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Background: Sleep deprivation, malnutrition and lack of physical activity are contemporary stress-related factors present in the student population. Stress activates the HPA and often suppresses the HPG axis, but also influences cytokine synthesis and consequently regulates immune response. Since magnesium deficiency facilitates negative pathophysiological consequences, a reasonable question imposes, wheth er Mg supplementation might correct the adrenal/go nadal hormone balance and immuno-endocrine function. Methods: Fifteen male students were given 2 x 250 mg Mg for four weeks. Serum levels of FSH, LH, testosterone (T), ACTH and cortisol

Magnesium has a fundamental role in human body and it is necessary for many processes such as: transmembrane ion flux, neuronal activity, neurotransmitter release, regulation of adenylate cyclase and hormone receptor binding. In the central nervous system magnesium blocks the activity of NMDA receptors and magnesium-deficiency leads to NMDA receptors overactivity, possibly causing neuronal injury and neurological dysfunction, which consequently may manifest as major depression. Numerous pre-clinical and clinical studies confirmed that magnesium influences several systems associated with development of depression. On the other hand, standard antidepressants are ineffective in 40% of cases, and have some unpleasant side-effects. Even though the first positive effect of magnesium in patients with agitated depression was reported in 1921, unfortunately, only small number of studies that favor magnesium's effectiveness in treating depression was published in past decades, including one randomized clinical trial in which magnesium was as effective as imipramine in depressed elderly patients that suffered from diabetes. Even though much more clinical research is needed to extend this important line of research and to confirm its efficacy, due to its safety magnesium preparations could be considered as a potential addition for treatment resistant depression cases., Magnezijum ima značajnu fiziološku ulogu u humanom organizmu i neophodan je za mnoge procese, uključujući: transmembransko kretanje jona, aktivnost neurona, oslobađanje neurotransmitera, regulaciju adenilat ciklaze i vezivanje pojedinih hormona za receptore. U centralnom nervnom sistemu magnezijum blokira aktivnost NMDA receptora, a deficit magnezijuma dovodi do prekomerne aktivacije NMDA receptora, što za posledicu može imati oštećenja neurona i neurološke disfunkcije i u krajnjoj liniji, može se manifestovati razvojem velike depresije. Brojna pretklinička i klinička ispitivanja potvrđuju da magnezijum utiče na nekoliko sistema uključenih u razvoj depresije. Sa druge strane, oko 40% pacijenata pokazuje rezistenciju na tretman standardnim antidepresivima, kojima se pripisuju i brojni neprijatni neželjeni efekti. Iako je prvi pozitivan učinak magnezijuma kod pacijenata koji pate od agitirane depresije prikazan još 1921, nažalost, samo mali broj studija koje govore u prilog efikasnosti magnezijuma u tretmanu depresije je publikovan tokom proteklih decenija, uključujući jedno randomizovano kliničko ispitivanje koje je pokazalo podjednaku efikasnost magnezijuma i imipramina kod starijih depresivnih pacijenata koji boluju od dijabetesa. Iako je neophodno sprovesti veći broj kliničkih ispitivanja i proširiti ovo polje istraživanja u cilju potvrđivanja njegove efikasnosti, usled svoje bezbednosti, magnezijum bi se potencijalno mogao uvesti kao dodatni tretman u lečenju depresije rezistentne na terapiju.

This aim of this study was to evaluate the predictive value of adrenocorticotropic hormone (ACTH), cortisol and ACTH receptor polymorphism (ACTHRP) for left ventricular (LV) remodeling. Thirty-six elite male athletes, as chronic stress adaptation models, and twenty sedentary age and sex-mached subjects emabarked on standard and tissue Doppler echocardiography to assess cardiac parameters at rest. They performed maximal cardiopulmonary test, which was used as an acute stress model. ACTH and cortisol were measured at rest (10 min before test), at beginning, at maximal effort, at 3rd min of recovery, using radioimmunometric and radioimmunoassey techniques, respectively. Promoter region of ACTHR gene (18p11.2) was analysed from blood samples using reverse polymerization reaction with the analysis of restriction fragment length polimorphisam by SacI restriction enzyme. Normal genotype was CTC/CTC, heterozygot for ACTHRP CTC/CCC and homozygot CCC/CCC. In all participants, ACTH and cortisol increased during acute stress, whereas in recovery ACTH increased and cortisol remained unchanged. 49/56 examiners manifested CTC/CTC, 7/56 CTC/CCC and 0/56 CCC/CCC. There was no difference in ACTHRP frequency between groups (chi(2)((1))= 0.178, p = 0.67). LV mass (LVM) and LV end-diastolic volume (LVVd) were higher in athletes than in controls (p lt 0.01) and lower in CTC/CTC than in CTC/CCC genotype (219.43 +/- 46.59(SD)g vs. 276.34 +/- 48.86(SD)g, p = 0.004; 141.24 +/- 24.46(SD)ml vs. 175.29 +/- 37.07(SD)ml, p = 0.002; respectively). In all participants, predictors of LVM and LVVd were ACTH at rest (B = -1.00, -0.44; beta= -0.30, -0.31; p = 0.026,0.012, respectively) and ACTHRP (B = 56.63,34; beta= 0.37,0.40; p = 0.003,0.001, respectively). These results demonstrate that ACTH and ACTHRP strongly predict cardiac morphology suggesting possible regulatory role of stress system activity and sensitivity in cardiac remodeling.

