scholarly journals Modulation of CRMP2 via (S)-Lacosamide shows therapeutic promise but is ultimately ineffective in a mouse model of CLN6-Batten disease

2019 ◽  
Vol 3 (2) ◽  
Author(s):  
Katherine A. White ◽  
Jacob T. Cain ◽  
Helen Magee ◽  
Seul Ki Yeon ◽  
Ki Duk Park ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neurodegenerative Disorder ◽  
Batten Disease ◽  
Glial Activation ◽  
Neuronal Cultures ◽  
Term Survival ◽  
Collapsin Response Mediator Protein ◽  
Mediator Protein

Abstract CLN6-Batten disease is a rare neurodegenerative disorder with no cure, characterized by accumulation of lipofuscin in the lysosome, glial activation, and neuronal death. Here we test the therapeutic efficacy of modulating collapsin response mediator protein 2 (CRMP2) activity via S-N-benzy-2-acetamido-3-methoxypropionamide ((S)-Lacosamide) in a mouse model of CLN6-Batten disease. Promisingly, mouse neuronal cultures as well as Cln6 patient fibroblasts treated with varying concentrations of (S)-Lacosamide showed positive restoration of lysosomal associated deficits. However, while acute in vivo treatment enhanced glial activation in 3-month-old Cln6 mutant mice, chronic treatment over several months did not improve behavioral or long-term survival outcomes. Therefore, modulation of CRMP2 activity via (S)-Lacosamide alone is unlikely to be a viable therapeutic target for CLN6-Batten disease.

scholarly journals Partial Decellularization for Segmental Tracheal Scaffold Tissue Engineering: A Preliminary Study in Rabbits

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 866
Author(s):  
Luong Huu Dang ◽  
Yuan Tseng ◽  
How Tseng ◽  
Shih-Han Hung
Keyword(s):  
Mechanical Stability ◽  
Vital Staining ◽  
Potential Method ◽  
Term Survival ◽  
Long Term Survival ◽  
Cartilage Cells ◽  
Preliminary Study ◽  
Epithelial Layers

In this study, we developed a new procedure for the rapid partial decellularization of the harvested trachea. Partial decellularization was performed using a combination of detergent and sonication to completely remove the epithelial layers outside of the cartilage ring. The post-decellularized tracheal segments were assessed with vital staining, which showed that the core cartilage cells remarkably remained intact while the cells outside of the cartilage were no longer viable. The ability of the decellularized tracheal segments to evade immune rejection was evaluated through heterotopic implantation of the segments into the chest muscle of rabbits without any immunosuppressive therapy, which demonstrated no evidence of severe rejection or tissue necrosis under H&E staining, as well as the mechanical stability under stress-pressure testing. Finally, orthotopic transplantation of partially decellularized trachea with no immunosuppression treatment resulted in 2 months of survival in two rabbits and one long-term survival (2 years) in one rabbit. Through evaluations of posttransplantation histology and endoscopy, we confirmed that our partial decellularization method could be a potential method of producing low-immunogenic cartilage scaffolds with viable, functional core cartilage cells that can achieve long-term survival after in vivo transplantation.

BONE STRUCTURE AND STRENGTH ADAPT TO LONG-TERM CYCLIC OVERLOADING IN AN IN VIVO MOUSE MODEL

2012 ◽  
Vol 45 ◽  
pp. S89 ◽  
Author(s):  
Floor M. Lambers ◽  
Kathleen Koch ◽  
Gisela Kuhn ◽  
Claudia Weigt ◽  
Friederike A. Schulte ◽  
...  
Keyword(s):  
Mouse Model ◽  
Bone Structure

FTY720 Application Following Isolated Warm Liver Ischemia Improves Long-Term Survival and Organ Protection in a Mouse Model

2007 ◽  
Vol 39 (2) ◽  
pp. 493-498 ◽  
Author(s):  
C.P. Kaudel ◽  
M. Frink ◽  
M. van Griensven ◽  
U. Schmiddem ◽  
C. Probst ◽  
...  
Keyword(s):  
Mouse Model ◽  
Liver Ischemia ◽  
Organ Protection ◽  
Term Survival ◽  
Long Term Survival ◽  
Warm Liver Ischemia

scholarly journals Constitutive expression of bcl-2 in B cells causes a lethal form of lupuslike autoimmune disease after induction of neonatal tolerance to H-2b alloantigens.

