Actions of octocoral and tobacco cembranoids on nicotinic receptors

Nicotinic acetylcholine receptors (AChRs) are pentameric proteins that form agonist-gated cation channels through the plasma membrane. AChR agonists and antagonists are potential candidates for the treatment of neurodegenerative diseases. Cembranoids are naturally occurring diterpenoids that contain a 14-carbon ring. These diterpenoids interact with AChRs in complex ways: as irreversible inhibitors at the agonist sites, as noncompetitive inhibitors, or as positive modulators, but no cembranoid was ever shown to have agonistic activity on AChRs. The cembranoid eupalmerin acetate displays positive modulation of agonist-induced currents in the muscle-type AChR and in the related gamma-aminobutyric acid (GABA) type A receptor. Moreover, cembranoids display important biological effects, many of them mediated by nicotinic receptors. Cembranoids from tobacco are neuroprotective through a nicotinic anti-apoptotic mechanism preventing excitotoxic neuronal death which in part could result from anti-inflammatory properties of cembranoids. Moreover, tobacco cembranoids also have anti-inflammatory properties which could enhance their neuroprotective properties. Cembranoids from tobacco affect nicotine-related behavior: they increase the transient initial ataxia caused by first nicotine injection into naive rats and inhibit the expression of locomotor sensitization to repeated injections of nicotine. In addition, cembranoids are known to act as anti-tumor compounds. In conclusion, cembranoids provide a promising source of lead drugs for many clinical areas, including neuroprotection, smoking-cessation, and anti-cancer therapies. (C) 2009 Elsevier Ltd. All rights reserved.

Metabotropic glutamate receptors transduce signals for neurite outgrowth after binding of the prion protein to laminin gamma 1 chain

The prion protein (PrP(C)) is highly expressed in the nervous system, and its abnormal conformer is associated with prion diseases. PrP(C) is anchored to cell membranes by glycosylphosphatidylinositol, and transmembrane proteins are likely required for PrP(C)-mediated intracellular signaling. Binding of laminin (Ln) to PrP(C) modulates neuronal plasticity and memory. We addressed signaling pathways triggered by PrP(C)-Ln interaction in order to identify transmembrane proteins involved in the transduction of PrP(C)-Ln signals. The Ln gamma 1-chain peptide, which contains the Ln binding site for PrP(C), induced neuritogenesis through activation of phospholipase C (PLC), Ca(2+) mobilization from intracellular stores, and protein kinase C and extracellular signal-regulated kinase (ERK1/2) activation in primary cultures of neurons from wild-type, but not PrP(C)-null mice. Phage display, coimmunoprecipitation, and colocalization experiments showed that group I metabotropic glutamate receptors (mGluR1/5) associate with PrP(C). Expression of either mGluR1 or mGluR5 in HEK293 cells reconstituted the signaling pathways mediated by PrP(C)-Ln gamma 1 peptide interaction. Specific inhibitors of these receptors impaired PrP(C)-Ln gamma 1 peptide-induced signaling and neuritogenesis. These data show that group I mGluRs are involved in the transduction of cellular signals triggered by PrP(C)-Ln, and they support the notion that PrP(C) participates in the assembly of multiprotein complexes with physiological functions on neurons.-Beraldo, F. H., Arantes, C. P., Santos, T. G., Machado, C. F., Roffe, M., Hajj, G. N., Lee, K. S., Magalhaes, A. C., Caetano, F. A., Mancini, G. L., Lopes, M. H., Americo, T. A., Magdesian, M. H., Ferguson, S. S. G., Linden, R., Prado, M. A. M., Martins, V. R. Metabotropic glutamate receptors trans-duce signals for neurite outgrowth after binding of the prion protein to laminin gamma 1 chain. FASEB J. 25, 265-279 (2011). www.fasebj.org

Directed Differentiation of Neural Progenitors into Neurons Is Accompanied by Altered Expression of P2X Purinergic Receptors

Neural differentiation has been extensively studied in vitro in a model termed neurospheres, which consists of aggregates of neural progenitor cells. Previous studies suggest that they have a great potential for the treatment of neurological disorders. One of the major challenges for scientists is to control cell fate and develop ideal culture conditions for neurosphere expansion in vitro, without altering their features. Similar to human neural progenitors, rat neurospheres cultured in the absence of epidermal and fibroblast growth factors for a short period increased the levels of beta-3 tubulin and decreased the expression of glial fibrillary acidic protein and nestin, compared to neurospheres cultured in the presence of these factors. In this work, we show that rat neurospheres cultured in suspension under mitogen-free condition presented significant higher expression of P2X2 and P2X6 receptor subunits, when compared to cells cultured in the presence of growth factors, suggesting a direct relationship between P2X2/6 receptor expression and induction of neuronal differentiation in mitogen-free cultured rat neurospheres.

