. To encourage students to think and form their own opinions with regards to their role as engineers in a modern technological society, the book is complemented by other materials such as videos, newspaper articles and some other relevant books. Students are also encouraged to write reports that reflect their own opinion on subjects such as what kind of engineers they intend to be, or what do ethics mean to them? The paper will conclude by giving a course evaluation including students' response, highlighting valuable experiences and stating the importance of further developing this topic in engineering education.

  14. Shenzhen: city of suspended possibility.

    PubMed

    Bach, Jonathan

    2011-01-01

    This essay on Shenzhen, China, presents three vignettes addressing the question of home in a city of migrants. The first section explores the ubiquitous narratives of success forming the city's foundational myth. The second follows this myth into the world of a Shenzhen filmmaker and his characters, as they navigate the tension between the idea of home and the urge to start anew, resulting in the suspended possibility of the title. The last section looks at young architects who hope to preserve the city's heterotopic sites of migrants and original villagers through architectural innovations. The cases show how an economy of desire supplements the political economy of this export-driven city. The city appears as an urban desiring machine that produces itself as an object of desire for the migrants of all classes who flock to its factories, "urban villages", white-collar jobs, luxury villas and underground economy. The essay is an encounter with the mythology of success and failure, the intertwining of home as an end and home as the beginning, and with the manipulation of space that allows residents to control their own subjectivity.

  15. Is JPC = 3-+ molecule possible?

    NASA Astrophysics Data System (ADS)

    Zhu, Wei; Liu, Yan-Rui; Yao, Tao

    2015-02-01

    The confirmation of charged charmonium-like states indicates that heavy quark molecules should exist. Here we discuss the possibility of a molecule state with JPC = 3-+. In a one-boson-exchange model investigation for the S wave C = + D*D¯2* states, one finds that the strongest attraction is in the case J = 3 and I = 0 for both π and σ exchanges. Numerical analysis indicates that this hadronic bound state might exist if a phenomenological cutoff parameter around 2.3 GeV (1.5 GeV) is reasonable with a dipole (monopole) type form factor in the one-pion-exchange model. The cutoff for binding solutions may be reduced to a smaller value once the σ exchange contribution is included. If a state around the D*D¯2* threshold (≈4472 MeV) in the channel J/ψω (P wave) is observed, the heavy quark spin symmetry implies that it is not a cc¯ meson and the JPC are likely to be 3-+. Supported by National Natural Science Foundation of China (11275115), Shandong Province Natural Science Foundation (ZR2010AM023), SRF for ROCS, SEM, and Independent Innovation Foundation of Shandong University

  16. Anal involvement in pemphigus vularis.

    PubMed

    Khezri, Somayeh; Mahmoudi, Hamid-Reza; Masoom, Seyedeh Nina; Daneshpazhooh, Maryam; Balighi, Kamran; Hosseini, S Hamed; Chams-Davatchi, Cheyda

    2013-01-01

    Background. Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin and mucosa. Anal mucosa may be involved in PV, but the frequency and clinical profile are not fully ascertained. Objective. The aim was to investigate the involvement of the anal area in newly diagnosed PV patients. Patients and Methods. A total of 168 consecutive newly diagnosed PV patients were enrolled. Anal symptoms and signs, involvement of other body sites, and severity of disease were recorded. Results. A total of 47 out of 168 patients (27.9%) had involvement of the anal area. Anal involvement was significantly associated with PV lesions in ophthalmic (P = 0.03), nasal (P = 0.02), and genital mucosa (P < 0.001) but not the oral cavity (P = 0.24). There was a significant association between number of involved mucosal sites and anal involvement (P < 0.001). Anal involvement was associated with oral severity (P = 0.02). Constipation was the most frequent symptom (73.8%) followed by pain on defecation (50%). Seventeen patients (36%) were symptom-free. Erosion was the most frequent sign (91.5%). Conclusion. Anal involvement in PV seems to be more frequent than previously assumed. Routine anal examination is recommended even in asymptomatic patients as anal involvement appears to correlate with the severity of PV.

  17. Sacroiliac joint involvement in psoriasis.

    PubMed

    Kaçar, Cahit; Sezer, Ilhan; Kocabaş, Hilal; Cay, Hasan Fatih; Cevikol, Can; Alpsoy, Erkan; Melikoğlu, Meltem Alkan; Akman, Ayşe

    2010-07-01

    Psoriasis is a skin disorder that is associated with arthritis. Sacroiliac joint involvement is considered to be less frequent than the other types of psoriatic arthritis. Additionally, the psoriatic sacroiliitis is considered to be asymmetric in general. We aimed to define the frequency and type of sacroiliac involvement in patients with psoriasis. Patients with psoriasis were included the study. Characteristics of skin, nail and articular involvement were noted. Psoriasis area and severity index was calculated. Antero-posterior pelvic X-rays were obtained and graded by two rheumatologists and a radiologist independently. One hundred and thirty-three patients were included. Thirty-seven of patients (27%) have articular involvement symptomatically. The sacroiliac joint involvement was observed in 34 (26%) of patients. More than one-half of sacroiliac involvement was bilateral while less than one-half was in symptomatic patients regarding sacroiliitis. Fifty-seven percentages of all patients have psoriatic nail involvement. Sacroiliac joint involvement did not show any significant association with psoriatic nail involvement or the severity of skin disease. We found higher frequency of sacroiliac joint involvement and bilateral sacroiliitis in patients with psoriasis. This is in contrast to present information about the association of psoriasis and sacroiliitis. These findings need confirmation by further studies and with more sophisticated techniques such as magnetic resonance imaging.

  18. Monoarticular Hip Involvement in Pseudogout

    PubMed Central

    Kocyigit, Figen; Kuyucu, Ersin; Kocyigit, Ali

    2015-01-01

    Pseudogout is the acutest form of arthritis in the elderly. Although clinical manifestations vary widely, polyarticular involvement is typical mimicking osteoarthritis or rheumatoid arthritis. Monoarticular involvement is relatively rare and is generally provoked by another medical condition. There are reported cases of hip involvement by pseudogout in monoarticular form. However, all of the cases were presented as septic arthritis. In this report, we present a case of monoarticular hip involvement mimicking soft tissue abscess. We confirmed the pseudogout diagnosis after ultrasonographic evaluation of the involved hip joint and pathological and biochemical analysis of synovial fluid analysis. Diagnosis is important to avoid unnecessary medical and surgical treatment in cases of the bizarre involvement of hip in pseudogout. PMID:25838961

  19. Making Space Travel to Jupiter Possible

    NASA Technical Reports Server (NTRS)

    Barker, Samuel P.

    2004-01-01

    From man landing on the moon to a simple satellite being launched into orbit, many incredible space accomplishments have been witnessed by us all. However, what goes un-noticed to the common man is the extensive research and testing that lasts months, years, and even decades. Much of this required research just so happens to take place in the corridors of the Glen Research Center building number 49. In the Advanced Materials division of G.R.C., a number of researchers have the responsibility of discovering which metal, ceramic, or polymer is best for a specific application. Under the guidance of mentor extraordinaire Frank Ritzert, I am involved in many critical projects dealing with refractory metals, two of which I will mention in this report. The Jupiter Icy Moons Orbiter (JIMO) project actually was under full swing back in the 50's and early 60's. To enable the 14 year trek to the icy moons of Europa, Callisto, and Ganymede, nuclear propulsion methods were selected. Due to the extreme temperature of the reactor and the extended time period, a refractory metal would need to be implemented. After years of research and progress, the program was suddenly canceled. About a decade ago, the JIMO project was re-instated and now has a goal for departure around 2014. However, a few obstacles lie in our way concerning the use of refractory metals. In certain areas of the orbiter a joint is required between the refractories and other less dense metals. Two of these joints are with nickel based super alloys. Being an intern for Frank Ritzert, the refractory metals expert, I have the opportunity to develop the best method to braze refractory metals to Nickel 201. This involves the actual brazing, electron microscopy and reporting the results. My second project involves a certain part of the orbiter where Niobium 1Zirconium, a refractory metal, is joined with Hastelloy-X a Ni based metal. Small quantities of oxygen, helium and other impurities in the Ni alloy could diffuse

  20. Possible Habitability of Ocean Worlds

    NASA Astrophysics Data System (ADS)

