Joanna Jaworska

Insights Into the Neuroinflammatory Responses After Neonatal Hypoxia-Ischemia.

Neonatal hypoxia-ischemia (HI) is one of the major causes of death and/or lifelong neurobehavioral and cognitive dysfunction. Undoubtedly, brain damage following HI insult is a complex process with multiple contributing mechanisms and pathways resulting in both early and delayed injury. It is increasingly recognized that one of the leading pathogenic factors of neonatal brain damage is inflammation, induced by activation of the central and peripheral immune system. Immune responses are induced within minutes and can expand for weeks and even months after the insult. Both activated intrinsic (glia) and infiltrating cells (mast cells, monocytes/macrophages) produce soluble inflammatory molecules such as cytokines, chemokines, reactive oxygen, and nitrogen species, which are thought to be pivotal mediators of persistent neuronal injury. This manuscript provides a brief summary of the current knowledge concerning the specific contribution of different cell types and soluble factors to injury of the developing brain caused by neonatal HI. Finally, we discuss the potential forthcoming treatments aimed at targeting inflammation and then attenuation of damaging effects caused by neonatal HI.

Histone deacetylases 1 and 2 are required for brain development

Epigenetic modifications of histones have been implicated in the regulation of cell specific expression of genes required for neuronal development. The best studied post-translational (epigenetic) modification of histones is the process of reversible acetylation. Two types of enzymes - histone acetyltransferases (HATs) and histone deacetylases (HDACs) establish and maintain specific patterns of histone acetylation in balance, thereby contributing to both transcriptional activation and repression of specific sets of genes. Histone deacetylases catalyze the removal of acetyl groups from selected lysine residues in the conserved tails of core histone proteins and are considered as transcriptional corepressors. A significant amount of data implicates HDACs in diverse biological processes, including tissue specific developmental program by silencing specific growth-inhibitory genes. In line with this, gene disruption studies have shown that the class I deacetylases, HDAC1 and HDAC2 play an essential role in nervous system development. In the present review, we briefly highlight current insights supporting the function of histone deacetylases in rodent brain development and discuss present knowledge referring to their role in neurogenesis, taking into consideration results obtained in culture systems and in in vivo studies.

Multifunctional PLGA/Parylene C Coating for Implant Materials: An Integral Approach for Biointerface Optimization

Functionalizing implant surfaces is critical for improving their performance. An integrated approach was employed to develop a multifunctional implant coating based on oxygen plasma-modified parylene C and drug-loaded, biodegradable poly(dl-lactide-co-glycolide) (PLGA). The key functional attributes of the coating (i.e., anti-corrosion, biocompatible, anti-infection, and therapeutic) were thoroughly characterized at each fabrication step by spectroscopic, microscopic, and biologic methods and at different scales, ranging from molecular, through the nano- and microscales to the macroscopic scale. The chemistry of each layer was demonstrated separately, and their mutual affinity was shown to be indispensable for the development of versatile coatings for implant applications.

Current and Experimental Pharmacological Approaches in Neonatal Hypoxic- Ischemic Encephalopathy

Neonatal hypoxic-ischemic (HI) injury still remains an important issue as it is a frequent cause of neonatal death and life-long neurobehavioral and cognitive dysfunction. In spite of the decades of research which led us to a better knowledge of the pathological mechanism of hypoxic-ischemic brain injury, the clinical use of potential neuroprotective drugs (including, among others, excitatory amino acids antagonists, free radical inhibitors and scavengers, growth factors, xenon, cannabinoids, anti-inflammatory and anti-apoptotic agents) became avoided owing to insufficiency and /or treatment-induced undesirable side effects. The only available effective treatment, hypothermia, neither provides complete brain protection nor stimulates the repair necessary for neurodevelopmental outcome. This fact brings about increased interest in alternative methods of therapy, such as regenerative medicine using stem cells. Growing number of in vivo preclinical studies revealed that mesenchymal stem cells as well as human cord blood cells may improve functional outcome after HI insult and may represent a new beneficial treatment modality for infants developing hypoxic-ischemic encephalopathy. In this review we briefly highlight the present and potential forthcoming therapeutic treatments aimed at attenuation of the detrimental effects of neonatal hypoxia-ischemia.

