scholarly journals Acid Sphingomyelinase Inhibition Stabilizes Hepatic Ceramide Content and Improves Hepatic Biotransformation Capacity in a Murine Model of Polymicrobial Sepsis

2018 ◽  
Vol 19 (10) ◽  
pp. 3163 ◽  
Author(s):  
Ha-Yeun Chung ◽  
C. Witt ◽  
Jorge Hurtado-Oliveros ◽  
Jonathan Wickel ◽  
Markus Gräler ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Acute Phase ◽  
Host Response ◽  
Study Groups ◽  
Acid Sphingomyelinase ◽  
Polymicrobial Sepsis ◽  
Wild Type ◽  
Ceramide Content ◽  
Hepatic Monooxygenase ◽  
Hepatic Biotransformation

Liver dysfunction during sepsis is an independent risk factor leading to increased mortality rates. Specifically, dysregulation of hepatic biotransformation capacity, especially of the cytochrome P450 (CYP) system, represents an important distress factor during host response. The activity of the conserved stress enzyme sphingomyelin phosphodiesterase 1 (SMPD1) has been shown to be elevated in sepsis patients, allowing for risk stratification. Therefore, the aim of the present study was to investigate whether SMPD1 activity has an impact on expression and activity of different hepatic CYP enzymes using an animal model of polymicrobial sepsis. Polymicrobial sepsis was induced in SMPD1 wild-type and heterozygous mice and hepatic ceramide content as well as CYP mRNA, protein expression and enzyme activities were assessed at two different time points, at 24 h, representing the acute phase, and at 28 days, representing the post-acute phase of host response. In the acute phase of sepsis, SMPD1+/+ mice showed an increased hepatic C16- as well as C18-ceramide content. In addition, a downregulation of CYP expression and activities was detected. In SMPD1+/− mice, however, no noticeable changes of ceramide content and CYP expression and activities during sepsis could be observed. After 28 days, CYP expression and activities were normalized again in all study groups, whereas mRNA expression remained downregulated in SMPD+/+ animals. In conclusion, partial genetic inhibition of SMPD1 stabilizes hepatic ceramide content and improves hepatic monooxygenase function in the acute phase of polymicrobial sepsis. Since we were also able to show that the functional inhibitor of SMPD1, desipramine, ameliorates downregulation of CYP mRNA expression and activities in the acute phase of sepsis in wild-type mice, SMPD1 might be an interesting pharmacological target, which should be further investigated.

scholarly journals Renal Dnase1 expression is regulated by FGF23 but loss of Dnase1 does not alter renal phosphate handling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniela Egli-Spichtig ◽  
Martin Y. H. Zhang ◽  
Alfred Li ◽  
Eva Maria Pastor Arroyo ◽  
Nati Hernando ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Actin Polymerization ◽  
Fibroblast Growth Factor 23 ◽  
Wild Type ◽  
Vitamin D Metabolism ◽  
Endocrine Hormone ◽  
Dnase 1 ◽  
Sodium Dependent ◽  
Renal Tubular ◽  
High Phosphate

AbstractFibroblast growth factor 23 (FGF23) is a bone-derived endocrine hormone that regulates phosphate and vitamin D metabolism. In models of FGF23 excess, renal deoxyribonuclease 1 (Dnase1) mRNA expression is downregulated. Dnase-1 is an endonuclease which binds monomeric actin. We investigated whether FGF23 suppresses renal Dnase-1 expression to facilitate endocytic retrieval of renal sodium dependent phosphate co-transporters (NaPi-IIa/c) from the brush border membrane by promoting actin polymerization. We showed that wild type mice on low phosphate diet and Fgf23−/− mice with hyperphosphatemia have increased renal Dnase1 mRNA expression while in Hyp mice with FGF23 excess and hypophosphatemia, Dnase1 mRNA expression is decreased. Administration of FGF23 in wild type and Fgf23−/− mice lowered Dnase1 expression. Taken together, our data shows that Dnase1 is regulated by FGF23. In 6-week-old Dnase1−/− mice, plasma phosphate and renal NaPi-IIa protein were significantly lower compared to wild-type mice. However, these changes were transient, normalized by 12 weeks of age and had no impact on bone morphology. Adaptation to low and high phosphate diet were similar in Dnase1−/− and Dnase1+/+ mice, and loss of Dnase1 gene expression did not rescue hyperphosphatemia in Fgf23−/− mice. We conclude that Dnase-1 does not mediate FGF23-induced inhibition of renal tubular phosphate reabsorption.