Neurotrofini čine familiju signalnih molekula sa brojnim uticajima na rast, preživljavanje, diferencijaciju i sinaptičku plastičnost postmitotskih neurona, kako u adultnom mozgu, tako i u mozgu tokom razvića. Neurotrofini (BDNF, NGF) se sa određenim afinitetom vezuju za Trk receptore, iniciraju njihovu dimerizaciju i autofosforilaciju i na taj način se pokreće aktivacija signalnih puteva kao što su PI3K/Akt i MAPK/ERK. Akt i ERK kinaze imaju ključne regulatorne uloge u mozgu u procesima kao što su neuronalna proliferacija, diferencijacija, razviće, migracija, preživljavanje i dugotrajna sinaptička plastičnost. Aktivan (fosforilisan) Akt štiti ćeliju od apoptoze tako što stimuliše ekspresiju proteina koji favorizuju preživljavanje ćelija i sa druge strane inhibira egzekutorske kaspaze. Aktivacija ERK1/2 kinaze pomoviše preživljavanje, međutim u određenim uslovima ERK1/2 može imati i pro-apoptotske odlike. S obzirom da je uloga neurotrofina u neurotoksičnosti koja je indukovana anestezijom tokom ranog postnatalnog razvića pokazana u nekoliko studija, cilj ove doktorske disertacije je bio da se na molekulskom nivou ispitaju promene u signalnom putu neurotrofina koje nastaju u kori i talamusu postnatalnih pacova nakon primene anestetske doze propofola, kao i da se utvrdi potencijal tretmana da indukuje ćelijsku smrt i/ili promene u sinaptičkoj plastičnosti. Nakon jednokratne primene propofola (25 mg/kg i.p.) ispitana je vremenska i prostorna ekspresija neurotrofina BDNF i NGF, njihovih aktiviranih receptora TrkB, TrkA i p75 receptora, kao i nishodnih kinaza Akt i ERK kod 14 dana starih (PND14) pacova. Ispitan je i potencijal propofolskog tretman da indukuje ćelijsku smrt, praćenjem ekspresije TNF-α, TNFR1, aktivnog fragmenta kaspaze-3, njegovog inhibitora XIAP proteina, kao i transkripcionog faktora NFκB. Finalno je ispitivan potencijal propofolskog tretmana da indukuje promene u ekspresiji markera sinaptičke plastičnosti (MAP-2, drebrina, GAP-43, sinaptofizina, sinukle, The neurotrophins are a family of secreted proteins that mediate numerous functions in both the developing and mature nervous system, including growth, survival, differentiation and synaptic plasticity of postmitotic neurons. The binding of neurotrophins (BDNF, NGF) to Trk receptors induces their dimerization which is followed by autophosphorylation of tyrosine residues within the intracellular kinase domain, that leads to the activation of signaling pathways such as the PI3K/Akt and MAPK/ERK pathways. Akt and ERK kinases play a crucial role in regulating various processes in the brain, including neuronal proliferation, differentiation, development, migration, survival and long-term synaptic plasticity. Phosphorylated Akt can protect cells from apoptosis via stimulation of the expression of proteins that favor cell survival and by inhibiting executor caspases. Activation of ERK1/2 generally promotes cell survival, although under certain conditions, ERK1/2 can possess proapoptotic properties. Since several studies have revealed a role for neurotrophins in anesthesia-induced neurotoxicity in the developing brain, the goal of this study was to explore the potential of anesthetic dose of propofol to influence neurotrophic signaling pathway in the cortex and thalamus of 14-day-old (PND14) rats, and also to investigate whether same treatment is able to induce neurodegeneration and/or changes in synaptic plasticity. In this study we monitored the spatial and temporal expression of neurotrophic signaling molecules (BDNF, NGF, TrkA, TrkB, p75, Akt and ERK) in the brain of PND14 Wistar rats after the application of a single propofol dose (25 mg/kg i.p). The potential of propofol treatment to induce cell death was also examined, following the expression of TNF-α, TNFR1, cleaved caspase-3 fragment, XIAP and NFκB. Finally, we investigated the changes in the markers of synaptic plasticity (MAP-2, drebrin, GAP-43, synaptophysin, synuclein-1 and N-cadherin) after the propofol treat

