scholarly journals BCL-B (BCL2L10) is overexpressed in patients suffering from multiple myeloma (MM) and drives an MM-like disease in transgenic mice

2016 ◽  
Vol 213 (9) ◽  
pp. 1705-1722 ◽  
Author(s):  
Mohamed-Amine Hamouda ◽  
Arnaud Jacquel ◽  
Guillaume Robert ◽  
Alexandre Puissant ◽  
Valentine Richez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Transgenic Mice ◽  
Renal Tubules ◽  
Wild Type ◽  
Malignant Plasma Cell ◽  
Lytic Lesions ◽  
Premalignant Condition ◽  
B Mice ◽  
Characteristic Features

Multiple myeloma (MM) evolves from a premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS). However, the factors underlying the malignant transformation of plasmocytes in MM are not fully characterized. We report here that Eµ-directed expression of the antiapoptotic Bcl-B protein in mice drives an MM phenotype that reproduces accurately the human disease. Indeed, with age, Eµ-bcl-b transgenic mice develop the characteristic features of human MM, including bone malignant plasma cell infiltration, a monoclonal immunoglobulin peak, immunoglobulin deposit in renal tubules, and highly characteristic bone lytic lesions. In addition, the tumors are serially transplantable in irradiated wild-type mice, underlying the tumoral origin of the disease. Eµ-bcl-b plasmocytes show increased expression of a panel of genes known to be dysregulated in human MM pathogenesis. Treatment of Eµ-bcl-b mice with drugs currently used to treat patients such as melphalan and VELCADE efficiently kills malignant plasmocytes in vivo. Finally, we find that Bcl-B is overexpressed in plasmocytes from MM patients but neither in MGUS patients nor in healthy individuals, suggesting that Bcl-B may drive MM. These findings suggest that Bcl-B could be an important factor in MM disease and pinpoint Eµ-bcl-b mice as a pertinent model to validate new therapies in MM.

A Transgenic Model Of Multiple Myeloma Bone Disease Shows Profound Mesenchymal Stem Cell Impairment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 130-130 ◽  
Author(s):  
Monica Gomez-Palou ◽  
Huang Fang ◽  
Richard Kremer ◽  
Michael Sebag
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Mesenchymal Stem Cells ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Bone Disease ◽  
Ex Vivo ◽  
Wild Type ◽  
Lytic Lesions ◽  
Msc Differentiation

Abstract Bone disease affects 70% of Multiple Myeloma (MM) patients during the course of their illness. While new treatments for the MM itself have prolonged their survival, patients are living longer with their bone disease. Bisphophonates have been shown to reduce skeletal related events in MM, but they neither eliminate these events nor reverse skeletal damage. The transgenic mouse model of MM (vk*myc) is the only mouse model that has been shown to faithfully recapitulate the clinical disease, including its bony abnormalities. The original publication of the model showed principally a decrease in bone mineral density of affected animals but scant lytic lesions. We have cross bred this model with a substrain of C56/BL6 mice, KaLwRiJ, that is the basis of a competing model of MM and its bone disease the 5T33 model. This new transgenic substrain shows significant number bony lesions on x-ray and microCT analyses. Immunohistochemistry of the femurs and spines of these animals show an increased number of osteoclast and a decreased number of osteoblasts as compared to non-transgenic wild type mice of the same substrain. Dynamic labeling of bone shows a decreased mineral apposition rate (1.21mm/day ±0.03 vs 2.05mm/day ±0.04) in mice with MM vs wild type mice. In addition to the demineralization associated with MM bone disease and unique to this model, we show a dramatic decrease in the formation of osteoblasts from cultured mesenchymal stem cells (MSCs). These are grown ex-vivo from affected transgenic mice and induced to differentiate into osteoblasts in culture. We demonstrate a close to 90% reduction in observed and quantified mineralized colonies indicating a dramatic impairment in MSC differentiation in these mice, similar to what is seen in human MM. Gene expression profiling analyses using mRNA from ex-vivo mesenchymal stem cells derived from transgenic and wild type mice reveal a number of pathways and genes that can potentially play a role in the inhibition of MSC differentiation in this model. These include the wnt signaling pathway as well as genes involved in histone acetyltransferase activity. The latter suggests that MSCs are ‘permanently’ affected by the presence of MM cells in vivo and that this inhibition does not improve even when they are separated from MM cells for a prolonged period of time. Bortezomib has been shown in MM patients to improve the appearance of MM lytic lesions radiographically as well as to improve serum markers of osteoblastic activity. This improvement is thought to be due to a reversal of MSC differentiation impairment. Wild type and transgenic mice with MM and bone disease were treated with bortezomib (0.5mg/Kg twice per week) for two weeks. CT analyses of mice pre and post bortezomib treatment showed a 28% improvement in the treated transgenic mice. We also show a concomitant improvement in the ex-vivo ability of MSCs to differentiate into osteoblasts. In summary, we present a unique animal model to study MM bone disease that shows profound MSC impairment. This model responds to a treatment strategy that has been shown to work in the human disease and opens itself to further study and use for future developments targeting MM bone disease. Disclosures: No relevant conflicts of interest to declare.

