Publikacje naukowe

Glycogen metabolism in brain and neurons - astrocytes metabolic cooperation can be altered by pre- and neonatal lead (Pb) exposure.

Toxicology. 2017 Sep 12;390:146-158. doi: 10.1016/j.tox.2017.09.007. 

Baranowska-Bosiacka I1, Falkowska A2, Gutowska I3, Gąssowska M4, Kolasa-Wołosiuk A5, Tarnowski M6, Chibowska K2, Goschorska M2, Lubkowska A7, Chlubek D2.
Author information
Glycogen metabolism in brain and neurons - astrocytes metabolic cooperation can be altered by pre- and neonatal lead (Pb) exposure.
1 Department of Biochemistry and Medical Chemistry, Powstańców Wlkp. 72 St., 70-111 Szczecin, Pomeranian Medical University in Szczecin, Poland. Electronic address: Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..
2 Department of Biochemistry and Medical Chemistry, Powstańców Wlkp. 72 St., 70-111 Szczecin, Pomeranian Medical University in Szczecin, Poland.
3 Department of Biochemistry and Human Nutrition, Broniewskiego 24 St., 71-460 Szczecin, Pomeranian Medical University in Szczecin, Poland.
4 Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
5 Department of Histology and Embriology, Powstańców Wlkp. 72 St., 70-111 Szczecin, Pomeranian Medical University in Szczecin, Poland.
6 Department of Physiology, Powstańców Wlkp. 72 St., 70-111 Szczecin, Pomeranian Medical University in Szczecin, Poland.
7 Department of Functional Diagnostics and Physical Medicine, Pomeranian Medical University in Szczecin, Żołnierska 48 Str, 71-210 Szczecin, Poland.

ABSTRACT

Lead (Pb) is an environmental neurotoxin which particularly affects the developing brain but the molecular mechanism of its neurotoxicity still needs clarification. The aim of this paper was to examine whether pre- and neonatal exposure to Pb (concentration of Pb in rat offspring blood below the "threshold level") may affect the brain's energy metabolism in neurons and astrocytes via the amount of available glycogen. We investigated the glycogen concentration in the brain, as well as the expression of the key enzymes involved in glycogen metabolism in brain: glycogen synthase 1 (Gys1), glycogen phosphorylase (PYGM, an isoform active in astrocytes; and PYGB, an isoform active in neurons) and phosphorylase kinase β (PHKB). Moreover, the expression of connexin 43 (Cx43) was evaluated to analyze whether Pb poisoning during the early phase of life may affect the neuron-astrocytes' metabolic cooperation. This work shows for the first time that exposure to Pb in early life can impair brain energy metabolism by reducing the amount of glycogen and decreasing the rate of its metabolism. This reduction in brain glycogen level was accompanied by a decrease in Gys1 expression. We noted a reduction in the immunoreactivity and the gene expression of both PYGB and PYGM isoform, as well as an increase in the expression of PHKB in Pb-treated rats. Moreover, exposure to Pb induced decrease in connexin 43 immunoexpression in all the brain structures analyzed, both in astrocytes as well as in neurons. Our data suggests that exposure to Pb in the pre- and neonatal periods results in a decrease in the level of brain glycogen and a reduction in the rate of its metabolism, thereby reducing glucose availability, which as a further consequence may lead to the impairment of brain energy metabolism and the metabolic cooperation between neurons and astrocytes.

KEYWORDS:

Brain glycogen metabolism; Glycogen phosphorylase brain isoform (PYGB); Glycogen phosphorylase kinase (PHKB); Glycogen phosphorylase muscle isoform (PYGM); Glycogen synthase (Gys1); Lead (Pb) neurotoxicity

Phenotypic, Functional, and Safety Control at Preimplantation Phase of MSC-Based Therapy.

Stem Cells Int. 2016;2016:2514917. doi: 10.1155/2016/2514917. Epub 2016 Aug 29.

Lech W1, Figiel-Dabrowska A1, Sarnowska A1, Drela K1, Obtulowicz P1, Noszczyk BH2, Buzanska L1, Domanska-Janik K1.

Phenotypic, Functional, and Safety Control at Preimplantation Phase of MSC-Based Therapy.

Author information

1 Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106 Warsaw, Poland.

2 Department of Plastic Surgery at the Medical Center for Postgraduate Education, Warsaw School of Medicine, 01-828 Warsaw, Poland.