    Noack, Lena; Höning, Dennis; Bredehöft, Jan H.; Lammer, Helmut

    2014-05-01

    In the last decade, the number of detected exoplanets has increased to over thousand confirmed planets and more as yet unconfirmed planet candidates. The scientific community mainly concentrates on terrestrial planets (up to 10 Earth masses) in the habitable zone, which describes the distance from the host star where liquid water can exist at the surface (Kasting et al., 1993). Another target group of interest are ocean worlds, where a terrestrial-like body (i.e. with an iron core and a silicate mantle) is covered by a thick water-ice layer - similar to the icy moons of our solar system but with several Earth masses (e.g. Grasset et al., 2009). When an exoplanet is detected and confirmed as a planet, typically the radius and the mass of it are known, leading to the mean density of the planet that gives hints to possible interior structures. A planet with a large relative iron core and a thick ocean on top of the silicate mantle for example would have the same average planet density as a planet with a more Earth-like appearance (where the main contributor to the mass is the silicate mantle). In this study we investigate how the radius and mass of a planet depend on the amount of water, silicates and iron present (after Wagner et al., 2011) the occurence of high-pressure-ice in the water-ice layer (note: we only consider surface temperatures at which liquid water exists at the surface) if the ocean layer influences the initiation of plate tectonics We assume that ocean worlds with a liquid ocean layer (and without the occurence of high-pressure ice anywhere in the water layer) and plate tectonics (especially the occurence of subduction zones, hydrothermal vents and continental formation) may be called habitable (Class III/IV habitats after Lammer et al., 2009). References: Kasting, J.F., Whitmire, D.P., and Reynolds, R.T. (1993). Habitable Zones around Main Sequence Stars. Icarus 101, 108-128. Grasset, O., Schneider, J., and Sotin, C. (2009). A study of the accuracy

  1. Preparing Teachers for Parent Involvement.

    ERIC Educational Resources Information Center

    Safran, Daniel

    This paper examines the potential impact of parent involvement in the formal education of their children and suggests ways that teacher education can be restructured to prepare teachers to work with parents. This paper attempts to answer five questions: (1) Why should parents be involved in the formal education of their children? (2) Why should…

  2. Parental Involvement and Academic Achievement

    ERIC Educational Resources Information Center

    Goodwin, Sarah Christine

    2015-01-01

    This research study examined the correlation between student achievement and parent's perceptions of their involvement in their child's schooling. Parent participants completed the Parent Involvement Project Parent Questionnaire. Results slightly indicated parents of students with higher level of achievement perceived less demand or invitations…

  3. Parent Involvement: Support or Stress?

    ERIC Educational Resources Information Center

    Seefeldt, Carol

    1985-01-01

    Argues for a reexamination of goals and methods of traditional parent involvement which has revolved around the welfare of children rather than emphasizing the benefits for parents themselves. Calls for a reconceptualization of parent involvement based on: (1) being sensitive to family needs, (2) offering real support for families, and (3)…

  4. A Handbook for Community Involvement.

    ERIC Educational Resources Information Center

    Georgia State Dept. of Education, Atlanta. Office of Administrative Services.

    To help Georgia school administrators, educators, and community members, this handbook suggests ideas and plans for strengthening school-community relations and increasing community involvement in schools. The first section lays out the four steps district administrators should take in developing a systemwide community involvement program,…

  5. Dark Dune Spots: possible biomarkers on Mars?

    PubMed

    Gánti, Tibor; Horváth, András; Bérczi, Szaniszló; Gesztesi, Albert; Szathmáry, Eörs

    2003-10-01

    Dark Dune Spots (DDSs) are transitional geomorphologic formations in the frost-covered polar regions of Mars. Our analysis of the transformations and arrangements of subsequent stages of DDSs into time sequence revealed their: (i) hole-like characteristics, (ii) development and formation from the bottom of the frosted layer till the disapperance of the latter, (iii) repeated (seasonal and annual) appearance in a pattern of multiple DDSs on the surface, and (iv) probable origin. We focused our studies on a model in which DDSs were interpreted as objects triggered by biological activity involved in the frosting and melting processes. We discuss two competing interpretations of DDSs: development by defrosting alone, and by defrosting and melting enhanced by the activity of Martian Surface Organisms (MSOs). MSOs are hypothetical Martian photosynthetic surface organisms thought to absorb sunlight. As a result they warm up by late winter and melt the ice around them, whereby their growth and reproduction become possible. The ice cover above the liquid water lens harbouring the MSOs provides excellent heat and UV insulation, prevents fast evaporation, and sustains basic living conditions until the ice cover exists. When the frost cover disappears MSOs go to a dormant, desiccated state. We propose further studies to be carried out by orbiters and landers travelling to Mars and by analysis of partial analogues on earth.

  6. Neuropeptides as possible targets in sleep disorders.

    PubMed

    Nishino, Seiji; Fujiki, Nobuhiro

    2007-01-01

    Insomnia and hypersomnia are frequent sleep disorders, and they are most often treated pharmacologically with hypnotics and wake-promoting compounds. These compounds act on classical neurotransmitter systems, such as benzodiazepines on GABA-A receptors, and amfetamine-like stimulants on monoaminergic terminals to modulate neurotransmission. In addition, acetylcholine, amino acids, lipids and proteins (cytokines) and peptides, are known to significantly modulate sleep and are, therefore, possibly involved in the pathophysiology of some sleep disorders. Due to the recent developments of molecular biological techniques, many neuropeptides have been newly identified, and some are found to significantly modulate sleep. It was also discovered that the impairment of the hypocretin/orexin neurotransmission (a recently isolated hypothalamic neuropeptide system) is the major pathophysiology of narcolepsy, and hypocretin replacement therapy is anticipated to treat the disease in humans. In this article, the authors briefly review the history of neuropeptide research, followed by the sleep modulatory effects of various neuropeptides. Finally, general strategies for the pharmacological therapeutics targeting the peptidergic systems for sleep disorders are discussed.

  7. Human resources and their possible forensic meanings.

    PubMed

    Russo, Andrea; Urlić, Ivan; Kasum, Josip

    2015-09-01

    Forensics (forensic--before the Forum) means the application of knowledge from different scientific fields in order to define facts in judicial and/or administrative procedures. Nowadays forensics, besides this, finds its application even in different economic processes. For example, forensics enters the commercial areas of business intelligence and of different security areas. The European Commission recognized the importance of forensics, and underscored the importance of development of its scientific infrastructure in member States. We are witnessing the rise of various tragedies in economic and other kinds of processes. Undoubtedly, the world is increasingly exposed to various forms of threats whose occurrences regularly involve people. In this paper we are proposing the development of a new approach in the forensic assessment of the state of human resources. We are suggesting that in the focus should be the forensic approach in the psychological assessment of awareness of the individual and of the critical infrastructure sector operator (CISO) in determining the level of actual practical, rather than formal knowledge of an individual in a particular field of expertise, or in a specific scientific field, and possible forensic meanings.

  8. Employee involvement: motivation or manipulation?

    PubMed

    McConnell, C R

    1998-03-01

    Employee involvement is subject to a great deal of verbal tribute; there is hardly a manager at work today who will not praise the value of employee input. However, many employee involvement efforts leave employees feeling more manipulated than motivated. This occurs because supervisors and managers, while expecting employees to change the way they work, are themselves either unwilling to change or remain unconscious of the need to change. The result is that, although employee input is regularly solicited in a number of forms, it is often discounted, ignored, or altered to fit the manager's preconceptions. Often the employee is left feeling manipulated. Since the opportunity for involvement can be a strong motivator, it becomes the manager's task to learn how to provide involvement opportunity in manipulative fashion. This can be accomplished by providing involvement opportunity accompanied by clear outcome expectations and allowing employees the freedom to pursue those outcomes in their own way.

  9. Involvement of serotonin system in bullimia

    SciTech Connect

    Marazziti, D.; Macchi, E.; Rotondo, A.; Placidi, G.F.; Cassano, G.B.

    1988-01-01

    Platelet /sup 3/H-imipramine binding was investigated in 8 patients affected by bulimia according to DSM III criteria, and in 7 health volunteers. The Bmax /+ -/SD (fmol/mg protein) was 356 /+ -/ 53 in patients, and 1144 /+ -/ 134 in controls. The Kd /+ -/ SD (nM) was 1.35 /+ -/ 0.44 in patients, and 1.90 /+ -/ 0.72 in controls. There was a significant difference in Bmax values in the two groups, whereas no significant difference was observed in Kd values. This study suggests the possible involvement of the indoleamine system in bullimia.

  10. Possible Selves and Satisfaction with Career Choice--A Longitudinal Analysis.

    ERIC Educational Resources Information Center

    Inglehart, Marita; And Others

    Possible selves are concrete images of what people think they might become, what they would like to become, and what they are afraid of becoming in the future. It was hypothesized that the satisfaction with achieving the possible self will be higher the more the person has focused on this possible self and the more emotionally involved the person…

  11. Ocular involvement in pemphigus vulgaris.

    PubMed

    Akhyani, Maryam; Keshtkar-Jafari, Alireza; Chams-Davatchi, Cheyda; Lajevardi, Vahide; Beigi, Sara; Aghazadeh, Nessa; Rayati Damavandi, Maede; Arami, Shabnam

    2014-07-01

    Pemphigus vulgaris (PV) is an autoimmune disorder affecting the skin and mucous membranes. Ocular involvement in PV has been reported but its prevalence and clinical characteristics are not well defined. This prospective cross-sectional study of 103 PV patients was designed to determine the prevalence, clinical types and epidemiological trends of ocular involvement in a population of Iranian patients with PV. Ocular involvement was present in 17 (16.5%) patients. Conjunctivitis was the most prevalent type of ocular involvement (9/17, 52.9%), followed by erosion of the palpebral conjunctiva (7/17, 41.2%). Erosion of the bulbar conjunctiva was noted in only one patient (5.9%). The most commonly reported symptoms were eye irritation (76.5%) and redness (76.5%). No significant relation was found between ocular involvement and disease activity (partial remission or relapse). Mucoid discharge was significantly more common in patients with conjunctival erosions as compared to patients with conjunctivitis (P = 0.038). We conclude that ocular involvement is not rare in PV; 16.5% of PV patients develop ocular disease independent of the disease activity and extension. Conjunctivitis is the most common type of involvement, however, palpebral conjunctival erosion is more frequent than previously realized.

