Creatine transport and pathological changes in creatine transporter deficient mice

2021 ◽  
Author(s):  
Adam M. Wawro ◽  
Chandresh R. Gajera ◽  
Steven A. Baker ◽  
Jeffrey J. Nirschl ◽  
Hannes Vogel ◽  
...  
Keyword(s):  
Pathological Changes ◽  
Creatine Transporter ◽  
Creatine Transport ◽  
Deficient Mice

scholarly journals Ligneous Conjunctivitis in Plasminogen-Deficient Mice

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1616-1624 ◽  
Author(s):  
A.F. Drew ◽  
A.H. Kaufman ◽  
K.W. Kombrinck ◽  
M.J.S. Danton ◽  
C.C. Daugherty ◽  
...  
Keyword(s):  
Genetic Background ◽  
Direct Evidence ◽  
Therapeutic Strategies ◽  
Pathological Changes ◽  
Rare Form ◽  
Lesion Development ◽  
Ligneous Conjunctivitis ◽  
Plasminogen Deficiency ◽  
Human And Mouse ◽  
Deficient Mice

Abstract Ligneous conjunctivitis is a rare form of chronic pseudomembranous conjunctivitis that is associated with systemic membranous pathological changes. A probable link between plasminogen and ligneous conjunctivitis has been indicated by the recent diagnoses of plasminogen deficiency in five patients suffering from ligneous conjunctivitis. The current study reports that plasminogen-deficient mice develop conjunctival lesions indistinguishable from human ligneous conjunctivitis in both appearance and histology. Both human and mouse lesions contain acellular material rich in fibrin, and aberrant or disrupted epithelium. The incidence of lesion development in mice increases with age and is strongly influenced by genetic background. Interestingly, ligneous conjunctivitis was not observed in plasminogen-deficient mice simultaneously lacking fibrinogen. This study provides direct evidence that plasminogen deficiency is one cause of ligneous conjunctivitis and suggests that plasminogen-deficient mice may be an excellent model for the development of therapeutic strategies for the treatment of this debilitating disease.

scholarly journals Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

2014 ◽  
Vol 2 (1) ◽  
Author(s):  
Yoshinori Tanaka ◽  
James K Chambers ◽  
Takashi Matsuwaki ◽  
Keitaro Yamanouchi ◽  
Masugi Nishihara
Keyword(s):  
Pathological Changes ◽  
Lysosomal Dysfunction ◽  
The Brain ◽  
Deficient Mice

scholarly journals Down-Regulation of the Na+,Cl- Coupled Creatine Transporter CreaT (SLC6A8) by Glycogen Synthase Kinase GSK3ß

2016 ◽  
Vol 40 (5) ◽  
pp. 1231-1238 ◽  
Author(s):  
Myriam Fezai ◽  
Mohamed Jemaà ◽  
Hajar Fakhri ◽  
Hong Chen ◽  
Bhaeldin Elsir ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Xenopus Laevis Oocytes ◽  
Induced Current ◽  
Wild Type ◽  
Creatine Transporter ◽  
Electrode Voltage ◽  
Creatine Transport ◽  
The Brain ◽  
Current Kinetic

Background: The Na+,Cl- coupled creatine transporter CreaT (SLC6A8) is expressed in a variety of tissues including the brain. Genetic defects of CreaT lead to mental retardation with seizures. The present study explored the regulation of CreaT by the ubiquitously expressed glycogen synthase kinase GSK3ß, which contributes to the regulation of neuroexcitation. GSK3ß is phosphorylated and thus inhibited by PKB/Akt. Moreover, GSK3ß is inhibited by the antidepressant lithium. The present study thus further tested for the effects of PKB/Akt and of lithium. Methods: CreaT was expressed in Xenopus laevis oocytes with or without wild-type GSK3ß or inactive K85RGSK3ß. CreaT and GSK3ß were further expressed without and with additional expression of wild type PKB/Akt. Creatine transport in those oocytes was quantified utilizing dual electrode voltage clamp. Results: Electrogenic creatine transport was observed in CreaT expressing oocytes but not in water-injected oocytes. In CreaT expressing oocytes, co-expression of GSK3ß but not of K85RGSK3ß, resulted in a significant decrease of creatine induced current. Kinetic analysis revealed that GSK3ß significantly decreased the maximal creatine transport rate. Exposure of CreaT and GSK3ß expressing oocytes for 24 hours to Lithium was followed by a significant increase of the creatine induced current. The effect of GSK3ß on CreaT was abolished by co-expression of PKB/Akt. Conclusion: GSK3ß down-regulates the creatine transporter CreaT, an effect reversed by treatment with the antidepressant Lithium and by co-expression of PKB/Akt.