 

ABSTRACT

Mesenchymal stem cells (MSC) exhibit enormous heterogeneity which can modify their regenerative properties and therefore influence therapeutic effectiveness as well as safety of these cells transplantation. In addition the high phenotypic plasticity of MSC population makes it enormously sensitive to any changes in environmental properties including fluctuation in oxygen concentration. We have shown here that lowering oxygen level far below air atmosphere has a beneficial impact on various parameters characteristic for umbilical cord Wharton Jelly- (WJ-) MSC and adipose tissue- (AD-) derived MSC cultures. This includes their cellular composition, rate of proliferation, and maintenance of stemness properties together with commitment to cell differentiation toward mesodermal and neural lineages. In addition, the culture genomic stability increased significantly during long-term cell passaging and eventually protected cells against spontaneous transformation. Also by comparing of two routinely used methods of MSCs isolation (mechanical versus enzymatic) we have found substantial divergence arising between cell culture properties increasing along the time of cultivation in vitro. Thus, in this paper we highlight the urgent necessity to develop the more sensitive and selective methods for prediction and control cells fate and functioning during the time of growth in vitro.

Sensitivity of hiPSC-derived neural stem cells (NSC) to Pyrroloquinoline quinone depends on their developmental stage.

Toxicol In Vitro. 2017 May 31. pii: S0887-2333(17)30133-9. doi: 10.1016/j.tiv.2017.05.017. [Epub ahead of print]

Sensitivity of hiPSC-derived neural stem cells (NSC) to Pyrroloquinoline quinone depends on their developmental stage.

Augustyniak J1, Lenart J2, Zychowicz M1, Lipka G1, Gaj P3, Kolanowska M4, Stepien PP5, Buzanska L6.

Author information

1 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Poland.

2 Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, Poland.

3 Laboratory of Human Cancer Genetics, Centre of New Technologies, CENT, University of Warsaw, Warsaw, Poland.

4 Laboratory of Human Cancer Genetics, Centre of New Technologies, CENT, University of Warsaw, Warsaw, Poland; Genomic Medicine, Medical University of Warsaw, Warsaw, Poland.

5 Department of Genetics, Faculty of Biology, University of Warsaw, Poland; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw; Centre for New Technologies, University of Warsaw, Poland.

6 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Poland. Electronic address: Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

ABSTRACT

Pyrroloquinoline quinone (PQQ) is a factor influencing on the mitochondrial biogenesis. In this study the PQQ effect on viability, total cell number, antioxidant capacity, mitochondrial biogenesis and differentiation potential was investigated in human induced Pluripotent Stem Cells (iPSC) - derived: neural stem cells (NSC), early neural progenitors (eNP) and neural progenitors (NP). Here we demonstrated that sensitivity to PQQ is dependent upon its dose and neural stage of development. Induction of the mitochondrial biogenesis by PQQ at three stages of neural differentiation was evaluated at mtDNA, mRNA and protein level. Changes in NRF1, TFAM and PPARGC1A gene expression were observed at all developmental stages, but only at eNP were correlated with the statistically significant increase in the mtDNA copy numbers and enhancement of SDHA, COX-1 protein level. Thus, the "developmental window" of eNP for PQQ-evoked mitochondrial biogenesis is proposed. This effect was independent of high antioxidant capacity of PQQ, which was confirmed in all tested cell populations, regardless of the stage of hiPSC neural differentiation. Furthermore, a strong induction of GFAP, with down regulation of MAP2 gene expression upon PQQ treatment was observed. This indicates a possibility of shifting the balance of cell differentiation in the favor of astroglia, but more research is needed at this point.

KEYWORDS:

Developmental neurotoxicity; Mitochondrial biogenesis; Neural progenitors; Neural stem cells; PQQ; hiPSC

Epigenetic Modulation of Stem Cells in Neurodevelopment: The Role of Methylation and Acetylation.

Front Cell Neurosci. 2017 Feb 7;11:23. doi: 10.3389/fncel.2017.00023. eCollection 2017.

Podobinska M1, Szablowska-Gadomska I2, Augustyniak J1, Sandvig I3, Sandvig A3, Buzanska L1.

Epigenetic Modulation of Stem Cells in Neurodevelopment: The Role of Methylation and Acetylation.

Author information

1 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences Warsaw, Poland.

2 Pharmacology Department, Institute of Mother and Child Warsaw, Poland.

3 Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU) Trondheim, Norway.

ABSTRACT

The coordinated development of the nervous system requires fidelity in the expression of specific genes determining the different neural cell phenotypes. Stem cell fate decisions during neurodevelopment are strictly correlated with their epigenetic status. The epigenetic regulatory processes, such as DNA methylation and histone modifications discussed in this review article, may impact both neural stem cell (NSC) self-renewal and differentiation and thus play an important role in neurodevelopment. At the same time, stem cell decisions regarding fate commitment and differentiation are highly dependent on the temporospatial expression of specific genes contingent on the developmental stage of the nervous system. An interplay between the above, as well as basic cell processes, such as transcription regulation, DNA replication, cell cycle regulation and DNA repair therefore determine the accuracy and function of neuronal connections. This may significantly impact embryonic health and development as well as cognitive processes such as neuroplasticity and memory formation later in the adult.