  12. 2009 Community Involvement Training Conference

    EPA Pesticide Factsheets

    A dynamic training conference that brings together more than 450 people from EPA and the Agency’s partners and stakeholders who plan and implement environmental community involvement, partnership, stewardship, outreach, and education programs.

  13. EPA Community Involvement Training Conferences

    EPA Pesticide Factsheets

    A dynamic training conference that brings together more than 450 people from EPA and the Agency’s partners and stakeholders who plan and implement environmental community involvement, partnership, stewardship, outreach, and education programs.

  14. 2013 Community Involvement Training Conference

    EPA Pesticide Factsheets

    A dynamic training conference that brings together more than 450 people from EPA and the Agency’s partners and stakeholders who plan and implement environmental community involvement, partnership, stewardship, outreach, and education programs.

  15. 2011 Community Involvement Training Conference

    EPA Pesticide Factsheets

    A dynamic training conference that brings together more than 450 people from EPA and the Agency’s partners and stakeholders who plan and implement environmental community involvement, partnership, stewardship, outreach, and education programs.

  16. 2015 Community Involvement Training Conference

    EPA Pesticide Factsheets

    A dynamic training conference that brings together more than 450 people from EPA and the Agency’s partners and stakeholders who plan and implement environmental community involvement, partnership, stewardship, outreach, and education programs.

  17. Community Involvement During Emergency Responses

    EPA Pesticide Factsheets

    Involvement occurs in different forms, but is always geared towards improving the public's understanding of the presence of hazardous substances in the community, and how to address any issues that may arise.

  18. 2007 Community Involvement Training Conference

    EPA Pesticide Factsheets

    A dynamic training conference that brings together more than 450 people from EPA and the Agency’s partners and stakeholders who plan and implement environmental community involvement, partnership, stewardship, outreach, and education programs.

  19. Public Involvement in BOSC Activities

    EPA Pesticide Factsheets

    EPA policy and the Federal Advisory Committee Act provide for public involvement in committee activities primarily by open access to meetings and records and by providing the public an opportunity to submit comments to the committee.

  20. 2017 Community Involvement Training Program

    EPA Pesticide Factsheets

    A dynamic training event that brings together more than 450 people from EPA and the Agency’s partners and stakeholders who plan and implement environmental community involvement, partnership, stewardship, outreach, and education programs, t

  1. Pauci-immune lupus nephritis: possibility or co-incidence?

    PubMed Central

    Cansu, Döndü Üsküdar; Temiz, Gökhan; Açıkalın, Mustafa F.; Korkmaz, Cengiz

    2017-01-01

    Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized with immune complex formation and renal involvement of lupus and may include several kinds of pathological conditions, but mostly, it is associated with immune complex-induced glomerular disease. Pauci-immune lupus nephritis is a very rare condition. We describe a 45-year-old female patient with pauci-immune crescentic necrotizing lupus nephritis and briefly discuss the possible mechanism and pathogenesis. PMID:28293460

  2. Preliminary study of possible ORELA replacement options

    SciTech Connect

    Olsen, D.K.; Martin, J.A.; Horen, D.J.

    1984-06-01

    Based on two conceptual design studies performed by the LANL Accelerator Technology Division, the possibilities in terms of accelerator systems for replacing ORELA with a more intense Maxwellian-type continuous-energy neutron source are summarized and discussed. The neutron intensities from ORELA are compared with those from existing or potential accelerator systems used for cross-section and condensed-matter studies. The best replacement options seem to involve a spallation source from 200- to 400-MeV protons on an ORELA-like target. Pulsing and intensity desiderata with such a source are discussed which correspond to a spectrum-averaged 100-fold improved figure of merit over ORELA for TOF measurements with only a tenfold increased source strength. Existing accelerator designs seem to be inadequate for such a source. Consequently, two conceptual designs were developed for this study by the LANL Accelerator Technology Division. The first conceptual design is for a 200-MeV large linac capable of accelerating 1.3 A during a macropulse; this linac standing alone could serve as an ORELA replacement source. The second conceptual design is for a much smaller 250-MeV PIGMI linac with a 28-mA macropulse current which feeds a proton accumulator ring and bunch-compressor transport line. This linac-ring-compressor (LIRIC) option would give a more cost-effective neutron source for cross-section measurements, whereas the large linac, or a modified version of it, would give a much simpler system more suitable for expansion. In particular, both conceptual designs would incorporate the present ORELA building and would provide approximately 100-fold improved neutron sources over ORELA for cross-section measurements. The total estimated cost of the LIRIC system would be $43M (1984), whereas the cost of the large linac would be about a factor of two more. 55 references, 11 figures, 19 tables.

  3. An analysis of aircraft accidents involving fires

    NASA Technical Reports Server (NTRS)

    Lucha, G. V.; Robertson, M. A.; Schooley, F. A.

    1975-01-01

    All U. S. Air Carrier accidents between 1963 and 1974 were studied to assess the extent of total personnel and aircraft damage which occurred in accidents and in accidents involving fire. Published accident reports and NTSB investigators' factual backup files were the primary sources of data. Although it was frequently not possible to assess the relative extent of fire-caused damage versus impact damage using the available data, the study established upper and lower bounds for deaths and damage due specifically to fire. In 12 years there were 122 accidents which involved airframe fires. Eighty-seven percent of the fires occurred after impact, and fuel leakage from ruptured tanks or severed lines was the most frequently cited cause. A cost analysis was performed for 300 serious accidents, including 92 serious accidents which involved fire. Personal injury costs were outside the scope of the cost analysis, but data on personnel injury judgements as well as settlements received from the CAB are included for reference.

  4. Genetic Variations Involved in Vitamin E Status

    PubMed Central

    Borel, Patrick; Desmarchelier, Charles

    2016-01-01

    Vitamin E (VE) is the generic term for four tocopherols and four tocotrienols that exhibit the biological activity of α-tocopherol. VE status, which is usually estimated by measuring fasting blood VE concentration, is affected by numerous factors, such as dietary VE intake, VE absorption efficiency, and VE catabolism. Several of these factors are in turn modulated by genetic variations in genes encoding proteins involved in these factors. To identify these genetic variations, two strategies have been used: genome-wide association studies and candidate gene association studies. Each of these strategies has its advantages and its drawbacks, nevertheless they have allowed us to identify a list of single nucleotide polymorphisms associated with fasting blood VE concentration and α-tocopherol bioavailability. However, much work remains to be done to identify, and to replicate in different populations, all the single nucleotide polymorphisms involved, to assess the possible involvement of other kind of genetic variations, e.g., copy number variants and epigenetic modifications, in order to establish a reliable list of genetic variations that will allow us to predict the VE status of an individual by knowing their genotype in these genetic variations. Yet, the potential usefulness of this area of research is exciting with regard to personalized nutrition and for future clinical trials dedicated to assessing the biological effects of the various isoforms of VE. PMID:27983595

  5. Thinking about possible people: a comment on Tooley and Rachels.

    PubMed

    McKie, J

    2001-04-01

    Most people believe it would be wrong to bring a child into the world if in all likelihood its life would be miserable. But if pain and suffering count against bringing someone into existence, why do pleasure and happiness not count in favour of bringing them into existence? Recently in this journal Michael Tooley has re-affirmed his rights-based explanation for this asymmetry. In a nutshell: to create an individual whose life is not worth living would be to wrong that individual--to create an obligation that cannot be fulfilled--but it is not possible to wrong an individual who is not brought into existence. In the same issue of this journal, in an article covering a range of arguments for and against the claim that it would be good for additional people to exist, Stuart Rachels objects to Tooley's account on the ground that it has counterintuitive implications. His most interesting argument involves a Parfit-style counterexample: a woman is about to take a fertility pill that will result in twins, one of whom will be healthy and the other of whom will not. Does it make a difference, morally speaking, if the woman knows which of the twins will be healthy and which will not? In this paper I argue that both Rachels' criticism of Tooley's rights-based account, and Tooley's own defence of it, are unsuccessful due to their failure to come to grips with the semantics of names for possible individuals. Both of them implicitly assume that it is possible to have a potential person in mind, in a way that misleads them about the fairness of actions that involve possible people. The significance of this extends to other areas such as abortion, population policy, and embryo experimentation, where examples involving possible people are common.

  6. [Neurological involvement in Wegener's granulomatosis].

