<p>Quantification of each morphological type of microglial cell (<a href="http://ww... more <p>Quantification of each morphological type of microglial cell (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037215#pone-0037215-t002" target="_blank">Table 2</a>) is depicted as the percentage distribution per AL and CR groups as a function of time following injury. Percentage of both <i>intense</i> and <i>moderate</i> microglial cells was much higher in the AL group compared to the CR group at all time points. By far the greatest percentage of <i>intense</i> microglial cells was observed in the AL group on the 2<sup>nd</sup> day following injury (83%). In the CR group the percentage of activated microglia (both <i>intense</i> and <i>moderate</i>) did not exceed 15% of the microglia population. c – physiological control; 2, 7, 14, 28 – days following injury.</p
Circulatory and Developmental Aspects of Brain Metabolism, 1980
The relationship between the various anatomical and chemical compartments of the developing brain... more The relationship between the various anatomical and chemical compartments of the developing brain changes continuously as a result of many processes. They reach their “optimum” level during early adulthood but thereafter do exhibit some effects with age (1, 19, 42).
Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized ... more Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by cognitive decline and total brain atrophy. Despite the substantial scientific effort, the pathological mechanisms underlying neurodegeneration in AD are currently unknown. In most studies, amyloid β peptide has been considered the key pathological change in AD. However, numerous Aβ-targeting treatments have failed in clinical trials. This implies the need to shift the research focus from Aβ to other pathological features of the disease. Objective: The aim of this study was to examine the interplay between mitochondrial dysfunction, oxidative stress and blood-brain barrier (BBB) disruption in AD pathology, using a novel approach that involves the application of electron paramagnetic resonance (EPR) spectroscopy. Methods: In vivo and ex vivo EPR spectroscopy using two spin probes (aminoxyl radicals) exhibiting different cell-membrane and BBB permeability were employed to assess BBB inte...
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2019
Adolescent neurodevelopment confer vulnerability to the actions of treatments that produce adapta... more Adolescent neurodevelopment confer vulnerability to the actions of treatments that produce adaptations in neurocircuitry underlying motivation, impulsivity and reward. Considering wide usage of a sedative-hypnotic agent propofol in clinical practice, we examined whether propofol is a challenging treatment for peripubertal brain. Motivation/hedonic behavior (sucrose preference test), approach/avoidance behavior (elevated plus maze test) and response to dissociative drug phencyclidine (PCP) were studied in peripubertal rats (the rodent model of periadolescence) after propofol anesthesia exposure (PAE). Neurodegeneration (Fluoro-Jade staining) and the expression of proteins (Western blot) involved in excitatory synaptic transmission and activity-dependent synaptic stabilization in the medial prefrontal cortex (mPFC) and striatum (components of motivation/reward circuitry; process both appetitive and aversive events) were examined as well. In peripubertal rats PAE produced 1) transient brain-region specific changes in the expression of N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B, PSD-95 and N-cadherin, without neurotoxicity, 2) hyperlocomotor response to PCP, 3) no changes in preference for palatable 1% sucrose solution and a decrease in food eaten, 4) preference for 20% sucrose solution without changes in food eaten, 5) stretch-attended postures and open arms entries in the elevated plus maze test. Overall, these novel findings show that PAE leaves transient synaptic trace recognized as early form of synaptic plasticity related to passive drug exposure in the brain systems implicated in motivation/ reward, increases drug-responsiveness, favors risk-taking and preference of novel/intense stimuli repairing otherwise present motivational deficiency. These findings accentuate multifaceted response to propofol in peripuberty and the importance of environmental stability for the most favorable neurobehavioral recovery.