KEYWORDS:

acetylation; epigenetics; methylation; neurodevelopment; neuroplasticity; stem cells

Concise Review: MSC Adhesion Cascade-Insights into Homing and Transendothelial Migration.

Stem Cells. 2017 Jun;35(6):1446-1460. doi: 10.1002/stem.2614. Epub 2017 Apr 3.

Nitzsche F1,2, Müller C1, Lukomska B3, Jolkkonen J4, Deten A5, Boltze J1,5,6.

Concise Review: MSC Adhesion Cascade-Insights into Homing and Transendothelial Migration.

Author information:

1 Department of Ischemia Research, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.

2 Department of Radiology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

3 NeuroRepair Department, Mossakowski Medical Research Centre, Warsaw, Poland.

4 Department of Neurology, Institute of Clinical Medicine, University of Eastern, Kuopio, Finland.

5 Translational Centre for Regenerative Medicine, Leipzig University, Leipzig, Germany.

6 Department of Translational Medicine and Cell Technology, Fraunhofer Research Institution for Marine Biotechnology and Institute for Medical and Marine Biotechnology, University of Lübeck, Lübeck, Germany.

 

ABSTRACT

Mesenchymal stem cells (MSCs) are promising candidates for adult cell therapies in regenerative medicine. To fully exert their potential, efficient homing and migration toward lesion sites play an important role. Local transplantation deposits MSC in spatial proximity to the lesion, but often requires invasive procedures. Systemic administration routes are favored, but require the targeted extravasation of the circulating MSC at the site of injury. Transplanted MSC can indeed leave the blood flow and transmigrate through the endothelial barrier, and reach the lesion site. However, the underlying processes are not completely dissolved yet. Recent in vitro and in vivo research identified some key molecules scattered light on the extravasation mechanism. This review provides a detailed overview over the current knowledge of MSC transendothelial migration. We use the leukocyte extravasation process as a role model to build a comprehensive concept of MSC egress mechanisms from the blood stream and identified relevant similarities as well as important differences between the extravasation mechanisms. Stem Cells 2017;35:1446-1460.

KEYWORDS:

Cell adhesion molecules; Cell migration; Chemokine receptors; Integrins; Leukocytes; Mesenchymal stem cells; Stem/progenitor cel.

Mechanisms of Excessive Extracellular Glutamate Accumulation in Temporal Lobe Epilepsy.

Neurochem Res. 2017 Jun;42(6):1724-1734. doi: 10.1007/s11064-016-2105-8. Epub 2016 Nov 21.

Albrecht J1, Zielińska M2.

Mechanisms of Excessive Extracellular Glutamate Accumulation in Temporal Lobe Epilepsy.

Author information

1 Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

2     Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland.

ABSTRACT:

There is compelling evidence that initiation and maintenance of epileptic seizures in temporal lobe epilepsy (TLE) is facilitated by excessive accumulation in the extracellular (perisynaptic) space of the excitatory neurotransmitter glutamate (Glu). This review discusses the mechanisms underlying this phenomenon. Glu released from neurons is taken up by astrocytes and activated there by glutamine synthetase (GS) to form glutamine (Gln) which upon entry to neurons is degraded back to Glu by phosphate-activated glutaminase (PAG): this chain of reactions has been defined as the glutamine/glutamate/cycle (GGC). In the initial phase of epileptogenesis, increased Glu supply is a consequence of activation of its turnover in GGC by Glu released by a primary chemical or physical stimulus. In chronic TLE, profound astrogliosis and demise of neurons which culminate in hippocampal sclerosis, are associated with changes in GGC which act in concert towards increasing the extracellular Glu concentration. Deficiency of GS and of the astrocytic Glu transporter, GLT-1, impede Glu inactivation, whereas Glu release from neurons appears facilitated by activation of PAG and increased activity of the neuronal Glu transporter EAAC1. Conclusions derived from measurements of activities/expression patterns of the GGC enzymes and transporter moieties find support in metabolic studies employing 13C labeled Glu precursors. Glu reuptake by astrocytes is additionally impeded by unfavorable ion gradients resulting from ion and water dyshomeostasis, and extracellular Glu concentration is further increased by reduction of extracellular space due to edema and altered cytoarchitecture of the hippocampus. Missing links in the scenario are discussed in concluding comments.

KEYWORDS:

Astrocytes; Extracellular glutamate; Glutamine glutamate cycle; Neurons; Temporal lobe epilepsy

MicroRNA Signatures and Molecular Subtypes of Glioblastoma: The Role of Extracellular Transfer.