Corrosion resistance of PLGA-coated biomaterials

The aim of the study was to determine the influence of PLGA bioresorbable polymer coating on corrosion resistance of metal biomaterial. Polymer coating deposited by immersion method was applied. Corrosion resistance of metal biomaterials (stainless steel, Ti6Al4V, Ti6Al7Nb) coated with PLGA polymer, after 90 days exposure to Ringers solution was tested. The amount of metal ions released to the solution was also investigated (inductively coupled plasma-atomic emission spectrometry (ICP-AES) method). The surface of the samples was observed using atomic force microscopy (AFM) and scanning electron microscopy (SEM). Degradation of PLGA was monitored with the use of the 1H NMR spectroscopy and GPC (Gel Permeation Chromatography). The studies were carried out for non-sterilized (NS) and sterilized (S) samples. Application of the polymer coating causes a reduction of release of metal ions to the solution. Depending on metal substrate different course of destruction of polymer layer was observed. After 90 days of incubation in Ringers solution polymer layer was highly degraded, however, the composition of copolymer (ratio of the comonomeric units in the chain) remained unchanged during the whole process, which suggests even degradation. The polymer layer reduced degradation kinetics of the metal substrate. Moreover, degradation process did not change surface morphology of metal substrate and did not disturb its integrity. The results obtained indicate that the applied polymer layer improves corrosion resistance of the alloys being investigated. Thus, the developed implants with bioresorbable coatings could be advantageous for medical applications.

OGD induced modification of FAK- and PYK2-coupled pathways in organotypic hippocampal slice cultures.

Focal adhesion kinase (FAK) and proline-rich tyrosine kinase (PYK2) are two related non-receptor tyrosine kinases which are thought to play a role in transducing extracellular matrix (ECM)-derived survival signals into cells. The functions of FAK and PYK2 are linked to autophosphorylation of their specific tyrosine residues, Tyr-397 in FAK and Tyr-402 in PYK2, and then association with different signalling proteins which mediate activation of downstream targets such as ERK and JNK mitogen-activated kinase cascades. Thus, modulation of FAK as well as PYK2 autophosphorylation may affect several intracellular pathways and may participate in a variety of pathological settings. The present study provides a systematic investigation of the influence of experimental ischemia, induced by oxygen-glucose-deprivation, on the FAK- and PYK2-mediated signalling in organotypic hippocampal slice cultures. OGD induced primary down-regulation of FAK and PYK2 autophosphorylation (at Tyr 397 and Tyr 402, respectively) at 24-48 h of reoxygenation was accompanied by the diminution of phosphorylation/activation of Src and JNK. In contrast, the activity of Akt and ERK1/2 remained on the control level. It indicates that Akt kinase as well as ERK1/2 does not interfere with OGD-induced neuronal damage. The inhibition of the early step of FAK and PYK2 activation demonstrated by the decrease of tyrosine autophosphorylation may comprise an important portion of the response expressed by modulation of some coupled signal transduction pathways.

Histone Deacetylase Inhibitors: A Therapeutic Key in Neurological Disorders?

Understanding the contribution of imbalance in protein acetylation levels and dysfunction of transcription to neurodegenerative diseases provides the rationale for the use of epigenetic modulators such as histone deacetylase (HDAC) inhibitors to combat neurodegenerative conditions. It is now widely recognized that various low-molecular weight HDAC inhibitors are broadly neuroprotective, preventing or delaying neuronal death and dysfunction in many rodent models of neurodegeneration. The beneficial effects result in part from modifications of histones and nonhistone proteins. This review describes evidence indicating that HDAC inhibitors have emerged as a promising new strategy in treating neurodegenerative disorders and summarizes treatment strategies from clinical trials currently underway.

