scholarly journals Effects of Rivastigmine and Donepezil on Brain Acetylcholine Levels in Acetylcholinesterase-Deficient Mice

2009 ◽  
Vol 12 (1) ◽  
pp. 79 ◽  
Author(s):  
Runa S. Naik ◽  
Joachim Hartmann ◽  
Cornelia Kiewert ◽  
Ellen G. Duysen ◽  
Oksana Lockridge ◽  
...  
Keyword(s):  
Late Stage ◽  
Ache Activity ◽  
In Vivo Microdialysis ◽  
Selective Inhibitor ◽  
Wild Type ◽  
Extracellular Concentration ◽  
Ache Inhibitors ◽  
Brain Acetylcholine ◽  
Deficient Mice

Purpose. Alzheimer´s disease is characterized by a dysfunction of central cholinergic systems and is treated by inhibitors of acetylcholinesterase (AChE). This study tests the effect of two AChE inhibitors in therapeutic use, rivastigmine and donepezil, in mice that are devoid of AChE (AChE-/- mice). Rivastigmine is an inhibitor of both AChE and butyrylcholinesterase (BChE) whereas donepezil is a selective inhibitor of AChE. Methods. We have used in vivo microdialysis to investigate the effects of the two drugs on the extracellular concentration of acetylcholine (ACh) in the hippocampus of AChE-/- mice. Results. Extracellular ACh levels in the hippocampus were 30-fold elevated in AChE-/- mice compared to wild-type (AChE+/+) animals. Infusion of rivastigmine (1 and 10 µM) caused a further doubling of ACh levels in AChE-/- mice within 90-120 min. In contrast, infusion of donepezil (1 µM) did not affect hippocampal ACh levels in AChE-/- mice although it increased ACh levels more than twofold in wild-type mice. Conclusions. In the absence of AChE, rivastigmine enhances the levels of extracellular ACh by inhibiting BChE. This finding may be of therapeutic relevance because BChE activity is preserved, but AChE activity is strongly decreased, in late-stage Alzheimer´s disease.

scholarly journals Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4+ T Cell Responses during Chronic Helicobacter pylori Infection

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Adria Carbo ◽  
Danyvid Olivares-Villagómez ◽  
Raquel Hontecillas ◽  
Josep Bassaganya-Riera ◽  
Rupesh Chaturvedi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Wild Type ◽  
Content Type ◽  
Interleukin 21 ◽  
H Pylori ◽  
Deficient Mice

ABSTRACTThe development of gastritis duringHelicobacter pyloriinfection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa duringH. pyloriinfection, we combined mathematical modeling of CD4+T cell differentiation within vivomechanistic studies. We infected IL-21-deficient and wild-type mice withH. pyloristrain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. ChronicallyH. pylori-infected IL-21-deficient mice had higherH. pyloricolonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. Thesein vivodata were used to calibrate anH. pyloriinfection-dependent, CD4+T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronicH. pyloriinfection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4+splenocyte-specifictbx21androrcexpression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4+T cell-specific IL-10 expression inH. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronicH. pyloriinfection in a STAT1- and STAT3-dependent manner, therefore playing a major role controllingH. pyloriinfection and gastritis.IMPORTANCEHelicobacter pyloriis the dominant member of the gastric microbiota in more than 50% of the world’s population.H. pyloricolonization has been implicated in gastritis and gastric cancer, as infection withH. pyloriis the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis duringH. pyloriinfection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized withH. pylorias an alternative to aggressive antibiotics.

Urokinase-dependent plasminogen activation is required for efficient skeletal muscle regeneration in vivo

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1703-1711 ◽  
Author(s):  
Frederic Lluı́s ◽  
Josep Roma ◽  
Mònica Suelves ◽  
Maribel Parra ◽  
Gloria Aniorte ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Plasminogen Activator ◽  
Muscle Regeneration ◽  
Plasminogen Activators ◽  
Skeletal Muscle Regeneration ◽  
Plasminogen Activation ◽  
Wild Type ◽  
Type Plasminogen Activator ◽  
Deficient Mice