Stem Cell Reports. 2017 Jun 6;8(6):1497-1505. doi: 10.1016/j.stemcr.2017.04.024. Epub 2017 May 18.
Godlewski J1, Ferrer-Luna R2, Rooj AK3, Mineo M3, Ricklefs F4, Takeda YS3, Nowicki MO3, Salińska E5, Nakano I6, Lee H7, Weissleder R8, Beroukhim R2, Chiocca EA3, Bronisz A9.
MicroRNA Signatures and Molecular Subtypes of Glioblastoma: The Role of Extracellular Transfer.
Author information
1   Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..
2    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Cancer Program, BROAD Institute of MIT and Harvard, Cambridge, MA 02142, USA.
3    Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4    Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
5  Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences 02-106 Warsaw, Poland.
6  Department of Neurosurgery and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35243, USA.
7 Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
8   Department of Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
9    Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

ABSTRACT:
Despite the importance of molecular subtype classification of glioblastoma (GBM), the extent of extracellular vesicle (EV)-driven molecular and phenotypic reprogramming remains poorly understood. To reveal complex subpopulation dynamics within the heterogeneous intratumoral ecosystem, we characterized microRNA expression and secretion in phenotypically diverse subpopulations of patient-derived GBM stem-like cells (GSCs). As EVs and microRNAs convey information that rearranges the molecular landscape in a cell type-specific manner, we argue that intratumoral exchange of microRNA augments the heterogeneity of GSC that is reflected in highly heterogeneous profile of microRNA expression in GBM subtypes.
Published by Elsevier Inc.
KEYWORDS:
GBM; cancer heterogeneity; cancer stem cells; exosomes; extracellular vesicles; glioblastoma; microRNA; subtypes

Fast-Acting Insulin Aspart Improves Glycemic Control in Basal-Bolus Treatment for Type 1 Diabetes: Results of a 26-Week Multicenter, Active-Controlled, Treat-to-Target, Randomized, Parallel-Group Trial (onset 1).

Russell-Jones D1, Bode BW2, De Block C3, Franek E4, Heller SR5, Mathieu C6, Philis-Tsimikas A7, Rose L8, Woo VC9, Østerskov AB10, Graungaard T10, Bergenstal RM11.

Diabetes Care. 2017 Jul;40(7):943-950. doi: 10.2337/dc16-1771. Epub 2017 Mar 29.

Fast-Acting Insulin Aspart Improves Glycemic Control in Basal-Bolus Treatment for Type 1 Diabetes: Results of a 26-Week Multicenter, Active-Controlled, Treat-to-Target, Randomized, Parallel-Group Trial (onset 1).

 1   Diabetes and Endocrinology, Royal Surrey County Hospital, and University of Surrey, Guildford, U.K. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

2 Atlanta Diabetes Associates, Atlanta, GA.

3  Department of Endocrinology, Diabetology, and Metabolism, Antwerp University Hospital, Antwerp, Belgium.

4  Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland.

5    Department of Oncology and Metabolism, University of Sheffield, Sheffield, U.K.

6    Clinical and Experimental Endocrinology, University Hospital Leuven, Catholic University of Leuven, Leuven, Belgium.

7    Scripps Whittier Diabetes Institute, Scripps Health, San Diego, CA.

8    Institute of Diabetes Research, Münster, Germany.

9    Section of Endocrinology and Metabolism, University of Manitoba, Winnipeg, Manitoba, Canada.

10     Novo Nordisk A/S, Søborg, Denmark.

11     International Diabetes Center at Park Nicollet, Minneapolis, MN.

 

ABSTRACT:

OBJECTIVE:

This multicenter, treat-to-target, phase 3 trial evaluated the efficacy and safety of fast-acting insulin aspart (faster aspart) versus conventional insulin aspart (IAsp) in adults with type 1 diabetes.

RESEARCH DESIGN AND METHODS:

The primary end point was change from baseline in HbA1c after 26 weeks. After an 8-week run-in, subjects were randomized (1:1:1) to double-blind mealtime faster aspart (n = 381), IAsp (n = 380), or open-label postmeal faster aspart (n = 382)-each with insulin detemir.

RESULTS:

HbA1c was reduced in both treatment groups, and noninferiority to IAsp was confirmed for both mealtime and postmeal faster aspart (estimated treatment difference [ETD] faster aspart-IAsp, mealtime, -0.15% [95% CI -0.23; -0.07], and postmeal, 0.04% [-0.04; 0.12]); mealtime faster aspart statistically significantly reduced HbA1c versus IAsp (P = 0.0003). Postprandial plasma glucose (PPG) increments were statistically significantly lower with mealtime faster aspart at 1 h (ETD -1.18 mmol/L [95% CI -1.65; -0.71], -21.21 mg/dL [-29.65; -12.77]; P < 0.0001) and 2 h (-0.67 mmol/L [-1.29; -0.04], -12.01 mg/dL [-23.33; -0.70]; P = 0.0375) after the meal test; superiority to IAsp for the 2-h PPG increment was confirmed. The overall rate of severe or blood glucose-confirmed (plasma glucose <3.1 mmol/L [56 mg/dL]) hypoglycemic episodes and safety profiles were similar between treatments.

