A Brain Region-Dependent Alteration in the Expression of Vasopressin, Corticotropin-Releasing Factor, and Their Receptors Might Be in the Background of Kisspeptin-13-Induced Hypothalamic-Pituitary-Adrenal Axis Activation and Anxiety in Rats

Previously, we reported that intracerebroventricularly administered kisspeptin-13 (KP-13) induces anxiety-like behavior and activates the hypothalamic-pituitary-adrenal (HPA) axis in rats. In the present study, we aimed to shed light on the mediation of KP-13′s stress-evoking actions. The relative gene expressions of the corticotropin-releasing factor (Crf, Crfr1, and Crfr2) and arginine vasopressin (Avp, Avpr1a, and Avpr1b) systems were measured in the amygdala and hippocampus of male Wistar rats after icv KP-13 treatment. CRF and AVP protein content were also determined. A different set of animals received CRF or V1 receptor antagonist pretreatment before the KP-13 challenge, after which either an open-field test or plasma corticosterone levels measurement was performed. In the amygdala, KP-13 induced an upregulation of Avp and Avpr1b expression, and a downregulation of Crf. In the hippocampus, the mRNA level of Crf increased and the level of Avpr1a decreased. A significant rise in AVP protein content was also detected in the amygdala. KP-13 also evoked anxiety-like behavior in the open field test, which the V1 receptor blocker antagonized. Both CRF and V1 receptor blockers reduced the KP-13-evoked rise in the plasma corticosterone level. This suggests that KP-13 alters the AVP and CRF signaling and that might be responsible for its effect on the HPA axis and anxiety-like behavior

Kupffer sejt blokád jelentősége normál és kóros immunválasztásban = The role of Kupffer cell blockade in health and disease

Kimutattuk, hogy a májba transzplantált xenograft túlélése meghosszabbítható. Hasonlóképpen kimutattuk, hogy a Kupffer sejtek működésének gátlása növeli a birkavörösvértestekkel kiváltott humorális immunválaszt, mely 51-krómizotóppal jelölt idegen vörösvértestekkel végzett vizsgálataink szerint arra vezethető vissza, hogy a Kupffer sejt blokád hatására az antigén túlfolyik a májon és az immunválasz szempontjából fontos extrahepatikus szervekben, így a lépben kerül felvételre. Azonban a makrofágok nemcsak a szervezet védekezésében és az immunválasz szabályozásában játszanak fontos szerepet, hanem túlzott aktiválodásuk és a sejtpusztító, immunszuppressziót kiváltó mediátorok fokozott felszabadulása hozzájárulhat a szervek működésének összeomlásához és súlyos sokkállapotokban a többszervi elégtelenség kialakulásához. Kimutattuk, hogy a gadolínium kloriddal kiváltott Kupffer sejt blokád mérsékli, az antiglükokortikoid RU 38486 súlyosbítja a kísérletesen létrehozott biliaris obstrukcióban szenvedő állatok endotoxin érzékenységét és az endotoxinnal kiváltott citokin felszabadulást. Folyamatban lévő kísérleteink szerint a krónikusan adagolt gadolínium klorid gátolja a biliaris cirrhosis kialakulását. Vizsgálatainkban jelentős szinergizmust találtunk a bakteriális endotoxin és az adenovírus fertőzés között. A vírusfertőzés és endotoxin hatására kialakult túlaktivált gyulladásos válaszreakció eredményezi az endotoxin lethalis hatásának fokozódását | The gadolinium chloride (GdCl3)-iduced Kupffer cell blockade prolongs the rejection of discordant xenograft transplanted into the liver. Kupffer cell phagocytosis blockade was also found to increase the humoral immune response to sheep red blood cells.The augmentation of the humoral immune response in GdCl3-pretreated animals is a consequence of the spillover of the antigen from the liver into the spleen and other extrahepatic reticuloendothelials organs, which are important in the immune response. However, macrophages not only act as a first line of defence and have pivotal roles in regulating the immune response, but also the over-activatin of macrophages and the excessive release of macrophage-derived destructive and immunosuppressive products may contribute to organ damage and the develoment of ?multiple organ failure? in severe stress and injurues such as shock states. It has been shown that the GdCl3-iduced Kupffer cell blockade decreases and the antiglucocorticoid RU 38486 increases the endotoxin-induced mortality and cytokine liberation in experimental bile ligated rats. Our experiments show that the GdCl3 inhibits the development of biliary fibrosis/cirrhosis. We observed a remarkable synergism of adenoviruses and lipopysacchaide (LPS) in triggering the production of tumor necrosis factor alpha. The over-activation of inflammatory responses may explain the augmentation of the lethal effect of LPS in mice pre-exposed to adenoviruse