    PubMed

    Asakura, Kunihiko; Muto, Tatsuro

    2013-11-01

    Abstract Wegener's granulomatosis is a rare autoimmune disease associated with granulomatous inflammation and anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis. Following the discovery of ANCA, ANCA-associated vasculitis is established as a disease entity of Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Clinical and experimental studies have provided evidences that myeloperoxidase (MPO) and proteinase 3 (PR3), which are major antigenic targets for ANCA in neutrophils, are not only disease markers but also involved in the pathogenesis. In addition, recent studies have revealed another potential antigen for ANCA, lysosomal-associated membrane protein-2 (LAMP-2). Though nervous system manifestations of Wegener's granulomatosis are less frequent than classical manifestations in the lungs and kidneys, 20-50% of patients demonstrate neurological involvements. Peripheral nervous system involvement (in generalized Wegener's granulomatosis) is more frequent than central nervous system (CNS) involvement. Multiple mononeuropathy and multiple cranial neuropathy are the most prevalent symptoms. CNS manifestations include cerebrovascular events, pachymeningitis, seizures, and reversible posterior leukoencephalopathy syndrome. Here we discuss the pathogenic mechanism of ANCA and review the literature regarding neurological involvement in Wegener's granulomatosis.

  7. Liver involvement in systemic infection

    PubMed Central

    Minemura, Masami; Tajiri, Kazuto; Shimizu, Yukihiro

    2014-01-01

    The liver is often involved in systemic infections, resulting in various types of abnormal liver function test results. In particular, hyperbilirubinemia in the range of 2-10 mg/dL is often seen in patients with sepsis, and several mechanisms for this phenomenon have been proposed. In this review, we summarize how the liver is involved in various systemic infections that are not considered to be primarily hepatotropic. In most patients with systemic infections, treatment for the invading microbes is enough to normalize the liver function tests. However, some patients may show severe liver injury or fulminant hepatic failure, requiring intensive treatment of the liver. PMID:25276279

  8. Vascular involvement in relapsing polychondritis.

    PubMed Central

    Esdaile, J.; Hawkins, D.; Gold, P.; Freedman, S. O.; Duguid, W. P.

    1977-01-01

    Review of four cases of relapsing polychondritis (RP) seen at one hospital in the 12-year period 1963 to 1974 revealed that one patient had aortic insufficiency with large artery involvement, two others had involvement of medium and large arteries and the fourth may have had mucocutaneous vasculitis. Valvular disease has occurred in 9% of all cases of RP reported in the literature and, if vasculitis beyong the aortic root is included, 25% of cases of RP manifested inflammatory vascular disease. The frequency of pseudotumour of the orbit and cochlear-labyrinthine dysfunction is also high and may be a manifestation of vasculitis. PMID:870159

  9. Parental Involvement in Norwegian Schools

    ERIC Educational Resources Information Center

    Paulsen, Jan Merok

    2012-01-01

    This article examines findings on key challenges of school-parent relations in Norway. The review is based on recent large-scale studies on several issues, including formalized school-parent cooperation, parental involvement in the pedagogical discourse, and teacher perspectives on the parents' role in the school community. Findings suggest a…

  10. Parental Involvement through Better Communication

    ERIC Educational Resources Information Center

    Reilly, Edel

    2008-01-01

    Building strong bonds between home and school is one of National Middle School Association's (2003) 14 characteristics for successful middle schools set forth in "This We Believe". Getting teachers to actually believe in the value of parental involvement is not always easy. This article examines a range of key issues in the literature on…

  11. Parent Involvement as Ritualized Practice

    ERIC Educational Resources Information Center

    Doucet, Fabienne

    2011-01-01

    This article examines parent involvement (PI) as a ritual system using Turner's concept of root paradigms. Through a twofold analysis, I argue that the highly ritualized nature of PI practices creates a group identity among mainstream parents and schools that marginalizes diverse families. First, I point out three root paradigms in the ritual…

  12. Home/School/Community Involvement.

    ERIC Educational Resources Information Center

    Decker, Larry E.; Decker, Virginia A.

    Today's schools are entering a second wave of reform in response to changing demographics, public demand for accountability, and societal changes expanding the traditional time frame for learning. To meet these challenges, schools need help through home and community involvement. This book offers seven strategies illustrated by success stories…

  13. Promoting Active Involvement in Classrooms

    ERIC Educational Resources Information Center

    Conderman, Greg; Bresnahan, Val; Hedin, Laura

    2012-01-01

    This article presents a rationale for using active involvement techniques, describes large- and small-group methods based on their documented effectiveness and applicability to K-12 classrooms, and illustrates their use. These approaches include ways of engaging students in large groups (e.g., unison responses, response cards, dry-erase boards,…

  14. Managing Parent Involvement during Crisis

    ERIC Educational Resources Information Center

    Merriman, Lynette S.

    2008-01-01

    In the wake of 9/11, Hurricane Katrina, and the Virginia Tech shooting tragedy, it is no surprise that concern for students' safety is the primary reason attributed to parents' increased involvement. Parents and university administrators share in their commitment to student safety. However, college and university staff who assume responsibility…

  15. Parental Involvement and Educational Achievement

    ERIC Educational Resources Information Center

    Driessen, Geert; Smit, Frederik; Sleegers, Peter

    2005-01-01

    Parental involvement is seen as an important strategy for the advancement of the quality of education. The ultimate objective of this is to expand the social and cognitive capacities of pupils. In addition, special attention is paid to the children of low-educated and ethnic minority parents. Various forms of both parental and school-initiated…

  16. Predictors of Residence Hall Involvement

    ERIC Educational Resources Information Center

    Arboleda, Ana; Wang, Yongyi; Shelley, Mack C., II; Whalen, Donald F.

    2003-01-01

    Residence hall students' (N = 1,186, 52% male, 90% White, 66% freshmen) involvement in their living community is influenced significantly by precollege student characteristics (gender, ethnicity), classification, attitudes (toward hall director, house cabinet, academic comfort, social environment, group study), and environmental variables (noise,…

  17. A Boy or a Girl: Is It Possible to Load the Dice?

    ERIC Educational Resources Information Center

    Ridley, Matt

    1993-01-01

    Presents scientific theories and related research concerning the possibility that animal species, among which are humans, can consciously, or otherwise, biologically determine the sex of their children. Discusses cases involving insects, fish, opossums, primates, and New Zealand women. (MDH)

  18. Smart aircraft routing - a possibility for mitigation?

    NASA Astrophysics Data System (ADS)

    Mannstein, H.; Gierens, K.; Graf, K.; Waibel, A.; Meilinger, S.; Seifert, A.; Köhler, C.

    2009-12-01

    Air traffic affects the energy balance of the earth in various ways. Emission of CO2 with atmospheric residence times measured in decades contributes to the greenhouse effect as well as emission of nitrous oxides, with their impact on ozone and methane chemistry. Soot has a direct effect on the net radiation and, much more important, is involved in the production of contrails and the triggering of contrail cirrus, which can be visible for several hours. These artificial clouds are initiated when flying in sufficiently cold and moist air. In total, their net radiative forcing is of the same order of magnitude as the forcing by the emitted CO2. The impact of contrail cirrus on net radiation results from the conversion of ambient moisture in ice super-saturated regions into ice crystals and depends strongly on the conditions of the ambient radiation field. It ranges from a warming at night or over bright low clouds to cooling during daytime over dark surfaces like the ocean. For the time being these effects are not at all taken into consideration in aircraft routing: the production of contrails and contrail cirrus happens by chance. The dependency of the radiative forcing by contrail cirrus clouds on the weather conditions opens the possibility for mitigation: Avoiding warming (and perhaps also producing cooling) contrails and contrail cirrus by changes of the flight routes has the potential to reduce the man-made imbalance in radiative forcing. As contrails are produced only in 10%- 20% of the flown distances and only the warming contrails should be avoided, the impact on the traffic system is likely to be limited. The basic idea of the project ’Environmentally compatible flight route optimisation’, funded by the German Ministry for Research and Education is, to predict the time integrated radiative forcing of a potential contrail cirrus based on the information given by a weather forecast model. This information is used in relation to total forcing of the

  19. Smart aircraft routing - a possibility for mitigation?

    NASA Astrophysics Data System (ADS)

    Mannstein, H.; Gierens, K.; Waibel, A.; Meilinger, S.; Seifert, A.; Köhler, C.; Kühne, H.