Background: The effects of anesthetic drugs on postoperative cognitive function in children are n... more Background: The effects of anesthetic drugs on postoperative cognitive function in children are not well defined and have not been experimentally addressed. Aims: The present study aimed to examine the influence of propofol anesthesia exposure on nonaversive hippocampus-dependent learning and biochemical changes involved in memory process in the dorsal hippocampus, in peripubertal rats as the rodent model of periadolescence. Methods: The intersession spatial habituation and the novel object recognition tasks were used to assess spatial and nonspatial, nonaversive hippocampus-dependent learning. The exposure to anesthesia was performed after comparably long acquisition phases in both tasks. Behavioral testing lasted for 2 consecutive days (24-hour retention period). Changes in the expression of molecules involved in memory retrieval/reconsolidation were examined in the dorsal hippocampus by Western blot and immunohistochemistry, at the time of behavioral testing. Results: Exposure to propofol anesthesia resulted in inappropriate assessment of spatial novelty at the beginning of the test session and affected continuation of acquisition in the spatial habituation test. The treatment did not affect recognition of the novel object at the beginning of the test session but it attenuated overall preference to novelty, reflecting retrieval of a weak memory. The expression of phosphorylated extracellular signal-regulated kinase 2 (involved in memory retrieval) was decreased while the level of phosphorylated Ca 2+ /calmodulin-dependent protein kinase IIa and early growth response protein 1 (involved in memory reconsolidation) was increased in the dorsal hippocampus. The level of Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog B (neuronal activity indicator) was increased in the dorsal dentate gyrus. Enhanced exploratory activity was still evident in the propofol anesthesia exposure (PAE) group 48 hour after the treatment in both tasks. Conclusion: In peripubertal rats, propofol anesthesia exposure affects memory retrieval and acquisition of new learning in the spatial and nonspatial, nonaversive learning tasks 24 hour after the treatment, along with the expression of molecules that participate in memory retrieval/reconsolidation in the dorsal hippocampus. These results may have clinical implications, favoring control of basic cognitive functions in older children after the propofol exposure.
Results of recent studies confirmed that oxidative stress negatively affects sperm motility and c... more Results of recent studies confirmed that oxidative stress negatively affects sperm motility and causes sperm DNA damage. Produced by nitric oxide synthase 3 (NOS3), nitric oxide is considered to be one of the important mediators of oxidative stress in testis tissue. The aim of this study was to assess the possible association of three genetic variants (rs2070744, rs1799983 and intron variant 4a/4b) in NOS3 gene and infertility occurrence in two groups of infertile men (idiopathic azoospermia and oligoasthenozoospermia) and fertile controls. Genotypes for the single-nucleotide genetic variants rs1799983 and rs2070744 were determined by PCR-RFLP, while genotyping of intron 4 variant 4a/4b was performed by gel electrophoresis of PCR products. Statistical analysis was performed by SNPStats software. No significant association between the three genetic variants of the NOS3 gene and infertility risk was determined comparing allele and genotype frequencies among group of patients diagnosed with azoospermia and the control group. Nevertheless, there was a significant positive association between 4a/4b and infertility in the group of males diagnosed with oligoasthenozoospermia, under overdominant genetic model. Our findings suggest that tandem repeat variant within intron 4 of the NOS3 gene is associated with an increased risk of infertility in men diagnosed with idiopathic oligoasthenozoospermia.
Cold Spring Harbor Symposia on Quantitative Biology, 1983
Recent advances in molecular biology have led to the determination of the general features of euk... more Recent advances in molecular biology have led to the determination of the general features of eukaryotic genes and to an understanding of the processes required for the expression of these genes as mature polypep-tide-coding mRNAs. It is now possible to determine the level at which the regulation of gene expression occurs--at ranscription, processing, mRNA stability, or translation. A topic of much current interest in developmental neurobiology is the investigation of the molecular mechanisms that regulate the expression of genes coding for neuron-specific proteins. This interest arises from the observation that the nervous ystem is composed of a great number of different cell types that exhibit a complex array of interconnections and func-tions and from the inference that this diversity must re-
Numerous beneficial effects of food restriction on aging and age-related pathologies are well doc... more Numerous beneficial effects of food restriction on aging and age-related pathologies are well documented. It is also well-established that both short- and long-term food restriction regimens induce elevated circulating levels of glucocorticoids, stress-induced hormones produced by adrenal glands that can also exert deleterious effects on the brain. In the present study, we examined the effect of long-term food restriction on the glucocorticoid hormone/glucocorticoid receptor (GR) system in the cortex during aging, in 18- and 24-month-old rats. Corticosterone level was increased in the cortex of aged ad libitum-fed rats. Food restriction induced its further increase, accompanied with an increase in the level of 11β-hydroxysteroid dehydrogenase type 1. However, alterations in the level of GR phosphorylated at Ser232 were not detected in animals on food restriction, in line with unaltered CDK5 level, the decrease of Hsp90, and an increase in a negative regulator of GR function, FKBP51....