Efficacy of Biologics Targeting Tumour Necrosis Factor-alpha, Interleukin-17 -12/23, -23 and Small Molecules Targeting JAK and PDE4 in the Treatment of Nail Psoriasis: A Network Meta-analysis

The comparative efficacy of registered anti-psoriatic biologics and small molecules in treating nail symptoms has not been systematically evaluated. The aim of this study was to perform a network meta-analysis to determine the efficacy of biologics and small molecules in nail psoriasis. A Bayesian network meta-analysis of 17 randomized clinical trials (a total of 6,053 nail psoriatic patients) was performed, comparing the short-term (week 10–16) efficacy of biologics and small molecules in the treatment of nail psoriasis. All active treatments were found to be superior to placebo. Ixekizumab 80 mg every 4 weeks (Nail Psoriasis Severity Index (NAPSI) % improvement, Surface Under the Cumulative Ranking (SUCRA)=0.92) and etanercept 50 mg twice weekly (probability of achieving NAPSI 50, SUCRA=0.82) proved the best short-term treatment options. However, efficacy end-points in psoriasis trials were not optimized for nail assessment, and outcome parameters were highly heterogeneous, limiting comparability. In conclusion, outcome parameters and efficacy endpoints of nail psoriasis trials should be standardized

Diszkrét és folytonos: a gráfelmélet, algebra, analízis és geometria találkozási pontjai = Discrete and Continuous: interfaces between graph theory, algebra, analysis and geometry

Sok eredmény született a gráfok növekvő konvergens sorozataival és azok limesz-objektumaival, ill. az ezek vizsgálatára szolgáló gráf-algebrákkal kapcsolatban. Kidolgozásra kerültek a nagyon nagy sűrű gráfok (hálózatok) matematikai elméletének alapjai, és ezek alkalmazásai az extremális gráfelmélet területén. Aktív és eredményes kutatás folyt a diszkrét matematika más, klasszikus matematikai területekkel való kapcsolatával kapcsolatban: topológia (a topológiai módszer alkalmazása gráfok magjára, ill a csomók elmélete), geometriai szerkezetek merevsége (a Molekuláris Sejtés bizonyítása 2 dimenzióban), diszkrét geometriai (Bang sejtésének bizonyítása), véges geometriák (lefogási problémák, extremális problémák q-analogonjai), algebra (félcsoport varietások, gráfhatványok színezése), számelmélet (additív számelmélet, Heilbronn probléma), továbbá gráfalgoritmusok (stabilis párosítások, biológiai alkalmazások)) területén. | Several results were obtained in connection with convergent growing sequences of graphs and their limit objects, and with graph algebras facilitating their study. Basic concepts for the study of very large dense graphs were worked out, along with their applications to extremal graph theory. Active and successful research was conducted concerning the interaction of discrete mathematics with other, classical areas of mathematics: topology (applications of topology in the study of kernels of graphs, and the theory of knots), rigidity of geometric structures (proof of the Molecular Conjecture in 2 dimensions), discrete geometry (proof of the conjecture of Bang), finite geometries (blocking problems, q-analogues of extremal problems), algebra (semigroup varieties, coloring of graph powers), number theory (additive number theory, heilbronn problem), and graph algorithms (stable matchings, applications in biology)

Obestatin prevents analgesic tolerance to morphine and reverses the effects of mild morphine withdrawal in mice