    2009-04-01

    Air traffic affects the energy balance of the earth in various ways. Emission of CO2 with atmospheric residence times measured in decades contributes to the greenhouse effect as well as emission of nitrous oxides, with their impact on ozone and methane chemistry. Soot has a direct effect on the net radiation and, much more important, is involved the production of contrails and the triggering of contrail cirrus, which can be visible for several hours. These artificial clouds are initiated when flying in sufficiently cold and moist air. In total their net radiative forcing is of the same order of magnitude as the forcing by the emitted CO2. The impact of contrail cirrus on net radiation results from the conversion of ambient moisture in ice super-saturated regions into ice crystals and depends strongly on the conditions of the ambient radiation field. It ranges from a warming at night or over bright low clouds to cooling during daytime over dark surfaces like the ocean. For the time being these effects are not at all taken into consideration in aircraft routing: the production of contrails and contrail cirrus happens by chance. in. The dependency of the radiative forcing by contrail cirrus clouds on the weather conditions opens the possibility for a soft version of geo-engineering: Avoiding warming (and perhaps also producing cooling) contrails and contrail cirrus by small changes of the flight routes has the potential to reduce the man-made imbalance in radiative forcing by a few percent - not much compared to other geo-engineering strategies, but without any adverse consequences. With the exception of a small amount of additional fuel usage no other substances have to be brought into the atmosphere. As contrails are produced only in 10%-20% of the flown distances and only the warming contrails should be avoided, the impact on the traffic system is limited. The basic idea of the project 'Environmentally compatible flight route optimisation', funded by the German

  20. [Eye involvement of borrelia aetiology].

    PubMed

    Krbková, Lenka; Vodicková, Kristýna; Pellarová, Hana; Bednárová, Jana; Cápová, Iva

    2007-06-01

    We present a case of eye involvement -- intermediate uveitis -- during tick-borne borreliosis in a 10-year-old boy. Ophthalmologic examination revealed impaired vision, apparent thick floating whitish opacity in the vitreous humour of the left eye and fine fibres in the vitreous humour of the right eye. Sonographic examination confirmed hyperechogenic opacity in the vitreous humour. An autoimmune process was suspected but not confirmed. Serological examination showed IgG antibodies against three pathogenic borreliae and borderline values of IgM antibodies against Borrelia garinii were found by immunoblot. The boy was treated with intravenous ceftriaxone for 21 days. The subsequent sonographic examination showed only minute sporadic echogenicity. Biomicroscopically, only residual opacity in the vitreous humour was found. Isolated eye involvement of borrelia aetiology is rare. The discussion provides a review of similar cases of uveitis including diagnosis of the eye form as published in literature.

  1. Fusion excitation functions involving transitional nuclei

    SciTech Connect

    Rehm, K.E.; Jiang, C.L.; Esbensen, H.

    1995-08-01

    Measurements of fusion excitation functions involving transitional nuclei {sup 78}Kr and {sup 100}Mo showed a different behavior at low energies, if compared to measurements with {sup 86}Kr and {sup 92}Mo. This points to a possible influence of nuclear structure on the fusion process. One way to characterize the structure of vibrational nuclei is via their restoring force parameters C{sub 2} which can be calculated from the energy of the lowest 2{sup +} state and the corresponding B(E2) value. A survey of the even-even nuclei between A = 28-150 shows strong variations in C{sub 2} values spanning two orders of magnitude. The lowest values for C{sub 2} are observed for {sup 78}Kr, {sup 104}Ru and {sup 124}Xe followed by {sup 74,76}Ge, {sup 74,76}Se, {sup 100}Mo and {sup 110}Pd. In order to learn more about the influence of {open_quotes}softness{close_quotes} on the sub-barrier fusion enhancement, we measured cross sections for evaporation residue production for the systems {sup 78}Kr + {sup 104}Ru and {sup 78}Kr + {sup 76}Ge with the gas-filled magnet technique. For both systems, fusion excitation functions involving the closed neutron shell nucleus {sup 86}Kr were measured previously. The data are presently being analyzed.

  2. Major regulatory mechanisms involved in sperm motility.

    PubMed

    Pereira, Rute; Sá, Rosália; Barros, Alberto; Sousa, Mário

    2017-01-01

    The genetic bases and molecular mechanisms involved in the assembly and function of the flagellum components as well as in the regulation of the flagellar movement are not fully understood, especially in humans. There are several causes for sperm immotility, of which some can be avoided and corrected, whereas other are related to genetic defects and deserve full investigation to give a diagnosis to patients. This review was performed after an extensive literature search on the online databases PubMed, ScienceDirect, and Web of Science. Here, we review the involvement of regulatory pathways responsible for sperm motility, indicating possible causes for sperm immotility. These included the calcium pathway, the cAMP-dependent protein kinase pathway, the importance of kinases and phosphatases, the function of reactive oxygen species, and how the regulation of cell volume and osmolarity are also fundamental components. We then discuss main gene defects associated with specific morphological abnormalities. Finally, we slightly discuss some preventive and treatments approaches to avoid development of conditions that are associated with unspecified sperm immotility. We believe that in the near future, with the development of more powerful techniques, the genetic causes of sperm immotility and the regulatory mechanisms of sperm motility will be better understand, thus enabling to perform a full diagnosis and uncover new therapies.

  3. Major regulatory mechanisms involved in sperm motility

    PubMed Central

    Pereira, Rute; Sá, Rosália; Barros, Alberto; Sousa, Mário

    2017-01-01

    The genetic bases and molecular mechanisms involved in the assembly and function of the flagellum components as well as in the regulation of the flagellar movement are not fully understood, especially in humans. There are several causes for sperm immotility, of which some can be avoided and corrected, whereas other are related to genetic defects and deserve full investigation to give a diagnosis to patients. This review was performed after an extensive literature search on the online databases PubMed, ScienceDirect, and Web of Science. Here, we review the involvement of regulatory pathways responsible for sperm motility, indicating possible causes for sperm immotility. These included the calcium pathway, the cAMP-dependent protein kinase pathway, the importance of kinases and phosphatases, the function of reactive oxygen species, and how the regulation of cell volume and osmolarity are also fundamental components. We then discuss main gene defects associated with specific morphological abnormalities. Finally, we slightly discuss some preventive and treatments approaches to avoid development of conditions that are associated with unspecified sperm immotility. We believe that in the near future, with the development of more powerful techniques, the genetic causes of sperm immotility and the regulatory mechanisms of sperm motility will be better understand, thus enabling to perform a full diagnosis and uncover new therapies. PMID:26680031

  4. Alternate-fueled transport aircraft possibilities

    NASA Technical Reports Server (NTRS)

    Aiken, W. S.

    1977-01-01

    The paper is organized to describe: (1) NASA's cryogenically fueled aircraft program; (2) LH2 subsonic and supersonic transport design possibilities (3) the fuel system and ground side problems associated with LH2 distribution; (4) a comparison of LCH4 with LH2; (5) the design possibilities for LCH4 fueled aircraft; and (6) a summary of where NASA's cryogenically fueled programs are headed.

  5. Digital Storytelling: Expanding Media Possibilities for Learning

    ERIC Educational Resources Information Center

    McLellan, Hilary, Ed.

    2008-01-01

    Stories offer a powerful framework for engagement, reflection, and other important skills that young people need to learn. As digital media have expanded, so have the possibilities for creating stories. Here, several examples of those new possibilities are examined, examples that highlight student-produced online broadcasting initiatives,…

  6. Cardiac Involvement in Peripheral Neuropathies.

    PubMed

    Burakgazi, Ahmet Z; AlMahameed, Soufian

    2016-03-01

    Cardiac autonomic neuropathy (CAN) is the least recognized and understood complication of peripheral neuropathy. However, because of its potential adverse effects including sudden death, CAN is one of the most important forms of autonomic neuropathies. CAN presents with different clinical manifestations including postural hypotension, exercise intolerance, fluctuation of blood pressure and heart rate, arrhythmia, and increased risk of myocardial infarction. In this article, the prevalence, clinical presentations, and management of cardiac involvement in certain peripheral neuropathies, including diabetic neuropathy, Guillain-Barré syndrome, chronic inflammatory polyneuropathy, human immunodeficiency virus-associated neuropathy, hereditary neuropathies, and amyloid neuropathy are examined in detail.

  7. 20 CFR 655.184 - Applications involving fraud or willful misrepresentation.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 20 Employees' Benefits 3 2014-04-01 2014-04-01 false Applications involving fraud or willful... Applications involving fraud or willful misrepresentation. (a) Referral for investigation. If the CO discovers possible fraud or willful misrepresentation involving an Application for Temporary Employment...

  8. 20 CFR 655.184 - Applications involving fraud or willful misrepresentation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 20 Employees' Benefits 3 2013-04-01 2013-04-01 false Applications involving fraud or willful... Applications involving fraud or willful misrepresentation. (a) Referral for investigation. If the CO discovers possible fraud or willful misrepresentation involving an Application for Temporary Employment...

  9. 20 CFR 655.184 - Applications involving fraud or willful misrepresentation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 20 Employees' Benefits 3 2012-04-01 2012-04-01 false Applications involving fraud or willful... Applications involving fraud or willful misrepresentation. (a) Referral for investigation. If the CO discovers possible fraud or willful misrepresentation involving an Application for Temporary Employment...

  10. 49 CFR 225.17 - Doubtful cases; alcohol or drug involvement.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Doubtful cases; alcohol or drug involvement. 225..., AND INVESTIGATIONS § 225.17 Doubtful cases; alcohol or drug involvement. (a) The reporting officer of... the possible involvement of alcohol or drug use or impairment in such accident or incident. If...

