Az ""alacsony T3 szindróma"" kialakulásáért felelős központi idegrendszeri szabályozó mechanizmusok tanulmányozása patkányban = Central regulatory mechanisms involved in the development of the 'low T3 syndrome'

A pályázat fő célja az éhezés és fertőzés hatására kialakuló centrális hipotiroidizmus kialakulásáért felelős központi idegrendszeri szabályozó mechanizmusok tanulmányozása volt. Kimutattuk, hogy a leptin, inzulin és glükóz eltérő hatást fejt ki az arcuatus idegmag sejtjeire és csak a leptin képes kivédeni az éhezés hatására kialakuló centrális hipotiroidizmust. Leírtuk, hogy az AGRP TRH idegsejtekre kifejtett gátló hatását elsősorban a 4-es típusú melanokortin receptor (MC4-R) közvetíti. Igazoltuk, hogy a PVN MC4-R tartalmú idegsejtjein a legtöbb AGRP tartalmú terminális közelében nem figyelhetők meg ?-MSH-tartalmú végződések, valószínűsítve, hogy az AGRP a PVN-ben inverz agonistaként hathat. Leírtuk, hogy LPS kezelés a pajzsmirigyhormonok szintjének változásától függetlenül D2 aktivitás fokozódást eredményez a mediobazális hipotalamuszban a tanycytákban. Továbbá azonosítottuk a D2 promoter NF-kB kötőhelyét. Ezek alapján feltételezzük, hogy LPS hatására a megemelkedett D2 aktivitás az eredményezett lokális hipertiroidizmus révén hozzájárul a TRH idegsejtek gátlásához. | The long term goal of the proposed studies was the examination of the hypothalamic regulatory systems involved in the development of the central hypothyroidism induced by fasting or infection. We have described that leptin, insulin and glucose have different effects on the neurons of the arcuate nucleus. In addition, only leptin is able to reverse the fasting induced changes of the hypothalamic-pituitary-thyroid axis. We have demonstrated that the effect of AGRP on the hypophysiotropic TRH neurons is primarily mediated by the melanocortin 4 receptor (MC4-R). In addition, we have provided evidence that ?-MSH-containing varicosities are not present in the proximity of the AGRP terminals on the surface of the MC4-R-producing cells in the PVN, suggesting that AGRP acts as an inverse agonist in the PVN. We have demonstrated that LPS induces an increase of D2 activity in the tanycytes of the mediobasal hypothalamus. These changes are independent from the changes of the peripheral thyroid hormone level. Furthermore, we have identified the NF-kB binding cite of the D2 promoter. Based on these data, we hypothesize that the LPS induced increase of D2 activity results in a local hyperthyroidism in the PVN that contribute to the LPS induced inhibition of the hypophysiotropic TRH neurons

Distribution of type 1 cannabinoid receptor expressing neurons in the septal-hypothalamic region of the mouse. Colocalization with GABAergic and glutamatergic markers.

Type 1 cannabinoid receptor (CB1) is the principal mediator of retrograde endocannabinoid signaling in the brain. In this study, we addressed the topographic distribution and amino acid neurotransmitter phenotype of endocannabinoid-sensitive hypothalamic neurons in mice. The in situ hybridization detection of CB1 mRNA revealed high levels of expression in the medial septum (MS) and the diagonal band of Broca (DBB), moderate levels in the preoptic area and the hypothalamic lateroanterior (LA), paraventricular (Pa), ventromedial (VMH), lateral mammillary (LM) and ventral premammillary (PMV) nuclei, and low levels in many other hypothalamic regions including the suprachiasmatic (SCh) and arcuate (Arc) nuclei. This regional distribution pattern was compared to location of GABAergic and glutamatergic cell groups, as identified by the expression of glutamic acid decarboxylase 65 (GAD65) and type 2 vesicular glutamate transporter (VGLUT2) mRNAs, respectively. The MS, DBB and preoptic area showed overlaps between GABAergic and CB1-expressing neurons, whereas hypothalamic sites with moderate CB1 signals, including the LA, Pa, VMH, LM and PMV, were dominated by glutamatergic neurons. Low CB1 mRNA levels were also present in other glutamatergic and GABAergic regions. Dual-label in situ hybridization experiments confirmed the cellular co-expression of CB1 with both glutamatergic and GABAergic markers. In this report we provide a detailed anatomical map of hypothalamic glutamatergic and GABAergic systems whose neurotransmitter release is controlled by retrograde endocannabinoid signaling from hypothalamic and extrahypothalamic target neurons. This neuroanatomical information contributes to the understanding of the role that the endocannabinoid system plays in the regulation of endocrine and metabolic functions. J. Comp. Neurol., 2011. (c) 2011 Wiley-Liss, Inc

