Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Decreased cytosolic [Ca2+] and impaired Ca2+ release in response to an IP3 challenge are among perturbations in hepatocyte Ca2+ homeostasis associated with endotoxemia and sepsis. These changes are consistent with the accompanying alterations in appropriate physiologic functions, e.g., activation of glycogen phosphorylase and gluconeogenesis, mediated by [Ca2+]c and defective phosphorylation of relevant enzymes. Attenuation of IP3 binding to the subcellular fractions that are imputed to be targets of IP3 and a decrease in the size of the IP3-sensitive pool of releasable Ca2+ are underlying components of the mechanism of the reduced Ca2+ release upon IP3 stimulation and its metabolic sequelae. ET treatment leads to a significant increase in Ca2+ associated with the cell surface compartment of adipocytes, a reduction in 45Ca2+ uptake by endoplasmic reticulum and higher cytosolic [Ca2+] under basal conditions and upon ACTH stimulation than that observed in cells of control rats. The reduced 45Ca2+ uptake is also manifest in adipocytes of septic rats. Alterations in adipocyte metabolism induced by ET include increased oxidation of glucose to CO2 (an insulin-like effect) and increased lipolysis upon NE and ACTH stimulation.
 ...
PMID:Altered Ca2+ homeostasis and functional correlates in hepatocytes and adipocytes in endotoxemia and sepsis. 225 82

The purpose of this study was to investigate possible alterations induced by sepsis and endotoxicosis in the late phase of Ca2+-dependent signaling in rat liver. Hepatocytes isolated from septic or chronically endotoxin (ET)-treated rats were labeled with [32P]H3PO4 and stimulated with various agents. Proteins were resolved by one-dimensional polyacrylamide gel electrophoresis and autoradiographed. Vasopressin (VP)- and phenylephrine (PE)-induced responses were attenuated in both septic and ET-treated rats for cytosolic and membrane proteins compared with their respective controls. Glucagon and 12-O-myristate phorbol-13-acetate (TPA) affected only the phosphorylation of membrane proteins. Glucagon-induced changes in the phosphorylation of membrane proteins were affected by both sepsis and endotoxicosis, whereas TPA-stimulated phosphorylation was lowered only in endotoxicosis. Response to the Ca2+ ionophore A23187 was depressed in septic rats for cytosolic proteins. The phosphorylation of two cytosolic proteins, i.e., 93 and 61 kDa (previously identified as glycogen phosphorylase and pyruvate kinase, respectively), in response to VP, PE, and A23187 was severely impaired by endotoxicosis and sepsis. TPA did not affect the phosphorylation state of these two proteins. The results show that sepsis and endotoxicosis produce perturbations of the phosphorylation step in Ca2+ transmembrane signaling. Such changes can explain alterations of glycogenolysis and gluconeogenesis associated with sepsis and endotoxicosis.
 ...
PMID:Protein phosphorylation in isolated hepatocytes of septic and endotoxemic rats. 258 48

Our results reviewed here may be summarized as follows: 1. Continuous endotoxemia significantly interferes with Ca2+-dependent information flow in the liver. 2. The subcellular sites where these molecular lesions can be localized include: a.) the plasma membrane-there are effects at the level of alpha 1-adrenergic and vasopressin binding, and also in the coupling of receptor activation to inositol lipid metabolism in terms of PIP2 degradation and resynthesis b.) the endoplasmic reticulum in terms of Ca2+ release and PI synthesis. Another one of the sequelae of Ca2+-associated receptor activation, namely, cytosolic ionized Ca2+ concentration is also affected. 3. Finally, in addition to seeing the impact of acute or continuous endotoxemia at the level of receptor activation and signal generation, we can also document alterations in the expression of physiologic function subserved by these Ca2+- and inositol lipid-associated signaling processes--i.e. in glycogen phosphorylase activity-being consistent with the above described changes. In conclusion, we state that a causal link is shown between receptor binding, agonist-induced phosphoinositide hydrolysis, intracellular Ca2+ mobilization and activation of phosphorylase a in the liver, suggesting that these alterations may underlie some of the metabolic consequences of chronic sepsis.
 ...
PMID:Perturbation of transmembrane signaling mechanisms in acute and chronic endotoxemia. 303 27

Rats were treated with Escherichia coli endotoxin (ET) either acutely or chronically or rendered septic by cecal ligation and puncture. At 6 h after ET injection, at various intervals of continuous ET infusion, and at 17-18 h after the onset of peritonitis, animals were killed and hepatocytes were isolated. Cytosolic [Ca2+] ([Ca2+]c) was measured by quin 2 during the resting state and after stimulation with epinephrine and vasopressin. Basal and epinephrine-, vasopressin- and glucagon-stimulated glycogen phosphorylase activity were also determined. In hepatocytes from acutely ET-treated rats, resting levels of [Ca2+]c were decreased 46% from 245.8 +/- 11.0 to 131.0 +/- 8.5 nM (n = 4-6, P less than 0.05). In septic rats a 39.5% decrease was noted [i.e., from 154.0 +/- 17.7 (n = 4, sham) to 93.3 +/- 91 nM (n = 5, septic, P less than 0.05)]. These decreased [Ca2+]c levels were associated with changes of glycogen phosphorylase activity in a manner suggesting a cause and effect relationship; e.g., acute ET treatment resulted in greater than 80% depression of phosphorylase a activity, whereas sepsis induced a 58% decrease in the activity of this enzyme. In ET-infused rats the resting level of [Ca2+]c and its response to hormonal stimulation were not different from hepatocytes of saline-infused rats, although glycogen phosphorylase activity was less responsive to these hormones. The effect on the enzyme's response to Ca2+-mobilizing hormones was more marked than to glucagon. This is consistent with the concept that information flow in the Ca2+-messenger system is a site of metabolic lesions produced by endotoxicosis and sepsis.
 ...
PMID:Rat liver free cytosolic Ca2+ and glycogen phosphorylase in endotoxicosis and sepsis. 353 41