  11. 20 CFR 655.184 - Applications involving fraud or willful misrepresentation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 20 Employees' Benefits 3 2011-04-01 2011-04-01 false Applications involving fraud or willful... Applications involving fraud or willful misrepresentation. (a) Referral for investigation. If the CO discovers possible fraud or willful misrepresentation involving an Application for Temporary Employment...

  12. 20 CFR 655.184 - Applications involving fraud or willful misrepresentation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Applications involving fraud or willful... Applications involving fraud or willful misrepresentation. (a) Referral for investigation. If the CO discovers possible fraud or willful misrepresentation involving an Application for Temporary Employment...

  13. [Glucocorticoid involvement in memory consolidation].

    PubMed

    Sandi, C

    Glucocorticoids, hormones secreted by the adrenal cortex, can get access to the brain, where they induce a variety of cellular, molecular, and functional actions. Recent evidence showed that glucocorticoids are potent modulators of cognitive processes, such as learning, memory, and retrieval. In particular, the stress response induced by learning a new task, together with the consequent release of glucocorticoids, have been critically involved in memory consolidation processes. In general, these hormones induce facilitating effects on the strength at which newly acquired information is stored into a long term memory, mainly by activating intracellular glucocorticoid receptors. Such receptors belong to the family of nuclear hormone receptors and exert their actions by modulating the transcription of a variety of genes and, therefore, by critically regulating the synthesis of a wide number of proteins. Since protein synthesis appears to be a requirement of almost all forms of long term memory, glucocorticoids might induce their cognitive effects by affecting gene expression. This review focus on the involvement of glucocorticoids and their receptors in a variety of animal models for learning and memory.

  14. Renal involvement in antiphospholipid syndrome.

    PubMed

    Sciascia, Savino; Cuadrado, Maria José; Khamashta, Munther; Roccatello, Dario

    2014-05-01

    Antiphospholipid syndrome (APS) is an autoimmune disease defined by the presence of arterial or venous thrombotic events and/or pregnancy morbidity in patients who test positive for antiphospholipid antibodies (aPLs). APS can be isolated (known as primary APS) or associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE; known as secondary APS). The kidney is a major target organ in APS and renal thrombosis can occur at any level within the vasculature of the kidney (renal arteries, intrarenal arteries, glomerular capillaries and renal veins); events reflect the site and size of the involved vessels. Histological findings vary widely, including ischaemic glomeruli and thrombotic lesions without glomerular or arterial immune deposits on immunofluorescence. Renal prognosis is affected by the presence of aPLs in patients with lupus nephritis and can be poor. In patients with SLE and aPLs, biopsy should be performed because inflammatory and thrombotic lesions require different therapeutic approaches. Renal involvement in patients with definite APS is treated by anticoagulation with long-term warfarin. The range of renal manifestations associated with APS is broadening and, therefore, aPLs have increasing relevance in end-stage renal disease, transplantation and pregnancy.

  15. Possible role of calmodulin in excystation of Giardia lamblia.

    PubMed

    Bernal, R M; Tovar, R; Santos, J I; Muñoz, M L

    1998-09-01

    The protozoan Giardia lamblia initiates infection when trophozoites emerge from a cyst in the hosts by the excystation process. Although this process is crucial to the initiation of infection by G. lamblia, little is known about its regulation. To study the possible involvement of calmodulin (CaM) in excystation we tested the effect of several CaM antagonists (TFP, W-7, and W-5) on this cellular function. Except for W-5 the rest of these compounds inhibited excystation. The protein kinase C inhibitor H-7 had no effect on excystation, suggesting that CaM antagonists acted by selectively inhibiting CaM. Furthermore, CaM was redistributed after the induction of excystation and there was an increase in its fluorescence and activity. These results suggest that a CaM-dependent process is involved in G. lamblia excystation.

  16. Some Possible Cases of Escape Mimicry in Neotropical Butterflies.

    PubMed

    Pinheiro, C E G; Freitas, A V L

    2014-10-01

    The possibility that escape or evasive mimicry evolved in butterflies and other prey insects in a similar fashion to classical Batesian and Müllerian mimicry has long been advanced in the literature. However, there is a general disagreement among lepidopterists and evolutionary biologists on whether or not escape mimicry exists, as well as in which mimicry rings this form of mimicry has evolved. Here, we review some purported cases of escape mimicry in Neotropical butterflies and suggest new mimicry rings involving several species of Archaeoprepona, Prepona, and Doxocopa (the "bright blue bands" ring) and species of Colobura and Hypna (the "creamy bands" ring) where the palatability of butterflies, their ability to escape predator attacks, geographic distribution, relative abundance, and co-occurrence in the same habitats strongly suggest that escape mimicry is involved. In addition, we also indicate other butterfly taxa whose similarities of coloration patterns could be due to escape mimicry and would constitute important case studies for future investigation.

  17. Neuronal involvement in muscular atrophy.

    PubMed

    Cisterna, Bruno A; Cardozo, Christopher; Sáez, Juan C

    2014-01-01

    The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation. Consequently, denervated myofibers manifest atrophy, which is preceded by an increase in sarcolemma permeability. Recently, de novo expression of hemichannels (HCs) formed by connexins (Cxs) and other none selective channels, including P2X7 receptors (P2X7Rs), and transient receptor potential, sub-family V, member 2 (TRPV2) channels was demonstrated in denervated fast skeletal muscles. The denervation-induced atrophy was drastically reduced in denervated muscles deficient in Cxs 43 and 45. Nonetheless, the transduction mechanism by which the nerve represses the expression of the above mentioned non-selective channels remains unknown. The paracrine action of extracellular signaling molecules including ATP, neurotrophic factors (i.e., brain-derived neurotrophic factor (BDNF)), agrin/LDL receptor-related protein 4 (Lrp4)/muscle-specific receptor kinase (MuSK) and acetylcholine (Ach) are among the possible signals for repression for connexin expression. This review discusses the possible role of relevant factors in maintaining the normal functioning of fast skeletal muscles and suppression of connexin hemichannel expression.

  18. Aluminum runway surface as possible aid to aircraft braking

    NASA Technical Reports Server (NTRS)

    Miller, C. D.; Pinkel, I. I.

    1973-01-01

    Several concepts are described for use singly or in combination to improve aircraft braking. All involve a thin layer of aluminum covering all or part of the runway. Advantage would derive from faster heat conduction from the tire-runway interface. Heating of tread surface with consequent softening and loss of friction coefficient should be reduced. Equations are developed indicating that at least 99 percent of friction heat should flow into the aluminum. Preliminary test results indicate a coefficient of sliding friction of 1.4, with predictably slight heating of tread. Elimination of conventional brakes is at least a remote possibility.

  19. [New possibilities will open up in human gene therapy].

    PubMed

    Portin, Petter

    2016-01-01

    Gene therapy is divided into somatic and germ line therapy. The latter involves reproductive cells or their stem cells, and its results are heritable. The effects of somatic gene therapy are generally restricted to a single tissue of the patient in question. Until now, all gene therapies in the world have belonged to the regime of somatic therapy, germ line therapy having been a theoretical possibility only. Very recently, however, a method has been developed which is applicable to germ line therapy as well. In addition to technical challenges, severe ethical problems are associated with germ line therapy, demanding opinion statement.

  20. [Care in Heidegger: an ontological possibility for nursing].

    PubMed

    de Oliveira, Marília de Fátima Vieira; Carraro, Telma Elisa

    2011-01-01

    Given the dimensions involving human care, this study aimed at providing a reflection on nursing care as an ontological possibility. In Heidegger we consider the concepts that underlie the foundation of his thought. These reflections offer theoretical resource that allows the recognition that live in the everyday actions of nursing is a challenge that leads us to a new look at the magnitude of care. However, the actions of care should not target only the perspective of a philosopher, but live with that thought in search of reflection, and find, scrutinizing everything you contribute to a nursing care committed to the right, with ethics, and with respect for others.

  1. Possible steps in the evolutionary development of bird navigation

    NASA Technical Reports Server (NTRS)

    Bellrose, F. C.

    1972-01-01

    Hypotheses are presented to explain the evolutionary development of navigational ability in migratory birds. Areas of discussion to describe the possible techniques are: (1) sun compass, (2) bicoordinate navigation, (3) star compass, (4) wind cues, (5) earth magnetic field, and (6) landscape features. It is concluded that landscape is the single most important cue for orientation of nonmigratory birds. The long range migratory birds appear to use a combination of cues with the relative importance of the cue dependent upon the species of the bird involved.

  2. Possible Side-Effects from Vaccines

    MedlinePlus

    ... Resources News Newsletters Events Possible Side-effects from Vaccines Recommend on Facebook Tweet Share Compartir On this ... risk of contracting a potentially deadly disease. Adenovirus vaccine side-effects What are the risks from Adenovirus ...

  3. Possible radio-emission signatures of exoplanets

    NASA Astrophysics Data System (ADS)

    Budding, E.; Slee, O. B.; Johnston-Hollitt, M.