1996 ◽  
Vol 183 (6) ◽  
pp. 2523-2531 ◽  
Author(s):  
M López-Hoyos ◽  
R Carrió ◽  
R Merino ◽  
L Buelta ◽  
S Izui ◽  
...  
Keyword(s):  
B Cells ◽  
Autoimmune Disease ◽  
Constitutive Expression ◽  
Systemic Autoimmune Disease ◽  
Spleen Cells ◽  
Term Survival ◽  
F1 Hybrid ◽  
Wide Range

The bcl-2 protooncogene has been shown to provide a survival signal to self-reactive B cells, but it fails to override their developmental arrest after encounter with antigen. Furthermore, constitutive expression of bcl-2 in B cells does not promote the development of autoimmune disease in most strains of mice, indicating that signals other than those conferred by bcl-2 are required for long-term survival and differentiation of self-reactive B cells in vivo. To further examine the factors that are required for the pathogenesis of autoimmune disease, we have assessed the effect of bcl-2 overexpression on the development of host-versus-graft disease, a self-limited model of systemic autoimmune disease. In this model, injection of spleen cells from (C57BL/6 x BALB/c)F1 hybrid mice into BALB/c newborn parental mice induces immunological tolerance to donor tissues and activation of autoreactive F1 donor B cells through interactions provided by allogeneic host CD4+ T cells. BALB/c newborns injected with spleen cells from (C57BL/6 x BALB/c)F1 mice expressing a bcl-2 transgene in B cells developed high levels of anti-single-stranded DNA and a wide range of pathogenic autoantibodies that were not or barely detectable in mice injected with nontransgenic spleen cells. In mice injected with transgenic B cells, the levels of pathogenic autoantibodies remained high during the course of the study and were associated with long-term persistence of donor B cells, development of a severe autoimmune disease, and accelerated mortality. These results demonstrate that bcl-2 can provide survival signals for the maintenance and differentiation of autoreactive B cells, and suggest that both increased B cell survival and T cell help play critical roles in the development of certain forms of systemic autoimmune disease.

scholarly journals Loading Imatinib inside targeted nanoparticles to prevent Bronchiolitis Obliterans Syndrome

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Laura Pandolfi ◽  
Roberta Fusco ◽  
Vanessa Frangipane ◽  
Ramona D’Amico ◽  
Marco Giustra ◽  
...  
Keyword(s):  
Mouse Model ◽  
Bronchiolitis Obliterans ◽  
Neutrophil Infiltration ◽  
Bronchiolitis Obliterans Syndrome ◽  
Lung Fibroblasts ◽  
Surrounding Tissue ◽  
Term Survival ◽  
Targeted Nanoparticles ◽  
Tracheal Transplantation

AbstractBronchiolitis Obliterans Syndrome seriously reduces long-term survival of lung transplanted patients. Up to now there is no effective therapy once BOS is established. Nanomedicine introduces the possibility to administer drugs locally into lungs increasing drug accumulation in alveola reducing side effects. Imatinib was loaded in gold nanoparticles (GNP) functionalized with antibody against CD44 (GNP-HCIm). Lung fibroblasts (LFs) were derived from bronchoalveolar lavage of BOS patients. GNP-HCIm cytotoxicity was evaluated by MTT assay, apoptosis/necrosis and phosphorylated-cAbl (cAbl-p). Heterotopic tracheal transplantation (HTT) mouse model was used to evaluate the effect of local GNP-HCIm administration by Alzet pump. GNP-HCIm decreased LFs viability compared to Imatinib (44.4 ± 1.8% vs. 91.8 ± 3.2%, p < 0.001), inducing higher apoptosis (22.68 ± 4.3% vs. 6.43 ± 0.29; p < 0.001) and necrosis (18.65 ± 5.19%; p < 0.01). GNP-HCIm reduced cAbl-p (0.41 GNP-HCIm, 0.24 Imatinib vs. to control; p < 0.001). GNP-HCIm in HTT mouse model by Alzet pump significantly reduced tracheal lumen obliteration (p < 0.05), decreasing apoptosis (p < 0.05) and TGF-β-positive signal (p < 0.05) in surrounding tissue. GNP-HCIm treatment significantly reduced lymphocytic and neutrophil infiltration and mast cells degranulation (p < 0.05). Encapsulation of Imatinib into targeted nanoparticles could be considered a new option to inhibit the onset of allograft rejection acting on BOS specific features.

scholarly journals Development and long-term evaluation of a new 68Ge/68Ga generator based on nano-SnO2 for PET imaging

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Eduardo Romero ◽  
Alfonso Martínez ◽  
Marta Oteo ◽  
Marta Ibañez ◽  
Mirentxu Santos ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mouse Model ◽  
Pet Imaging ◽  
Research Reactor ◽  
On Demand ◽  
Term Evaluation ◽  
Investigation Period ◽  
Direct Use