Traumatska povreda mozga (engl. traumatic brain injury, TBI) predstavlja povredu moždanog tkiva uzrokovanu mehaničkom povredom glave. TBI je jedan od vodećih uzroka smrtnosti i invaliditeta u svetu, u populaciji ljudi do 45 godina starosti. Posledice TBI zavise od lokalizacije i količine oštećenja moždanog tkiva i mogu varirati od blažih motoričkih i kognitivnih smetnji, pa sve do težih oblika invaliditeta i smrti. Traumatska povreda mozga dovodi do narušavanja krvno-moždane barijere, što rezultuje tačno određenim sledom događaja u povređenom tkivu CNS-a. Naime, akutna faza, označena kao primarna povreda, nastaje direktnim delovanjem mehaničke sile na moždano tkivo i javlja se u trenutku povrede. Događaji koji slede nakon toga označeni su kao sekundarna povreda koja nastaje kao posledica inicijalnog oštećenja, a obuhvata procese koji dovode do daljeg oštećenja tkiva u danima i nedeljama nakon povrede. To su pre svega zapaljenski procesi koji dovode do smrti neurona koji prvobitno nisu bili zahvaćeni mehaničkom povredom. Smatra se da je broj neurona koji umre usled širenja sekundarne povrede daleko veći od broja neurona koji strada usled primarne povrede. Činjenica da se većina procesa u okviru sekundarne povrede odigrava relativno kasno (satima i danima nakon povrede) čini ih podložnim različitim terapeutskim intervencijama. Već decenijama je poznato da restrikcija hrane povoljno deluje na čitav organizam tako što odlaže starosno-zavisne fiziološke promene i smanjuje incidencu različitih obolenja (kancer, autoimunske bolesti, Parkinsonova i Alchajmerova bolest, itd.) Međutim, tek u poslednjih desetak godina intenzivno se istražuje uticaj smanjenog unosa hrane na procese oporavka nakon povrede. Dosadašnja istraživanja na ovom polju su pokazala da restrikcija hrane u trajanju od nekoliko meseci pre povrede CNS-a ima neuroprotektivno dejstvo i promoviše funkcionalni oporavak u nekoliko različitih modela povrede..., Traumatic brain injury (TBI) represents a brain tissue injury caused by mechanical head injury. TBI is one of the leading causes of death and disability in the world human population, up to 45 years of age. Consequences of brain injury depend on the location and amount of brain tissue damage, and can range from mild motor and cognitive impairment, to severe forms of disability and death. Traumatic brain injury leads to impairment of blood-brain barrier, resulting in a precisely defined sequence of events in injured CNS tissue. Two main phases could be distinguished: acute phase, which is called the primary injury that occurs by direct action of mechanical forces on the brain tissue and occurs at the time of injury. The events that followed thereafter are called the secondary injury. Secondary injury occurs as a result of the initial damage, and includes the processes that lead to further tissue damage in the days and weeks following injury. These are primarily inflammatory processes that lead to the death of neurons that initially were not affected by mechanical injury. It is believed that the neuronal cell death caused by secondary injury is far greater than the one caused by primary injury. The fact that most of the processes within the secondary injury occur relatively late (hours and days following injury) makes them subject to various therapeutic interventions. For decades, it is known that food restriction has a beneficial effect on the entire organism by delaying age-dependent physiological changes and reducing the incidence of various diseases (cancer, autoimmune disease, Parkinson's and Alzheimer's, etc). However, only in the last ten years has been to investigate the influence reduced food intake in the recovery process following injury. Previous research in this field has shown that several months long food restriction prior to CNS injury has neuroprotective effects and promotes functional recovery in several different models of injury...

Traumatska povreda mozga (engl. traumatic brain injury, TBI) predstavlja povredu moždanog tkiva uzrokovanu mehaničkom povredom glave. TBI je jedan od vodećih uzroka smrtnosti i invaliditeta u svetu, u populaciji ljudi do 45 godina starosti. Posledice TBI zavise od lokalizacije i količine oštećenja moždanog tkiva i mogu varirati od blažih motoričkih i kognitivnih smetnji, pa sve do težih oblika invaliditeta i smrti. Traumatska povreda mozga dovodi do narušavanja krvno-moždane barijere, što rezultuje tačno određenim sledom događaja u povređenom tkivu CNS-a. Naime, akutna faza, označena kao primarna povreda, nastaje direktnim delovanjem mehaničke sile na moždano tkivo i javlja se u trenutku povrede. Događaji koji slede nakon toga označeni su kao sekundarna povreda koja nastaje kao posledica inicijalnog oštećenja, a obuhvata procese koji dovode do daljeg oštećenja tkiva u danima i nedeljama nakon povrede. To su pre svega zapaljenski procesi koji dovode do smrti neurona koji prvobitno nisu bili zahvaćeni mehaničkom povredom. Smatra se da je broj neurona koji umre usled širenja sekundarne povrede daleko veći od broja neurona koji strada usled primarne povrede. Činjenica da se većina procesa u okviru sekundarne povrede odigrava relativno kasno (satima i danima nakon povrede) čini ih podložnim različitim terapeutskim intervencijama. Već decenijama je poznato da restrikcija hrane povoljno deluje na čitav organizam tako što odlaže starosno-zavisne fiziološke promene i smanjuje incidencu različitih obolenja (kancer, autoimunske bolesti, Parkinsonova i Alchajmerova bolest, itd.) Međutim, tek u poslednjih desetak godina intenzivno se istražuje uticaj smanjenog unosa hrane na procese oporavka nakon povrede. Dosadašnja istraživanja na ovom polju su pokazala da restrikcija hrane u trajanju od nekoliko meseci pre povrede CNS-a ima neuroprotektivno dejstvo i promoviše funkcionalni oporavak u nekoliko različitih modela povrede. Efekti dijetalne restrikcije na različite aspekte sekunda