A novel physiological property of snake bradykinin-potentiating peptides-Reversion of MK-801 inhibition of nicotinic acetylcholine receptors

The first naturally occurring angiotensin-converting enzyme (ACE) inhibitors described are pyroglutamyl proline-rich oligopeptides, found in the venom of the viper Bothrops jararaca, and named as bradykinin-potentiating peptides (BPPs). Biochemical and pharmacological properties of these peptides were essential for the development of Captopril, the first active site-directed inhibitor of ACE, currently used for the treatment of human hypertension. However, a number of data have suggested that the pharmacological activity of BPPs could not only be explained by their inhibitory action on enzymatic activity of somatic ACE. In fact, we showed recently that the strong and long-lasting anti-hypertensive effect of BPP-10c [receptors expressed in blood vessels have been related to blood pressure regulation. Therefore, we have studied the effects of BPP-10c on acetylcholine receptor function in the PC12 pheochromocytoma cell line, which following induction to neuronal differentiation expresses most of the nicotinic receptor subtypes. BPP-10c did not induce receptor-mediated ion flux, nor potentiated carbamoylcholine-provoked receptor activity as determined by whole-cell recording. This peptide, however, alleviated MK-801-induced inhibition of nicotinic acetylcholine receptor activity. Although more data are needed for understanding the mechanism of the BPP-10c effect on nicotinic receptor activity and its relationship with the anti-hypertensive activity, this work reveals possible therapeutic applications for BPP-10c in establishing normal acetylcholine receptor activity. (C) 2008 Elsevier Inc. All rights reserved.

Valet för livet? : En kvantitativ undersökning om hur elever på SP- programmet motiverar sitt gymnasieval och hur skolornas marknadsföring ser ut.

Syftet med uppsatsen var att undersöka vilka faktorer som påverkar samhällsprogrammets elevers val av skola. För att undersöka detta genomfördes en enkätundersökning på tre gymnasieskolor och skolornas respektive marknadsföring undersöktes. Undersökningen visade att samhällsprogramseleverna i sitt skolval framförallt påverkats mest av skolornas Öppna hus samt at skolorna hade rykte om att ha bra lärare, valbara kurser, skolmat och allmän stämning på skolan. Dessutom spelar skolans geografiska läge en roll. Vi kom fram till att de flesta eleverna vill att skolan ligger nära tåg och buss och ganska centralt. I den kommunala skolan var närheten till hemmet avgörande. Eleverna anser själva att föräldrarna och kompisarnas påverkan inte är avgörande för deras gymnasieval. Dessutom kom vi fram till att den större delen av eleverna hade högutbildade föräldrar och de flesta hade en svensk bakgrund. På den kommunala skolan, som låg på landsbygden, var andelen elever med utländska föräldrar störst. Vårt resultat stämmer överrens med tidigare forskning, då det redan tidigare har kommit fram till att elever med utländsk bakgrund oftast går till skolor som ligger i förorter från större städer. Dessutom är andelen elever med utländska föräldrar mycket mindre på fristående skolor än på kommunala skolor. I tidigare forskning har ytterligare kommit fram att högutbildade föräldrar gör ett mer medvetet och aktivt val när de väljer gymnasium och att fler högutbildade föräldrar väljer en fristående skola, än lågutbildade föräldrar. På de skolors SP-programelever vi undersökte såg vi att den största delen av föräldrarna var högutbildade och att en stor grupp var lärare. SP-programmet är studieförberedande och därför kan det vara så att eleverna påverkats av föräldrarnas socioekonomiska status i sitt val, vilket skulle stämma överens med tidigare forskning, även om de själva ser det som ett fritt och självständigt val.

När lanthandeln stänger : En studie av lanthandelns betydelse för flyttning in och ut och för människorna i byn

In Sweden the number of rural food shops has decreased for more than 50 years. Often the closing of a village shop is supposed to affect the migration patterns in the area it has been serving. However, according to this study, neither in- nor out-migration in the area affected by the closing is affected. The deficits of migration usual in those areas are established at least 10-12 years before the closing year. Thus, the typical closing takes place subsequent to a long term population decline. On the other hand, localities hosting a shop that survived during the study period 1990-2004 have a bigger total population and show tendencies towards decreasing deficit of migration at any potential closing year. These statistical results are supported by interviews carried out in three villages where the last shop has closed. They indicate that the shop has already lost its importance as supplier when it closes. By then the village shop is primarily used as complement to nearby towns or shopping centres. Each of the two studies accounted for here point at a relative un-importance of the village shop as a service point at the closing time. However, as it often offer the last public space in the village the village shop serves a key function as a meeting point for some households. When the shop has closed, the village holds private homes only. That is a situation increasing loneliness to some inhabitants.