scholarly journals Role for nsP2 Proteins in the Cessation of Alphavirus Minus-Strand Synthesis by Host Cells

2006 ◽  
Vol 80 (1) ◽  
pp. 360-371 ◽  
Author(s):  
Dorothea L. Sawicki ◽  
Silvia Perri ◽  
John M. Polo ◽  
Stanley G. Sawicki
Keyword(s):  
Host Response ◽  
Rna Synthesis ◽  
Late Phase ◽  
Host Cells ◽  
Minus Strand ◽  
Wild Type ◽  
Persistent Infections ◽  
Infected Cells ◽  
Replicative Intermediates ◽  
Transcription Complexes

ABSTRACT In order to establish nonlytic persistent infections (PI) of BHK cells, replicons derived from Sindbis (SIN) and Semliki Forest (SFV) viruses have mutations in nsP2. Five different nsP2 PI replicons were compared to wild-type (wt) SIN, SFV, and wt nsPs SIN replicons. Replicon PI BHK21 cells had viral RNA synthesis rates that were less than 5% of those of the wt virus and ∼10% or less of those of SIN wt replicon-infected cells, and, in contrast to wt virus and replicons containing wt nsP2, all showed a phenotype of continuous minus-strand synthesis and of unstable, mature replication/transcription complexes (RC+) that are active in plus-strand synthesis. Minus-strand synthesis and incorporation of [3H]uridine into replicative intermediates differed among PI replicons, depending on the location of the mutation in nsP2. Minus-strand synthesis by PI cells appeared normal; it was dependent on continuous P123 and P1234 polyprotein synthesis and ceased when protein synthesis was inhibited. The failure by the PI replicons to shut off minus-strand synthesis was not due to some defect in the PI cells but rather was due to the loss of some function in the mutated nsP2. This was demonstrated by showing that superinfection of PI cells with wt SFV triggered the shutdown of minus-strand synthesis, which we believe is a host response to infection with alphaviruses. Together, the results indicate alphavirus nsP2 functions to engage the host response to infection and activate a switch from the early-to-late phase. The loss of this function leads to continuous viral minus-strand synthesis and the production of unstable RC+.

scholarly journals Nutritional Effects on Host Response to Lung Infections with Mucoid Pseudomonas aeruginosa in Mice

2004 ◽  
Vol 72 (3) ◽  
pp. 1479-1486 ◽  
Author(s):  
Anna M. van Heeckeren ◽  
Mark Schluchter ◽  
Lintong Xue ◽  
Juan Alvarez ◽  
Steven Freedman ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Docosahexaenoic Acid ◽  
Knockout Mice ◽  
Host Response ◽  
Inflammatory Responses ◽  
Liquid Diet ◽  
Wild Type ◽  
Agarose Beads ◽  
Lung Infections

ABSTRACT In cystic fibrosis, a recessive genetic disease caused by defects in the cystic fibrosis conductance regulator (CFTR), the main cause of death is lung infection and inflammation. Nutritional deficits have been proposed to contribute to the excessive host inflammatory response in both humans and Cftr-knockout mice. Cftr-knockout mice and gut-corrected Cftr-knockout mice expressing human CFTR primarily in the gut were challenged with Pseudomonas aeruginosa-laden agarose beads; they responded similarly with respect to bronchoalveolar lavage cell counts and levels of the acute-phase cytokines tumor necrosis factor alpha, interleukin-1β (IL-1β), and IL-6. Wild-type mice fed the liquid diet used to prevent intestinal obstruction in Cftr-knockout mice had inflammatory responses to P. aeruginosa-laden agarose beads similar to those of wild-type mice fed an enriched solid diet, so dietary effects are unlikely to account for differences between wild-type mice and mice with cystic fibrosis. Finally, since cystic fibrosis patients and Cftr-knockout mice have an imbalance in fatty acids (significantly lower-than-normal levels of docosahexaenoic acid), the effects of specific supplementation with docosahexaenoic acid of wild-type and Cftr-knockout mice on their inflammatory responses to P. aeruginosa-laden agarose beads were tested. There were no significant differences (P = 0.35) in cumulative survival rates between Cftr-knockout mice and wild-type mice provided with either the liquid diet Peptamen or Peptamen containing docosahexaenoic acid. In conclusion, diet and docosahexaenoic acid imbalances alone are unlikely to explain the differences in the host response to lung infections with mucoid P. aeruginosa between mice with cystic fibrosis and their wild-type counterparts.