Inorganic arsenic removal from water using low-cost adsorbents is presented in this paper. Selective removal of As(III) and As(V) from water was performed with natural materials (zeolite, bentonite, sepiolite, pyrolusite and limonite) and industrial by-products (waste filter sand as a water treatment residual and blast furnace slag from steel production); all inexpensive and locally available. Kinetic and equilibrium studies were realized using batch system techniques under conditions that are likely to occur in real water treatment systems. The natural zeolite and the industrial by-products were found to be good and inexpensive sorbents for arsenic while bentonite and sepiolite clays showed little affinity towards arsenic. The highest maximum sorption capacities were obtained for natural zeolite, 4.07 mg As(V) g-1, and waste iron slag, 4.04 mg As(V) g-1., U ovom radu su prikazani rezultati ispitivanja efikasnosti prirodnih i otpadnih materijala za uklanjanje arsena iz vode. Efikasnost uklanjanja arsena, As(III,V) ispitana je u šaržnom sistemu. Kao sorbenti korišćeni su prirodni materijali (zeolit, bentonit, sepiolit, piroluzit i limonit) i otpadni materijali (otpadni filtarski pesak sa postrojenja za prečišćavanje voda i otpadna šljaka iz proizvodnje čelika). Ispitivanja su pokazala da otpadni materijali mogu efikasno ukloniti i As(III) i As(V) iz vode, ali da se efikasnost razlikuje i zavisi od valentnog stanja arsena, početne koncentracije i pH vrednosti vode. Eksperimenti na osnovu kojih su dobijene krive kinetike sorpcije i sorpcione izoterme su rađeni u uslovima kakvi vladaju u realnim sistemima za prečišćavanje vode. Prirodni zeolit o otpadni materijali su se pokazali kao relativno dobri materijali za uklanjanje arsena iz vode dok su bentonit, sepiolit, limonit i piroluzit pokazali slab afinitet prema arsenu. Najveći maksimalni sorpcioni kapacitet su pokazali prirodni zeolit (4,07 mgAs(V) g-1), i otpadna šljaka (4,04 mgAs(V) g-1).

Alpha(1)-adrenoceptors (alpha(1)-ARs) are involved in neuro-thymic and thymic intercellular communications, and consequently modulation of T-cell development. Ageing is associated with a number of changes in noradrenergic neuro-effector transmission, and possibly intercellular noradrenaline (NA)-mediated communication resulting in altered responses of target cells to NA. Thus, in old animals an altered NA modulation of thymopoiesis via alpha(1)-ARs may be expected. To test this hypothesis, in old and young adult Wistar rats we examined: 1) thymic NA levels, density of noradrenergic innervation and NA synthesizing cells, as well as alpha(1)-AR expression, and 2) then the effects of 14-day-long treatment with the alpha(1)-AR blocker, urapidil, on thymocyte development. Overall, the first part of study suggested augmented NA signalling to thymic cells via alpha(1)-ARs due to increased NA availability and alpha(1)-AR thymocyte surface density in old rats. The second part of study supported this assumption. Namely, although in rats of both ages urapidil affected the same thymocyte developmental steps ultimately leading to changes in the relative number of the most mature single positive TCR alpha beta(high) thymocytes, its effects were generally more prominent in old animals. Following urapidil treatment, the percentages of CD4+CD8- cells, including those showing a regulatory CD4+CD25+RT6.1- phenotype, were increased, while CD4-CD8+ cells decreased. In old rats, an augmented thymic escape of immature CD4+CD8+ cells was also registered. In rats of both ages the thymic changes were accompanied by alterations in the proportions of major cell populations in the T-lymphocyte compartment of both peripheral blood and spleen, leading to an increase in the CD4+/CD8+ T-cell ratio. These alterations were also more pronounced in old rats. Moreover, in old rats following urapidil treatment the proportion of TCR alpha beta + cells in the periphery was slightly greater reflecting, most