The aim of our study was to develop and characterize solid brain tumors in Wistar rats, which cou... more The aim of our study was to develop and characterize solid brain tumors in Wistar rats, which could be used in investigations concerning the molecular mechanisms that lay beneath the genesis of the gliomas as well as in the testing of curative potentials of various therapeutics. The tumors were induced by intracerebral inoculation of 9L glioma cells and characterized by morphometrical, histological and immunohistochemical analysis after 7, 14 and 21 postimplantation days. Immunohistochemical characterization included detection of the nuclear antigene Ki-67 as the proliferative cell marker, GFAP as a tracer of reactive gliosis surrounding the tumor mass, and CD4/CD8 and ED1 antigens, as markers of the immunological response. Our results showed that after 7 days all experimental animals developed solid, well-circumcised tumors, which were clearly separated from the surrounding brain tissue. Tumors showed progressive growth from the 7th to the 21st day despite the observed immunologica...
Epidermal growth factor (EGF) signaling has been implicated in the regulation of the differentiat... more Epidermal growth factor (EGF) signaling has been implicated in the regulation of the differentiation and proliferation of retinal progenitors. We assessed how different levels of EGF signaling, achieved either by increasing receptor expression or via addition of the exogenous ligand, or an increase in both, can affect the differentiation of progenitors in the first week of postnatal retinal development in the model system of retinal explants (REs). Proliferating progenitor cells in REs were infected with either the control CLV3/ESR-related peptide family (CLE)-green fluorescent protein (GFP)- or with EGF receptor (EGFR)-GFP-expressing retrovirus, and grown in the control medium or in the presence of exogenous EGF (10 ng/mL). The differentiation of infected cells into Muller glia (Sox9+), rod photoreceptors (rhodopsin+) and horizontal cells (calbindin+) was analyzed. In all the examined conditions, infected cells differentiated into Muller glia and rod photoreceptors that normally de...
International Journal of Developmental Neuroscience, 2009
Commonly used general anesthetics can have adverse effects on the developing brain by triggering ... more Commonly used general anesthetics can have adverse effects on the developing brain by triggering apoptotic neurodegeneration, as has been documented in the rat. The rational of our study was to examine the molecular mechanisms that contribute to the apoptotic action of propofol anesthesia in the brain of 7-day-old (P7) rats. The down-regulation of nerve growth factor (NGF) mRNA and protein expression in the cortex and thalamus at defined time points between 1 and 24 h after the propofol treatment, as well as a decrease of phosphorylated Akt were observed. The extrinsic apoptotic pathway was induced by over-expression of tumor necrosis factor (TNF) which led to the activation of caspase-3 in both examined structures. Neurodegeneration was confirmed by Fluoro-Jade B staining. Our findings provide direct experimental evidence that the anesthetic dose (25 mg/kg) of propofol induces complex changes that are accompanied by cell death in the cortex and thalamus of the developing rat brain.
In order to better understand pathogenesis of pulmonary emphysema, the model of experimentally in... more In order to better understand pathogenesis of pulmonary emphysema, the model of experimentally induced pulmonary emphysema in Chinchilla rabbits was used for the estimation of apoptotic clearance of pulmonary tissue. Bronchoalveolar lavage was performed in three groups of animals: experimental group-E on hypercholesterolemic diet (4% edible oil solution of crystalline cholesterol), control group-C 1 on standard diet for that animal species and animals on oily diet-C 2. Apoptotic detection in cytocentrifuge preparations of lung washings was evaluated by in situ TUNEL. The property of alveolar macrophages to engulf apoptotic cells was estimated by light microscopy including 300 features (related subsequent steps: adsorption, internalization and intracellular processing of free apoptotic bodies) and was evaluated by scoring and indexing method. Internalization of apoptotic bodies by alveolar macrophages, as well as free apoptotic bodies were decreased in E compared to both C 1 and C 2 group (p<0.01 and p<0.05 respectively). Intracellular processing of apoptotic bodies by alveolar macrophages is significantly decreased in C 2 in comparison with E (p<0.05) and C 1 group (p<0.01). Apoptotic capacity of pulmonary tissue is significantly decreased in C 2 in comparison with C 1 group (p<0.01). The results implicate that immuno-metabolic competence of pulmonary tissue might be essentially associated with tissue remodeling in pulmonary emphysema.