 

CONCLUSIONS:

Faster aspart effectively improved HbA1c, and noninferiority to IAsp was confirmed, with superior PPG control for mealtime faster aspart versus IAsp. Subjects randomized to postmeal faster aspart for all meals maintained HbA1c noninferior to that obtained with mealtime IAsp.

Cortical Synaptic Transmission and Plasticity in Acute Liver Failure Are Decreased by Presynaptic Events.

Popek M1, Bobula B2, Sowa J2, Hess G2, Polowy R3, Filipkowski RK3, Frontczak-Baniewicz M4, Zabłocka B5, Albrecht J1, Zielińska M6.

Cortical Synaptic Transmission and Plasticity in Acute Liver Failure Are Decreased by Presynaptic Events.

Author information:

1 Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.

2 Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12 St, 31-343, Cracow, Poland.

3 Behavior and Metabolism Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.

4 Electron Microscopy Platform, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.

5 Molecular Biology Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland.

6 Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

 

ABSTRACT:

Neurological symptoms of acute liver failure (ALF) reflect decreased excitatory transmission, but the status of ALF-affected excitatory synapse has not been characterized in detail. We studied the effects of ALF in mouse on synaptic transmission and plasticity ex vivo and its relation to distribution of (i) synaptic vesicles (sv) and (ii) functional synaptic proteins within the synapse. ALF-competent neurological and biochemical changes were induced in mice with azoxymethane (AOM). Electrophysiological characteristics (long-term potentiation, whole-cell recording) as well as synapse ultrastructure were evaluated in the cerebral cortex. Also, sv were quantified in the presynaptic zone by electron microscopy. Finally, presynaptic proteins in the membrane-enriched (P2) and cytosolic (S2) fractions of cortical homogenates were quantitated by Western blot. Slices derived from symptomatic AOM mice presented a set of electrophysiological correlates of impaired transmitter release including decreased field potentials (FPs), increased paired-pulse facilitation (PPF), and decreased frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs/mEPSCs) accompanied by reduction of the spontaneous transmitter release-driving protein, vti1A. Additionally, an increased number of sv per synapse and a decrease of P2 content and/or P2/S2 ratio for sv-associated proteins, i.e. synaptophysin, synaptotagmin, and Munc18-1, were found, in spite of decreased content of the sv-docking protein, syntaxin-1. Slices from AOM-treated asymptomatic mice showed impaired long-term potentiation (LTP) and increased PPF but no changes in transmitter release or presynaptic protein composition. Our findings demonstrate that a decrease of synaptic transmission in symptomatic ALF is associated with inefficient recruitment of sv proteins and/or impaired sv trafficking to transmitter release sites.

KEYWORDS:

Acute liver failure; Neurotransmission; Presynaptic events

Transplanted human glial-restricted progenitors can rescue the survival of dysmyelinated mice independent of the production of mature, compact myelin.

Exp Neurol. 2017 May;291:74-86. doi: 10.1016/j.expneurol.2017.02.005. Epub 2017 Feb 2.

Transplanted human glial-restricted progenitors can rescue the survival of dysmyelinated mice independent of the production of mature, compact myelin.

Lyczek A1, Arnold A1, Zhang J2, Campanelli JT3, Janowski M4, Bulte JW1, Walczak P5.

Author information:

1 Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, United States.

2 Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States.

3 Q Therapeutics, Inc., Salt Lake City, UT 84108, United States.

4 Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, United States; Dept. of Neurosurgery, Mossakowski Med. Res. Center, Polish Acad. of Sci., Warsaw, Poland; Dept. of NeuroRepair, Mossakowski Med. Res. Center, Polish Acad. of Sci., Warsaw, Poland.

5 Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, United States; Dept. of Neurology and Neurosurgery, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland. Electronic address: Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

ABSTRACT:

The therapeutic effect of glial progenitor transplantation in diseases of dysmyelination is currently attributed to the formation of new myelin. Using magnetic resonance imaging (MRI), we show that the therapeutic outcome in dysmyelinated shiverer mice is dependent on the extent of cell migration but not the presence of mature and compact myelin. Human or mouse glial restricted progenitors (GRPs) were transplanted into rag2-/- shiverer mouse neonates and followed for over one year. Mouse GRPs produced mature myelin as detected with multi-parametric MRI, but showed limited migration without extended animal lifespan. In sharp contrast, human GRPs migrated extensively and significantly increased animal survival, but production of mature myelin did not occur until 46weeks post-grafting. We conclude that human GRPs can extend the survival of transplanted shiverer mice prior to production of mature myelin, while mouse GRPs fail to extend animal survival despite the early presence of mature myelin. This paradox suggests that transplanted GRPs provide therapeutic benefits through biological processes other than the formation of mature myelin capable to foster rapid nerve conduction, challenging the current dogma of the primary role of myelination in regaining function of the central nervous system.