scholarly journals C/EBPα Is Critical for the Neonatal Acute-Phase Response to Inflammation

1998 ◽  
Vol 18 (12) ◽  
pp. 7269-7277 ◽  
Author(s):  
Bonnie L. Burgess-Beusse ◽  
Gretchen J. Darlington
Keyword(s):  
Dna Binding ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Northern Blot Analysis ◽  
Protein Gene ◽  
Phase Response ◽  
Wild Type ◽  
Neonatal Mice ◽  
Enhancer Binding Protein

ABSTRACT Members of the C/EBP (CCAAT/enhancer binding protein) family of transcription factors play important roles in mediating the acute-phase response (APR), an inflammatory process resulting from infection and/or tissue damage. Among the C/EBP family of proteins, C/EBPβ and -δ were thought to be the primary mediators of the APR. The function of C/EBPα in the APR has not been fully characterized to date. Here, we investigate the role of C/EBPα in the APR by using neonatal mice that lack C/EBPα expression. Northern blot analysis of acute-phase protein gene expression in neonatal mice treated with purified bacterial lipopolysaccharide or recombinant interleukin 1β as an inflammation stimulus showed a strong APR in wild-type mice, but a response in C/EBPα null animals was completely lacking. The C/EBPα knockout and wild-type mice demonstrated elevations in C/EBPβ and -δ mRNA expression and DNA binding as well as increased DNA binding of NF-κB, all of which are known to be important in the APR. Null mice, however, failed to activate STAT3 binding in response to lipopolysaccharide. Our results provide the first evidence that C/EBPα is absolutely required for the APR in neonatal mice, is involved in STAT3 regulation, and cannot be compensated for by other C/EBP family members.

scholarly journals The Cytolethal Distending Toxin Induces Receptor Activator of NF-κB Ligand Expression in Human Gingival Fibroblasts and Periodontal Ligament Cells

2005 ◽  
Vol 73 (1) ◽  
pp. 342-351 ◽  
Author(s):  
G. N. Belibasakis ◽  
A. Johansson ◽  
Y. Wang ◽  
C. Chen ◽  
S. Kalfas ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Mrna Expression ◽  
Periodontal Ligament ◽  
Aggressive Periodontitis ◽  
Periodontal Ligament Cells ◽  
Cytolethal Distending Toxin ◽  
Gingival Fibroblasts ◽  
Wild Type ◽  
Rankl Expression ◽  
Receptor Activator

ABSTRACT Actinobacillus actinomycetemcomitans is associated with localized aggressive periodontitis, a disease characterized by rapid loss of the alveolar bone surrounding the teeth. Receptor activator of NF-κB Ligand (RANKL) and osteoprotegerin (OPG) are two molecules that regulate osteoclast formation and bone resorption. RANKL induces osteoclast differentiation and activation, whereas OPG blocks this process by acting as a decoy receptor for RANKL. The purpose of this study was to investigate the effect of A. actinomycetemcomitans on the expression of RANKL and OPG in human gingival fibroblasts and periodontal ligament cells. RANKL mRNA expression was induced in both cell types challenged by A. actinomycetemcomitans extract, whereas OPG mRNA expression remained unaffected. Cell surface RANKL protein was also induced by A. actinomycetemcomitans, whereas there was no change in OPG protein secretion. A cytolethal distending toxin (Cdt) gene-knockout strain of A. actinomycetemcomitans did not induce RANKL expression, in contrast to its wild-type strain. Purified Cdt from Haemophilus ducreyi alone, or in combination with extract from the A. actinomycetemcomitans cdt mutant strain, induced RANKL expression. Pretreatment of A. actinomycetemcomitans wild-type extract with Cdt antiserum abolished RANKL expression. In conclusion, A. actinomycetemcomitans induces RANKL expression in periodontal connective tissue cells. Cdt is crucial for this induction and may therefore be involved in the pathological bone resorption during the process of localized aggressive periodontitis.