The growing body of data implies that SARS-CoV-2 infection may affect the nervous system. We here... more The growing body of data implies that SARS-CoV-2 infection may affect the nervous system. We here present a short, taciturn overview of described neurological impairments related to SARS-CoV-2 infection. While it is obvious that neurological impairments can be diagnosed in a portion of COVID-19 patients, evidence of SARS-CoV-2 neurovirulence in humans is still lacking. The existing data on the incidence of neurological impairments among COVID-19 patients is highly variable, probably because they (most often) come from small, single-center retrospective studies. These data are practically published in real-time, and the question remains when larger studies will be available, given that the pandemic is continuing. We here also shortly address the other issues related to neurological disorders and COVID-19 pandemic, including the concern for people with existing chronic neurological disorders and possible long-term neurological consequences of SARS-CoV-2 infection.
Dysregulation of neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus has ... more Dysregulation of neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus has been related to cognitive deficits and memory loss in neurodegenerative diseases, such as Alzheimer's disease (AD). Members of the B group of SOX transcription factors play critical roles in regulating neurogenesis in the embryonic and adult nervous system, including maintaining the multipotency, renewal, and cell fate decision of neural stem/progenitor cells. The aim of the present study was to evaluate the expression patterns of selected SOXB proteins in the SGZ, of 8-week-old male and female 5xFAD mice, which represent a transgenic model of AD with a severe and very early development of amyloid pathology. Immunohistochemical analysis showed a significant decrease in the number of cells expressing SOX1, SOX2, and SOX21 transcription factors within the SGZ of 5xFAD mice in comparison to their non-transgenic counterparts which coincidences with reduced number of doublecortin immunoreactive immature neurons found in Tg males. Despite observed changes in expressional pattern of examined SOXB proteins, the proliferative capacity evaluated by the number of Ki-67 immunoreactive cells remained unaffected in transgenic mice of both genders. Based on our results, we suggest that SOXB proteins might be considered as new biomarkers for the detection of early impairments in adult neurogenesis in different animal models or/and new targets in human regenerative medicine.
The recovery period following cortical injury (CI) is characterized by a dynamic and highly compl... more The recovery period following cortical injury (CI) is characterized by a dynamic and highly complex interplay between beneficial and detrimental events. The aim of this study was to examine the expressions of Glial Fibrillary Acidic Protein (GFAP), Apolipoprotein E (ApoE) and Amyloid Precursor Protein (APP), all of which are involved in brain plasticity and neurodegeneration. Our results reveal that CI strongly influenced GFAP, ApoE and APP mRNA expression, as well as GFAP and ApoE protein expression. Considering the pivotal role of these proteins in the brain, the obtained results point to their potential contribution in neurodegeneration and consequent Alzheimer's disease development.
Dystrophic neurites and activated microglia are one of the main neuropathological characteristics... more Dystrophic neurites and activated microglia are one of the main neuropathological characteristics of Alzheimer's disease (AD). Although the use of supplements with omega-3 fatty acids has been associated with reduced risk and lessened AD pathology, it still remains elusive whether such a treatment could affect dystrophic neurites (DNs) formation and microglia/macrophage behavior in the early phase of disease. We analyzed the effects of shortterm (3 weeks) fish oil supplementation on DNs formation, tau hyperphosphorylation, Amyloid-beta peptide 1-42 (Aβ42) levels and microglial/macrophage response to AD pathology in the parietal cortex of 4-month-old 5xFAD mice, a mouse model of AD. The present study shows for the first time that short-term FO supplementation applied in presymptomatic stage of AD, alters the behaviour of microglia/macrophages prompting them to establish a physical barrier around amyloid plaques. This barrier significantly suppresses DNs formation through the reduction of both Aβ content and tau hyperphosphorylation. Moreover, the short-term FO treatment neither suppresses inflammation nor enhances phagocytic properties of microglia/macrophages in the response to Aβ pathology, the effects most commonly attributed to the fish oil supplementation. Our findings suggest that fish oil consumption may play an important role in modulating microglial/macrophage response and ameliorating the AD pathology in presymptomatic stage of Alzheimer's disease. OPEN ACCESS Citation: Jović M, Lončarević-Vasiljković N, Ivković S, Dinić J, Milanović D, Zlokovic B, et al. (2019)
<p>Quantification of each morphological type of microglial cell (<a href="http://ww... more <p>Quantification of each morphological type of microglial cell (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037215#pone-0037215-t002" target="_blank">Table 2</a>) is depicted as the percentage distribution per AL and CR groups as a function of time following injury. Percentage of both <i>intense</i> and <i>moderate</i> microglial cells was much higher in the AL group compared to the CR group at all time points. By far the greatest percentage of <i>intense</i> microglial cells was observed in the AL group on the 2<sup>nd</sup> day following injury (83%). In the CR group the percentage of activated microglia (both <i>intense</i> and <i>moderate</i>) did not exceed 15% of the microglia population. c – physiological control; 2, 7, 14, 28 – days following injury.</p
Circulatory and Developmental Aspects of Brain Metabolism, 1980
The relationship between the various anatomical and chemical compartments of the developing brain... more The relationship between the various anatomical and chemical compartments of the developing brain changes continuously as a result of many processes. They reach their “optimum” level during early adulthood but thereafter do exhibit some effects with age (1, 19, 42).
Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized ... more Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by cognitive decline and total brain atrophy. Despite the substantial scientific effort, the pathological mechanisms underlying neurodegeneration in AD are currently unknown. In most studies, amyloid β peptide has been considered the key pathological change in AD. However, numerous Aβ-targeting treatments have failed in clinical trials. This implies the need to shift the research focus from Aβ to other pathological features of the disease. Objective: The aim of this study was to examine the interplay between mitochondrial dysfunction, oxidative stress and blood-brain barrier (BBB) disruption in AD pathology, using a novel approach that involves the application of electron paramagnetic resonance (EPR) spectroscopy. Methods: In vivo and ex vivo EPR spectroscopy using two spin probes (aminoxyl radicals) exhibiting different cell-membrane and BBB permeability were employed to assess BBB inte...
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2019
Adolescent neurodevelopment confer vulnerability to the actions of treatments that produce adapta... more Adolescent neurodevelopment confer vulnerability to the actions of treatments that produce adaptations in neurocircuitry underlying motivation, impulsivity and reward. Considering wide usage of a sedative-hypnotic agent propofol in clinical practice, we examined whether propofol is a challenging treatment for peripubertal brain. Motivation/hedonic behavior (sucrose preference test), approach/avoidance behavior (elevated plus maze test) and response to dissociative drug phencyclidine (PCP) were studied in peripubertal rats (the rodent model of periadolescence) after propofol anesthesia exposure (PAE). Neurodegeneration (Fluoro-Jade staining) and the expression of proteins (Western blot) involved in excitatory synaptic transmission and activity-dependent synaptic stabilization in the medial prefrontal cortex (mPFC) and striatum (components of motivation/reward circuitry; process both appetitive and aversive events) were examined as well. In peripubertal rats PAE produced 1) transient brain-region specific changes in the expression of N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B, PSD-95 and N-cadherin, without neurotoxicity, 2) hyperlocomotor response to PCP, 3) no changes in preference for palatable 1% sucrose solution and a decrease in food eaten, 4) preference for 20% sucrose solution without changes in food eaten, 5) stretch-attended postures and open arms entries in the elevated plus maze test. Overall, these novel findings show that PAE leaves transient synaptic trace recognized as early form of synaptic plasticity related to passive drug exposure in the brain systems implicated in motivation/ reward, increases drug-responsiveness, favors risk-taking and preference of novel/intense stimuli repairing otherwise present motivational deficiency. These findings accentuate multifaceted response to propofol in peripuberty and the importance of environmental stability for the most favorable neurobehavioral recovery.
