Treatment with lithium carbonate does not improve disease progression in two different strains of SOD1 mutant mice

2009 ◽  
Vol 10 (4) ◽  
pp. 221-228 ◽  
Author(s):  
Chiara Pizzasegola ◽  
Ilaria Caron ◽  
Cristina Daleno ◽  
Anna Ronchi ◽  
Claudio Minoia ◽  
...  
2010 ◽  
Vol 20 (2) ◽  
pp. 150-158 ◽  
Author(s):  
Stella Gagliardi ◽  
Paolo Ogliari ◽  
Annalisa Davin ◽  
Manuel Corato ◽  
Emanuela Cova ◽  
...  

2005 ◽  
Vol 289 (5) ◽  
pp. L731-L738 ◽  
Author(s):  
Janet S. Lee ◽  
Charles W. Frevert ◽  
Gustavo Matute-Bello ◽  
Mark M. Wurfel ◽  
Venus A. Wong ◽  
...  

We examined the role of Toll-like receptor (TLR)-4 in modifying the lung inflammatory response and its effects on the bacterial recovery from the lungs following inhaled Escherichia coli in two different strains of TLR-4 mutant mice that are hyporesponsive to LPS. The C57BL/10ScN( tlr4lps-del) mice containing a deletion mutation in the TLR-4 gene showed lower proinflammatory cytokine levels, lower lung MPO activity, and less parenchymal and peribronchial inflammation compared with the C57BL/10ScSn mice, a related TLR-4 wild-type substrain. However, the C57BL/10ScN( tlr4lps-del) mutant showed lower bacterial recovery in the lungs following inhaled E. coli associated with a rapid but transient increase in air space neutrophil counts at 6 h. In comparison, the C3H/HeJ( tlr4Lps-d) mutant mice containing a Pro712His substitution in TLR-4 demonstrated lower proinflammatory cytokine levels, lower lung MPO activity, and lower neutrophil accumulation in the air spaces but showed no differences in the bacterial burden of inhaled E. coli at 6 h, when compared with the TLR-4 wild-type C3H/HeSnJ mice. Thus two different TLR-4 mutants showed attenuated inflammatory responses in the lungs, but the reduced inflammatory responses were not consistently associated with either improved or impaired bacterial elimination from the lungs. Our findings indicate that the inflammatory response to inhaled E. coli is TLR-4 dependent, but bacterial elimination depends on other factors in addition to TLR-4.


2012 ◽  
Vol 112 (5) ◽  
pp. 704-710 ◽  
Author(s):  
Rebecca A. Johnson ◽  
Maxine Lam ◽  
Antonio M. Punzo ◽  
Hongda Li ◽  
Benjamin R. Lin ◽  
...  

Rett syndrome (RTT), caused by mutations in the methyl-CpG binding protein 2 gene ( MECP2), is a debilitating autism spectrum developmental disorder predominantly affecting females. Mecp2 mutant mice have reduced levels of brain-derived neurotrophic factor (BDNF) in the brain; conditional deletion and overexpression of BDNF in the brain accelerates and slows, respectively, disease progression in Mecp2 mutant mice. Thus we tested the hypothesis that 7,8-dihydroxyflavone (7,8-DHF), a small molecule reported to activate the high affinity BDNF receptor (TrkB) in the CNS, would attenuate disease progression in Mecp2 mutant mice. Following weaning, 7,8-DHF was administered in drinking water throughout life. Treated mutant mice lived significantly longer compared with untreated mutant littermates (80 ± 4 and 66 ± 2 days, respectively). 7,8-DHF delayed body weight loss, increased neuronal nuclei size and enhanced voluntary locomotor (running wheel) distance in Mecp2 mutant mice. In addition, administration of 7,8-DHF partially improved breathing pattern irregularities and returned tidal volumes to near wild-type levels. Thus although the specific mechanisms are not completely known, 7,8-DHF appears to reduce disease symptoms in Mecp2 mutant mice and may have potential as a therapeutic treatment for RTT patients.