Samhällsnyttiga budskap i reklamform : Har påverkansfilmen potential att nå ut till flera?

I uppsatsen undersöks huruvida icke kommersiella påverkansfilmer på internet eventuellt skulle kunna anta ett mer reklamliknande format för att nå ut till flera. Frågeställningen delades upp i form av påverkansfilmens struktur som teman målgrupper, påverkan & effekt, längd, som reklam på internet, ambassadörer & avsändare, plattformar samt musik. Uppsatsen inleddes med tidigare forskning på hur dels icke kommersiell marknadsföring kan se ut, dels hur den kommersiella marknadsföringen kan te sig, med fokus på den undermedvetna förledandemodellen som fungerar på ett mer subliminalt sätt. Som metod genomfördes en studie med två kvalitativa undersökningar för att kunna påvisa mönster gällande synen på påverkansfilmer. Undersökning 1 med utgångspunkt från ett avsändarperspektiv i form av telefonintervjuer med kommunikationsföreträdare på Greenpeace och Naturskyddsföreningen, och Undersökning 2 med utgångspunkt från ett mottagarperspektiv i form av fokusgruppsintervjuer med medie- och icke mediestuderande. Resultaten och analysen visade att även om påverkansfilmen för närvarande teman verkar fungera relativt tillfredsställande, finns indikationer på att de kan behövas ses över. Det kan där finnas potential för att nå ut ytterligare. Denna uppsats kan således användas för vidare forskning, då möjligen med en kvantitativ metod som exempelvis en undersökning med medföljande enkät, för ett mer generaliserbart resultat.

Heteronormen - hur ser den ut i sex- och samlevnadsundervisningen på en jämställdcertifierad låg- och mellanstadieskola?

Sex- och samlevnadsundervisningen handlar idag mycket om jämställdhetsarbete, normer och människors lika värde. Kunskapsområdet ska integreras i alla skolans ämnen för att alla elever ska känna sig inkluderade i undervisningen. Studiens syfte är att ta reda på hur lärarna på låg- och mellanstadiet arbetar med sin egen medvetenhet angående heteronormen samt att ta reda på hur de kommunicerar detta med eleverna. Studien har samlat kvalitativ data genom halvstrukturerade intervjuer med sex lärare på en jämställdhetscertifierad skola i Sverige. Studiens resultat visar genom lärarnas resonemang att de arbetar aktivt med normer och jämställdhet, vilket de kopplar till skolans certifikat. Lärarna beskriver att de lyfter och diskuterar dessa frågor i kollegiet samt granskar det undervisningsmaterial de använder sig av i verksamheten. Lärarna pratar om normer och jämställdhet med eleverna och är noggranna med att det ska ske på ett sätt som inkluderar alla elever och inte pekar ut hbt-personer som annorlunda, något som de anser kan vara ett dilemma. Lärarna berättar att de ibland kan känna att kunskapen brister angående hbt-frågor, men direkt när eleverna kränker någon eller har frågor som grundar sig i heteronormen diskuteras det med eleverna. Skolan har i och med sex- och samlevnadsundervisningen ett stort ansvar i jämställdhetsarbetet.

Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes

AIMS/HYPOTHESIS: Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) contribute to experimental diabetic kidney disease, a condition with substantially increased cardiovascular risk when present in patients. Therefore, we aimed to explore the levels of sTNFRs, and their association with prevalent kidney disease, incident cardiovascular disease, and risk of mortality independently of baseline kidney function and microalbuminuria in a cohort of patients with type 2 diabetes. In pre-defined secondary analyses we also investigated whether the sTNFRs predict adverse outcome in the absence of diabetic kidney disease. METHODS: The CARDIPP study, a cohort study of 607 diabetes patients [mean age 61 years, 44 % women, 45 cardiovascular events (fatal/non-fatal myocardial infarction or stroke) and 44 deaths during follow-up (mean 7.6 years)] was used. RESULTS: Higher sTNFR1 and sTNFR2 were associated with higher odds of prevalent kidney disease [odd ratio (OR) per standard deviation (SD) increase 1.60, 95 % confidence interval (CI) 1.32-1.93, p < 0.001 and OR 1.54, 95 % CI 1.21-1.97, p = 0.001, respectively]. In Cox regression models adjusting for age, sex, glomerular filtration rate and urinary albumin/creatinine ratio, higher sTNFR1 and sTNFR2 predicted incident cardiovascular events [hazard ratio (HR) per SD increase, 1.66, 95 % CI 1.29-2.174, p < 0.001 and HR 1.47, 95 % CI 1.13-1.91, p = 0.004, respectively]. Results were similar in separate models with adjustments for inflammatory markers, HbA1c, or established cardiovascular risk factors, or when participants with diabetic kidney disease at baseline were excluded (p < 0.01 for all). Both sTNFRs were associated with mortality. CONCLUSIONS/INTERPRETATIONS: Higher circulating sTNFR1 and sTNFR2 are associated with diabetic kidney disease, and predicts incident cardiovascular disease and mortality independently of microalbuminuria and kidney function, even in those without kidney disease. Our findings support the clinical utility of sTNFRs as prognostic markers in type 2 diabetes.