Impact of neonatal hypoxia‐ischaemia on oligodendrocyte survival, maturation and myelinating potential

Hypoxic‐ischaemic episodes experienced at the perinatal period commonly lead to a development of neurological disabilities and cognitive impairments in neonates or later in childhood. Clinical symptoms often are associated with the observed alterations in white matter in the brains of diseased children, suggesting contribution of triggered oligodendrocyte/myelin pathology to the resulting disorders. To date, the processes initiated by perinatal asphyxia remain unclear, hampering the ability to develop preventions. To address the issue, the effects of temporal hypoxia‐ischaemia on survival, proliferation and the myelinating potential of oligodendrocytes were evaluated ex vivo using cultures of hippocampal organotypic slices and in vivo in rat model of perinatal asphyxia. The potential engagement of gelatinases in oligodendrocyte maturation was assessed as well. The results pointed to a significant decrease in the number of oligodendrocyte progenitor cells (OPCs), which is compensated for to a certain extent by the increased rate of OPC proliferation. Oligodendrocyte maturation seemed however to be significantly altered. An ultrastructural examination of selected brain regions performed several weeks after the insult showed however that the process of developing central nervous system myelination proceeds efficiently resulting in enwrapping the majority of axons in compact myelin. The increased angiogenesis in response to neonatal hypoxic‐ischaemic insult was also noticed. In conclusion, the study shows that hypoxic‐ischaemic episodes experienced during the most active period of nervous system development might be efficiently compensated for by the oligodendroglial cell response triggered by the insult. The main obstacle seems to be the inflammatory process modulating the local microenvironment.

Effect of vascular scaffold composition on release of sirolimus

Graphical abstract Figure. No Caption available. Abstract Despite extensive development of bioresorbable drug‐eluting vascular scaffolds it is still challenging to achieve controlled drug delivery. The lack of capacity for adjusting the drug dose and inadequate release behavior are one of the main reasons of the side effects. However, so far, mainly biodegradable drug‐eluting coatings of metallic stents have been studied in regard to explain drug release mechanisms. The objective of this study was to develop degradable polymer coatings applicable to bioresorbable polymer‐based scaffolds. Moreover, a detailed analysis of sirolimus release and scaffold degradation has been conducted. Coating layers of the same composition were applied by the same method on the surface of two different kinds of scaffolds in order to explain the effect of scaffold structure on release process. The developed coatings showed controlled release of antiproliferative agent with elimination of burst effect. However, differences in drug release profile from two kinds of scaffolds were observed. Scaffold composed of polymer with higher lactide content showed slower and bi‐phasic, erosion‐controlled release of sirolimus. On the contrary, sirolimus release from scaffold composed of polymer with lower content of lactide was mainly controlled by diffusion. These results demonstrate that characteristics of scaffold is another crucial factor that must be considered in further development of bioresorbable vascular scaffolds (BRS) with controlled release of antiproliferative agent.

Efect Of Sterylization And Long-Term Exposure To Artificial Urine On Corrosion Behaviour Of Metallic BiomaterialsWith Poly(Glikolide-Co-Kaprolactone) Coatings

Novel implants based on metallic alloys (stainless steel 316 LVM, Ti6Al4V ELI and Ti6Al7Nb alloys) prepared by self-developed method of surface modification are presented in this study. Implants were coated with biodegradable and bioresorbable layer of poly(glycolide-co-caprolactone). Next, half of the perpetrated specimens was subjected to radiation sterilization. After that, samples were divided in to two groups: I - initial state (samples with sterilized “S” and nonsterilized polymer “NS”; II - samples with sterilized “S90” and non-sterilized polymer coating “NS90” after 90 days of exposure to artificial urine. As a result of the conducted research, it was found that after long-term exposure the polymer degradation was even and inconsiderable. However, reduction of adhesion and finally, retraction of the coatings on the titanium alloys has been observed. Moreover, the influence of sterilization process on the kinetics of metallic ion release to corrosion environment for all metallic biomaterials has been observed.