A commonly held view that ovarian hormones are causally involved in age-associated thymic involution has been recently challenged. In particular, their relevance in the progression of thymic involution has been disputed. To reassess this issue 10-month-old rats with well advanced thymic involutive changes were ovariectomized (Ovx), and after 1 month thymic cellularity, thymocyte development and levels of recent thymic emigrants (RTEs) were examined in peripheral blood and spleen. In addition, the distribution of major conventional and regulatory T-cell subsets was analyzed in the same peripheral lymphocyte compartments. Ovariectomy increased thymic weight and cellularity above the levels in both 10-month-old and age-matched controls indicating that ovarian hormone ablation not only prevented further progression of thymic involution, hut also reversed it. The increased thymic cellularity was accompanied by altered thymocyte differentiation/maturation culminating in increased thymic output of nave T cells as indicated by elevated levels of both CD4 + and CD8 + RTEs in peripheral blood and spleen. The changes in T-cell development produced: (i) a disproportional increase in cellularity across thymocyte subsets, so that relative proportions of cells at all maturational stages preceding the CD4 + CD8 + T cell receptor (TCR)alpha beta(low) stage were reduced; the relative numbers of CD4 + CD8 + TCR alpha beta(low) cells entering positive selection and their immediate CD4 + CD8 + TCR alpha beta(high) descendents were increased, while those of the most mature CD4 + CD8 and CD4 CD8 + TCR alpha beta(high) cells remained unaltered; (ii) enhanced cell proliferation across all thymocyte subsets and (iii) reduced apoptosis of cells within the CD4 + CD8 + thymocyte subset. The augmented thymic output of naive T cells in Ovx rats most likely reflected an early disinhibition of thymocyte development followed by increased positive/reduced negative selection, at least partly, due to r

There is evidence that the major mediators of stress, i.e., catecholamines and glucocorticoids, play an important role in modulating thymopoiesis and consequently immune responses. Furthermore, there are data suggesting that glucocorticoids influence catecholamine action. Therefore, to assess the putative relevance of glucocorticoid-catecholamine interplay in the modulation of thymopoiesis we analyzed thymocyte differentiation/maturation in non-adrenalectomized and andrenalectomized rats subjected to treatment with propranolol (0.4 mg.100 g body weight(-1).day(-1)) for 4 days. The effects of beta-adrenoceptor blockade on thymopoiesis in non-adrenalectomized rats differed not only quantitatively but also qualitatively from those in adrenalectomized rats. In adrenalectomized rats, besides a more efficient thymopoiesis [judged by a more pronounced increase in the relative proportion of the most mature single-positive TCR alpha beta(high) thymocytes as revealed by two-way ANOVA; for CD4(+)CD8(-)F (1,20) = 10.92, P lt 0.01; for CD4(-)CD8(+)F (1,20) = 7.47, P lt 0.05], a skewed thymocyte maturation towards the CD4(-)CD8(+) phenotype, and consequently a diminished CD4(+)CD8(-)/CD4(-)CD8(+) mature TCR alpha beta(high) thymocyte ratio (3.41 +/- 0.21 in non-adrenalectomized rats vs 2.90 +/- 0.31 in adrenalectomized rats, P lt 0.05) were found. Therefore, we assumed that catecholaminergic modulation of thymopoiesis exhibits a substantial degree of glucocorticoid-dependent plasticity. Given that glucocorticoids, apart from catecholamine synthesis, influence adrenoceptor expression, we also hypothesized that the lack of adrenal glucocorticoids affected not only beta-adrenoceptor- but also alpha-adrenoceptor-mediated modulation of thymopoiesis.

The present study was undertaken to reassess the recently challenged role of ovarian hormones in age-associated thymic involution. For this purpose, in eleven-month-old peripubertally ovariectomized (Ox) rats we analyzed: i) thymic weight and cellularity, ii) size of CD4+CD8+ double-positive (DP) thymocyte population, which is believed to correlate to the thymic capacity to export mature T cells, iii) number of recent thymic emigrants (RTEs), and iv) number of peripheral blood CD4+ and CD8+ lymphocytes. It was found that both thymic weight and cellularity were greater in Ox than in control rats. In addition, in Ox rats the numbers of DP thymocytes and both CD4+ and CD8+ RTEs, were significantly greater than in controls, indicating a more efficient generation of T cells in these rats. Furthermore, these findings, coupled with data indicating that the number of neither CD4+ nor CD8+ peripheral blood lymphocytes was affected by ovariectomy, most likely, suggest a reduced homeostatic proliferation of memory cells in Ox rats, i.e. broadening of TCR peripheral repertoire without changes in the overall number of T cells leading to a more efficient response to newly encountered antigens. The results indicate that the ovarian steroid deprivation from early peripubertal period leads to a long lasting postponement/alleviation of age-associated decline in T-cell mediated immune response., Ova istraživanja su preduzeta sa ciljem da se preispita uloga gonadnih hormona u involuciji timusa, koja je nedavno dovedena u pitanje. U tom cilju je kod 11 meseci starih ženki pacova, koje su ovarijektomisane (Ox) u peripubertetnom uzrastu, analizirana: i) težina i celularnost timusa, ii) broj CD4+CD8+ dvostruko pozitivnih (DP) timocita, za koji se smatra da odražavaju sposobnost organa da generiše zrele T limfocite, iii) broj neposrednih emigranata iz timusa (RTE) i iv) ukupan broj CD4+ i CD8+ limfocita u perifernoj krvi. Dokazano je da su težina i celularnost timusa bile značajno veće u Ox životinja. Kod ovih životinja je nađen i povećan broj DP timocita, kao i CD4+ i CD8+ RTE, što ukazuje na efikasniju produkciju T ćelija u njihovom timusu. Ovaj nalaz, u kontekstu nepromenjenog broja CD4+ i CD8+ ćelija u perifernoj krvi, takođe sugeriše smanjenu homeostatsku proliferaciju memorijskih ćelija, odnosno ukazuje na kvalitativne promene u perifernom T ćelijskom repertoaru (koje obezbeđuju efikasniji odgovor na nove antigene) bez kvantitativnih promena. U celini, rezultati ukazuju da u odsustvu hormona ovarijuma počevši od ranog peripubertetnog uzrasta dolazi do značajnog odlaganja/ublažavanja involucije timusa i posledičnih promena na periferiji.