KEYWORDS:

Glial progenitors; MRI; Myelin; Shiverer; Transplantation

Ischemia/Reperfusion-Induced Translocation of PKCβII to Mitochondria as an Important Mediator of a Protective Signaling Mechanism in an Ischemia-Resistant Region of the Hippocampus

Krupska O1, Sarnowska A2, Fedorczyk B3, Gewartowska M4, Misicka A3,5, Zablocka B1, Beresewicz M6.

 

Ischemia/Reperfusion-Induced Translocation of PKCβII to Mitochondria as an Important Mediator of a Protective Signaling Mechanism in an Ischemia-Resistant Region of the Hippocampus.

 

1 Molecular Biology Unit, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.

2 Stem Cell Bioengineering Unit, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.

3 Faculty of Chemistry, University of Warsaw, Warsaw, Poland.

4 Electron Microscopy Platform, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.

5 Department of Neuropeptides, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.

6 Molecular Biology Unit, Mossakowski Medical Research Centre, PAS, Warsaw, Poland. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

ABSTRACT:

Emerging reports indicate that activated PKC isoforms that translocate to the mitochondria are pro- or anti-apoptotic to mitochondrial function. Here, we concentrate on the role of PKCβ translocated to mitochondria in relation to the fate of neurons following cerebral ischemia. As we have demonstrated previously ischemia/reperfusion injury (I/R) results in translocation of PKCβ from cytoplasm to mitochondria, but only in ischemia-resistant regions of the hippocampus (CA2-4, DG), we hypothesize that this translocation may be a mediator of a protective signaling mechanism in this region. We have therefore sought to demonstrate a possible relationship between PKCβII translocation and ischemic resistance of CA2-4, DG. Here, we reveal that I/R injury induces a marked elevation of PKCβII protein levels, and consequent enzymatic activity, in CA2-4, DG in the mitochondrial fraction. Moreover, the administration of an isozyme-selective PKCβII inhibitor showed inhibition of I/R-induced translocation of PKCβII to the mitochondria and an increase in neuronal death following I/R injury in CA1 and CA2-4, DG in both an in vivo and an in vitro model of ischemia. The present results suggest that PKCβII translocated to mitochondria is involved in providing ischemic resistance of CA2-4, DG. However, the exact mechanisms by which PKCβII-mediated neuroprotection is achieved are in need of further elucidation.

KEYWORDS:

Cerebral ischemia; Endogenous neuroprotection; Mitochondria; PKCβII; Protein kinase C

Perinatal exposure to lead (Pb) induces ultrastructural and molecular alterations in synapses of rat offspring.

Gąssowska M1, Baranowska-Bosiacka I2, Moczydłowska J3, Frontczak-Baniewicz M4, Gewartowska M4, Strużyńska L5, Gutowska I6, Chlubek D7, Adamczyk A8.

Toxicology. 2016 Dec 12;373:13-29. doi: 10.1016/j.tox.2016.10.014. Epub 2016 Oct 29.

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Real-time MRI for precise and predictable intra-arterial stem cell delivery to the central nervous system.

Walczak P1, Wojtkiewicz J2, Nowakowski A3, Habich A2, Holak P4, Xu J5, Adamiak Z4, Chehade M6, Pearl MS7, Gailloud P7, Lukomska B3, Maksymowicz W8, Bulte JW9, Janowski M10.

J Cereb Blood Flow Metab. 2016 Sep 12. pii: 0271678X16665853. [Epub ahead of print]

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Label-free CEST MRI Detection of Citicoline-Liposome Drug Delivery in Ischemic Stroke.

Liu H1, Jablonska A2, Li Y3, Cao S4, Liu D5, Chen H5, Van Zijl PC3, Bulte JW3, Janowski M6, Walczak P2, Liu G3.

 Theranostics. 2016 Jun 18;6(10):1588-600. doi: 10.7150/thno.15492. eCollection 2016.

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Altered arginine metabolism in cells transfected with human wild-type beta amyloid precursor protein (βAPP).

Jęśko H, Wilkaniec A, Cieślik M, Hilgier W, Gąssowska M, Lukiw WJ, Adamczyk A

Altered arginine metabolism in cells transfected with human wild-type beta amyloid precursor protein (βAPP).