The state of Hungarian radiotherapy

BackgroundHungary suffers from one of the highest levels of cancer morbidity, with over 700 new cases per 100000 inhabitants per year. This situation necessitates, among others, investigation of the current state of radiotherapeutic care, and its infrastructural and staffing conditions.AimThe aim of this paper is to present the current state of Hungarian radiotherapy.ResultsAlthough the number of radiation treatments increased substantially between 1995 and 2003 (16544 vs. 26316), together with a considerable increase in the linear accelerator equivalent (LAE) value (15.9 vs 29.45), about one-third of the patients who would profit from radiotherapy do not receive this form of treatment. Radiotherapeutic care is provided at 13 centers in 7 geographical regions, with widely varying infrastructural and staffing conditions, characterized by a mean LAE value of 4.2 (range: 0–8.45), a 1 LAE value for a mean of 343500 inhabitants (range: 0–731500), and a mean annual workload of 353 patients per radiation oncologist (range: 255–424), 532 patients per physicist (range: 255–911) and 149 per radiation technologist (range: 71–300). These conditions result in a waiting list of between 0 and 42 days for non-emergency cases and a mean of 260 radiotherapy-treated patients per 100000 inhabitants (range: 111–434) in the different geographical regions, which is far below the expected Hungarian value of 403 radiotherapy-treated cases/year.ConclusionsAttainment of an adequate radiotherapeutic service with an acceptable waiting time throughout Hungary requires the creation of 2 additional centers and the reconstruction of 1 existing center, the provision of 9 new linacs, the replacement of 10 functioning telecobalt units with linacs, and increases of 54% in the number of radiation oncologists, 51% in the number of physicists and 65% in the number of radiation technologists

Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats.

OBJECTIVE Blockade of the CB1 receptor is one of the promising strategies for the treatment of obesity. Although antagonists suppress food intake and reduce body weight, the role of central versus peripheral CB1 activation on weight loss and related metabolic parameters remains to be elucidated. We therefore specifically assessed and compared the respective potential relevance of central nervous system (CNS) versus peripheral CB1 receptors in the regulation of energy homeostasis and lipid and glucose metabolism in diet-induced obese (DIO) rats. RESEARCH DESIGN AND METHODS Both lean and DIO rats were used for our experiments. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR, and euglycemic-hyperinsulinemic clamps were used for insulin sensitivity and glucose metabolism studies. RESULTS Specific CNS-CB1 blockade decreased body weight and food intake but, independent of those effects, had no beneficial influence on peripheral lipid and glucose metabolism. Peripheral treatment with CB1 antagonist (Rimonabant) also reduced food intake and body weight but, in addition, independently triggered lipid mobilization pathways in white adipose tissue and cellular glucose uptake. Insulin sensitivity and skeletal muscle glucose uptake were enhanced, while hepatic glucose production was decreased during peripheral infusion of the CB1 antagonist. However, these effects depended on the antagonist-elicited reduction of food intake. CONCLUSIONS Several relevant metabolic processes appear to independently benefit from peripheral blockade of CB1, while CNS-CB1 blockade alone predominantly affects food intake and body weight

Chronic Amyloid beta Oligomer Infusion Evokes Sustained Inflammation and Microglial Changes in the Rat Hippocampus via NLRP3

Microglia are instrumental for recognition and elimination of amyloid beta1-42 oligomers (AbetaOs), but the long-term consequences of AbetaO-induced inflammatory changes in the brain are unclear. Here, we explored microglial responses and transciptome-level inflammatory signatures in the rat hippocampus after chronic AbetaO challenge. Middle-aged Long Evans rats received intracerebroventricular infusion of AbetaO or vehicle for 4weeks, followed by treatment with artificial CSF or MCC950 for the subsequent 4weeks. AbetaO infusion evoked a sustained inflammatory response including activation of NF-kappaB, triggered microglia activation and increased the expression of pattern recognition and phagocytic receptors. Abeta1-42 plaques were not detectable likely due to microglial elimination of infused oligomers. In addition, we found upregulation of neuronal inhibitory ligands and their cognate microglial receptors, while downregulation of Esr1 and Scn1a, encoding estrogen receptor alpha and voltage-gated sodium-channel Na(v)1.1, respectively, was observed. These changes were associated with impaired hippocampus-dependent spatial memory and resembled early neurological changes seen in Alzheimer's disease. To investigate the role of inflammatory actions in memory deterioration, we performed MCC950 infusion, which specifically blocks the NLRP3 inflammasome. MCC950 attenuated AbetaO-evoked microglia reactivity, restored expression of neuronal inhibitory ligands, reversed downregulation of ERalpha, and abolished memory impairments. Furthermore, MCC950 abrogated AbetaO-invoked reduction of serum IL-10. These findings provide evidence that in response to AbetaO infusion microglia change their phenotype, but the resulting inflammatory changes are sustained for at least one month after the end of AbetaO challenge. Lasting NLRP3-driven inflammatory alterations and altered hippocampal gene expression contribute to spatial memory decline

Az ösztrogének lehetséges szerepe a vastagbéldaganatok kialakulásában = Potential role of estrogens in colorectal tumour development