Using both immunocytochemical and flow cytometric analyses of rat peritoneal exudate cells constitutive expression of tyrosine hydroxylase and both beta(2)- and alpha(1)-adrenoceptors on macrophages was revealed. Furthermore, according to the characteristic assemblage of tyrosine hydroxylase and adrenoceptor subtype expression different macrophage subsets were identified. In vitro treatment of macrophages with the nonselective alpha,beta-adrenoceptor agonist arterenol and/or the beta-adrenoceptor antagonist propranolol indicated that beta-adrenoceptors potentiated nitric oxide (NO) production and suggested alpha-adrenoceptor-mediated suppression of hydrogen peroxide (H2O2) production. An increase in H2O2 production in the presence of the alpha(1)-adrenoceptor antagonist ebrantil provided support for this. Chronic propranolol treatment in vivo led to increased NO and H2O2 production by peritoneal macrophages. Furthermore, this treatment resulted in opposing effects on the expression Of beta(2)- and alpha(1)-adrenoceptors on peritoneal macrophages (a stimulatory effect on beta(2)-adrenoceptors and a suppressive effect on alpha(1)-adrenoceptors). In conclusion, a subset of resident peritoneal macrophages synthesizes catecholamines, which may exert differential effects on H2O2 and NO production via distinct adrenoceptors. Finally, chronic propranolol treatment affected adrenoceptor expression on peritoneal macrophages and altered their capacity to generate NO and H2O2. (C) 2009 Elsevier B.V. All rights reserved.

In its simplest form, effective T cell-mediated immunity emanates from the expansion of specific T cells activated tit response to antigen. In establishing and maintaining the peripheral T-cell pool, the thymus plays a critical role. It does so by providing a microenvironment within which T cell precursors proliferate, differentiate and Undergo selection processes to create a fully functional population of major histocompatibility complex restricted, self-tolerant T cells. The control of the thymic function involves intrathymic, as well as sympathetic nervous and endocrine system signalling. In addition to postganglionic noradrenergic fibres, both thymic lymphoid and non-lymphoid cells, including epithelial cells and macrophages. have been demo nstrated to express tyrosine hydroxylase (TH), and Suggested to form a local non-neural catecholaminergic cell network. A higher level of noradrenaline has been found in male than in female rat thymi. and a role of,gonadal hormones ill providing this dimorphism has been demonstrated. In addition, thymic lymphoid and non-lymphoid cells, including those expressing TH, have been found to bear beta- and alpha(1)-adrenoceptors (ARs) and a role of gonadal hormones in regulation of, at least. beta-AR density and signalling has been Suggested. These findings have also entailed conclusion that catecholamiens (CAs) influence T-cell development, not only via neurocrine/endocrine, but also via autocrine/paracrine action. Generally, CAs have been shown to exert an inhibitory influence on thymopoiesis. Role of alpha(1)- and beta-R-mediated mechanisms in maintaining thymic homeostasis and in fine tuning of both conventional and regulatory T-cell development is discussed in the Manuscript. (C) 2008 Elsevier B.V. All rights reserved.

