scholarly journals Absence of receptor guanylyl cyclase C enhances ileal damage and reduces cytokine and antimicrobial peptide production during oralSalmonellaTyphimurium infection

2017 ◽  
Author(s):  
Shamik Majumdar ◽  
Vishwas Mishra ◽  
Somesh Nandi ◽  
Mudabir Abdullah ◽  
Anaxee Barman ◽  
...  
Keyword(s):  
Guanylyl Cyclase ◽  
Cell Damage ◽  
Ion Homeostasis ◽  
Serum Cortisol ◽  
Oral Route ◽  
Intestinal Cell ◽  
Guanylyl Cyclase C ◽  
Wild Type ◽  
Double Positive ◽  
Susceptibility To Infection

AbstractNon-typhoidalSalmonelladisease contributes towards significant morbidity and mortality across the world. Host factors including IFN-γ, TNF-α and gut microbiota, significantly influence the outcome ofSalmonellapathogenesis. However, the entire repertoire of host protective mechanisms contributing toSalmonellapathogenicity is not completely appreciated. Here, we have investigated the roles of receptor guanylyl cyclase C (GC-C) that is predominantly expressed in the intestine, and regulates intestinal cell proliferation and fluid-ion homeostasis. Mice deficient in GC-C (Gucy2c-/-) displayed accelerated mortality following infection via the oral route, in spite of possessing comparative systemicSalmonellainfection burden. Survival following intra-peritoneal infection remained similar, indicating that GC-C offered protection via a gut-mediated response. Serum cortisol was higher inGucy2c-/-mice, in comparison to wild type (Gucy2c+/+) mice, and an increase in infection-induced thymic atrophy, with loss in immature CD4+CD8+double positive thymocytes, was observed. Accelerated and enhanced damage in the ileum, including submucosal edema, epithelial cell damage, focal tufting and distortion of villus architecture, was seen inGucy2c-/-mice, concomitant with a larger number of ileal tissue-associated bacteria. Transcription of key mediators inSalmonella-induced inflammation (IL-22/Reg3β) were altered inGucy2c-/-mice in comparison toGucy2c+/+mice. A reduction in fecal Lactobacilli, which are protective against Salmonella infection, was observed inGucy2c-/-mice.Gucy2c-/-mice cohoused with wild type mice continued to show reduced Lactobacilli and increased susceptibility to infection. Our study therefore suggests that receptor GC-C confers a survival advantage during gut-mediatedS. Typhimurium pathogenesis, presumably by regulatingSalmonella-effectormechanisms and maintaining a beneficial microbiome.

scholarly journals Absence of Receptor Guanylyl Cyclase C Enhances Ileal Damage and Reduces Cytokine and Antimicrobial Peptide Production during OralSalmonella entericaSerovar Typhimurium Infection

2018 ◽  
Vol 86 (5) ◽  
Author(s):  
Shamik Majumdar ◽  
Vishwas Mishra ◽  
Somesh Nandi ◽  
Mudabir Abdullah ◽  
Anaxee Barman ◽  
...  
Keyword(s):  
Guanylyl Cyclase ◽  
Cell Damage ◽  
Ion Homeostasis ◽  
Intestinal Cell ◽  
Serum Cortisol Level ◽  
Guanylyl Cyclase C ◽  
Wild Type ◽  
Double Positive ◽  
Necrosis Factor Alpha ◽  
Content Type