Interactions of insulin-like growth factor (IGF)-II and growth hormone in vivo: circulating levels of IGF-I and IGF-binding proteins in transgenic mice

1997 ◽  
pp. 701-708 ◽  
Author(s):  
A Blackburn ◽  
RA Dressendorfer ◽  
WF Blum ◽  
M Erhard ◽  
G Brem ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Transgene Expression ◽  
High Protein Diet ◽  
High Protein ◽  
Protein Diet ◽  
Standard Diet ◽  
Igf I ◽  
Igf Binding ◽  
B Mice

To study interactions between insulin-like growth factor-II (IGF-II) and growth hormone (GH) in vivo, we crossed hemizygous transgenic mice carrying phosphoenolpyruvate carboxykinase (PEPCK)-IGF-II fusion genes with hemizygous PEPCK-bovine GH (bGH) transgenic mice. Offspring harbouring both transgenes (IB), the IGF-II transgene (I) or the bGH transgene (B), and non-transgenic littermates (C) were obtained. Blood samples were taken before (end of week 12) and after (end of week 14) the mice had received a diet high in protein and low in carbohydrates to stimulate PEPCK promoter-controlled transgene expression. Mean serum GH concentrations of both B and IB mice corresponded to 900 ng/ml and increased more than twofold (P < 0.001) after 1 week of the high-protein diet. GH concentrations in controls and I mice were less than 20 ng/ml. Serum IGF-II concentrations in I and IB mice were three-to fourfold higher than those in C and B mice. Whereas IGF-II concentrations were not changed by the high-protein diet in the last two groups, serum IGF-II increased significantly in I (P < 0.001) and IB mice (P < 0.05). This increase was significantly (P < 0.05) less pronounced in IB than in C and I mice. Circulating IGF-I concentrations were about twofold (P < 0.001) higher in B and IB than in C and I mice, and showed a tendency to be lower in I than in C and in IB than in B mice when animals were maintained on the standard diet. The high-protein diet did not change circulating IGF-I concentrations in controls and B mice, but resulted in a significant reduction of serum IGF-I concentrations in I (P < 0.05) and IB mice (P < 0.001). Consequently, after PEPCK-IGF-II transgene expression was stimulated, serum IGF-I concentrations were significantly (P < 0.05) lower in I than in C and in IB than in B mice. Serum IGF-binding protein (IGFBP)-2 concentrations were significantly (P < 0.05) higher in I mice than in all other groups when mice were maintained on the standard diet, with a tendency to reduced IGFBP-2 concentrations in B mice. After the high-protein diet, serum IGFBP-2 concentrations did not change in C and I mice, but increased by two- to threefold in B and IB mice (P < 0.001). Serum IGFBP-3 concentrations tended to be greater in B and IB than in C and I mice, but these differences were mostly not significant. IGFBP-4 concentrations were significantly (P < 0.001) increased by GH overproduction in B and IB mice. Our data suggest that the reduction in circulating IGF-I concentrations by increased IGF-II is most probably due to the limited serum IGF binding capacity and the short half-life of free IGFs, rather than to a reduction in GH-dependent IGF-I production. Effects of GH overproduction on serum IGFBP-2 concentrations depend on dietary factors and may be both inhibitory and stimulatory.