In the present study, rat cardiac sarcoplasmic reticulum (SR) phospholamban (PLB) phosphatase was partially purified by chromatography on DEAE-Sephacel. This PLB phosphatase was indentical to phosphatase-1. It was shown on electrophoresis of SDS-PAGE autoradiography that the PLB phosphatase in rats during early sepsis (ES) depressed dephosphorylation of substrates (32P-phosphorylase a and 32P-SR). However, dephosphorylation of the substrates by the partially purified phosphatase during late sepsis (LS) was same as that in control rats. The partially purified PLB phosphatase activity in ES rats was significantly decreased, but showed no change in LS rats. The results above were confirmed by a studing of the substrate concentration (enzyme concentration, time)--enzyme reaction velocity curve in showing that both affinity and maximum initial velocity (Vmax) of the phosphatase in the ES rats were decreased, but had no change in those in the LS rats.
 ...
PMID:[Alteration of phospholamban phosphatase activity associated with cardiac sarcoplasmic reticulum during sepsis in rats]. 748 77

Human anaphylatoxin C3a had previously been shown to increase glycogenolysis in perfused rat liver and prostanoid formation in rat liver macrophages. Surprisingly, human C5a, which in other systems elicited stronger responses than C3a, did not increase glycogenolysis in perfused rat liver. Species incompatibilities within the experimental system had been supposed to be the reason. The current study supports this hypothesis: (1) In rat liver macrophages that had been maintained in primary culture for 72 h recombinant rat anaphylatoxin C5a in concentrations between 0.1 and 10 micrograms/ml increased the formation of thromboxane A2, prostaglandin D2, E2 and F2 alpha 6- to 12-fold over basal within 10 min. In contrast, human anaphylatoxin C5a did not increase prostanoid formation in rat Kupffer cells. (2) The increase in prostanoid formation by recombinant rat C5a was specific. It was inhibited by a neutralizing monoclonal antibody. (3) In co-cultures of rat hepatocytes and rat Kupffer cells but not in hepatocyte mono-cultures recombinant rat C5a increased glycogen phosphorylase activity 3-fold over basal. This effect was inhibited by incubation of the co-cultures with 500 microM acetylsalicyclic acid. Thus, C5a generated either locally in the liver or systemically e.g. in the course of sepsis, may increase hepatic glycogenolysis by a prostanoid-mediated intercellular communication between Kupffer cells and hepatocytes.
 ...
PMID:Stimulation of glycogen phosphorylase in rat hepatocytes via prostanoid release from Kupffer cells by recombinant rat anaphylatoxin C5a but not by native human C5a in hepatocyte/Kupffer cell co-cultures. 755 29

Recent evidence indicates that inflammatory cytokines are involved in changes of blood glucose concentrations and hepatic glucose metabolism in infectious diseases, including sepsis. However, little is known regarding how cytokines interact with glucoregulatory hormones such as insulin. The objective of the present study is to investigate if and how cytokines influence insulin-stimulated glycogen metabolism in the liver. Interleukin 1beta (IL-1beta) and interleukin 6 (IL-6) markedly inhibited the increase of glycogen deposition stimulated by insulin in primary rat hepatocyte cultures; however, tumor necrosis factor alpha had no effect. Labeling experiments revealed that both cytokines counteracted insulin action by decreasing [14C]-glucose incorporation into glycogen and by increasing [14C]-glycogen degradation. Furthermore, it was discovered that IL-1beta and IL-6 inhibited glycogen synthase activity and, in contrast, accelerated glycogen phosphorylase activity. In experiments with kinase inhibitors, serine/threonine kinase inhibitor K252a blocked IL-1beta- and IL-6-induced inhibitions of glycogen deposition, as well as glycogen synthase activity, whereas another kinase inhibitor staurosporine blocked only IL-6-induced inhibition. Tyrosine kinase inhibitor herbimycin A blocked only IL-1beta-induced inhibition. These results indicate that IL-1beta and IL-6 regulate insulin-stimulated glycogen synthesis through different pathways involving protein phosphorylation in hepatocytes. They may mediate the change of hepatic glucose metabolism under pathological and even physiological conditions by modifying insulin action in vivo.
 ...
PMID:Interleukin 1beta and interleukin 6, but not tumor necrosis factor alpha, inhibit insulin-stimulated glycogen synthesis in rat hepatocytes. 958 83

We report a false negative histochemical reaction for myophosphorylase in the case of an 11 year old with fulminant Staphylococcus aureus. Due to increased creatine kinase levels and marked myoglobinuria a muscle biopsy was performed prior to death. The biopsy revealed rhabdomyolysis, glycogen depletion and absent myophosphorylase reactivity. Subsequent myophosphorylase quantification was normal. This unique case of a false negative myophosphorylase histochemical reaction is apparently related to sepsis.
 ...
PMID:False negative histochemical reaction for myophosphorylase activity in fulminant sepsis due to methicillin resistant Staphylococcus aureus. 1771 80