CCSP modulates airway dysfunction and host responses in an Ova-challenged mouse model

2001 ◽  
Vol 281 (5) ◽  
pp. L1303-L1311 ◽  
Author(s):  
Shan-Ze Wang ◽  
Cynthia L. Rosenberger ◽  
Teresa M. Espindola ◽  
Edward G. Barrett ◽  
Yohannes Tesfaigzi ◽  
...  
Keyword(s):  
Airway Epithelium ◽  
Host Response ◽  
Secretory Protein ◽  
Allergic Airway Disease ◽  
Clara Cell ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Airway Reactivity ◽  
Mucus Production

Clara cell secretory protein (CCSP) is synthesized by nonciliated bronchiolar cells in the lung and modulates lung inflammation to infection. To determine the role of CCSP in the host response to allergic airway disease, CCSP-deficient [(−/−)] mice were immunized twice with ovalbumin (Ova) and challenged by Ova (2 or 5 mg/m3) aerosol. After 2, 3, and 5 days of Ova aerosol challenge (6 h/day), airway reactivity was increased in CCSP(−/−) mice compared with wild-type [CCSP(+/+)] mice. Neutrophils were markedly increased in the bronchoalveolar lavage fluid of CCSP(−/−) Ova mice, coinciding with increased myeloperoxidase activity and macrophage inflammatory protein-2 levels. Lung histopathology and inflammation were increased in CCSP(−/−) compared with wild-type mice after Ova challenge. Mucus production, as assessed by histological staining, was increased in the airway epithelium of CCSP(−/−) Ova mice compared with that in CCSP(+/+) Ova mice. These data suggest a role for CCSP in airway reactivity and the host response to allergic airway inflammation and provide further evidence for the role of the airway epithelium in regulating airway responses in allergic disease.

scholarly journals Downregulated mRNA expression of ASPP and the hypermethylation of the 5′-untranslated region in cancer cell lines retaining wild-type p53

FEBS Letters ◽  
2005 ◽  
Vol 579 (7) ◽  
pp. 1587-1590 ◽  
Author(s):  
Ze-Jun Liu ◽  
Xin Lu ◽  
Yun Zhang ◽  
Shan Zhong ◽  
Shou-Zhi Gu ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Lines ◽  
Cancer Cell ◽  
Untranslated Region ◽  
Cancer Cell Lines ◽  
Wild Type ◽  
Wild Type P53

Interleukin-6 promotes myogenic differentiation of mouse skeletal muscle cells: role of the STAT3 pathway

2013 ◽  
Vol 304 (2) ◽  
pp. C128-C136 ◽  
Author(s):  
Miriam Hoene ◽  
Heike Runge ◽  
Hans Ulrich Häring ◽  
Erwin D. Schleicher ◽  
Cora Weigert
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Myogenic Differentiation ◽  
Muscle Cells ◽  
C2c12 Cells ◽  
Skeletal Muscle Cells ◽  
Wild Type ◽  
C2c12 Myoblasts ◽  
Sequence Of Events ◽  
Primary Mouse

Myogenic differentiation of skeletal muscle cells is characterized by a sequence of events that include activation of signal transducer and activator of transcription 3 (STAT3) and enhanced expression of its target gene Socs3. Autocrine effects of IL-6 may contribute to the activation of the STAT3-Socs3 cascade and thus to myogenic differentiation. The importance of IL-6 and STAT3 for the differentiation process was studied in C2C12 cells and in primary mouse wild-type and IL-6−/− skeletal muscle cells. In differentiating C2C12 myoblasts, the upregulation of IL-6 mRNA expression and protein secretion started after increased phosphorylation of STAT3 on tyrosine 705 and increased mRNA expression of Socs3 was observed. Knockdown of STAT3 and IL-6 mRNA in differentiating C2C12 myoblasts impaired the expression of the myogenic markers myogenin and MyHC IIb and subsequently myotube fusion. However, the knockdown of IL-6 did not prevent the induction of STAT3 tyrosine phosphorylation. The IL-6-independent activation of STAT3 was verified in differentiating primary IL-6−/− myoblasts. The phosphorylation of STAT3 and the expression levels of STAT3, Socs3, and myogenin during differentiation were comparable in the primary myoblasts independent of the genotype. However, IL-6−/− cells failed to induce MyHC IIb expression to the same level as in wild-type cells and showed reduced myotube formation. Supplementation of IL-6 could partially restore the fusion of IL-6−/− cells. These data demonstrate that IL-6 depletion during myogenic differentiation does not reduce the activation of the STAT3-Socs3 cascade, while IL-6 and STAT3 are both necessary to promote myotube fusion.

scholarly journals Anabolic Actions of Parathyroid Hormone during Bone Growth Are Dependent on c-fos