Background: The effects of anesthetic drugs on postoperative cognitive function in children are n... more Background: The effects of anesthetic drugs on postoperative cognitive function in children are not well defined and have not been experimentally addressed. Aims: The present study aimed to examine the influence of propofol anesthesia exposure on nonaversive hippocampus-dependent learning and biochemical changes involved in memory process in the dorsal hippocampus, in peripubertal rats as the rodent model of periadolescence. Methods: The intersession spatial habituation and the novel object recognition tasks were used to assess spatial and nonspatial, nonaversive hippocampus-dependent learning. The exposure to anesthesia was performed after comparably long acquisition phases in both tasks. Behavioral testing lasted for 2 consecutive days (24-hour retention period). Changes in the expression of molecules involved in memory retrieval/reconsolidation were examined in the dorsal hippocampus by Western blot and immunohistochemistry, at the time of behavioral testing. Results: Exposure to propofol anesthesia resulted in inappropriate assessment of spatial novelty at the beginning of the test session and affected continuation of acquisition in the spatial habituation test. The treatment did not affect recognition of the novel object at the beginning of the test session but it attenuated overall preference to novelty, reflecting retrieval of a weak memory. The expression of phosphorylated extracellular signal-regulated kinase 2 (involved in memory retrieval) was decreased while the level of phosphorylated Ca 2+ /calmodulin-dependent protein kinase IIa and early growth response protein 1 (involved in memory reconsolidation) was increased in the dorsal hippocampus. The level of Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog B (neuronal activity indicator) was increased in the dorsal dentate gyrus. Enhanced exploratory activity was still evident in the propofol anesthesia exposure (PAE) group 48 hour after the treatment in both tasks. Conclusion: In peripubertal rats, propofol anesthesia exposure affects memory retrieval and acquisition of new learning in the spatial and nonspatial, nonaversive learning tasks 24 hour after the treatment, along with the expression of molecules that participate in memory retrieval/reconsolidation in the dorsal hippocampus. These results may have clinical implications, favoring control of basic cognitive functions in older children after the propofol exposure.
Results of recent studies confirmed that oxidative stress negatively affects sperm motility and c... more Results of recent studies confirmed that oxidative stress negatively affects sperm motility and causes sperm DNA damage. Produced by nitric oxide synthase 3 (NOS3), nitric oxide is considered to be one of the important mediators of oxidative stress in testis tissue. The aim of this study was to assess the possible association of three genetic variants (rs2070744, rs1799983 and intron variant 4a/4b) in NOS3 gene and infertility occurrence in two groups of infertile men (idiopathic azoospermia and oligoasthenozoospermia) and fertile controls. Genotypes for the single-nucleotide genetic variants rs1799983 and rs2070744 were determined by PCR-RFLP, while genotyping of intron 4 variant 4a/4b was performed by gel electrophoresis of PCR products. Statistical analysis was performed by SNPStats software. No significant association between the three genetic variants of the NOS3 gene and infertility risk was determined comparing allele and genotype frequencies among group of patients diagnosed with azoospermia and the control group. Nevertheless, there was a significant positive association between 4a/4b and infertility in the group of males diagnosed with oligoasthenozoospermia, under overdominant genetic model. Our findings suggest that tandem repeat variant within intron 4 of the NOS3 gene is associated with an increased risk of infertility in men diagnosed with idiopathic oligoasthenozoospermia.
Cold Spring Harbor Symposia on Quantitative Biology, 1983
Recent advances in molecular biology have led to the determination of the general features of euk... more Recent advances in molecular biology have led to the determination of the general features of eukaryotic genes and to an understanding of the processes required for the expression of these genes as mature polypep-tide-coding mRNAs. It is now possible to determine the level at which the regulation of gene expression occurs--at ranscription, processing, mRNA stability, or translation. A topic of much current interest in developmental neurobiology is the investigation of the molecular mechanisms that regulate the expression of genes coding for neuron-specific proteins. This interest arises from the observation that the nervous ystem is composed of a great number of different cell types that exhibit a complex array of interconnections and func-tions and from the inference that this diversity must re-
Numerous beneficial effects of food restriction on aging and age-related pathologies are well doc... more Numerous beneficial effects of food restriction on aging and age-related pathologies are well documented. It is also well-established that both short- and long-term food restriction regimens induce elevated circulating levels of glucocorticoids, stress-induced hormones produced by adrenal glands that can also exert deleterious effects on the brain. In the present study, we examined the effect of long-term food restriction on the glucocorticoid hormone/glucocorticoid receptor (GR) system in the cortex during aging, in 18- and 24-month-old rats. Corticosterone level was increased in the cortex of aged ad libitum-fed rats. Food restriction induced its further increase, accompanied with an increase in the level of 11β-hydroxysteroid dehydrogenase type 1. However, alterations in the level of GR phosphorylated at Ser232 were not detected in animals on food restriction, in line with unaltered CDK5 level, the decrease of Hsp90, and an increase in a negative regulator of GR function, FKBP51....