AbstractRadionuclide generator systems can routinely provide radionuclides on demand such as 68Ga produced by a 68Ge/68Ga generator without the availability of an on-site accelerator or a research reactor. Thus, in this work nano-SnO2 was used to develop a new 68Ge/68Ga generator which was evaluated over a period of 17 months and 305 elution cycles. The elution yield was 91.1 ± 1.8% in the first 7 mL (1 M HCl as eluent) when the generator was new and then it decreased with time and use to 73.8 ± 1.9%. Around 80% of the elutable 68Ga activity was obtained in 1 mL and the 68Ge content in the eluate did not exceed 1 × 10–4% over the investigation period when it was eluted regularly. The described generator provided adequate results for radiolabelling of DOTA-TOC with direct use of eluate. In addition, [68Ga]Ga-DOTA-TOC was tested satisfactorily for in vivo tumor detection by microPET/CT imaging in a lung cancer mouse model.

scholarly journals Repeated social defeat induces transient glial activation and brain hypometabolism: A positron emission tomography imaging study

2017 ◽  
Vol 39 (3) ◽  
pp. 439-453 ◽  
Author(s):  
Paula Kopschina Feltes ◽  
Erik FJ de Vries ◽  
Luis E Juarez-Orozco ◽  
Ewelina Kurtys ◽  
Rudi AJO Dierckx ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Positron Emission Tomography Imaging ◽  
Imaging Study ◽  
Social Defeat ◽  
Glial Activation ◽  
Emission Tomography ◽  
Biochemical Alterations ◽  
Positron Emission

Psychosocial stress is a risk factor for the development of depression. Recent evidence suggests that glial activation could contribute to the development of depressive-like behaviour. This study aimed to evaluate in vivo whether repeated social defeat (RSD) induces short- and long-term inflammatory and metabolic alterations in the brain through positron emission tomography (PET). Male Wistar rats ( n = 40) were exposed to RSD by dominant Long-Evans rats on five consecutive days. Behavioural and biochemical alterations were assessed at baseline, day 5/6 and day 24/25 after the RSD protocol. Glial activation (11C-PK11195 PET) and changes in brain metabolism (18F-FDG PET) were evaluated on day 6, 11 and 25 (short-term), and at 3 and 6 months (long-term). Defeated rats showed transient depressive- and anxiety-like behaviour, increased corticosterone and brain IL-1β levels, as well as glial activation and brain hypometabolism in the first month after RSD. During the third- and six-month follow-up, no between-group differences in any investigated parameter were found. Therefore, non-invasive PET imaging demonstrated that RSD induces transient glial activation and reduces brain glucose metabolism in rats. These imaging findings were associated with stress-induced behavioural changes and support the hypothesis that neuroinflammation could be a contributing factor in the development of depression.

scholarly journals The longevity-associated variant of BPIFB4 improves a CXCR4-mediated striatum–microglia crosstalk preventing disease progression in a mouse model of Huntington’s disease

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Alba Di Pardo ◽  
Elena Ciaglia ◽  
Monica Cattaneo ◽  
Anna Maciag ◽  
Francesco Montella ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Motor Dysfunction ◽  
Cag Repeats ◽  
Huntingtin Protein ◽  
Human Microglia

Abstract The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) has been found significantly enriched in long-living individuals. Neuroinflammation is a key player in Huntington’s disease (HD), a neurodegenerative disorder caused by neural death due to expanded CAG repeats encoding a long polyglutamine tract in the huntingtin protein (Htt). Herein, we showed that striatal-derived cell lines with expanded Htt (STHdh Q111/111) expressed and secreted lower levels of BPIFB4, when compared with Htt expressing cells (STHdh Q7/7), which correlated with a defective stress response to proteasome inhibition. Overexpression of LAV-BPIFB4 in STHdh Q111/111 cells was able to rescue both the BPIFB4 secretory profile and the proliferative/survival response. According to a well-established immunomodulatory role of LAV-BPIFB4, conditioned media from LAV-BPIFB4-overexpressing STHdh Q111/111 cells were able to educate Immortalized Human Microglia—SV40 microglial cells. While STHdh Q111/111 dying cells were ineffective to induce a CD163 + IL-10high pro-resolving microglia compared to normal STHdh Q7/7, LAV-BPIFB4 transduction promptly restored the central immune control through a mechanism involving the stromal cell-derived factor-1. In line with the in vitro results, adeno-associated viral-mediated administration of LAV-BPIFB4 exerted a CXCR4-dependent neuroprotective action in vivo in the R6/2 HD mouse model by preventing important hallmarks of the disease including motor dysfunction, body weight loss, and mutant huntingtin protein aggregation. In this view, LAV-BPIFB4, due to its pleiotropic ability in both immune compartment and cellular homeostasis, may represent a candidate for developing new treatment for HD.

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