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Rad govori o promjeni izražaja heat shock proteina gp96 (imunomodulatora) za vrijeme izloženosti stresu

Background. Copper chelator cuprizone (CPZ) is neurotoxicant. which selectively disrupts oligodendroglial respiratory chain, leading to oxidative stress and subsequent apoptosis. Demyelination is, however, followed by spontaneous remyelination owing to the activation of intrinsic CNS repair mechanisms. During this process cysteine rich metallothioneins (MT). which through free radical scavenging and intracellular Zn/Cu regulation provide cytoprotection. Furthermore, it has been postulated that secreted MT-I/II might be bind on surface receptors belonging to the family of low- density lipoprotein receptor related proteins (LRP), such as LRP-2/megalin and LRP-1. which in turn activate the signal transduction pathways that support neurite outgrowth and survival. Aim. The goal of this study was to visualize MT/ megalin interaction in the brain tissue of mice affected by CPZ and to determine if this binding leads to the activation of serine/threonine-protein kinase-AKT-l/Protein kinase B signaling cascade. Methods. Experiments were performed in female C57BL/6 mice fed with 0.25% CPZ during 5 weeks. MT/megalin co- localization and interactions were examined by double immunofluorescence and proximity ligation assay (PLA). which enables in situ recognation of two potentially interacting proteins, respectively. The post-translational modifications in target cells were evaluated by the presence of phosphorylated AKT-I (pAKT-1 ; phospho threonine 308). Results. CPZ-induced demyelination was followed by high astrogliosis and enhanced expression of MTs and megalin in white and gray matter of the brain. PLA clearly showed that MT-l/ll interacted with megalin in cortical tissue and in hippocampal subgranular zone of dentate gyrus. Moreover, in most of megalin expressing cortical NeuN+ neurons nuclear expression of pAKT-1 was found.

Background. Copper chelator cuprizone (CPZ) is neurotoxicant, which selectively disrupts oligodendroglial respiratory chain, leading to oxidative stress and subsequent apoptosis. Demyelination is, however, followed by spontaneous remyelination owing to the activation of intrinsic CNS repair mechanisms. To the later contribute also cysteine rich metallothioneins (MT), which through free radical scavenging and intracellular Zn/Cu regulation provide cytoprotection. Besides, it has been postulated that secreted MT-I/II might be bind on surface receptors belonging to the family of low-density lipoprotein receptor related proteins (LRP), such as LRP-2/megalin and LRP-1, which in turn activate the signal transduction pathways that support neurite outgrowth and survival. Aim. The goal of this study was to visualize MT/ megalin interaction in the brain tissue of mice affected by CPZ and to determine if this binding leads to the activation of serine/threonine-protein kinase-AKT-1/Protein kinase B signaling cascade. Methods. Experiments were performed in female C57BL/6 mice fed with 0.25% CPZ during 5 weeks. MT/megalin co-localization and interactions were examined by double immunofluorescence and proximity ligation assay (PLA), which enables in situ recognation of two potentially interacting proteins, respectively. The post-translational modifications in target cells were evaluated by the presence of phosphorylated AKT-1 (pAKT-1 ; phospho threonine 308). Results. CPZ-induced demyelination was followed by high astrogliosis and enhanced expression of MTs and megalin in white and gray matter of the brain. PLA clearly showed that MT-I/II interacted with megalin in cortical tissue and in hippocampal subgranular zone of dentate gyrus. Moreover, in most of megalin expressing cortical NeuN+ neurons nuclear expression of pAKT-1 was found. Conclusion. The data imply that astrocyte-derived MT-I/II modulates cell signaling and neuronal repair through direct contact with megalin and suggest that internalization of MT-I/II and accelerated phosphorylation of AKT-1 contribute to activation of signal transduction pathways that protect cortical neurons and neuronal progenitors against toxic effects of CPZ