Endocrinology ◽  
2002 ◽  
Vol 143 (10) ◽  
pp. 4038-4047 ◽  
Author(s):  
Burak Demiralp ◽  
Hen-Li Chen ◽  
Amy J. Koh ◽  
Evan T. Keller ◽  
Laurie K. McCauley
Keyword(s):  
Trabecular Bone ◽  
Mrna Expression ◽  
Bone Growth ◽  
Critical Role ◽  
Calcium Content ◽  
Wild Type ◽  
Mineral Density ◽  
Femoral Bone Mineral Density ◽  
Endochondral Bone ◽  
Ash Weight

Abstract PTH has anabolic and catabolic actions in bone that are not clearly understood. The protooncogene c-fos and other activating protein 1 family members are critical transcriptional mediators in bone, and c-fos is up-regulated by PTH. The purpose of this study was to examine the mechanisms of PTH and the role of c-fos in PTH-mediated anabolic actions in bone. Mice with ablation of c-fos (−/−) and their wild-type (+/+) and heterozygous (+/−) littermates were administered PTH for 17 d. The +/+ mice had increased femoral bone mineral density (BMD), whereas −/− mice had reduced BMD after PTH treatment. PTH increased the ash weight of +/+ and +/−, but not −/−, femurs and decreased the calcium content of −/−, but not +/+ or +/−, femurs. Histomorphometric analysis showed that PTH increased trabecular bone volume in c-fos +/+, +/− vertebrae, but, in contrast, decreased trabecular bone in −/− vertebrae. Serum calcium levels in +/+ mice were greater than those in −/− mice, and PTH increased calcium in −/− mice. Histologically, PTH resulted in an exacerbation of the already widened growth plate and zone of hypertrophic chondrocytes but not the proliferating zone in −/− mice. PTH also increased calvarial thickness in +/+ mice, but not −/− mice. The c-fos −/− mice had lower bone sialoprotein and osteocalcin (OCN), but unaltered PTH-1 receptor mRNA expression in calvaria, suggesting an alteration in extracellular matrix. Acute PTH injection (8 h) resulted in a decrease in osteocalcin mRNA expression in wild-type, but unaltered expression in −/−, calvaria. These data indicate that c-fos plays a critical role in the anabolic actions of PTH during endochondral bone growth.

Upregulation of Escherichia coli heat-stable enterotoxin receptor in regenerating rat liver

1994 ◽  
Vol 266 (5) ◽  
pp. G899-G906 ◽  
Author(s):  
D. W. Laney ◽  
J. A. Bezerra ◽  
J. L. Kosiba ◽  
S. J. Degen ◽  
M. B. Cohen
Keyword(s):  
Escherichia Coli ◽  
Mrna Expression ◽  
Partial Hepatectomy ◽  
Rat Liver ◽  
Acute Phase ◽  
Chloride Secretion ◽  
Hepatocyte Proliferation ◽  
Heat Stable ◽  
Hepatocyte Regeneration ◽  
Regenerating Rat Liver

Guanylate cyclase C (GC-C) is a transmembrane protein that serves as a receptor for the recently characterized endogenous ligand guanylin and for Escherichia coli heat-stable toxin (STa). Binding of either guanylin or STa to intestinal GC-C results in net chloride secretion. Although GC-C is expressed in the rat intestine throughout life, its expression in the rat liver has previously been shown to occur only during the perinatal period. As a step toward elucidating the role of this receptor in the liver, we tested the hypothesis that GC-C mRNA expression could be induced in the adult rat liver following 1) partial hepatectomy, a stimulus for hepatocyte proliferation; 2) intraperitoneal carbon tetrachloride injection, a model of hepatocyte regeneration in the presence of inflammatory changes; and 3) subcutaneous turpentine injection, which generates an acute phase response without hepatocyte proliferation. We demonstrated expression of GC-C mRNA in the regenerating rat liver following either partial hepatectomy or CCl4-induced hepatic necrosis. We have also shown that GC-C mRNA expression occurred in association with an acute phase reaction. Coordinate with the expression of GC-C mRNA, there was upregulation of radiolabeled STa binding to liver plasma membranes prepared from turpentine-treated rats. Maximal expression of GC-C occurred in preparations enriched for the canalicular domain. Although the function of GC-C in the liver is unknown, localization to the canalicular domain would be consistent with a role for GC-C in hepatic chloride secretion, especially in the perinatal liver and during hepatocyte regeneration.

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