The aim of our study was to develop and characterize solid brain tumors in Wistar rats, which cou... more The aim of our study was to develop and characterize solid brain tumors in Wistar rats, which could be used in investigations concerning the molecular mechanisms that lay beneath the genesis of the gliomas as well as in the testing of curative potentials of various therapeutics. The tumors were induced by intracerebral inoculation of 9L glioma cells and characterized by morphometrical, histological and immunohistochemical analysis after 7, 14 and 21 postimplantation days. Immunohistochemical characterization included detection of the nuclear antigene Ki-67 as the proliferative cell marker, GFAP as a tracer of reactive gliosis surrounding the tumor mass, and CD4/CD8 and ED1 antigens, as markers of the immunological response. Our results showed that after 7 days all experimental animals developed solid, well-circumcised tumors, which were clearly separated from the surrounding brain tissue. Tumors showed progressive growth from the 7th to the 21st day despite the observed immunologica...
Epidermal growth factor (EGF) signaling has been implicated in the regulation of the differentiat... more Epidermal growth factor (EGF) signaling has been implicated in the regulation of the differentiation and proliferation of retinal progenitors. We assessed how different levels of EGF signaling, achieved either by increasing receptor expression or via addition of the exogenous ligand, or an increase in both, can affect the differentiation of progenitors in the first week of postnatal retinal development in the model system of retinal explants (REs). Proliferating progenitor cells in REs were infected with either the control CLV3/ESR-related peptide family (CLE)-green fluorescent protein (GFP)- or with EGF receptor (EGFR)-GFP-expressing retrovirus, and grown in the control medium or in the presence of exogenous EGF (10 ng/mL). The differentiation of infected cells into Muller glia (Sox9+), rod photoreceptors (rhodopsin+) and horizontal cells (calbindin+) was analyzed. In all the examined conditions, infected cells differentiated into Muller glia and rod photoreceptors that normally de...
International Journal of Developmental Neuroscience, 2009
Commonly used general anesthetics can have adverse effects on the developing brain by triggering ... more Commonly used general anesthetics can have adverse effects on the developing brain by triggering apoptotic neurodegeneration, as has been documented in the rat. The rational of our study was to examine the molecular mechanisms that contribute to the apoptotic action of propofol anesthesia in the brain of 7-day-old (P7) rats. The down-regulation of nerve growth factor (NGF) mRNA and protein expression in the cortex and thalamus at defined time points between 1 and 24 h after the propofol treatment, as well as a decrease of phosphorylated Akt were observed. The extrinsic apoptotic pathway was induced by over-expression of tumor necrosis factor (TNF) which led to the activation of caspase-3 in both examined structures. Neurodegeneration was confirmed by Fluoro-Jade B staining. Our findings provide direct experimental evidence that the anesthetic dose (25 mg/kg) of propofol induces complex changes that are accompanied by cell death in the cortex and thalamus of the developing rat brain.
In order to better understand pathogenesis of pulmonary emphysema, the model of experimentally in... more In order to better understand pathogenesis of pulmonary emphysema, the model of experimentally induced pulmonary emphysema in Chinchilla rabbits was used for the estimation of apoptotic clearance of pulmonary tissue. Bronchoalveolar lavage was performed in three groups of animals: experimental group-E on hypercholesterolemic diet (4% edible oil solution of crystalline cholesterol), control group-C 1 on standard diet for that animal species and animals on oily diet-C 2. Apoptotic detection in cytocentrifuge preparations of lung washings was evaluated by in situ TUNEL. The property of alveolar macrophages to engulf apoptotic cells was estimated by light microscopy including 300 features (related subsequent steps: adsorption, internalization and intracellular processing of free apoptotic bodies) and was evaluated by scoring and indexing method. Internalization of apoptotic bodies by alveolar macrophages, as well as free apoptotic bodies were decreased in E compared to both C 1 and C 2 group (p<0.01 and p<0.05 respectively). Intracellular processing of apoptotic bodies by alveolar macrophages is significantly decreased in C 2 in comparison with E (p<0.05) and C 1 group (p<0.01). Apoptotic capacity of pulmonary tissue is significantly decreased in C 2 in comparison with C 1 group (p<0.01). The results implicate that immuno-metabolic competence of pulmonary tissue might be essentially associated with tissue remodeling in pulmonary emphysema.