Plasminogen activators urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) are extracellular proteases involved in various tissue remodeling processes. A requirement for uPA activity in skeletal myogenesis was recently demonstrated in vitro. The role of plasminogen activators in skeletal muscle regeneration in vivo in wild-type, uPA-deficient, and tPA-deficient mice is investigated here. Wild-type and tPA−/− mice completely repaired experimentally damaged skeletal muscle. In contrast, uPA−/− mice had a severe regeneration defect, with decreased recruitment of blood-derived monocytes to the site of injury and with persistent myotube degeneration. In addition, uPA-deficient mice accumulated fibrin in the degenerating muscle fibers; however, the defibrinogenation of uPA-deficient mice resulted in a correction of the muscle regeneration defect. A similar severe regeneration deficit with persistent fibrin deposition was also reproducible in plasminogen-deficient mice after injury, suggesting that fibrinolysis by uPA-mediated plasminogen activation plays a fundamental role in skeletal muscle regeneration. In conclusion, the uPA-plasmin system is identified as a critical component of the mammalian skeletal muscle regeneration process, possibly because it prevents intramuscular fibrin accumulation and contributes to the adequate inflammatory response after injury. These studies demonstrate the requirement of an extracellular proteolytic cascade during muscle regeneration in vivo.

scholarly journals An in vivo inflammatory loop potentiates KRAS blockade

2019 ◽  
Author(s):  
Kristina A.M. Arendt ◽  
Giannoula Ntaliarda ◽  
Vasileios Armenis ◽  
Danai Kati ◽  
Christin Henning ◽  
...  
Keyword(s):  
Interleukin 1Β ◽  
Wild Type ◽  
Poor Survival ◽  
Murine Bone Marrow ◽  
Chemokine Ligand ◽  
Isoprenylcysteine Carboxylmethyltransferase ◽  
Chemokine Ligand 2 ◽  
Deficient Mice

ABSTRACTKRAS inhibitors perform inferior to other targeted drugs. To investigate a possible reason for this, we treated cancer cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRASG12C), and silenced/overexpressed mutant KRAS using custom vectors. We show that KRAS-mutant tumor cells exclusively respond to KRAS blockade in vivo, because the oncogene co-opts host myeloid cells via a C-C-motif chemokine ligand 2/interleukin-1β signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in Ccr2 and Il1b gene-deficient mice, but were deltarasin-sensitive in wild-type and Ccr2-deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high KRAS mutation prevalence and predicted poor survival. Hence the findings support that in vitro systems are suboptimal for anti-KRAS drug screens, and suggest that interleukin-1β blockade might be specific for KRAS-mutant cancers.

Endothelial E- and P-selectin expression in iNOS- deficient mice exposed to polymicrobial sepsis

2001 ◽  
Vol 280 (2) ◽  
pp. G291-G297 ◽  
Author(s):  
Cameron W. Lush ◽  
Gediminas Cepinskas ◽  
William J. Sibbald ◽  
Peter R. Kvietys
Keyword(s):  
Leukocyte Adhesion ◽  
Cecal Ligation ◽  
Leukocyte Rolling ◽  
Wild Type ◽  
Endothelial Adhesion Molecule ◽  
Acute Peritonitis ◽  
Leukocyte Accumulation ◽  
Deficient Mice

In vitro, nitric oxide (NO) decreases leukocyte adhesion to endothelium by attenuating endothelial adhesion molecule expression. In vivo, lipopolysaccharide-induced leukocyte rolling and adhesion was greater in inducible NO synthase (iNOS)−/− mice than in wild-type mice. The objective of this study was to assess E- and P-selectin expression in the microvasculature of iNOS−/− and wild-type mice subjected to acute peritonitis by cecal ligation and perforation (CLP). E- and P-selectin expression were increased in various organs within the peritoneum of wild-type animals after CLP. This CLP-induced upregulation of E- and P-selectin was substantially reduced in iNOS−/− mice. Tissue myeloperoxidase (MPO) activity was increased to a greater extent in the gut of wild-type than in iNOS−/− mice subjected to CLP. In the lung, the reduced expression of E-selectin in iNOS−/− mice was not associated with a decrease in MPO. Our findings indicate that NO derived from iNOS plays an important role in sepsis-induced increase in selectin expression in the systemic and pulmonary circulation. However, in iNOS−/− mice, sepsis-induced leukocyte accumulation is affected in the gut but not in the lungs.

scholarly journals A Role for Mac-1 (CDIIb/CD18) in Immune Complex–stimulated Neutrophil Function In Vivo: Mac-1 Deficiency Abrogates Sustained Fcγ Receptor–dependent Neutrophil Adhesion and Complement-dependent Proteinuria in Acute Glomerulonephritis

1997 ◽  
Vol 186 (11) ◽  
pp. 1853-1863 ◽  
Author(s):  
Tao Tang ◽  
Alexander Rosenkranz ◽  
Karel J.M. Assmann ◽  
Michael J. Goodman ◽  
Jose-Carlos Gutierrez-Ramos ◽  
...  
Keyword(s):  
Immune Complex ◽  
Mutant Mice ◽  
Polymorphonuclear Neutrophil ◽  
Complement C3 ◽  
Acute Glomerulonephritis ◽  
Wild Type ◽  
Filamentous Actin ◽  
Deficient Mice