AMPK and substrate availability regulate creatine transport in cultured cardiomyocytes

2011 ◽  
Vol 300 (5) ◽  
pp. E870-E876 ◽  
Author(s):  
Marcus D. Darrabie ◽  
Antonio Jose Luis Arciniegas ◽  
Rajashree Mishra ◽  
Dawn E. Bowles ◽  
Danny O. Jacobs ◽  
...  
Keyword(s):  
Heart Failure ◽  
Energy Homeostasis ◽  
Cardiac Cells ◽  
Substrate Availability ◽  
Human Heart Failure ◽  
Positive Role ◽  
Creatine Transporter ◽  
Neonatal Cardiomyocytes ◽  
Transporter Protein ◽  
Creatine Transport

Profound alterations in myocellular creatine and phosphocreatine levels are observed during human heart failure. To maintain its intracellular creatine stores, cardiomyocytes depend upon a cell membrane creatine transporter whose regulation is not clearly understood. Creatine transport capacity in the intact heart is modulated by substrate availability, and it is reduced in the failing myocardium, likely adding to the energy imbalance that characterizes heart failure. AMPK, a key regulator of cellular energy homeostasis, acts by switching off energy-consuming pathways in favor of processes that generate energy. Our objective was to determine the effects of substrate availability and AMPK activation on creatine transport in cardiomyocytes. We studied creatine transport in rat neonatal cardiomyocytes and HL-1 cardiac cells expressing the human creatine transporter cultured in the presence of varying creatine concentrations and the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR). Transport was enhanced in cardiomyocytes following incubation in creatine-depleted medium or AICAR. The changes in transport were due to alterations in Vmax that correlated with changes in total and cell surface creatine transporter protein content. Our results suggest a positive role for AMPK in creatine transport modulation for cardiomyocytes in culture.

scholarly journals Involvement of Nitric Oxide Released from Microglia–Macrophages in Pathological Changes of Cathepsin D-Deficient Mice

2001 ◽  
Vol 21 (19) ◽  
pp. 7526-7533 ◽  
Author(s):  
Hiroshi Nakanishi ◽  
Jian Zhang ◽  
Masato Koike ◽  
Tsuyoshi Nishioku ◽  
Yoshiko Okamoto ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cathepsin D ◽  
Pathological Changes ◽  
Deficient Mice

scholarly journals Determination of Intrinsic Creatine Transporter (Slc6a8) Activity and Creatine Transport Function of Leukocytes in Rats

2020 ◽  
Vol 43 (3) ◽  
pp. 474-479 ◽  
Author(s):  
Ayaka Taii ◽  
Masanori Tachikawa ◽  
Yusuke Ohta ◽  
Ken-ichi Hosoya ◽  
Tetsuya Terasaki
Keyword(s):  
Transport Function ◽  
Creatine Transporter ◽  
Creatine Transport

Efficacy of an inhibitor of adhesion molecule expression (GI270384X) in the treatment of experimental colitis

2007 ◽  
Vol 293 (4) ◽  
pp. G739-G748 ◽  
Author(s):  
Julián Panés ◽  
Montserrat Aceituno ◽  
Fèlix Gil ◽  
Rosa Miquel ◽  
Josep M Piqué ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Clinical Signs ◽  
Experimental Colitis ◽  
Serum Levels ◽  
Experimental Models ◽  
Severe Form ◽  
Adhesion Molecule Expression ◽  
Pathological Changes ◽  
Amyloid A ◽  
Deficient Mice