Department of Cellular Signalling, Department of Neurotoxicology, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

Curr Alzheimer Res. 2016 Mar 14. [Epub ahead of print]

 

Abstract

 

Alterations of enzymes linked to arginine metabolism have been recently implicated in Alzheimer's disease (AD). Despite strong association of arginine changes with nitric oxide (NO) pathway, the impact of amyloid β (Aβ) peptides on arginine degradation and re-synthesis is unknown. In the present study we compared expression levels of arginases (ARG1, ARG2), neuronal, endothelial and inducible NO synthase isoforms (NNOS, ENOS, INOS), enzymes that metabolize arginine or resynthesize it from citrulline and the levels of corresponding amino acids in rat pheochromocytoma (PC12) cells overexpressing human Aβ precursor protein (APPwt cells). Moreover, we investigated the changes in miRNAs responsible for modulation of arginine metabolism in AD brains. Real-time PCR analysis revealed in APPwt cells significant decreases of ARG1 and ARG2 which are responsible for lysing arginine into ornithine and urea; this reduction was followed by significantly lower enzyme activity. NNOS and ENOS mRNAs were elevated in APPwt cells while iNOS was undetectable in both cell lines. The expression of argininosuccinate synthase (ASS) that metabolizes citrulline was down-regulated without changes in argininosuccinate lyase (ASL). Ornithine decarboxylase (ODC), which decarboxylates ornithine to form putrescine was also reduced. Arginine, the substrate for both arginases and NOS, was unchanged in APPwt cells. However, citrulline concentration was significantly higher. Elevated miRNA-9 and miRNA-128a found in AD brain tissues might modulate the expression of ASS and NOS, respectively. Our results indicate that Aβ affects arginine metabolism and this influence might have important role in the pathomechanism of AD.

 

PMID:26971935 [PubMed - as supplied by publisher]

 

Perinatal exposure to lead (Pb) promotes Tau phosphorylation in the rat brain in a GSK-3β and CDK5 dependent manner: Relevance to neurological disorders.

Gąssowska Ma, Baranowska-Bosiacka Ib, Moczydłowska Ja, Tarnowski Mc, Pilutin Ad, Gutowska Ie, Strużyńska Lf, Chlubek Db, Adamczyk Aa

Perinatal exposure to lead (Pb) promotes Tau phosphorylation in the rat brain in a GSK-3β and CDK5 dependent manner: Relevance to neurological disorders.

a Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw

b Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin

c Department of Physiology, Pomeranian Medical University, Szczecin

d Department of Histology and Embryology, Pomeranian Medical University, Szczecin

e Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Szczecin

f Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw

 

Toxicology. 2016 Mar 10;347-349:17-28. doi: 10.1016/j.tox.2016.03.002. Epub 2016 Mar 21.

 

Abstract

 

Hyperphosphorylation of Tau is involved in the pathomechanism of neurological disorders such as Alzheimer's, Parkinson's diseases as well as Autism. Epidemiological data suggest the significance of early life exposure to lead (Pb) in etiology of disorders affecting brain function. However, the precise mechanisms by which Pb exerts neurotoxic effects are not fully elucidated. The purpose of this study was to evaluate the effect of perinatal exposure to low dose of Pb on the Tau pathology in the developing rat brain. Furthermore, the involvement of two major Tau-kinases: glycogen synthase kinase-3 beta (GSK-3β) and cyclin-dependent kinase 5 (CDK5) in Pb-induced Tau modification was evaluated. Pregnant female rats were divided into control and Pb-treated group. The control animals were maintained on drinking water while females from the Pb-treated group received 0.1% lead acetate (PbAc) in drinking water, starting from the first day of gestation until weaning of the offspring. During the feeding of pups, mothers from the Pb-treated group were still receiving PbAc. Pups of both groups were weaned at postnatal day 21 and then until postnatal day 28 received only drinking water. 28-day old pups were sacrificed and Tau mRNA and protein level as well as Tau phosphorylation were analyzed in forebrain cortex (FC), cerebellum (C) and hippocampus (H). Concomitantly, we examined the effect of Pb exposure on GSK-3β and CDK5 activation. Our data revealed that pre- and neonatal exposure to Pb (concentration of Pb in whole blood below 10μg/dL, considered safe for humans) caused significant increase in the phosphorylation of Tau at Ser396 and Ser199/202 with parallel rise in the level of total Tau protein in FC and C. Tau hyperphosphorylation in Pb-treated animals was accompanied by elevated activity of GSK-3β and CDK5. Western blot analysis revealed activation of GSK-3β in FC and C as well as CDK5 in C, via increased phosphorylation of Tyr-216 and calpain-dependent p25 formation, respectively. In conclusion, perinatal exposure to Pb up-regulates Tau protein level and induces Tau hyperphosphorylation in the rat brain cortex and cerebellum. We suggest that neurotoxic effect of Pb might be mediated, at least in part, by GSK-3β and CDK5-dependent Tau hyperphosphorylation, which may lead to the impairment of cytoskeleton stability and neuronal dysfunction.