Absztrakt: A colorectalis carcinoma (CRC) az egyik leggyakrabban előforduló daganatos megbetegedés világszerte. A sporadikus vastagbélrák incidenciája ötvenéves kor alatt alacsonyabb, majd az életkor előrehaladtával nő, továbbá jellegzetes klinikai, lokalizáció szerinti és molekuláris eltérést mutathat a nők és a férfiak között. Epidemiológiai és molekuláris biológiai kutatások eredményei szerint az ösztradiol (E2) által szabályozott jelútrendszer meghatározó szerepet játszik a CRC kialakulásában és prognosztikájában, döntően a vastagbélhámban domináns ösztrogénreceptor-bétán (ERβ) keresztül. Az ösztradiol emésztőrendszeri hatásai igen sokrétűek, az ép és tumoros vastagbélhámsejtekre gyakorolt hatását in vitro és in vivo vizsgálatok egyaránt igazolták. Az ösztrogénreceptor-alfával (ERα) ellentétben az ERβ aktivációja a sejtosztódást gátolja és az apoptózist fokozza, a béta-receptor kifejeződése ugyanakkor mind az élettani öregedés, mind a vastagbél kórállapotaiban megváltozhat. Az ösztradiol ERβ által közvetített daganatellenes hatása a sejtproliferáció gátlása, az apoptózis serkentése, az áttétképzés gátlása és gyulladáscsökkentő hatása révén valósulhat meg. Sejtkultúra- és állatkísérletes kutatások eredményei alapján az ösztrogénreceptor-bétára szelektíven ható receptormodulátorok (szelektív ösztrogénreceptor-modulátor [SERM]) és a fitoösztrogének új, hozzáadott kezelési lehetőséget jelenthetnek az idült gyulladással és a kóros sejtproliferációval jellemezhető colorectalis megbetegedésekben. Orv Hetil. 2020; 161(14): 532–543. | Abstract: Colorectal cancer (CRC) is one of the most common types of cancers worldwide. The incidence of sporadic CRC is lower in individuals below 50 years and increases with age, furthermore, it shows typical clinical, macroscopic and molecular differences between females and males. According to the results of epidemiological and molecular biology studies, the estradiol-regulating signaling pathway plays an important role in the development and prognosis of CRC, predominantly through estrogen receptor beta (ERβ), which is dominant in the colonic epithelium. Estradiol has multiple gastrointestinal effects, which were confirmed by in vitro and in vivo studies on histologically intact and cancerous cells as well. In contrast to estrogen receptor alpha (ERα), the activation of ERβ inhibits cell proliferation and enhances apoptosis, nevertheless, the expression of estrogen receptor beta can change both during physiological ageing and in colorectal disorders. The ERβ-mediated antitumour effects of estradiol may be exerted through inhibition of cell proliferation, stimulation of apoptosis, inhibition of metastasis formation and its anti-inflammatory activity. Based on the results of cell culture and animal studies, selective modulators of estrogen receptor beta (selective estrogen receptor modulator [SERM]) and phytoestrogens can be new, additional therapeutic options in the treatment of colorectal diseases characterized by chronic inflammation and uncontrolled cell proliferation. Orv Hetil. 2020; 161(14): 532–543

The Orexigenic Effect of Ghrelin Is Mediated through Central Activation of the Endogenous Cannabinoid System

INTRODUCTION Ghrelin and cannabinoids stimulate appetite, this effect possibly being mediated by the activation of hypothalamic AMP-activated protein kinase (AMPK), a key enzyme in appetite and metabolism regulation. The cannabinoid receptor type 1 (CB1) antagonist rimonabant can block the orexigenic effect of ghrelin. In this study, we have elucidated the mechanism of the putative ghrelin-cannabinoid interaction. METHODS The effects of ghrelin and CB1 antagonist rimonabant in wild-type mice, and the effect of ghrelin in CB1-knockout animals, were studied on food intake, hypothalamic AMPK activity and endogenous cannabinoid content. In patch-clamp electrophysiology experiments the effect of ghrelin was assessed on the synaptic inputs in parvocellular neurons of the hypothalamic paraventricular nucleus, with or without the pre-administration of a CB1 antagonist or of cannabinoid synthesis inhibitors. RESULTS AND CONCLUSIONS Ghrelin did not induce an orexigenic effect in CB1-knockout mice. Correspondingly, both the genetic lack of CB1 and the pharmacological blockade of CB1 inhibited the effect of ghrelin on AMPK activity. Ghrelin increased the endocannabinoid content of the hypothalamus in wild-type mice and this effect was abolished by rimonabant pre-treatment, while no effect was observed in CB1-KO animals. Electrophysiology studies showed that ghrelin can inhibit the excitatory inputs on the parvocellular neurons of the paraventricular nucleus, and that this effect is abolished by administration of a CB1 antagonist or an inhibitor of the DAG lipase, the enzyme responsible for 2-AG synthesis. The effect is also lost in the presence of BAPTA, an intracellular calcium chelator, which inhibits endocannabinoid synthesis in the recorded parvocellular neuron and therefore blocks the retrograde signaling exerted by endocannabinoids. In summary, an intact cannabinoid signaling pathway is necessary for the stimulatory effects of ghrelin on AMPK activity and food intake, and for the inhibitory effect of ghrelin on paraventricular neurons