Introduction. Demyelinating autoimmune diseases, such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are often followed by cognitive deficits associated with the inflammation, neuronal injury and altered neurogenesis within the hippocampus. Pathogenic mechanisms include the appearance of "danger signals" that contribute to neuronal dyshomeostasis and activation o f innate and adaptive immunity, as well as those that provide neuroprotection and ensure the restoration of tolerance. Aim. To estimate the expression profiles of endoplasmic reticulum (ER)-resident chaperon gp96 and its receptors - CD91 and Toll- like receptor 2 (TLR2) in hippocampi of DA rats during the course of EAE, since these pathways are involved in unfolded protein response (UPR) and F.R-associated degradation of the misfolded proteins, as well as in activation of immune response. Methods: Rats were immunized with BBH in complete Freund's adjuvant (CFA) or only with CFA. The expressions of gp96, CD91 and TLR2 were estimated on days 12 and 22 after immunization by PCR. Western blot and immunohistochemistry. Results: Granular cells constitutively expressed gp96. but its mRNA decreased in early phase of EAE and arose during remission of disease. CD9I and TLR2 genes expression increased in both phases of EAE. but protein expression of CD91 was greater in acute than in late phase of EAE. In contrast. TLR2 protein expression increased particularly in remission phase of EAE. Moreover, in late phase of EAE gp96 was co-localized with CD91 in granular neurons, as well as with TLR2 in numerous doublecortin positive neuroblasts in SGZ of dentate gyros Conclusions: The data point to time-dependent expression of gp96 during EAE and its receptors and imply that during an autoimmune reaction gp96 may through UPR and CD91 and TLR2 signaling affect the reestablishment of hippocampal integrity and adult neurogenesis.

Donedavno se smatralo da se živčane stanice prestaju dijeliti u ranoj postnatalnoj životnoj dobi, no posljednjih 20 godina mnoga istraživanja na tom polju dokazala su suprotno. Neurogeneza u odraslom mozgu dokazana je u većine sisavaca, uključujući i čovjeka. Proces se u fiziološkim uvjetima spontano odvija pretežno u dvjema germinativnim regijama u mozgu u kojima se nalaze neuralne matične stanice; u subgranularnoj zoni dentatne vijuge hipokampusa te subventrikularnoj zoni lateralnog ventrikula. Neuralne matične stanice u njima imaju veću sposobnost proliferacije i diferencijacije prema novim budućim neuronima, astrocitima i oligodendrocitima u odnosu na neuralne matične stanice drugih područja živčanog sustava. Sposobnost proliferacije i regeneracije koju ove dvije „niše“ posjeduju ima važnu ulogu u prilagodbi mozga na vanjske podražaje tijekom odrastanja i sazrijevanja, što se naziva plastičnošću mozga. Germinativne „niše“ u mozgu su specifičan mikrookoliš u kojem se uskom interakcijom specifičnih proneurogenetskih čimbenika i rezidentnih neuralnih matičnih stanica te krvožilja stvaraju strogo kontrolirani uvjeti koji omogućuju proliferaciju, diferencijaciju, migraciju i sazrijevanje neuroblasta ili glioblastate preživljenje i integraciju novonastalih neurona i glijalnih stanica u postojeće sinaptičke mreže u mozgu. U slučaju narušavanja homeostaze tih i drugih germinativna središta u mozgu, dolazi do pojave raznih psihoneuroloških poremećaja. Boljim razumijevanjem funkcioniranja germinativnih mikrookoliša u mozgu otvaraju se nove mogućnosti u neuronanosti u pravcu manipuliranja adultnom neurogenezom potičući stvaranje neurona de novo te na taj način liječenja spomenutih psihoneuroloških poremećaja., Tillrecently was assumed that neural cells stop dividing in early postnatal period of life, but last two decades large ammount ofresearches on that field proved contrary. There are evidences confirming existance of adult neurogenesis in most mammalian species, including humans.This process occurs spontaneouslyin physiological termsin two germinal brain regionscontaining neural stem cells; in subgranular zone of hippocampal dentate gyrus and subventricular zone of lateral ventricule.Neural stem cells in this germinal regions posses higher proliferative and differential capacity toward new future neurons, astrocytes and oligidendrocytes than neural stem cells from other regions in nervous system. Proliferative and regenerative power of this two niches has important role in brain adjustment to exterior stimuli during life which is called neuroplasticity. Germinal niches in brain are specific microenvironment in which close interaction of specific proneurogenic factors and resident neural stem cells and blood vessels form strictly controled conditions providing neuroblast and glioblast proliferation, differentiation, migration andmaturation and also survival and integration of newly created neuron or glial cell in existing brain sinaptic cirtuits. In case of harming this and other germinal brain centers different psichoneurologic disorders occur. Better understanding of germinal microenvironment function in human brainopens a new possibilities in neuroscience for creating a therapy based on adult neurogenesis manipulation through creating neurons “de novo”.