 

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

 

KEYWORDS: CDK5; GSK-3β; Hyperphosphorylation; Lead neurotoxicity; Rat brain; Tau protein

 

The mechanisms regulating cyclin-dependent kinase 5 in hippocampus during systemic inflammatory response: The effect on inflammatory gene expression.

Czapski GA1, Gąssowska M2, Wilkaniec A2, Chalimoniuk M2, Strosznajder JB2, Adamczyk A2.

The mechanisms regulating cyclin-dependent kinase 5 in hippocampus during systemic inflammatory response: The effect on inflammatory gene expression.

1Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, ul. Pawińskiego 5, 02-106 Warsaw, Poland. Electronic address: Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..

2Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, ul. Pawińskiego 5, 02-106 Warsaw, Poland.

Neurochem Int. 2016 Feb;93:103-12. doi: 10.1016/j.neuint.2016.01.005. Epub 2016 Jan 21.

Abstract

Cyclin-dependent kinase 5 (Cdk5) is critical for nervous system's development and function, and its aberrant activation contributes to pathomechanism of Alzheimer's disease and other neurodegenerative disorders. It was recently suggested that Cdk5 may participate in regulation of inflammatory signalling. The aim of this study was to analyse the mechanisms involved in regulating Cdk5 activity in the brain during systemic inflammatory response (SIR) as well as the involvement of Cdk5 in controlling the expression of inflammatory genes. Genetic and biochemical alterations in hippocampus were analysed 3 and 12 h after intraperitoneal injection of lipopolysaccharide. We observed an increase in both Cdk5 gene expression and protein level. Moreover, phosphorylation of Cdk5 on Ser159 was significantly enhanced. Also transcription of Cdk5-regulatory protein (p35/Cdk5r1) was augmented, and the level of p25, calpain-dependent cleavage product of p35, was increased. All these results demonstrated rapid activation of Cdk5 in the brain during SIR. Hyperactivity of Cdk5 contributed to enhanced phosphorylation of tau and glycogen synthase kinase 3β. Inhibition of Cdk5 with Roscovitine reduced activation of NF-κB and expression of inflammation-related genes, demonstrating the critical role of Cdk5 in regulation of gene transcription during SIR.

Copyright © 2016 Elsevier Ltd. All rights reserved.

KEYWORDS: Cyclin-dependent kinase 5; Hippocampus; Lipopolysaccharide; Neuroinflammation; Systemic inflammation

 

Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease

Pająk B1,2, Kania E1, Orzechowski A1,2  

Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer's Disease

Oxid Med Cell Longev. 2016;2016:1805304. doi: 10.1155/2016/1805304. Epub 2016 Jan 6.

1Electron Microscopy Platform, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland;

2Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences (SGGW), Nowoursynowska 159, 02-776 Warsaw, Poland.

 

Abstract

This review is focused on the possible causes of mitochondrial dysfunction in AD, underlying molecular mechanisms of this malfunction, possible causes and known consequences of APP, Aβ, and hyperphosphorylated tau presence in mitochondria, and the contribution of altered lipid metabolism (nonsterol isoprenoids) to pathological processes leading to increased formation and accumulation of the aforementioned hallmarks of AD. Abnormal protein folding and unfolded protein response seem to be the outcomes of impaired glycosylation due to metabolic disturbances in geranylgeraniol intermediary metabolism. The origin and consecutive fate of APP, Aβ, and tau are emphasized on intracellular trafficking apparently influenced by inaccurate posttranslational modifications. We hypothesize that incorrect intracellular processing of APP determines protein translocation to mitochondria in AD. Similarly, without obvious reasons, the passage of Aβ and tau to mitochondria is observed. APP targeted to mitochondria blocks the activity of protein translocase complex resulting in poor import of proteins central to oxidative phosphorylation. Besides, APP, Aβ, and neurofibrillary tangles of tau directly or indirectly impair mitochondrial biochemistry and bioenergetics, with concomitant generation of oxidative/nitrosative stress. Limited protective mechanisms are inadequate to prevent the free radical-mediated lesions. Finally, neuronal loss is observed in AD-affected brains typically by pathologic apoptosis.

 

PMID: 26881014 [PubMed - in process]  PMCID: PMC4736771

Downregulation of GLS2 in glioblastoma cells is related to DNA hypermethylation but not to the p53 status.

Szeliga M, Bogacińska-Karaś M, Kuźmicz K, Rola R, Albrecht J.

Downregulation of GLS2 in glioblastoma cells is related to DNA hypermethylation but not to the p53 status.

Mol Carcinog. 2015 Aug 10. doi: 10.1002/mc.22372.

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