Mac-1 (αmβ2), a leukocyte adhesion receptor, has been shown in vitro to functionally interact with Fcγ receptors to facilitate immune complex (IC)–stimulated polymorphonuclear neutrophil (PMN) functions. To investigate the relevance of Mac-1–FcγR interactions in IC-mediated injury in vivo, we induced a model of Fc-dependent anti–glomerular basement membrane (GBM) nephritis in wild-type and Mac-1–deficient mice by the intravenous injection of anti-GBM antibody. The initial glomerular PMN accumulation was equivalent in Mac-1 null and wild-type mice, but thereafter increased in wild-type and decreased in mutant mice. The absence of Mac-1 interactions with obvious ligands, intercellular adhesion molecule 1 (ICAM-1), and C3 complement, is not responsible for the decrease in neutrophil accumulation in Mac-1– deficient mice since glomerular PMN accumulation in mice deficient in these ligands was comparable to those in wild-type mice. In vitro studies showed that spreading of Mac-1–null PMNs to IC-coated dishes was equivalent to that of wild-type PMNs at 5–12 min but was markedly reduced thereafter, and was associated with an inability of mutant neutrophils to redistribute filamentous actin. This suggests that in vivo, Mac-1 is not required for the initiation of Fc-mediated PMN recruitment but that Mac-1–FcγR interactions are required for filamentous actin reorganization leading to sustained PMN adhesion, and this represents the first demonstration of the relevance of Mac-1–FcγR interactions in vivo. PMN-dependent proteinuria, maximal in wild-type mice at 8 h, was absent in Mac-1 mutant mice at all time points. Complement C3–deficient mice also had significantly decreased proteinuria compared to wild-type mice. Since Mac-1 on PMNs is the principal ligand for ic3b, an absence of Mac-1 interaction with C3 probably contributed to the abrogation of proteinuria in Mac-1–null mice.

Differential response to myocardial reperfusion injury in eNOS-deficient mice

2002 ◽  
Vol 282 (6) ◽  
pp. H2422-H2426 ◽  
Author(s):  
Brent R. Sharp ◽  
Steven P. Jones ◽  
David M. Rimmer ◽  
David J. Lefer
Keyword(s):  
Ischemia Reperfusion ◽  
Myocardial Necrosis ◽  
In Vivo Model ◽  
Pcr Analysis ◽  
Inos Mrna ◽  
Mrna Levels ◽  
Wild Type ◽  
Significant Difference ◽  
Deficient Mice

Two strains of endothelial nitric oxide synthase (eNOS)-deficient (−/−) mice have been developed that respond differently to myocardial ischemia-reperfusion (MI/R). We evaluated both strains of eNOS−/− mice in an in vivo model of MI/R. Harvard (Har) eNOS−/− mice ( n = 12) experienced an 84% increase in myocardial necrosis compared with wild-type controls ( P < 0.05). University of North Carolina (UNC) eNOS−/−( n = 10) exhibited a 52% reduction in myocardial injury versus wild-type controls ( P < 0.05). PCR analysis of myocardial inducible NO synthase (iNOS) mRNA levels revealed a significant ( P < 0.05) increase in the UNC eNOS−/− mice compared with wild-type mice, and there was no significant difference between the Har eNOS−/− and wild-type mice. UNC eNOS−/− mice treated with an iNOS inhibitor (1400W) exacerbated the extent of myocardial necrosis. When treated with 1400W, Har eNOS−/− did not exhibit a significant increase in myocardial necrosis. These data demonstrate that two distinct strains of eNOS−/− mice display opposite responses to MI/R. Although the protection seen in the UNC eNOS−/− mouse may result from compensatory increases in iNOS, other genes may be involved.

Dephosphorylation of protamine 2 at serine 56 is crucial for murine sperm maturation in vivo

2019 ◽  
Vol 12 (574) ◽  
pp. eaao7232 ◽  
Author(s):  
Katsuhiko Itoh ◽  
Gen Kondoh ◽  
Hitoshi Miyachi ◽  
Manabu Sugai ◽  
Yoshiyuki Kaneko ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Sperm Maturation ◽  
Sperm Cells ◽  
Chromatin Binding ◽  
Wild Type ◽  
Underlying Mechanisms ◽  
Deficient Mice ◽  
Protamine 2