ABSTRACTNontyphoidalSalmonelladisease contributes toward significant morbidity and mortality across the world. Host factors, including gamma interferon, tumor necrosis factor alpha, and gut microbiota, significantly influence the outcome ofSalmonellapathogenesis. However, the entire repertoire of host protective mechanisms contributing toSalmonellapathogenicity is not completely appreciated. Here, we investigated the roles of receptor guanylyl cyclase C (GC-C), which is predominantly expressed in the intestine and regulates intestinal cell proliferation and fluid-ion homeostasis. Mice deficient in GC-C (Gucy2c−/−) displayed accelerated mortality compared with that for wild-type mice following infection via the oral route, even though both groups possessed comparable systemicSalmonellainfection burdens. Survival following intraperitoneal infection remained similar in both groups, indicating that GC-C offered protection via a gut-mediated response. The serum cortisol level was higher inGucy2c−/−mice than wild-type (Gucy2c+/+) mice, and an increase in infection-induced thymic atrophy with a loss of immature CD4+CD8+double-positive thymocytes was observed. Accelerated and enhanced damage in the ileum, including submucosal edema, epithelial cell damage, focal tufting, and distortion of the villus architecture, was seen inGucy2c−/−mice concomitantly with a larger number of ileal tissue-associated bacteria. Transcription of key mediators ofSalmonella-induced inflammation (interleukin-22/Reg3β) was altered inGucy2c−/−mice in comparison to that inGucy2c+/+mice. A reduction in fecal lactobacilli, which are protective againstSalmonellainfection, was observed inGucy2c−/−mice.Gucy2c−/−mice cohoused with wild-type mice continued to show reduced amounts of lactobacilli and increased susceptibility to infection. Our study, therefore, suggests that the receptor GC-C confers a survival advantage during gut-mediatedSalmonella entericaserovar Typhimurium pathogenesis, presumably by regulatingSalmonellaeffector mechanisms and maintaining a beneficial microbiome.

Guanylyl cyclase C deficient mice have more severe carbon tetrachloride (CCl4)-induced liver injury than wild-type controls

2000 ◽  
Vol 118 (4) ◽  
pp. A292
Author(s):  
Elizabeth A. Mann ◽  
Meg P. Sheil-Puopolo ◽  
Ralph A. Giannella
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Guanylyl Cyclase ◽  
Guanylyl Cyclase C ◽  
Wild Type ◽  
Deficient Mice

scholarly journals Intestinal Cell Proliferation and Senescence Are Regulated by Receptor Guanylyl Cyclase C and p21

2013 ◽  
Vol 289 (1) ◽  
pp. 581-593 ◽  
Author(s):  
Nirmalya Basu ◽  
Sayanti Saha ◽  
Imran Khan ◽  
Subbaraya G. Ramachandra ◽  
Sandhya S. Visweswariah
Keyword(s):  
Cell Proliferation ◽  
Guanylyl Cyclase ◽  
Intestinal Cell ◽  
Guanylyl Cyclase C

Comparison of receptors for Escherichia coli heat-stable enterotoxin: novel receptor present in IEC-6 cells

1993 ◽  
Vol 264 (1) ◽  
pp. G172-G178 ◽  
Author(s):  
E. A. Mann ◽  
M. B. Cohen ◽  
R. A. Giannella
Keyword(s):  
Escherichia Coli ◽  
Cell Lines ◽  
Guanylyl Cyclase ◽  
Receptor Expression ◽  
Cloning And Expression ◽  
Cyclase Activity ◽  
Intestinal Cell ◽  
Guanylyl Cyclase C ◽  
Heat Stable ◽  
Guanylyl Cyclase Activity

Enterotoxigenic Escherichia coli elaborate a heat-stable enterotoxin that causes diarrhea in humans and animals. The primary event in the diarrheal cascade is the binding of this enterotoxin to specific receptors on enterocytes and activation of guanylyl cyclase. Two intestinal cell lines, Caco-2 and IEC-6, were tested for the presence of these receptors. Although both cell lines exhibited specific binding, only the Caco-2 cell line responded to heat-stable enterotoxin with increased guanylyl cyclase activity. Cloning and expression studies confirmed that the receptor present in Caco-2 cells is a homologue of guanylyl cyclase C, a known transmembrane heat-stable enterotoxin receptor. Expression of the receptor in differentiating Caco-2 cells increases with cell maturation, indicating that these cells are a suitable model for future studies. However, Northern and polymerase chain reaction analyses demonstrated that guanylyl cyclase C is not expressed in IEC-6 cells, strongly suggesting the presence of a novel heat-stable enterotoxin receptor that is not coupled to guanylyl cyclase activity.

