Neuroimmune Support of Neuronal Regeneration and Neuroplasticity following Cerebral Ischemia in Juvenile Mice

Ischemic damage to the brain and loss of neurons contribute to functional disabilities in many stroke survivors. Recovery of neuroplasticity is critical to restoration of function and improved quality of life. Stroke and neurological deficits occur in both adults and children, and yet it is well documented that the developing brain has remarkable plasticity which promotes increased post-ischemic functional recovery compared with adults. However, the mechanisms underlying post-stroke recovery in the young brain have not been fully explored. We observed opposing responses to experimental cerebral ischemia in juvenile and adult mice, with substantial neural regeneration and enhanced neuroplasticity detected in the juvenile brain that was not found in adults. We demonstrate strikingly different stroke-induced neuroimmune responses that are deleterious in adults and protective in juveniles, supporting neural regeneration and plasticity. Understanding age-related differences in neuronal repair and regeneration, restoration of neural network function, and neuroimmune signaling in the stroke-injured brain may offer new insights for the development of novel therapeutic strategies for stroke rehabilitation

COVID-19 AND THE ENVIRONMENT – THE ROLE OF THE PUBLIC HEALTH INSTITUTE

The Croatian National Health Care Act defines the areas of activities of the public health institute, including the activities of the epidemiology of infectious diseases and chronic non-communicable diseases, public health, health promotion, environmental health, microbiology, school and adolescent medicine, mental health and addiction prevention at Zagreb City level. This paper reviews the highly variable activities in the Andrija Štampar Teaching Institute of Public Health with the aim of promoting a comprehensive approach to the COVID-19 pandemic. Human and analytical resources in the Institute, activities and rapid implementation of innovations testify to the high capacities for adaptation to emerging risks. In the Institute, it is possible to carry out a whole range of tests and to monitor the environmental factors with predominant impact on human health and safety of the Zagreb environment. The supply of safe water for human consumption in the Republic of Croatia during the current COVID-19 crisis has been uninterrupted and in accordance with applicable legislation. Also, our laboratories have been developing and introducing a method for wastewater testing for SARS-CoV-2 presence. The sludge from wastewater treatment plants is used in agriculture, and potential risks associated with the COVID-19 outbreak should be assessed prior to each application on the soil. Increased use of disinfectants during the epidemic may present a higher risk to the aquatic environment. Air quality monitoring indicates a positive impact on air quality as result of isolation measures

A Role for Protein Arginine Methyltransferase 7 in Repetitive and Mild Traumatic Brain Injury

Mild traumatic brain injury affects the largest proportion of individuals in the United States and world-wide. Pre-clinical studies of repetitive and mild traumatic brain injury (rmTBI) have been limited in their ability to recapitulate human pathology (i.e. diffuse rotational injury). We used the closed-head impact model of engineered rotation acceleration (CHIMERA) to simulate rotational injury observed in patients and to study the pathological outcomes post-rmTBI using C57BL/6J mice. Enhanced cytokine production was observed in both the cortex and hippocampus to suggest neuroinflammation. Furthermore, microglia were assessed via enhanced iba1 protein levels and morphological changes using immunofluorescence. In addition, LC/MS analyses revealed excess glutamate production, as well as diffuse axonal injury via Bielschowsky\u27s silver stain kit. Moreover, the heterogeneous nature of rmTBI has made it challenging to identify drug therapies that address rmTBI, therefore we sought to identify novel targets in the concurrent rmTBI pathology. The pathophysiological findings correlated with a time-dependent decrease in protein arginine methyltransferase 7 (PRMT7) protein expression and activity post-rmTBI along with dysregulation of PRMT upstream mediators s-adenosylmethionine and methionine adenosyltransferase 2 (MAT2) in vivo. In addition, inhibition of the upstream mediator MAT2A using the HT22 hippocampal neuronal cell line suggest a mechanistic role for PRMT7 via MAT2A in vitro. Collectively, we have identified PRMT7 as a novel target in rmTBI pathology in vivo and a mechanistic link between PRMT7 and upstream mediator MAT2A in vitro

PRMT7 Can Prevent Neurovascular Uncoupling, Blood-Brain Barrier Permeability, and Mitochondrial Dysfunction in Repetitive and Mild Traumatic Brain Injury

Mild traumatic brain injury (TBI) comprises the largest percentage of TBI-related injuries, with pathophysiological and functional deficits that persist in a subset of TBI patients. In our three-hit paradigm of repetitive and mild traumatic brain injury (rmTBI), we observed neurovascular uncoupling via decreased red blood cell velocity, microvessel diameter, and leukocyte rolling velocity 3 days post-rmTBI via intra-vital two-photon laser scanning microscopy. Furthermore, our data suggest increased blood-brain barrier (BBB) permeability (leakage), with corresponding decrease in junctional protein expression post-rmTBI. Mitochondrial oxygen consumption rates (measured via Seahorse XFe24) were also altered 3 days post-rmTBI, along with disrupted mitochondrial dynamics of fission and fusion. Overall, these pathophysiological findings correlated with decreased protein arginine methyltransferase 7 (PRMT7) protein levels and activity post-rmTBI. Here, we increased PRMT7 levels in vivo to assess the role of the neurovasculature and mitochondria post-rmTBI. In vivo overexpression of PRMT7 using a neuronal specific AAV vector led to restoration of neurovascular coupling, prevented BBB leakage, and promoted mitochondrial respiration, altogether to suggest a protective and functional role of PRMT7 in rmTBI

Corticosterone and Glucocorticoid Receptor in the Cortex of Rats during Aging—The Effects of Long-Term Food Restriction