CHIR258, a Novel Multi-Targeted Tyrosine Kinase Inhibitor, for the Treatment of t(4;14) Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 641-641 ◽  
Author(s):  
Suzanne Trudel ◽  
Zhi Hua Li ◽  
Ellen Wei ◽  
Marion Wiesmann ◽  
Katherine Rendahl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mouse Model ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Small Molecule ◽  
Kinase Inhibitor ◽  
Wild Type ◽  
Myeloma Cells

Abstract The t(4;14) translocation that occurs uniquely in a subset (15%) of multiple myeloma (MM) patients results in the ectopic expression of the receptor tyrosine kinase, Fibroblast Growth Factor Receptor3 (FGFR3). Wild-type FGFR3 induces proliferative signals in myeloma cells and appears to be weakly transforming in a hematopoeitic mouse model. The subsequent acquisition of FGFR3 activating mutations in some MM is associated with disease progression and is strongly transforming in several experimental models. The clinical impact of t(4;14) translocations has been demonstrated in several retrospective studies each reporting a marked reduction in overall survival. We have previously shown that inhibition of activated FGFR3 causes morphologic differentiation followed by apoptosis of FGFR3 expressing MM cell lines, validating activated FGFR3 as a therapeutic target in t(4;14) MM and encouraging the clinical development of FGFR3 inhibitors for the treatment of these poor-prognosis patients. CHIR258 is a small molecule kinase inhibitor that targets Class III–V RTKs and inhibits FGFR3 with an IC50 of 5 nM in an in vitro kinase assay. Potent anti-tumor and anti-angiogenic activity has been demonstrated in vitro and in vivo. We employed the IL-6 dependent cell line, B9 that has been engineered to express wild-type FGFR3 or active mutants of FGFR3 (Y373C, K650E, G384D and 807C), to screen CHIR258 for activity against FGFR3. CHIR258 differentially inhibited FGF-mediated growth of B9 expressing wild-type and mutant receptors found in MM, with an IC50 of 25 nM and 80 nM respectively as determined by MTT proliferation assay. Growth of these cells could be rescued by IL-6 demonstrating selectivity of CHIR258 for FGFR3. We then confirmed the activity of CHIR258 against FGFR3 expressing myeloma cells. CHIR258 inhibited the viability of FGFR3 expressing KMS11 (Y373C), KMS18 (G384D) and OPM-2 (K650E) cell lines with an IC50 of 100 nM, 250 nM and 80 nM, respectively. Importantly, inhibition with CHIR258 was still observed in the presence of IL-6, a potent growth factors for MM cells. U266 cells, which lack FGFR3 expression, displayed minimal growth inhibition demonstrating that at effective concentrations, CHIR258 exhibits minimal nonspecific cytotoxicity on MM cells. Further characterization of this finding demonstrated that inhibition of cell growth corresponded to G0/G1 cell cycle arrest and dose-dependent inhibition of downstream ERK phosphorylation. In responsive cell lines, CHIR258 induced apoptosis via caspase 3. In vitro combination analysis of CHIR258 and dexamethasone applied simultaneously to KMS11 cells indicated a synergistic interaction. In vivo studies demonstrated that CHIR258 induced tumor regression and inhibited growth of FGFR3 tumors in a plasmacytoma xenograft mouse model. Finally, CHIR258 produced cytotoxic responses in 4/5 primary myeloma samples derived from patients harboring a t(4;14) translocation. These data indicate that the small molecule inhibitor, CHIR258 potently inhibits FGFR3 and has activity against human MM cells setting the stage for a Phase I clinical trial of this compound in t(4;14) myeloma.