Abdominal hyperalgesia in secretory phospholipase A(2)-induced rat pancreatitis: Distinct roles of NK1 receptors

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Involvement of serotoninergic receptors in the anteroventral preoptic region on hypoxia-induced hypothermia

Hypoxia causes a regulated decrease in body temperature (Tb). There is circumstantial evidence that the neurotransmitter serotonin (5-HT) in the anteroventral preoptic region (AVPO) mediates this response. However, which 5-HT receptor(s) is (are) involved in this response has not been assessed. Thus, we investigated the participation of the 5-HT receptors (5-HT(1), 5-HT(2), and 5-HT(7)) in the AVPO in hypoxic hypothermia. To this end, Tb of conscious Wistar rats was monitored by biotelemetry before and after intra-AVPO microinjection of methysergide (a 5-HT(1) and 5-HT(2) receptor antagonist, 0.2 and 2 mu g/100 nL), WAY-100635 (a 5-HT(1A) receptor antagonist, 0.3 and 3 mu g/100 nL), and SB-269970 (a 5-HT(7) receptor antagonist, 0.4 and 4 mu/100 nL), followed by 60 min of hypoxia exposure (7% O(2)). During the experiments, the mean chamber temperature was 24.6 +/- 0.7 degrees C (mean +/- SE) and the mean room temperature was 23.5 +/- 0.8 degrees C (mean +/- SE). Intra-AVPO microinjection of vehicle or 5-HT antagonists did not change Tb during normoxic conditions. Exposure of rats to 7% of inspired oxygen evoked typical hypoxia-induced hypothermia after vehicle microinjection, which was not affected by both doses of methysergide. However, WAY-100635 and SB-269970 treatment attenuated the drop in Tb in response to hypoxia. The effect was more pronounced with the 5-HT7 antagonist since both doses (0.4 and 4 mu g/0.1 mu L) were capable of attenuating the hypothermic response. As to the 5-HT(1A) antagonist, the attenuation of hypoxia-induced hypothermia was only observed at the higher dose. Therefore, the present results are consistent with the notion that 5-HT acts on both 5-HT(1A) and 5-HT7 receptors in the AVPO to induce hypothermia, during hypoxia. (c) 2005 Elsevier B.V All rights reserved.

Serotoninergic receptors in the anteroventral preoptic region modulate the hypoxic ventilatory response

Hypothalamus is a site of integration of the hypoxic and thermal stimuli on breathing and there is evidence that serotonin (5-HT) receptors in the anteroventral preoptic region (AVPO) mediate hypoxic hypothermia. Once 5-HT is involved in the hypoxic ventilatory response (HVR), we investigated the participation of the 5-HT receptors (5-HT1, 5-HT2 and 5-HT7) in the AVPO in the HVR. To this end, pulmonary ventilation (V-E) of rats was measured before and after intra-AVPO microinjection of methysergide (a 5-HT1 and 5-HT2 receptor antagonist), WAY-100635 (a 5-HT1A receptor antagonist) and SB-269970 (a 5-HT7 receptor antagonist), followed by 60 min of hypoxia exposure (7% O-2). Intra-AVPO microinjection of vehicles or 5-HT antagonists did not change VE during normoxic conditions. Exposure of rats to 7% O-2 evoked typical hypoxia-induced hyperpnea after vehicle microinjection, which was not affected by methysergide. WAY-100635 and SB-269970 treatment caused an increased HVR, due to a higher tidal volume. Therefore, the current data provide the evidence that 5-HT acting on 5-HT1A and 5-HT7 receptors in the AVPO exert an inhibitory modulation on the HVR. (c) 2005 Elsevier B.V. All rights reserved.

Ionotropic glutamatergic receptors in the rostral medullary raphe modulate hypoxia and hypercapnia-induced hyperpnea

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Opioid mu-receptors in the rostral medullary raphe modulate hypoxia-induced hyperpnea in unanesthetized rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)