    2015-03-01

    A brief review of possibly detectable radio-effects from exoplanets is presented. Previous observations may show relevant effects, when appropriate theory is taken into account. Pointers to contemporary and future lines of investigation are also presented.

  4. Possible Problems: Inverted, Flat, or Pierced Nipples

    MedlinePlus

    ... Breastfeeding Crying & Colic Diapers & Clothing Feeding & Nutrition Preemie Sleep Teething & Tooth Care Toddler Preschool Gradeschool Teen Young Adult Healthy Children > Ages & Stages > Baby > Breastfeeding > Possible Problems: Inverted, Flat, or Pierced ...

  5. Possible link between ectopic pancreas and holoprosencephaly.

    PubMed

    Kin, Tatsuya; Korbutt, Gregory S; Shapiro, A M James

    2012-01-01

    We report on the incidental observation of ectopic pancreas in a donor for islet cell transplantation. The donor's clinical and imaging presentation was definitive for holoprosencephaly. This case report discusses a possible link between ectopic pancreas and holoprosencephaly.

  6. Towards A Possible Therapy for Diabetes Complications

    DTIC Science & Technology

    2014-12-01

    Towards A Possible Therapy for Diabetes Complications PRINCIPAL INVESTIGATOR: Massimo Trucco, M.D...September 2014 4. TITLE AND SUBTITLE Towards A Possible Therapy for Diabetes Complications 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-10-1-1055...of the beta cells. Consistently with this view, the standard of care for diabetic , and especially T1D patients is solely insulin-replacement therapy

  7. Towards a Possible Therapy for Diabetes Complications

    DTIC Science & Technology

    2016-03-01

    AWARD NUMBER: W81XWH-10-1-1055 TITLE: Towards A Possible Therapy for Diabetes Complications PRINCIPAL INVESTIGATOR: Massimo Trucco, M.D...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-10-1-1055 Towards A Possible Therapy for Diabetes Complications 5b. GRANT NUMBER 5c. PROGRAM...for favoring pro- insulin folding within the secretory granules of the beta cells. Consistently with this view, the standard of care for diabetic

  8. Towards a Possible Therapy for Diabetes Complications

    DTIC Science & Technology

    2013-10-01

    by C-peptide treatment of vascular and neural dysfunctions of diabetes is not mediated by stereospecific receptors or binding sites (Ido et al...Towards A Possible Therapy for Diabetes Complications PRINCIPAL INVESTIGATOR: Massimo Trucco, M.D...September 2013 4. TITLE AND SUBTITLE Towards A Possible Therapy for Diabetes Complications 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-10-1

  9. [Cardiovascular involvement in rheumatic diseases].

    PubMed

    Driazhenko, I V

    2005-01-01

    Cardiovascular system involvement with early development of atherosclerosis is characteristic for rheumatic diseases. Among causes of death in various rheumatic diseases cardiovascular pathology also prevails. This paper contains a review of most important studies of impairment of the heart, arterial and venous parts of cardiovascular system in patients with diffuse diseases of connective tissue, rheumatoid arthritis and systemic vasculitides. The role of immune mechanisms, endothelial dysfunction, dyslipidemia in pathogenesis of cardiovascular disturbances with development of myocardial and vascular remodeling in rheumatic diseases is also discussed. Major risk factors of cardiovascular pathology in rheumatic patients are presented. Treatment of a cardiovascular pathology in these patients presumes the use of angiotensin converting enzyme inhibitors, aldosterone antagonists and statins.

  10. Charmless B decays involving baryons

    NASA Astrophysics Data System (ADS)

    Gronau, Michael; Rosner, Jonathan L.

    1988-02-01

    Predictions are made for the fraction of B-meson decays involving specific final states of NN¯+nπ (n>=0), as functions of (a) decay dynamics, (b) models for multipion production, (c) the isospin of the final state, and (d) the ratio ||Vbu/Vbc|| of Kobayashi-Maskawa matrix elements. From recent observations of B+-->pp¯π+(+c.c.) and B0-->pp¯π+π- by the ARGUS Collaboration, it is concluded that ||Vbu/Vbc||>~0.08, similar to the ARGUS Collaboration's own estimate of 0.07. However, a more likely value for this ratio is near its present experimental upper limit. Predictions are made for further final states in NN¯+nπ and in other charmless B decays. We also comment briefly on prospects for observing CP violation in B-->NN¯+nπ.

  11. Diet, Obesity, and Political Involvement

    PubMed Central

    2015-01-01

    The views expressed are those of the author and may not necessarily reflect the views of the Editorial Board. Abstract: This essay is an opinion article addressed to the busy practitioner. It provides information on nutrition, diet, nutritional science, and obesity to serve as a reference in teaching his patients on these issues. It is composed by a gastroenterologist who has been engaged in clinical gastroenterology and nutrition, research, and teaching in an academic medical center for 35 years. It also relates the information to conclusions on reasonable involvement of the national government in these topics. Finally, its audience might include the interested, well-educated, lay public. Hence, excessive scientific parlance and referencing have been avoided. PMID:26106846

  12. Hirayama Disease with Proximal Involvement

    PubMed Central

    2016-01-01

    Hirayama disease is a slowly progressing benign motor neuron disease that affects the distal upper limb. A 29-year-old man visited the hospital with a 1-year history of weakened left proximal upper limb. He was diagnosed with Hirayama disease 9 years ago, while there was no further progression of the muscle weakness afterward. Atrophy and weakness was detected in proximal upper limb muscles. Magnetic resonance imaging and somatosensory evoked potentials were normal. Needle electromyography showed abnormal findings in proximal upper limb muscles. Our patient had Hirayama disease involving the proximal portion through secondary progression. Clinical manifestation and accurate electromyography may be useful for diagnosis. Rare cases with progression patterns as described here are helpful and have clinical meaning for clinicians. PMID:27550499

  13. Lung Involvement in Systemic Sclerosis

    PubMed Central

    Hassoun, Paul M.

    2011-01-01

    Summary Scleroderma is a multisystem disease characterized by a severe inflammatory process and exuberant fibrosis. Lung involvement is a frequent complication and a leading cause of morbidity and mortality in this syndrome. Two major pulmonary syndromes are associated with scleroderma; a pulmonary vascular disorder evolving over time into relatively isolated pulmonary arterial hypertension (PAH), and interstitial lung disease (ILD). Each syndrome, when present, is a cause of morbidity and significantly reduces survival of scleroderma patients when compared to patients free of lung complication. When pulmonary hypertension and ILD are combined, survival is further reduced. Current therapy appears to have no meaningful effect on either condition and, thus, there is a need for better understanding of underlying pathogenic mechanisms. This review focuses on clinical, diagnostic, and therapeutic features of PAH and ILD as well as other frequent but less debilitating lung complications of scleroderma. PMID:21195581

  14. [Hypothalamic involvement in multiple sclerosis].

    PubMed

    Darlix, A; Mathey, G; Monin, M-L; Sauvée, M; Braun, M; Schaff, J-L; Debouverie, M

    2012-05-01

    Hypothalamic involvement is a rare condition in patients with multiple sclerosis (MS). We report two patients with a long history of MS who presented with severe acute hypothermia with associated thrombocytopenia and elevated transaminase levels. Several cases of hypothermia or hyperthermia in patients with MS have been reported in the literature. They could be linked with hypothalamic lesions, in particular in the pre-optic area. However, other anatomical locations seem to be involved in thermoregulation and can be affected by MS. Besides, some cases of syndrome of inappropriate antidiuretic hormone secretion have been reported in patients with MS. Finally, some sleep disorders, particularly hypersomnia or narcolepsy, could be related to hypothalamic lesions, through the fall in hypocretin-1 in the cerebrospinal fluid. Hypocretin-1 is a neuropeptide that is secreted by some hypothalamic cells. It plays a role in the sleep-awake rhythm. We report one patient with narcolepsy and cataplexy before the first symptoms of MS appeared. Hypothalamic signs are rare in MS. However, several series of autopsies have shown a high frequency of demyelinating lesions in the hypothalamic area. Among these lesions, the proportion of active lesions seems elevated. Yet only few of them have a clinical or biological translation such as thermoregulation dysfunction, sleep disorders or natremia abnormalities. Thus, it seems unlikely that inflammatory hypothalamic lesions alone, even when bilateral, could be the explanation of these signs. A sufficient number of inflammatory demyelinating lesions, which we can observe in patients with a long history of MS and an already severe disability, is probably necessary to develop such a rare symptomatology. Hypothalamic signs might be a factor of poor prognosis for the disease course and progression of the disability.

  15. Community-Involved Learning to Expand Possibilities for Vulnerable Children: A Critical Communicative, Sen's Capability, and Action Research Approach

    ERIC Educational Resources Information Center

    Kim, Kyung Hi

    2014-01-01

    This research, based on a case study of vulnerable children in Korea, used a mixed methods transformative approach to explore strategies to support and help disadvantaged children. The methodological approach includes three phases: a mixed methods contextual analysis, a qualitative dominant analysis based on Sen's capability approach and critical…

  16. First evidence of TRPV5 and TRPV6 channels in human parathyroid glands: possible involvement in neoplastic transformation.