Obestatin is a 23-amino acid gut-derived neuropeptide, encoded by the same gene with ghrelin. The goal of this study was to examine the effects of obestatin on the acute and chronic analgesic actions of morphine and on mild morphine withdrawal. Open-field (OF) and elevated plus maze (EPM) tests were used to assess mild morphine withdrawal-induced behavior changes and the heat-radiant tail-flick assay was used to investigate analgesic actions of morphine. CFLP male mice were treated twice a day with graded doses of morphine in EPM and OF experiments and once a day in tail-flick studies. Obestatin (1.5mug/2mul) was administrated once a day in all experiments. Furthermore, 0.2mg/kg naloxone or saline was administered after the final injection of morphine at a dose of 20mg/kg in EPM and OF. These behavioral parameters were monitored in the OF: the percentage of center ambulation time and distance; whereas in the EPM: the time spent in open arms and the entries into open arms compared to the total time (%OAT) and entries (%OAE). In the OF, obestatin significantly decreased the percentage of time spent in the center in mice undergoing naloxone-precipitated mild morphine withdrawal. EPM results were similar to open field, but obestatin had no significant effect on parameters mentioned above. Besides, obestatin maintained the analgesic effect of morphine 90 and 120min after morphine injection in mice treated with morphine receiving obestatin compared to mice treated with morphine. In tolerance studies, obestatin diminished the analgesic tolerance to morphine on the 5th day. In this study we confirmed that obestatin reversed the effect of mild morphine withdrawal and enhances the analgesic effect of morphine. These data suggest that obestatin may have a role in opioid-induced analgesia and in behavioral responses induced by opioid withdrawal

The effect of obestatin on anxiety-like behaviour in mice

Obestatin is a 23 amino acid-peptide, derived from the same preproghrelin-gene as ghrelin. Obestatin was originally reported as a ghrelin antagonist with anorexigenic activity, but later it was proven to be involved in multiple processes including sleep, memory retention, anxiety, morphine-induced analgesia and withdrawal. In the present study, in male CFLP mice, by using computerised open field (OF) and elevated plus maze (EPM) tests we have investigated the behavioural effects of the acute intracerebroventricular (icv) administration of obestatin alone, and following ghrelin receptor blockage with [d-Lys3]-Growth Hormone Releasing Peptide-6 ([d-Lys3]- GHRP6) or corticotropin-releasing hormone (CRH) receptor 1 antagonism with antalarmin. Plasma corticosterone levels were measured for each treatment group by using chemofluorescent assay. Our results in the EPM test showed that obestatin reduced the percent of time spent in the open arms. The basal locomotor activity (ambulation distance and time, rearing and jumping) was not influenced significantly neither in the obestatin-treated groups, nor in those receiving pre-treatment with antalarmin or [d-Lys3]-GHRP6. The percentage of central ambulation distance however was decreased by obestatin, while the percentage of time spent in the central zone showed a decreasing tendency. The administration of antalarmin or [d-Lys3]-GHRP6 have both reversed the effect of obestatin on central ambulation. Plasma corticosterone levels were elevated by obestatin, which effect was antagonised by the injection of antalarmin. These are the first results to indicate that obestatin exerts anxiogenic-like effect in mice, which might be mediated through ghrelin receptor and CRH activation

The effect of pituitary adenylate cyclase-activating polypeptide on elevated plus maze behavior and hypothermia induced by morphine withdrawal

The aim of the present investigation was to study the effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on morphine withdrawal-induced behavioral changes and hypothermia in male CFLP mice. Elevated plus maze (EPM) and jump tests were used to assess naloxone-pptd. morphine withdrawal-induced behavior responses. Different doses of s.c. (s.c.) naloxone, (0.1 and 0.2 mg/kg, resp.) were used to ppt. the emotional and psychical aspects of withdrawal on EPM and 1 mg/kg (s.c.) was used to induce the somatic withdrawal signs such as jumping, and the changes in body temp. In our EPM studies, naloxone proved to be anxiolytic in mice treated with morphine. Chronic intracerebroventricular (i.c.v.) administration of PACAP alone had no significant effect on withdrawal-induced anxiolysis and total activity at doses of 500 ng and 1 μg. At dose of 500 ng, however, PACAP significantly counteracted the reduced motor activity in the EPM test in mice treated with morphine and diminished the hypothermia and shortened jump latency induced by naloxone in mice treated with morphine. These findings indicate that anxiolytic-like behavior may be mediated via a PACAP-involved pathway and PACAP may play an important role in chronic morphine withdrawal-induced hypothermia as well. [on SciFinder(R)