115 Abnormal sodium and calcium ion homeostasis and cell damage in cardiomyopathic hamster

2003 ◽  
Vol 2 (1) ◽  
pp. 16
Author(s):  
I YUKO ◽  
K YUKI ◽  
S MUNEKAZU
Keyword(s):  
Calcium Ion ◽  
Cell Damage ◽  
Ion Homeostasis ◽  
Cardiomyopathic Hamster

scholarly journals In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids of Holarrhena pubescens Wall. ex G. Don to Guanylyl Cyclase C: Implications in Designing of Novel Antidiarrheal Therapeutic Strategies

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4147
Author(s):  
Neha Gupta ◽  
Saurav Kumar Choudhary ◽  
Neeta Bhagat ◽  
Muthusamy Karthikeyan ◽  
Archana Chaturvedi
Keyword(s):  
Molecular Docking ◽  
Amino Acid ◽  
Guanylyl Cyclase ◽  
Extracellular Domain ◽  
Enterotoxigenic Escherichia Coli ◽  
Watery Diarrhea ◽  
Guanylyl Cyclase C ◽  
Amino Acid Residues ◽  
Lead Compounds

The binding of heat stable enterotoxin (STa) secreted by enterotoxigenic Escherichia coli (ETEC) to the extracellular domain of guanylyl cyclase c (ECDGC-C) causes activation of a signaling cascade, which ultimately results in watery diarrhea. We carried out this study with the objective of finding ligands that would interfere with the binding of STa on ECDGC-C. With this view in mind, we tested the biological activity of a alkaloid rich fraction of Holarrhena pubescens against ETEC under in vitro conditions. Since this fraction showed significant antibacterial activity against ETEC, we decided to test the screen binding affinity of nine compounds of steroidal alkaloid type from Holarrhena pubescens against extracellular domain (ECD) by molecular docking and identified three compounds with significant binding energy. Molecular dynamics simulations were performed for all the three lead compounds to establish the stability of their interaction with the target protein. Pharmacokinetics and toxicity profiling of these leads demonstrated that they possessed good drug-like properties. Furthermore, the ability of these leads to inhibit the binding of STa to ECD was evaluated. This was first done by identifying amino acid residues of ECDGC-C binding to STa by protein–protein docking. The results were matched with our molecular docking results. We report here that holadysenterine, one of the lead compounds that showed a strong affinity for the amino acid residues on ECDGC-C, also binds to STa. This suggests that holadysenterine has the potential to inhibit binding of STa on ECD and can be considered for future study, involving its validation through in vitro assays and animal model studies.

Identification of a binding region onEscherichia coli heat-stable enterotoxin to intestinal guanylyl cyclase C

1997 ◽  
Vol 4 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Makoto Hasegawa ◽  
Yuki Kawano ◽  
Kazuya Matsumoto ◽  
Yuji Hidaka ◽  
Takashi Sato ◽  
...  
Keyword(s):  
Guanylyl Cyclase ◽  
Guanylyl Cyclase C ◽  
Binding Region ◽  
Heat Stable

Evaluation of Guanylyl Cyclase C Lymph Node Status for Colon Cancer Staging and Prognosis

2011 ◽  
Vol 18 (12) ◽  
pp. 3261-3270 ◽  
Author(s):  
Daniel J. Sargent ◽  
Murray B. Resnick ◽  
Michael O. Meyers ◽  
Atoussa Goldar-Najafi ◽  
Thomas Clancy ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Lymph Node ◽  
Guanylyl Cyclase ◽  
Cancer Staging ◽  
Lymph Node Status ◽  
Guanylyl Cyclase C ◽  
Node Status

Sevoflurane but not propofol provided dual effects of cell survival in human neuroblastoma SH-SY5Y cells