Aim Because of its global role and status in the academic and research settings, the influence of English on the Croatian medical/dental terminology cannot be avoided. To contribute to the preservation and promotion of Croatian standard language the School of Dental Medicine, University of Zagreb joined the programme Development of Croatian Special Field Terminology (STRUNA). The School contributed to the development of standardized terminology in the fields of dental medicine, anatomy, physiology, and, currently, in the field of pharmacology (the projects Croatian Dental Terminology or HRSTON, Croatian Anatomical and Physiological Terminology or HRANAFINA, and Croatian Pharmacological Terminology or FARMANA). This work aims to promote the need for the development and use of standardized Croatian terminology among health professionals, medical/dental students, and scientists. Methods The work is based on a survey conducted to assess whether dental students would rather choose Croatian medical/dental terms instead of anglicisms for translation of English sentences allegedly extracted from dental literature. We give examples how translation of English terms with loanwords may result in word forms unacceptable to the corpus of Croatian lexems. Conclusion Loanwords adjusted to the standard Croatian language should be a part of the field- specific vocabulary. However, developing and using Croatian medical/dental terminology contributes to the preservation and enrichment of the Croatian language and may improve patients' understanding of medical information. STRUNA termbase can contribute to the consistent and unambiguous usage of Croatian terms in speech and writing and can help in minimising the occurence of improperly translated loanwords in Croatian professional terminology.

Inflammatory demyelinating diseases such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are often followed by cognitive deficits associated with the neuronal injury, synaptic loss and altered neurogenesis within the hippocampus. Changes depend on the genetic and epigenetic factors that ensure the cellular and environmental homeostasis and regulate the interactions of immunocompetent, glial and neural cells. Owing to high impact of stress proteins on these processes, in this study we compared the protein content of interleukin-6, transforming growth factor-β1, metallothioneins I/II (MTs) and glycoprotein 96 (gp96) in the hippocampus of DA and AO rats that differ in the susceptibility to the induction of EAE, and tested the relationship of MTs and gp96 to granule neurons, glial cells and neural progenitors in different subfields of dentate gyrus. Rats were immunized with bovine brain homogenate emulsified in complete Freund’s adjuvant or only with CFA. The data showed that acute attack of EAE in DA rats was followed by accumulation of IL-6, TGF-β1 and MTs proteins, by increased expression of MTs in molecular and granular cell layer, by reduced expression of gp96/granular cell, by apoptosis and by microgliosis with appearance of Iba-1+ cells, co-expressing MT I/II and gp96. Furthermore, in subgranular zone (SGZ) of DA rats an augmented number of GFAP+ precursors, but decreased number of doublecortin (DCX)+ neuroblasts and immature NeuN+ neurons were found, implying that in DA rats the neurogenesis was delayed or reduced. Besides, in SGZ of both strains several DCX+ and NeuN+ cells co-expressing gp96 and MT I/II were found.