Autophagy ◽  
2008 ◽  
Vol 4 (3) ◽  
pp. 290-293 ◽  
Author(s):  
Liang Li ◽  
Xiaojie Zhang ◽  
Weidong Le
Keyword(s):  

2007 ◽  
Vol 413 (3) ◽  
pp. 265-269 ◽  
Author(s):  
Jong-Ha Park ◽  
Yoon-Ho Hong ◽  
Hyun-Jung Kim ◽  
Sung-Min Kim ◽  
Min-Jeong Kim ◽  
...  

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 462-462
Author(s):  
Maria Zingariello ◽  
Barbara Ghinassi ◽  
Rosa Alba Rana ◽  
Maria Verrucci ◽  
Fabrizio Martelli ◽  
...  

Abstract Abstract 462 The marrow microenvironment in primary myelofibrosis and mouse models of the disease is characterized by increased levels of cytokines which regulate hematopoiesis including CXCL12, BMP4, VEGF and TGF-β. The observation that TGF-βnull myelofibrotic stem cells fail to transmit the disease by transplantation (Chagraoui et al, Blood 100:3495, 2002) has established an important role for TGF-β in disease development. Mice carrying the hypomorphic Gata1low mutation in which the enhancer that drives gene expression in megakaryocytes (MK) is deleted also develop myelofibrosis with age (Vannucchi et al, Blood 2002;100:1123). To clarify the role of TGF-β in development of myelofibrosis in the Gata1low mouse model, the levels of this factor in plasma and marrow of the mutant mice were measured. Gata1low mice express normal levels of TGF-β in plasma (1.8±0.7 vs 2.1±0.4 ng/mL) and levels of TGF-β mRNA (2.9±0.5 vs 1.5±0.3 arbitrary units, p<0.01) and protein (1.9±0.3 vs 0.86±0.2 ng/mL, p<0.01) only 2-times greater than normal in marrow. However, by immunoelectron microscopy, patchy TGF-β deposits associated with collagen fibers were observed in the marrow microenvironment of mutant mice (<3 vs >700 particles/field in wild-type and Gata1low marrow, respectively) indicating that fibrosis, by concentrating TGF-β locally, may contribute to disease progression also in Gata1low mice. To evaluate whether inhibition of TGF-β signaling would ameliorate myelofibrosis in this animal model, Gata1low mice were treated with SB431542 (C22H16N4O3, MW= 384.4), an inhibitor of TGF- β1/activin receptor-like kinases recently demonstrated to prevent renal fibrosis in mice (Petersen et al, Kidney Int 73:705, 2008.). Six males (7-9 months) and 6 females (12 months) were treated with SB431542 as described for renal fibrosis (see Figure). Equivalent numbers of mice treated with vehicle were used as control. Treatment was well tolerated (no deaths) and the SB43542-treated mice were easily recognized by being more active and with shinier coats. At the end of the 4th cycle, mice were sacrificed and analyzed for disease progression. The results were as follows: Blood: SB43542-treatment did not affect hematocrit levels (43.2±1.2 vs 41.3±0.9 in SB43542- and vehicle-treated mice, respectively), increased platelets numbers [0.34(±0.03)×106/μL vs 0.2(±0.009)×106/μL, p<0.01] but platelets remained larger than normal, reduced white blood cell counts [5.2(±0.19)×103/μL vs 6.5(±0.3)×103/μL, p<0.01] and frequency of poikilocytes (1 every 4–5 fields vs >4/field). Also, progenitor cell trafficking was not reduced (CD34posCD117pos cells: 1.45 vs 1.2% colony forming cells: 10.8±2.4 vs 8.0±0.1 CFC/μL). Marrow: Treatment increased total cell number [18.0(±0.7) ×106 vs 8.2(±0.4) ×106/femur, p<0.01] and frequency of erythroid cells (20.5±2.5 vs 13.2±0.7%, p<0.01) but not of MK (40.2±5.7 vs 38.7±0.9%) in the femur. However, fibrosis and microvessel density were reduced (Gomori-Silver and CD34 staining). Increased Mallory staining of bones was observed but the femur became resistant to fracture, suggesting that overall bone structure improved. Spleen: SB43542-treatment reduced spleen weight (0.2±0.6 vs 0.45±0.05 gr, p<0.01) and cell numbers [265(±30)×106 vs 385(±5)×106 cells, p<0.01]. Therefore, although the frequency of erythroid cells and MK in the organ remained high, overall hematopoiesis in spleen was reduced. Liver: SB43542-treatment restored the morphological appearance of the liver and reduced the frequency of MK (5.9±0.7 vs 20.4±4.7, p<0.01). These improvements were likely not due to an anti-inflammatory effect of the drug because parallel treatments with dexamethasone did not modify disease progression in Gata1low mice. Conclusion: SB43542-treatment reduced the myelofibrotic traits expressed by Gata1low mice, confirming that increased TGF-β1 levels play an important role in disease manifestations in this animal model. We have previously published that Aplidin treatment restores the hematopoietic stem cell properties of Gata1low mice (Verrucci et al, J Cell Physiol,2010, May20, Epub ahead of print). The observation that SB43542-treatment primarily reduced microenvironmental abnormalities suggests that the two drugs may have synergistic effects in the treatment of myelofibrosis. Disclosures: No relevant conflicts of interest to declare.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Agnes Badu-Mensah ◽  
Xiufang Guo ◽  
Christopher W. McAleer ◽  
John W. Rumsey ◽  
James J. Hickman