Hyperactivable NFAT1 Ameliorates Autoimmune Encephalitis In Vivo.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 711-711
Author(s):  
Srimoyee Ghosh ◽  
Sergei B Koralov ◽  
Irena Stevanovic ◽  
Mark S Sundrud ◽  
Yoshiteru Sasaki ◽  
...  
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Autoimmune Encephalitis ◽  
Cell Types ◽  
Wild Type ◽  
Ifn Γ

Abstract Abstract 711 Naïve CD4 T cells differentiate into diverse effector and regulatory subsets to coordinate the adaptive immune response. TH1 and TH2 effector subsets produce IFN-γ and IL-4, respectively, whereas proinflammatory TH17 cells are key regulators of autoimmune inflammation, characteristically produce IL-17 and IL-22 and differentiate in the presence of inflammatory cytokines like IL-6 and IL-21 together with TGF-β. Naive T cells can also differentiate into tissue-protective induced T regulatory (iTreg) cells. NFAT proteins are highly phosphorylated and reside in the cytoplasm of resting cells. Upon dephosphorylation by the Ca2+/calmodulin-dependent serine phosphatase calcineurin, NFAT proteins translocate to the nucleus, where they orchestrate developmental and activation programs in diverse cell types. In this study, we investigated the role of the Ca/NFAT signaling pathway in regulating T cell differentiation and the development of autoimmune diseases. We generated transgenic mice conditionally expressing a hyperactivable version of NFAT1 (AV-NFAT1) from the ROSA26 locus. To restrict AV-NFAT1 expression to the T cell compartment, ROSA26-AV-NFAT1 transgenic mice were bred to CD4-Cre transgenic mice. Naïve CD4 T cells freshly isolated from AV mice produced significantly less IL-2 but increased amounts of the inhibitory cytokine IL-10. To investigate the role of NFAT1 in the generation of TH1, TH2, Tregand TH17 cells, the respective cell types were generated from CD4 T cells of AV mice by in vitro differentiation. T cells from AV-NFAT1 mice exhibited a dysregulation of cytokine expression, producing more IFN-γ and less IL-4. While the numbers of CD4+CD25+ “natural” Treg cells in peripheral lymphoid organs and their in vitro suppressive functions were slightly decreased in AV mice, iTreg generation from CD4+CD25- T cells of AV mice as compared to wild type cells was markedly enhanced. Moreover, TH17 cells generated in vitro from CD4 T cells of AV mice in the presence of IL-6, IL-21 and TGF-β exhibited dramatically increased expression of both IL-10 and IL-17 as compared to wild type controls. To investigate putative NFAT binding sites in the IL-10 and IL-17 gene loci, we performed chromatin immunoprecipitation experiments. We show that NFAT1 can bind at the IL-17 locus at 3 out of 9 CNS regions which are accessible specifically during TH17 but not during TH1 and TH2 differentiation. Furthermore, we provide evidence that NFAT1 binds one CNS region in the IL10-locus in TH17 cells. To verify our observations in vivo, we induced experimental autoimmune encephalitis (EAE) in AV mice and wild type controls with the immunodominant myelin antigen MOG33-55 emulsified in complete Freund‘s adjuvant. While wild type animals showed a normal course of disease with development of tail and hind limb paralysis after approximately 10 days, AV mice showed a markedly weaker disease phenotype with less severe degrees of paralysis and accelerated kinetics of remission. Moreover at the peak of the response, there were fewer CD4+CD25- but more CD4+CD25+ T cells in the CNS of AV animals compared to wild type controls. Surprisingly, these cells produced significantly more IL-2, IL-17 and IFN-γ upon restimulation, even though they displayed decreased disease. In summary, our data provide strong evidence that NFAT1 contributes to the regulation of IL-10 and IL-17 expression in TH17 cells and show that increasing NFAT1 activity can ameliorate autoimmune encephalitis. This could occur in part through upregulation of IL-10 expression as observed in vitro, but is also likely to reflect increased infiltration of regulatory T cells into the CNS as well as increased conversion of conventional T cells into Foxp3+ regulatory T cells within the CNS. Disclosures: No relevant conflicts of interest to declare.