2021 ◽  
Vol 18 ◽  
Author(s):  
Xue Gao ◽  
Xiu Wang ◽  
Lei Zhang ◽  
Ge Liang ◽  
Rachel Mund ◽  
...  
Keyword(s):  
Cell Survival ◽  
Prolonged Exposure ◽  
Calcium Influx ◽  
Cell Damage ◽  
Cytosolic Calcium ◽  
Extracellular Calcium ◽  
Mitochondrial Calcium ◽  
General Anesthetics ◽  
Wild Type ◽  
Human Neuroblastoma

Background: We have hypothesized that the most commonly used intravenous (propofol) and inhalational (sevoflurane) general anesthetics affect cell survival concentration and duration dependently with different potency associated with their differential potency to affect intracellular calcium homeostasis. Methods: Human neuroblastoma SH-SY5Y cells stably transfected with either wild type or M146L mutant human presenilin 1 were cultured and exposed to equipotent of propofol or sevoflurane. Cell viability, cytosolic and mitochondrial calcium were measured. Results: Sevoflurane but not propofol, at clinically relevant concentrations and durations, promoted cell survival. Prolonged exposure (24 hours) of 1% sevoflurane resulted in significant cell damage in both types of cells. Both sevoflurane and propofol had significantly higher cell response rates to the elevation of cytosolic calcium or mitochondrial calcium in the presence of extracellular calcium. With the contribution of calcium influx, sevoflurane but not equipotent 1 MAC propofol, caused a significantly greater increase in peak and overall calcium in Alzheimer’s mutation cell than in wild type cells, but significantly more increase in overall mitochondrial calcium concentrations in wild type than mutation cells. In the absence of extracellular calcium influx, sevoflurane, but not propofol, caused more significant elevations of overall mitochondrial calcium concentration in mutation cells than control cells. Conclusion: Calcium influx contributed to the general anesthetics mediated elevation of cytosolic or mitochondrial calcium, which is especially true for propofol. Sevoflurane has a greater potency to either promote or inhibit cell survival than propofol, which may be associated with its ability to affect cytosolic or mitochondrial calcium.

scholarly journals Screening for Modulators of Spermine Tolerance Identifies Sky1, the SR Protein Kinase of Saccharomyces cerevisiae, as a Regulator of Polyamine Transport and Ion Homeostasis

2001 ◽  
Vol 21 (1) ◽  
pp. 175-184 ◽  
Author(s):  
Omri Erez ◽  
Chaim Kahana
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Kinase ◽  
Osmotic Shock ◽  
Ion Homeostasis ◽  
Inorganic Ions ◽  
Yeast Cells ◽  
Wild Type ◽  
Sr Protein ◽  
Polyamine Transport ◽  
Increased Sensitivity

ABSTRACT Although most cells are capable of transporting polyamines, the mechanism that regulates polyamine transport in eukaryotes is still largely unknown. Using a genetic screen for clones capable of restoring spermine sensitivity to spermine-tolerant mutants ofSaccharomyces cerevisiae, we have demonstrated that Sky1p, a recently identified SR protein kinase, is a key regulator of polyamine transport. Yeast cells deleted for SKY1 developed tolerance to toxic levels of spermine, while overexpression of Sky1p in wild-type cells increased their sensitivity to spermine. Expression of the wild-type Sky1p but not of a catalytically inactive mutant restored sensitivity to spermine. SKY1 disruption results in dramatically reduced uptake of spermine, spermidine, and putrescine. In addition to spermine tolerance, sky1Δ cells exhibit increased tolerance to lithium and sodium ions but somewhat increased sensitivity to osmotic shock. The observed halotolerance suggests potential regulatory interaction between the transport of polyamines and inorganic ions, as suggested in the case of the Ptk2p, a recently described regulator of polyamine transport. We demonstrate that these two kinases act in two different signaling pathways. While deletion or overexpression of SKY1 did not significantly affect Pma1p activity, the ability of overexpressed Sky1p, Ptk1p, and Ptk2p to increase sensitivity to LiCl depends on the integrity ofPPZ1 but not of ENA1.

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