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. Moreover, our data revealed that reduced food intake prevented age-related increase in the levels of NFκB, gfap, and bax, confirming its anti-inflammatory and anti-apoptotic effects. Along with an increase in the levels of c-fos, our study provides additional evidences that food restriction affects cortical responsiveness to glucocorticoids during aging

Perioperative myocardial ischemia in coronary artery disease patients undergoing abdominal nonvascular surgery

BACKGROUND: The incidence of perioperative myocardial ischemia (PMI) is the highest in patients who have coronary artery disease, and it is the best predictor of intrahospital morbidity and mortality. OBJECTIVE: To identify predictors of PMI in patients who have coronary artery disease and are undergoing abdominal nonvascular surgery. METHODS: A prospective, observational, clinical study of 111 consecutive patients with angiographically verified coronary artery disease, scheduled for open abdominal nonvascular surgery, was conducted. Patients received general anesthesia and were monitored by continuous electrocardiogram during surgery and immediately postsurgery (72 h period) in the intensive care unit at the University Clinical Center (Belgrade, Serbia). All of the patients had 12-lead electrocardiography immediately after the surgery, on postoperative days 1, 2 and 7, and one day before discharge from hospital. The patients were monitored until the 30th postoperative day. RESULTS: A total of 24 predictors for PMI were analyzed. The Pearson's chi(2) test and a binomial logistic regression model were used for statistical analysis. A significant difference in the incidence of PMI was found in the coronary artery disease patients with an associated risk factor (14 of 24 risk factors) compared with those without the risk factor. In particular, a highly significant difference in the incidence of PMI was found in coronary artery disease patients with angina pectoris, compared with those without angina pectoris. CONCLUSION: Using the multivariate logistic regression analysis, angina pectoris was an independent predictor of PMI

Long-term intermittent feeding restores impaired GR signaling in the hippocampus of aged rat

Diminished glucocorticoid signaling is associated with an age-related decline in hippocampal functioning. In this study we demonstrate the effect of intermittent, every other day (EOD) feeding on the glucocorticoid hormone/glucocorticoid receptor (GR) system in the hippocampus of middle-aged (18-month-old) and aged (24-month-old) Wistar rats. In aged ad libitum-fed rats, a decrease in the level of total GR and GR phosphorylated at Ser(232) (pGR) was detected. Conversely, aged rats subjected to EOD feeding, starting from 6 months of age, showed an increase in GR and pGR levels and a higher content of hippocampal corticosterone. Furthermore, prominent nuclear staining of pGR was observed in CM pyramidal and DG granule neurons of aged EOD-fed rats. These changes were accompanied by increased Sglc-1 and decreased GFAP transcription, pointing to upregulated transcriptional activity of GR. EOD feeding also induced an increase in the expression of the mineralocorticoid receptor. Our results reveal that intermittent feeding restores impaired GR signaling in the hippocampus of aged animals by inducing rather than by stabilizing GR signaling during aging. (C) 2015 Elsevier Ltd. All rights reserved.Ministry of Education, Science and Technological Development of the Republic of Serbia {[}ON173056, ON173008]; NIH {[}R03AG046216

The effects of dietary restriction and aging on amyloid precursor protein and presenilin-1 mRNA and protein expression in rat brain

The objective of this study was to examine the effects of aging and long-term dietary restriction (DR) on the level of amyloid precursor protein (APP) and presenilin-1 (PS-1), proteins that are critically involved in Alzheimer's disease. Changes in mRNA and protein expression were assessed by real-time PCR and western blot analysis during aging and long-term DR in the cortex and hippocampus of 6-, 12-, 18-, and 24-month-old rats. Prominent regional changes in expression were observed in response to aging and DR. Although the hippocampus displayed significant alterations in APP mRNA and protein expression and no significant changes in PS-1 expression, an opposite pattern was observed in the cortex. DR counteracted the age-related changes in APP mRNA expression in both structures of old animals. The observed DR-induced increase in mRNA levels in the hippocampus was accompanied by an increase in the level of full-length protein APP. These results indicate that although both structures are very sensitive to aging, a specific spatial pattern of changes in APP and PS-1 occurs during aging. Furthermore, these findings provide evidence that DR can affect APP and PS-1 expression in a manner consistent with its proposed `antiaging' effect.Ministry of Education, Science and Technological Development of the Republic of Serbia {[}173056

Anthraquinone-chalcone hybrids: Synthesis, preliminary antiproliferative evaluation and DNA-interaction studies

Novel anthraquinone based chalcone compounds were synthesized starting from 1-acetylanthraquinone in a Claisen-Schmidt reaction and evaluated for their anticancer potential against three human cancer cell lines. Compounds 4a, 4b and 4j showed promising activity in inhibition of HeLa cells with IC50 values ranging from 2.36 to 2.73 mu M and low cytotoxicity against healthy MRC-5 cell lines. The effects that compounds produces on the cell cycle were investigated by flow cytometry. It was found that 4a, 4b and 4j cause the accumulation of cells in the S and G2/M phases in a dose-dependent manner and induce caspase-dependent apoptosis. All of three compounds exhibit calf thymus DNA-binding activity. The determined binding constants by absorption titrations (2.65 x 10(3) M-1, 1.36 x 10(3) M(-1)and 2.51 x 10(3) M-1 of 4a/CT-DNA, 4b/CT-DNA and 4j/CT-DNA, respectively) together with fluorescence displacement analysis designate 4a, 4b and 4j as strong minor groove binders, but no cleavage of plasmid DNA was observed