PRMT5 Transgenic Mice Develop Aggressive Lymphoblastic Lymphomas

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2936-2936
Author(s):  
Porsha L. Smith ◽  
Fengting Yan ◽  
John T. Patton ◽  
Lapo Alinari ◽  
Vrajesh Karkhanis ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Transgenic Mouse Model ◽  
P Value ◽  
Wild Type ◽  
Over Expression ◽  
Epigenetic Modifier ◽  
F1 Generation

Abstract Introduction: Emerging data collected from whole genome and epigenomic studies in solid and blood cancers has pointed toward dysregulation of chromatin remodelers as a unique class of cancer drivers. Next generation sequencing of lymphoma has identified several mutations affecting enzymes that regulate epigenetic control of gene expression. The epigenetic modifier protein arginine methyltransferase 5 (PRMT5) that has been shown to be essential for Epstein-Barr virus-driven B-cell transformation, is overexpressed in several histologic subtypes of B-cell non-Hodgkin's lymphomas (NHL) and is required for the driver activity of oncogenes such as MYC and NOTCH. While these findings suggest that PRMT5 may act as a driver of lymphomagenesis, definitive experiments to address its driver activity have yet to be performed. To address this question, we developed a transgenic mouse model by immunoglobulin m heavy chain enhancer/promoter (Em)-driven PRMT5 over expression in the lymphoid compartment of FVB/N mice. Methods: Eµ-hPRMT5 transgenic mice were created by injecting a vector containing floxed human PRMT5 under the control of the Eµ enhancer/promoter into FVB/N pronuclei that were implanted into pseudo-pregnant FVB/N mice. We obtained 5 founder lines demonstrating the presence of transgene construct by genotype PCR analysis of tail snip DNA. Founder mice were crossed with wild type FVB/N mice to obtain a F1 generation. Mice were followed clinically in standard pathogen-free housing until exhibiting phenotypic features at which time necropsy was performed. Immunophenotypic analysis was performed by flow cytometry, clonality by T cell receptor (TCR) Vb PCR, and pathology by hematoxylin-eosin staining and tissue micro-arrays developed for immunohistochemical staining (IHCS). Statistical significance was determined using a two-tail t-test and survival analysis conducted using Kaplan Meier curves. Results: F1 generation Eµ-hPRMT5 mice significantly overexpressed PRMT5 mRNA in unpurified splenocytes or bone marrow relative to non-transgenic mice (p-value < 0.001). Sorting B (CD19), NK (NK1.1) and T-cell (CD3) mononuclear subsets from splenocytes collected from Eµ-hPRMT5 mice (n=3/group) revealed PRMT5 mRNA to be overexpressed 37-fold (p-value <0.01), 7-fold (p-value <0.01) and 6-fold (p-value <0.05), respectively compared to WT FVB/N mice. All 5 founder lines were found to develop aggressive lymphomas at a statistically significant higher incidence compared to wild type (WT) FVB/N mice (range 10.7-34.6% lymphomagenesis). Gross anatomical characterization of Lymphoma bearing mice demonstrated focal lymphoid tumors, lymphadenopathy, organomegaly (liver, spleen, kidney), and malignant atypical lymphocytosis. Flow cytometric and IHCS studies showed features consistent with immature pre B and T lymphoblastic lymphomas (LL). Pre B LLs were characterized by high surface IgM, TdT and CD19 expression as analyzed by flow cytometry. Pre T LL demonstrated cytoplasmic CD3, TdT, and CD43 expression. We successfully developed a T LL cell line (Tg813) from a pre T-LL tumor isolated from a thymic tumor. Tg813 was clonal (Vb-17), demonstrated complex cytogenetic features, and over-expressed PRMT5, CYCLIN D1, CYCLIN D3, C-MYC transcript and protein, and the PRMT5 histone mark, symmetric (Me2)-H4R3. Inhibition of PRMT5 with a small molecule inhibitor, shRNA or genetic deletion using CRISPR/CAS9 PRMT5-specific gRNA (targeting exon 2) led to reduced proliferation, apoptosis and loss of CYCLIN D1 and C-MYC expression in Tg813. Engraftment of the Tg813 LL into both SCID and immunocompetent FVB/N mice led to disseminated lymphomas 21 days post-engraftment. In vivo induced expression of PRMT5 gRNA in CAS9+ Tg813 tumors is currently underway. Conclusions:The spontaneous lymphomagenesis observed in the Eµ-hPRMT5 transgenic mouse model supports the hypothesis that PRMT5 over-expression can provide sufficient driver activity for this disease. We describe a novel in vivo and in vitro model of PRMT5-driven LL that provides a useful platform for studying the biologic role of this epigenetic modifier in cancer and for development of PRMT5 targeted therapeutic approaches for lymphoma. Disclosures Baiocchi: Essanex: Research Funding.