    PubMed

    Giusti, Laura; Cetani, Filomena; Da Valle, Ylenia; Pardi, Elena; Ciregia, Federica; Donadio, Elena; Gargini, Claudia; Piano, Ilaria; Borsari, Simona; Jaber, Ali; Caputo, Antonella; Basolo, Fulvio; Giannaccini, Gino; Marcocci, Claudio; Lucacchini, Antonio

    2014-10-01

    The parathyroid glands play an overall regulatory role in the systemic calcium (Ca(2+)) homeostasis. The purpose of the present study was to demonstrate the presence of the Ca(2+) channels transient receptor potential vanilloid (TRPV) 5 and TRPV6 in human parathyroid glands. Semi-quantitative and quantitative PCR was carried out to evaluate the presence of TRPV5 and TRPV6 mRNAs in sporadic parathyroid adenomas and normal parathyroid glands. Western blot and immunocytochemical assays were used to assess protein expression, cellular localization and time expression in primary cultures from human parathyroid adenoma. TRPV5 and TRPV6 transcripts were then identified both in normal and pathological tissues. Predominant immunoreactive bands were detected at 75-80 kD for both vanilloid channels. These channels co-localized with the calcium-sensing receptor (CASR) on the membrane surface, but immunoreactivity was also detected in the cytosol and around the nuclei. Our data showed that western blotting recorded an increase of protein expression of both channels in adenoma samples compared with normal glands suggesting a potential relation with the cell calcium signalling pathway and the pathological processes of these glands.

  17. Role of an adaptor protein Lin-7B in brain development: possible involvement in autism spectrum disorders.

    PubMed

    Mizuno, Makoto; Matsumoto, Ayumi; Hamada, Nanako; Ito, Hidenori; Miyauchi, Akihiko; Jimbo, Eriko F; Momoi, Mariko Y; Tabata, Hidenori; Yamagata, Takanori; Nagata, Koh-Ichi

    2015-01-01

    Using comparative genomic hybridization analysis for an autism spectrum disorder (ASD) patient, a 73-Kb duplication at 19q13.33 (nt. 49 562 755-49 635 956) including LIN7B and 5 other genes was detected. We then identified a novel frameshift mutation in LIN7B in another ASD patient. Since LIN7B encodes a scaffold protein essential for neuronal function, we analyzed the role of Lin-7B in the development of cerebral cortex. Acute knockdown of Lin-7B with in utero electroporation caused a delay in neuronal migration during corticogenesis. When Lin-7B was knocked down in cortical neurons in one hemisphere, their axons failed to extend efficiently into the contralateral hemisphere after leaving the corpus callosum. Meanwhile, enhanced expression of Lin-7B had no effects on both cortical neuron migration and axon growth. Notably, silencing of Lin-7B did not affect the proliferation of neuronal progenitors and stem cells. Taken together, Lin-7B was found to play a pivotal role in corticogenesis through the regulation of excitatory neuron migration and interhemispheric axon growth, while further analyses are required to directly link functional defects of Lin-7B to ASD pathophysiology. Lin-7 plays a pivotal role as a scaffold protein in synaptic development and plasticity. Based on genetic analyses we identified mutations in LIN-7B gene in some ASD (autism-spectrum disorder) patients. Functional defects in Lin-7B caused abnormal neuronal migration and interhemispheric axon growth during mouse brain development. Thus, functional deficiency in Lin-7B could be implicated in clinical phenotypes in some ASD patients through bringing about abnormal cortical architecture.

  18. Possible involvement of hydroxyl radical on the stimulation of tetrahydrobiopterin synthesis by hydrogen peroxide and peroxynitrite in vascular endothelial cells.

    PubMed

    Shimizu, Shunichi; Ishii, Masakazu; Miyasaka, Yoshiyuki; Wajima, Teruaki; Negoro, Takaharu; Hagiwara, Tamio; Kiuchi, Yuji

    2005-04-01

    We recently described that hydrogen peroxide (H2O2) stimulates the synthesis of tetrahydrobiopterin (BH4) through the induction of the rate-limiting enzyme GTP-cyclohydrolase I (GTPCH), and increases tetrahydrobiopterin content in vascular endothelial cells. Tetrahydrobiopterin is easily oxidized by peroxynitrite (ONOO-), but not by hydrogen peroxide. The aim of this study was to determine the effect of hydroxyl radical and peroxynitrite, which are both toxic biological oxidants, on tetrahydrobiopterin synthesis and the regulation of its content in vascular endothelial cells. In the cell-free assay system, tetrahydrobiopterin was rapidly oxidized by the hydroxyl radical and peroxynitrite, but not by hydrogen peroxide. However, the addition of not only hydrogen peroxide but also the hydroxyl radical and peroxynitrite to vascular endothelial cells transiently decreased tetrahydrobiopterin content, and then markedly increased its content. Interestingly, total biopterin content was also decreased by early treatment with oxidants. Moreover, oxidants induced the expression of GTP-cyclohydrolase I, and the increase of the tetrahydrobiopterin content was blocked by the treatment with GTP-cyclohydrolase I inhibitor. Both the hydrogen peroxide- and peroxynitrite-induced increases in tetrahydrobiopterin content and findings suggest that not only hydrogen peroxide but also the hydroxyl radical and peroxynitrite stimulates tetrahydrobiopterin synthesis through GTP-cyclohydrolase I expression, and that the hydroxyl radical plays a central role in the stimulation of tetrahydrobiopterin synthesis. Moreover, the transient decrease in BH4 to tetrahydrobiopterin.

  19. 5-Hydroxytryptamine-induced tachycardia in the pig: possible involvement of a new type of 5-hydroxytryptamine receptor.

    PubMed Central

    Bom, A. H.; Duncker, D. J.; Saxena, P. R.; Verdouw, P. D.

    1988-01-01

    1. The mechanism of 5-hydroxytryptamine (5-HT)-induced tachycardia is species-dependent and is mediated directly or indirectly either by '5-HT1-like' (cat), 5-HT2 (rat, dog) or 5-HT3 (rabbit) receptors, or by an action similar to tyramine (guinea-pig). The present investigation is devoted to the analysis of the positive chronotropic effect of 5-HT in the pentobarbitone-anaesthetized pig. 2. Intravenous bolus injections of 5-HT (3, 10 and 30 micrograms kg-1) in pigs resulted in dose-dependent increases in heart rate of 24 +/- 2, 38 +/- 3 and 51 +/- 3 beats min-1, respectively (n = 39). Topical application of a high concentration of 5-HT (150 micrograms kg-1 in 5 ml) on the right atrium was also followed by tachycardia (38 +/- 6 beats min-1, n = 4). 3. A number of drugs which antagonize responses mediated by different 5-HT receptors--phenoxybenzamine, methiothepin, metergoline, methysergide and mesulergine ('5-HT1-like' and 5-HT2 receptors), ketanserin, cyproheptadine, pizotifen and mianserin (5-HT2 receptors), and MDL 72222 and ICS 205-930 (5-HT3 receptors)--did not attenuate the chronotropic responses to 5-HT. 4. The 5-HT-induced tachycardia was also not affected by antagonists at alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors, and calcium channels. 5. Selective inhibitors of 5-HT-uptake, indalpine and fluvoxamine, themselves increased porcine heart rate and facilitated 5-HT-induced tachycardia both in magnitude and in duration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3370393

  20. Biphasic effects of baclofen on phrenic motoneurons: possible involvement of two types of gamma-aminobutyric acid (GABA) receptors.

    PubMed

    Lalley, P M

    1983-08-01

    Intravenous injections of baclofen have two general dose-dependent effects on phrenic motoneurons in anesthetized cats. Small doses (0.5-1.5 mg/kg) increase the frequency of action potentials recorded from single motoneurons and from the phrenic nerve, whereas large doses (2-10 mg/kg) reduce or abolish action potentials. The increase in frequency produced by small doses is accompanied by membrane depolarization and, in most experiments, by increased input resistance. Large doses hyperpolarize phrenic motoneurons and produce greater increases in input resistance. Extracellular recording during microelectrophoretic application of baclofen reveals only one effect, depression of cell firing, at all effective current strengths. The low dose stimulatory effect of i.v. baclofen is attributed to disinhibition, whereas the depression by large doses is attributed to disfacilitation. During incomplete inhibition by baclofen, CO2 administration further depresses phrenic nerve activity. Bicuculline (100-600 micrograms/kg i.v.) and picrotoxin (900 micrograms/kg i.v.) restore firing depressed by baclofen, whereas strychnine (80-1280 micrograms/kg) does not. 3-Aminopropanesulfonic acid (5-75 mg/kg i.v.) an agonist at gamma-aminobutyric acid-A receptor sites, depresses phrenic nerve activity. It is suggested that the low dose stimulatory effects are related to actions at gamma-aminobutyric acid-B receptors, whereas the high dose depressant effects are related, at least in part, to activation of gamma-aminobutyric acid-A receptors.