2018 ◽  
Vol 46 (6) ◽  
pp. 2358-2372 ◽  
Author(s):  
Binbin Deng ◽  
Wenjing Lv ◽  
Weisong Duan ◽  
Yakun Liu ◽  
Zhongyao Li ◽  
...  

Background: Myelination, degeneration and regeneration are implicated in crucial responses to injury in the peripheral nervous system. Considering the progression of amyotrophic lateral sclerosis (ALS), we used the superoxide dismutase 1 (SOD1)-G93A transgenic mouse model of ALS to investigate the effects of mutant SOD1 on the peripheral nerves. Methods: Changes in peripheral nerve morphology were analyzed in SOD1 mutant mice at various stages of the disease by toluidine blue staining and electron microscopy (EM). Schwann cell proliferation and recruitment of inflammatory factors were detected by immunofluorescence staining and quantitative reverse transcription PCR and were compared between SOD1 mutant mice and control mice. Furthermore, western blotting (WB) and TUNEL staining were used to investigate axonal damage and Schwann cell survival in the sciatic nerves of mice in both groups. Results: An analysis of the peripheral nervous system in SOD1-G93A mice revealed the following novel features: (i) Schwann cells and axons in mutant mice underwent changes that were similar to those seen in the control mice during the early development of peripheral nerves. (ii) The peripheral nerves of SOD1-G93A mice developed progressive neuropathy, which presented as defects in axons and myelin, leading to difficulty in walking and reduced locomotor capacity at a late stage of the disease. (iii) Macrophages were recruited and accumulated, and nerve injury and a deficit in the blood-nerve barrier were observed. (iv) Proliferation and the inflammatory micro-environment were inhibited, which impaired the regeneration and remyelination of axons after crush injury in the SOD1-G93A mice. Conclusions: The mutant human SOD1 protein induced axonal and myelin degeneration during the progression of ALS and participated in axon remyelination and regeneration in response to injury.


2018 ◽  
Vol 92 ◽  
pp. 12-16 ◽  
Author(s):  
Rachit Bakshi ◽  
Yuehang Xu ◽  
Kaly A. Mueller ◽  
Xiqun Chen ◽  
Eric Granucci ◽  
...  

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