The posttranslational modification of histones is crucial in spermatogenesis, as in other tissues; however, during spermiogenesis, histones are replaced with protamines, which are critical for the tight packaging of the DNA in sperm cells. Protamines are also posttranslationally modified by phosphorylation and dephosphorylation, which prompted our investigation of the underlying mechanisms and biological consequences of their regulation. On the basis of a screen that implicated the heat shock protein Hspa4l in spermatogenesis, we generated mice deficient in Hspa4l (Hspa4l-null mice), which showed male infertility and the malformation of sperm heads. These phenotypes are similar to those of Ppp1cc-deficient mice, and we found that the amount of a testis- and sperm-specific isoform of the Ppp1cc phosphatase (Ppp1cc2) in the chromatin-binding fraction was substantially less in Hspa4l-null spermatozoa than that in those of wild-type mice. We further showed that Ppp1cc2 was a substrate of the chaperones Hsc70 and Hsp70 and that Hspa4l enhanced the release of Ppp1cc2 from these complexes, enabling the freed Ppp1cc2 to localize to chromatin. Pull-down and in vitro phosphatase assays suggested the dephosphorylation of protamine 2 at serine 56 (Prm2 Ser56) by Ppp1cc2. To confirm the biological importance of Prm2 Ser56 dephosphorylation, we mutated Ser56 to alanine in Prm2 (Prm2 S56A). Introduction of this mutation to Hspa4l-null mice (Hspa4l−/−; Prm2S56A/S56A) restored the malformation of sperm heads and the infertility of Hspa4l−/− mice. The dephosphorylation signal to eliminate phosphate was crucial, and these results unveiled the mechanism and biological relevance of the dephosphorylation of Prm2 for sperm maturation in vivo.

Differential requirement for A2a and A3 adenosine receptors for the protective effect of inosine in vivo

Blood ◽  
2003 ◽  
Vol 102 (13) ◽  
pp. 4472-4478 ◽  
Author(s):  
Gregorio Gomez ◽  
Michail V. Sitkovsky
Keyword(s):  
Protective Effect ◽  
Adenosine Receptors ◽  
Tissue Damage ◽  
Wild Type ◽  
In Vivo Models ◽  
Inflammatory Conditions ◽  
Severe Liver Damage ◽  
Lung Tissue Damage ◽  
Deficient Mice

AbstractInosine is an endogenous nucleoside with immunosuppressive properties that is known to inhibit the accumulation of proinflammatory cytokines and protect mice from endotoxin-induced inflammation and lung tissue damage. There are no known receptors specific for inosine, but A3 adenosine receptors (A3Rs) have been shown to bind inosine, resulting in mast cell degranulation and increased vascular permeability. The present study specifically addresses the requirement for A2aR and/or A3R for the protective effect of inosine in 2 experimental in vivo models of inflammatory disease. The data show that A3R is essential for protection against ConA-induced fulminant hepatitis since only A3R-expressing mice were protected by inosine whereas wild-type and A2aR-deficient mice exhibited severe liver damage even after administration of inosine. In addition, we show in a model of LPS-induced endotoxemia that inosine protected both A2aR-/- and A3R-/- mice from inflammation, but not A2aA3R double-null mice, indicating that in this model both A2aR and A3R were used by inosine. Thus, we demonstrate that A2a and A3 adenosine receptors are differentially utilized by inosine for the down-regulation of tissue damage under different inflammatory conditions in vivo. (Blood. 2003;102:4472-4478)

scholarly journals Nucleotide-Binding Oligomerization Domain-1 and -2 Play No Role in ControllingBrucella abortusInfection in Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Fernanda S. Oliveira ◽  
Natalia B. Carvalho ◽  
Dario S. Zamboni ◽  
Sergio C. Oliveira
Keyword(s):  
Host Defense ◽  
Nucleotide Binding ◽  
Wild Type ◽  
Spleen Cells ◽  
Similar Reduction ◽  
Cytoplasmic Proteins ◽  
Cytokine Synthesis ◽  
Deficient Mice ◽  
Oligomerization Domain

Nucleotide-binding oligomerization domain proteins (NODs) are modular cytoplasmic proteins implicated in the recognition of peptidoglycan-derived molecules. Further, severalin vivostudies have demonstrated a role for Nod1 and Nod2 in host defense against bacterial pathogens. Here, we demonstrated that macrophages from NOD1-, NOD2-, and Rip2-deficient mice produced lower levels of TNF-αfollowing infection with liveBrucella abortuscompared to wild-type mice. Similar reduction on cytokine synthesis was not observed for IL-12 and IL-6. However, NOD1, NOD2, and Rip2 knockout mice were no more susceptible to infection with virulentB. abortusthan wild-type mice. Additionally, spleen cells from NOD1-, NOD2-, and Rip2-deficient mice showed unaltered production of IFN-γcompared to C57BL/6 mice. Taken together, this study demonstrates that NOD1, NOD2 and Rip2 are dispensable for the control ofB. abortusduringin vivoinfection.

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