The growing body of data implies that SARS-CoV-2 infection may affect the nervous system. We here... more The growing body of data implies that SARS-CoV-2 infection may affect the nervous system. We here present a short, taciturn overview of described neurological impairments related to SARS-CoV-2 infection. While it is obvious that neurological impairments can be diagnosed in a portion of COVID-19 patients, evidence of SARS-CoV-2 neurovirulence in humans is still lacking. The existing data on the incidence of neurological impairments among COVID-19 patients is highly variable, probably because they (most often) come from small, single-center retrospective studies. These data are practically published in real-time, and the question remains when larger studies will be available, given that the pandemic is continuing. We here also shortly address the other issues related to neurological disorders and COVID-19 pandemic, including the concern for people with existing chronic neurological disorders and possible long-term neurological consequences of SARS-CoV-2 infection.
Dysregulation of neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus has ... more Dysregulation of neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus has been related to cognitive deficits and memory loss in neurodegenerative diseases, such as Alzheimer's disease (AD). Members of the B group of SOX transcription factors play critical roles in regulating neurogenesis in the embryonic and adult nervous system, including maintaining the multipotency, renewal, and cell fate decision of neural stem/progenitor cells. The aim of the present study was to evaluate the expression patterns of selected SOXB proteins in the SGZ, of 8-week-old male and female 5xFAD mice, which represent a transgenic model of AD with a severe and very early development of amyloid pathology. Immunohistochemical analysis showed a significant decrease in the number of cells expressing SOX1, SOX2, and SOX21 transcription factors within the SGZ of 5xFAD mice in comparison to their non-transgenic counterparts which coincidences with reduced number of doublecortin immunoreactive immature neurons found in Tg males. Despite observed changes in expressional pattern of examined SOXB proteins, the proliferative capacity evaluated by the number of Ki-67 immunoreactive cells remained unaffected in transgenic mice of both genders. Based on our results, we suggest that SOXB proteins might be considered as new biomarkers for the detection of early impairments in adult neurogenesis in different animal models or/and new targets in human regenerative medicine.
The recovery period following cortical injury (CI) is characterized by a dynamic and highly compl... more The recovery period following cortical injury (CI) is characterized by a dynamic and highly complex interplay between beneficial and detrimental events. The aim of this study was to examine the expressions of Glial Fibrillary Acidic Protein (GFAP), Apolipoprotein E (ApoE) and Amyloid Precursor Protein (APP), all of which are involved in brain plasticity and neurodegeneration. Our results reveal that CI strongly influenced GFAP, ApoE and APP mRNA expression, as well as GFAP and ApoE protein expression. Considering the pivotal role of these proteins in the brain, the obtained results point to their potential contribution in neurodegeneration and consequent Alzheimer's disease development.
Dystrophic neurites and activated microglia are one of the main neuropathological characteristics... more Dystrophic neurites and activated microglia are one of the main neuropathological characteristics of Alzheimer's disease (AD). Although the use of supplements with omega-3 fatty acids has been associated with reduced risk and lessened AD pathology, it still remains elusive whether such a treatment could affect dystrophic neurites (DNs) formation and microglia/macrophage behavior in the early phase of disease. We analyzed the effects of shortterm (3 weeks) fish oil supplementation on DNs formation, tau hyperphosphorylation, Amyloid-beta peptide 1-42 (Aβ42) levels and microglial/macrophage response to AD pathology in the parietal cortex of 4-month-old 5xFAD mice, a mouse model of AD. The present study shows for the first time that short-term FO supplementation applied in presymptomatic stage of AD, alters the behaviour of microglia/macrophages prompting them to establish a physical barrier around amyloid plaques. This barrier significantly suppresses DNs formation through the reduction of both Aβ content and tau hyperphosphorylation. Moreover, the short-term FO treatment neither suppresses inflammation nor enhances phagocytic properties of microglia/macrophages in the response to Aβ pathology, the effects most commonly attributed to the fish oil supplementation. Our findings suggest that fish oil consumption may play an important role in modulating microglial/macrophage response and ameliorating the AD pathology in presymptomatic stage of Alzheimer's disease. OPEN ACCESS Citation: Jović M, Lončarević-Vasiljković N, Ivković S, Dinić J, Milanović D, Zlokovic B, et al. (2019)
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Papers by Selma Kanazir