The role of gonadal hormones in induction and, particularly, maintenance/ progression of rat thymic involution, which normally starts around puberty, was reassessed by examining the effects of peripubertal orchidectomy on thymic weight and morphometric parameters at different times up to the age of 10 months. Up to 6 months post-castration both thymic weight and cellularity in orchidectomized ( Cx) rats were greater than in age-matched control rats, sham Cx ( Sx). The increase in thymic cellularity reflected an increase in thymocyte proliferation rate ( the proportion of proliferating cells was 18.6 +/- 0.7% in 2-month-old Cx ( N = 5) vs 13.4 +/- 0.3% ( N = 5) in age-matched Sx rats) followed by reduced sensitivity to apoptotic signals ( apoptotic thymocytes were 9.8 +/- 0.9% in 2-month-old Cx ( N = 5) vs 15.5 +/- 0.3% ( N = 5) age-matched Sx rats). However, 9 months post-orchidectomy, neither thymic weight and cellularity nor any of the morphometric parameters analyzed differed between Cx and control rats. The reduction of thymic cellularity in Cx rats to control values may be related to increased sensitivity of their thymocytes to apoptotic signals in culture ( 72.6 +/- 1.2% in 10-month-old vs 9.8 +/- 0.9% in 2-month-old Cx rats) followed by reduced responsiveness to proliferative stimuli ( 14.1 +/- 0.2% in 10-month-old vs 18.6 +/- 0.7% in 2-month-old Cx rats). Thus, the study indicates that the effects of peripubertal orchidectomy on thymic weight and cellularity, as well as on the main morphometric indices, are long-lasting but not permanent, i.e., that removal of the testes can only postpone but not prevent age-related organ atrophy and consequently functional deterioration of the immune system.

Age-related increase in the density of thymic noradrenergic fibres and noradrenaline (NA) concentration is proposed to be associated with thymic involution and altered thymopoiesis. To test this hypothesis thymocyte differentiation/maturation and thymic structure were studied in 18-month-old male Wistar rats subjected to 14-day-long propranolol (P) blockade of ss-adrenoceptors (ss-ARs). The treatment primarily resulted in changes in the T-cell receptor (TCR)-dependent stages of thymopoiesis, which led to an increase in both the relative and absolute numbers of the most mature single positive (SP) CD4(+)CD8(-) (including cells with the CD4(+)CD25(+) regulatory phenotype) and CD4(-)CD8(+) TCR alpha ss(high) thymocytes. Accordingly, in the thymi of these rats an increase in both numerical density and absolute number of medullary thymocytes encompassing mainly the most mature SP cells was found. These findings, together with an increase in the thymocyte surface expression of the regulatory molecule Thy-1 (CD90) (implicated in negative regulation of TCR alpha beta-dependent thymocyte selection thresholds) in the same rats, may suggest increased positive/reduced negative thymocyte selection. Collectively, the results indicate that a decline in thymic efficiency in generating both conventional and regulatory T cells, and consequently in immune function, in aged rats may be, at least partly, attenuated by long-term blockade of beta-ARs with P. (c) 2007 Elsevier B.V. All rights reserved.

To test putative interdependence in the ontogenesis of the hypothalamic-pituitary-gonadal and thymic-lymphatic axes, thymocyte differentiation and maturation was examined in neonatally castrated (Cx) adult rats. In the hypercellular thymi of Cx rats, the proportion of the least mature CD4(-)CD8(-)TCR alpha beta(-) triple negative (TN) thymocytes was reduced, while the proportions of all downstream double positive (DP) subsets (TCR alpha beta(-), TCR alpha beta(low) and TCR alpha beta(high)) were increased when compared with neonatally sham-castrated (Sx) adult rats. This suggested an accelerated thymocyte transition from the TN to DP TCR alpha beta(low) developmental stage accompanied by an increased positive/reduced negative thymocyte selection. The increased thymocyte surface density of Thy-1, which is implicated in thymocyte hyposensitivity to negative selection, in Cx rats further supports the previous assumption. The finding that the proportions of both single positive (SP) TCR alpha beta(high) thymocyte subsets were reduced, while their numbers were increased (CD4(+)CD8(-)) or unaltered (CD4(-)CD8(+)), coupled with results demonstrating an increased level of CD4(-)CD8(+) cells without changes in that of CD4(+) 8(-) cells in the spleen indicate: (i) accelerated differentiation and maturation of the positively selected DP TCR alpha beta(high) thymocytes towards CD4(-)8(+) TCR alpha beta(high) cells followed by increased emigration of the mature cells and (ii) decelerated hi h differentiation and maturation towards CD4(+)8(-) TCR alpha beta(high) cells in Cx rats. Furthermore, the unaltered proportion of intrathymically developing CD4(+)CD25(+)Foxp3(+) regulatory cells in Cx rats, in light of putative hyposensitivity of thymocytes to negative selection suggesting reduced elimination of autoreactive cells, may provide a firm basis for understanding the reasons behind increased susceptibility of Cx rats to autoimmune disease induction.