scholarly journals Expression of Interleukin-9 Leads to Th2 Cytokine-Dominated Responses and Fatal Enteropathy in Mice with ChronicSchistosoma mansoni Infections

2000 ◽  
Vol 68 (10) ◽  
pp. 6005-6011 ◽  
Author(s):  
Padraic G. Fallon ◽  
Philip Smith ◽  
Emma J. Richardson ◽  
Frances J. Jones ◽  
Helen C. Faulkner ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Interleukin 4 ◽  
Moderate Increase ◽  
Wild Type ◽  
Schistosome Infection ◽  
Cell Hyperplasia ◽  
Necrosis Factor Alpha ◽  
Th2 Cytokine ◽  
Mucin Expression

ABSTRACT Mice infected with Schistosoma mansoni develop Th2 cytokine-mediated granulomatous pathology that is focused on the liver and intestines. In this study, transgenic mice constitutively expressing IL-9 were infected with S. mansoni and the outcome of infection was determined. Eight weeks after infection, transgenic mice with acute infections had a moderate increase in Th2 cytokine production but were overtly normal with respect to parasite infection and pathological responses. Transgenic mice with chronic infections died 10 weeks after infection, with 86% of transgenic mice dead by week 12 of infection, compared to 7% mortality in infected wild-type mice. Stimulation of mesenteric lymph node cells from infected transgenic mice with parasite antigen elicited elevated interleukin-4 (IL-4) and IL-5 production and reduced gamma interferon and tumor necrosis factor alpha production compared to the responses in wild-type mice. Morbid transgenic mice had substantial enlargement of the ileum, which was associated with muscular hypertrophy, mastocytosis, eosinophilia, goblet cell hyperplasia, and increased mucin expression. We also observed that uninfected transgenic mice exhibited alterations in their intestines. Although there was hepatic mastocytosis and eosinophilia in infected transgenic mice, there was no hepatocyte damage. Death of transgenic mice expressing IL-9 during schistosome infection was primarily associated with enteropathy. This study highlights the pleiotropic in vivo activity of IL-9 and demonstrates that an elevated Th2 cytokine phenotype leads to death during murine schistosome infection.

scholarly journals Regenerative capacity of the dystrophic (mdx) diaphragm after induced injury

2004 ◽  
Vol 287 (4) ◽  
pp. R961-R968 ◽  
Author(s):  
Stefan Matecki ◽  
Ghiabe H. Guibinga ◽  
Basil J. Petrof
Keyword(s):  
Connective Tissue ◽  
Isometric Force ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Wild Type ◽  
Regenerative Capacity ◽  
Generating Capacity ◽  
Massive Necrosis ◽  
Characteristic Features