Modulation of adhesion molecule expression or function is regarded as a promising therapy for inflammatory conditions. This study evaluates the effects of an inhibitor of adhesion molecule expression (GI270384X) in two experimental models of colitis. Colitis of different severity was induced in C57BL/6J mice by administering 1, 2, or 3% dextran sulfate sodium (DSS). GI270384X (3, 10, or 25 mg·kg−1·day−1) was administered as pretreatment or started 3 days after colitis induction. In IL-10-deficient mice, the highest dose was given for 2 wk. The clinical course of colitis, pathological changes, serum inflammatory biomarkers, expression of adhesion molecules, and leukocyte-endothelial cell interactions in colonic venules were measured in mice treated with vehicle or with active drug. In the most severe forms of colitis (2% and 3% DSS and IL-10-deficient mice), the magnitude of colonic inflammation was not modified by treatment with GI270384X. In a less severe form of colitis (1% DSS), GI270384X treatment dose dependently ameliorated the clinical signs of colitis, colonic pathological changes, and serum levels of biomarkers (IL-6 and serum amyloid A). Administration of 25 mg·kg−1·day−1 GI270384X abrogated upregulation of ICAM-1 in the inflamed colon but had no effect on VCAM-1 or E-selectin expression. This was associated with a significant reduction in number of rolling and firmly adherent leukocytes in colonic venules. These results indicate that GI270384X is effective in the treatment of experimental colitis of moderate severity. Reduced adhesion molecule expression and leukocyte recruitment to the inflamed intestine contribute to this beneficial effect.

scholarly journals Francisella tularensis Induces Extensive Caspase-3 Activation and Apoptotic Cell Death in the Tissues of Infected Mice

2009 ◽  
Vol 77 (11) ◽  
pp. 4827-4836 ◽  
Author(s):  
Jason R. Wickstrum ◽  
Sirosh M. Bokhari ◽  
Jeffrey L. Fischer ◽  
David M. Pinson ◽  
Hung-Wen Yeh ◽  
...  
Keyword(s):  
Cell Death ◽  
Francisella Tularensis ◽  
Caspase 3 ◽  
Type A ◽  
Pathological Changes ◽  
Wild Type ◽  
Caspase 1 ◽  
Extensive Cell Death ◽  
Extensive Cell ◽  
Deficient Mice

ABSTRACT Although Francisella tularensis subsp. tularensis is known to cause extensive tissue necrosis, the pathogenesis of tissue injury has not been elucidated. To characterize cell death in tularemia, C57BL/6 mice were challenged by the intranasal route with type A F. tularensis, and the pathological changes in infected tissues were characterized over the next 4 days. At 3 days postinfection, well-organized inflammatory infiltrates developed in the spleen and liver following the spread of infection from the lungs. By the next day, extensive cell death, characterized by the presence of pyknotic cells containing double-strand DNA breaks, was apparent throughout these inflammatory foci. Cell death was not mediated by activated caspase-1, as has been reported for cells infected with other Francisella subspecies. Mouse macrophages and dendritic cells that had been stimulated with type A F. tularensis did not release interleukin-18 in vitro, a response that requires the activation of procaspase-1. Dying cells within type A F. tularensis-infected tissues expressed activated caspase-3 but very little activated caspase-1. When caspase-1-deficient mice were challenged with type A F. tularensis, pathological changes, including extensive cell death, were similar to those seen in infected wild-type mice. In contrast, type A F. tularensis-infected caspase-3-deficient mice showed much less death among their F4/80+ spleen cells than did infected wild-type mice, and they retained the ability to express tumor necrosis factor alpha and inducible NO synthase. These findings suggest that type A F. tularensis induces caspase-3-dependent macrophage apoptosis, resulting in the loss of potentially important innate immune responses to the pathogen.

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