In order to provide a morphometrical description of the changes in the aged rat thymus and to relate them to apoptotic and proliferative activity of thymocytes, the thymuses from 3- and 18-month-old male Wistar rats and the percentages of bromodeoxyuridine-incorporating and apoptotic cells in cultures of thymocytes were assessed by stereological analysis and flow cytometry, respectively. In old rats the volume of lymphoepithelial thymic tissue is markedly reduced, reflecting a sharp decrease in the total number of thymocytes. A reduction in the proliferative capacity of thymocytes and increase in their susceptibility to apoptosis are, most likely, primarily responsible for a 7-fold reduction in thymic cellularity in old animals. Furthermore, only the volume of cortical compartment was affected by aging, while that of medulla, despite of reduced cellularity, was not significantly altered. The loss of functional tissue in aged thymus is compensated by a substantial increase in the volume of inter-lobular connective and adipose tissue, so the thymic weight remained unaltered in old rats. These results suggest that thymus of aged Wistar rats exhibits morphological characteristics similar to those found in aged human thymus and thus may serve as an animal model for further investigations of thymus-related changes in immunological aging.

Adult male Wistar rats were subjected to propranolol (P, 0.40 mg/100 g/day) or saline (S) administration (controls) over 14 days. The expression of major differentiation molecules on thymocytes and Thy-1 (CD90) molecules, which are shown to adjust thymocyte sensitivity to TCR alpha beta signaling, was studied. In addition, the sensitivity of thymocytes to induction of apoptosis and concanavalin A (Con A) signaling was estimated. The thymocytes from P-treated (PT) rats exhibited an increased sensitivity to induction of apoptosis, as well as to Con A stimulation. Furthermore, P treatment produced changes in the distribution of thymocyte subsets suggesting that more cells passed positive selection and further differentiated into mature CD4+ or CD8+ single positive (SP) TCR alpha beta(high) cells. These changes may, at least partly, be related to the markedly increased density of Thy-1 surface expression on TCR alpha beta(low) thymocytes from these rats. The increased frequency of cells expressing the CD4+25+ phenotype, which has been shown to be characteristic for regulatory cells in the thymus, may also indicate alterations in thymocyte selection following P treatment. Inasmuch as positive and negative selections play an important role in continuously reshaping the T-cell repertoire and maintaining tolerance, the hereby presented study suggests that pharmacological manipulations with beta-AR signaling, or chemically evoked alterations in catecholamine release, may interfere with the regulation of thymocyte selection, and consequently with the immune response.

Ethane dimethanesulphonate (EDS), an alkylating agent, caused marked atrophy of the adrenal cortex of adult male rats, in addition to its toxic effect on testicular Leydig cells. The aim of this work was to examine whether a 9-day treatment with ACTH (40 IU/kg/d), isoproterenol (120 mg/kg/d) or dexamethasone (0.25 mg/kg/d), which started 4 days prior to intraperitoneal administration of a single dose of EDS (75 mg/kg), affected the morphological changes in the adrenal cortex evoked by EDS alone. The animals were killed 15 days after EDS injection. Stereological analysis revealed that both ACTH and isoproterenol almost completely prevented cortical atrophy induced by EDS. They also considerably stimulated corticosterone secretion in EDS-injected animals. By contrast, in dexamethasone-suppressed rats, the deleterious effect of EDS on adrenocortical cells was augmented. The volume and cellularity of all cortical zones were reduced, but the remaining cells of the zona reticularis displayed considerable hypertrophy which was probably responsible for the maintenance of corticosterone secretion. These results clearly demonstrate that both ACTH and b adrenoceptor stimulation have protective action against the toxic effects of EDS on rat adrenal cortex, whereas dexamethasone exerts an opposite influence., Alkilirajući agens etandimetansulfonat (EDS), pored toksičnog delovanja na Lajdigove ćelije semenika, izaziva izraženu atrofiju kore nadbubrežne žlezde odraslih pacova. U ovom radu je ispitivan uticaj devetodnevnog tretmana sa ACTH (40 IU/kg/d), izoproterenolom (120 mg/kg/d) ili deksametazonom (0.25 mg/kg/d) na morfološke promene kore nadbubrega koje izaziva jedna intraperitonealna injekcija EDS (75 mg/kg). Tretmani su započeli 4 dana pre davanja EDS i nastavljeni su još 5 dana, a životinje su žrtvovane 15 dana posle aplikacije EDS. U prisustvu ACTH ili izoproterenola ne ispoljavaju se promene u stereološkim parametrima kore nadbubrega koje izaziva EDS. Oba tretmana značajno povećavaju i koncentraciju kortikosterona u serumu. Deksametazon, međutim, pojačava toksične efekte EDS; zapremina svih zona kore i broj parenhimskih ćelija u zonama su smanjeni, ali preostale ćelije retikularne zone pokazuju značajnu hipertrofiju, koja je verovatno odgovorna za održavanje sekrecije kortikosterona kod ovih životinja. Rezultati rada pokazuju da se toksični efekti EDS na koru nadbubrega mogu sprečiti visokim nivoom ACTH ili stimulacijom b adrenalinskih receptora, a potencirati egzogenim glukokortikoidom.