Duchenne muscular dystrophy is characterized by myofiber necrosis, muscle replacement by connective tissue, and crippling weakness. Although the mdx mouse also lacks dystrophin, most muscles show little myofiber loss or functional impairment. An exception is the mdx diaphragm, which is phenotypically similar to the human disease. Here we tested the hypothesis that the mdx diaphragm has a defective regenerative response to necrotic injury, which could account for its severe phenotype. Massive necrosis was induced in mdx and wild-type (C57BL10) mouse diaphragms in vivo by topical application of notexin, which destroys mature myofibers while leaving myogenic precursor satellite cells intact. At 4 h after acute exposure to notexin, >90% of diaphragm myofibers in both wild-type and mdx mice demonstrated pathological sarcolemmal leakiness, and there was a complete loss of isometric force-generating capacity. Both groups of mice showed strong expression of embryonic myosin within the diaphragm at 5 days, which was largely extinguished by 20 days after injury. At 60 days postinjury, wild-type diaphragms exhibited a persistent loss (∼25%) of isometric force-generating capacity, associated with a trend toward increased connective tissue infiltration. In contrast, mdx diaphragms achieved complete functional recovery of force generation to noninjured values, and there was no increase in muscle connective tissue over baseline. These data argue against any loss of intrinsic regenerative capacity within the mdx diaphragm, despite characteristic features of major dystrophic pathology being present. Our findings support the concept that significant latent regenerative capacity resides within dystrophic muscles, which could potentially be exploited for therapeutic purposes.

scholarly journals Trans ε-Viniferin Decreases Amyloid Deposits With Greater Efficiency Than Resveratrol in an Alzheimer’s Mouse Model

2022 ◽  
Vol 15 ◽  
Author(s):  
Aline Freyssin ◽  
Agnès Rioux Bilan ◽  
Bernard Fauconneau ◽  
Laurent Galineau ◽  
Sophie Serrière ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cognitive Status ◽  
Morris Water Maze Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Wild Type ◽  
Pet Tracer ◽  
Amyloid Deposits ◽  
Polyethylene Glycol 200 ◽  
Amyloid Load

In a previous study, we showed that viniferin decreased amyloid deposits and reduced neuroinflammation in APPswePS1dE9 transgenic mice between 3 and 6 months of age. In the present study, wild type and APPswePS1dE9 transgenic mice were treated from 7 to 11 or from 3 to 12 months by a weekly intraperitoneal injection of either 20 mg/kg viniferin or resveratrol or their vehicle, the polyethylene glycol 200 (PEG 200). The cognitive status of the mice was evaluated by the Morris water maze test. Then, amyloid burden and neuroinflammation were quantified by western-blot, Enzyme-Linked ImmunoSorbent Assay (ELISA), immunofluorescence, and in vivo micro-Positon Emission Tomography (PET) imaging. Viniferin decreased hippocampal amyloid load and deposits with greater efficiency than resveratrol, and both treatments partially prevented the cognitive decline. Furthermore, a significant decrease in brain uptake of the TSPO PET tracer [18F]DPA-714 was observed with viniferin compared to resveratrol. Expression of GFAP, IBA1, and IL-1β were decreased by viniferin but PEG 200, which was very recently shown to be a neuroinflammatory inducer, masked the neuroprotective power of viniferin.

In Vivo Analysis of Wild-type and FTDP-17 Tau Transgenic Mice

2006 ◽  
Vol 920 (1) ◽  
pp. 126-133 ◽  
Author(s):  
J. GÖTZ ◽  
R. BARMETTLER ◽  
A. FERRARI ◽  
M. GOEDERT ◽  
A. PROBST ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Wild Type ◽  
In Vivo Analysis

scholarly journals In Vivo Detection of Age- and Disease-Related Increases in Neuroinflammation by 18 F-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic Mice

2015 ◽  
Vol 35 (47) ◽  
pp. 15716-15730 ◽  
Author(s):  
Bin Liu ◽  
Kevin X. Le ◽  
Mi-Ae Park ◽  
Shuyan Wang ◽  
Anthony P. Belanger ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Wild Type ◽  
Micropet Imaging ◽  
In Vivo Detection
Sign in / Sign up

Export Citation Format

Share Document