Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF) is thought to be an important mediator of the septic response; intravenous administration of this cytokine provokes a wide range of metabolic and hemodynamic effects which closely resemble those known to follow endotoxin administration. These effects include damage to gut mucosa. Since the gut constitutes an internal reservoir of endotoxin and bacteria it is possible that some of TNF's effects might be secondary to an increased absorption of these agents. To test this hypothesis TNF was given both to intact dogs and also to animals in which the gut had been removed, from duodenum to anus ("enterectomy"). The data indicates that the effects of TNF upon systemic pressure, white count, and cortisol and glucagon levels were not affected by prior removal of the gut. For most other parameters the findings were less clear but in general the changes in enterectomized dogs were qualitatively similar to those described in the intact animal. We conclude that the effects observed following TNF infusion in the dog are not dependent on the intestinal tract as a secondary source of bacteria or mediators.
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PMID:The effects of tumor necrosis factor after removal of the gut. 842 37

The immune and endocrine mediators that are released during sepsis (e.g., tumor necrosis factor [TNF] alpha, interleukin [IL]-1, IL-6, transforming growth factor [TGF] beta, prostaglandin [PG] E2, catecholamines, vasopressin, glucagon, insulin, and glucocorticoids) can produce inappropriate detrimental cellular responses contributing to exacerbation of septic injury. Examples of such sepsis-related inappropriate responses are: exaggerated hepatic acute-phase protein (APP) expression and release skeletal muscle insulin resistance, and suppressed T-lymphocyte proliferation. The studies discussed in this article present evidence that the generation of the sepsis-related hepatic, skeletal muscle, and T-lymphocyte responses emanate from alterations in intracellular Ca2+ (Ca2+i) homeostasis. In hepatocytes, there is indication of a sepsis-mediated increase in Ca2+ influx from the extracellular milieu leading to a sustained increase in the apparent resting cell Ca2+i concentration ([Ca2+]i) and its depressed elevation on stimulation with Ca2+-mobilizing hormones such as catecholamines and vasopressin. These Ca(2+)- related changes can affect not only the signaling pathways in which Ca2+i itself serves as a signaling component, but also the signaling systems turned on by other sepsis-induced agonists which may not be dependent on Ca2+ signaling. TGF-beta, IL-1, TNF alpha, and IL-6 activate a primarily protein kinase C (PKC)-dependent intracellular signal system for the elicitation of a normal hepatic APP response (APPR). The increased apparent basal [Ca2+]i in sepsis can hypersensitize PKC activation and thus lead to an exaggerated APPR. In the skeletal muscle, an evident increase in Ca2+ membrane flux during sepsis pointed to an increase in the basal [Ca2+]i resulting from a plausible cytokine-mediated overactivation of the voltage-sensitive Ca2+ channels. The increased basal [Ca2+]i can negatively modulate the insulin-mediated stimulation of GLUT4-dependent glucose transport despite the possibility that Ca2+i might not participate as a component in the insulin-receptor-regulated signaling pathway. Increased [Ca2+]i in skeletal myocytes can either directly promote the phosphorylation of GLUT4 or prevent its dephosphorylation, both of which effectively block insulin stimulation of glucose uptake, thereby contributing to insulin resistance. In T lymphocytes, septic injury appears to induce an attenuation in the mitogen and, thus, presumably a T-cell antigen receptor (TCR)-mediated elevation in [Ca2+]i without affecting the basal [Ca2+]i. This decrease in TCR-related Ca2+i mobilization evidently contributes to the suppression of T lymphocyte proliferation during sepsis, probably via an in vivo action of prostaglandin (PG) E2 on the T cells during sepsis. The blockade of PGE2 production after indomethacin administration to septic animals prevents alterations in both T-cell Ca2+i mobilization and proliferation. PGE2 probably acts through its second messenger, cyclic adenosine 3'5'-monophosphate, which can antagonize Ca2+i signaling in T cells.
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PMID:Alterations in calcium signaling and cellular responses in septic injury. 868 77

The cytokine IL-1 beta has previously been demonstrated to induce the expression of the stress genes iNOS, hsp70, heme oxygenase and Mn-SOD in rat pancreatic islets in vitro. The aim of this study was to determine whether the IL-1 beta-induced effects are specific for the insulin producing beta-cell, or whether other islet cells, such as the glucagon-producing alpha-cell, respond to IL-1 beta addition. Purified rat alpha- and beta-cell suspensions were obtained by fluorescence-activated cell sorting and incubated with or without IL-1 beta (25 U/ml) for 24 h. The alpha- and beta-cell contents of hsp70, heme oxygenase and Mn-SOD and medium nitrite levels were determined. It was found that IL-1 beta exposure induced the production of nitric oxide in beta-cells, but not in alpha-cells. Moreover, the expression of hsp70, heme oxygenase and Mn-SOD was also induced in beta-cells, but not in alpha-cells. There were no detectable levels of hsp70 in alpha-cells. It is concluded that the stress gene response following IL-1 beta exposure is markedly different in alpha- and beta-cells. This finding may be of importance for the understanding of the autoimmune destruction of beta-cells in insulin-dependent diabetes mellitus.
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PMID:Interleukin-1 beta induces the expression of hsp70, heme oxygenase and Mn-SOD in FACS-purified rat islet beta-cells, but not in alpha-cells. 871 14

Existance of messenger ribonucleic acids of eleven functionally differentiated proteins in normal human cells and tumor cell lines was investigated using reverse transcription--nested polymerase chain reaction method. Examined gene transcripts were those of progesterone receptor, estrogen receptor, interleukin 2, CD8, parathyroid hormone, cholecystokinin/pancreozymin, glucagon, insulin, adrenocorticotropic hormone, enkephalin and thyroid stimulating hormone. In RT-PCR almost all primers were originally designed and sequences of PCR products were confirmed by the Sanger's method. Investigated cells were normal human peripheral mononuclear cells and their subsets, lymphokine-activated killer cells, gastric mucosal cells, sperm and fifteen established tumor cell lines. All of the examined mRNAs were detected in all of the above cell groups. Therefore, cells of independent tissues or tumors share same kinds of mRNA such as steroid hormone receptors, cytokine, lymphocyte surface molecule and parathyroid, digestive and cerebral hormones. These findings strongly suggest that every cell can express every mRNA. Beneath the cell differentiation there may exist a DNA-->RNA basal constant flow, the arrow of time captured in a cell.
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PMID:Gene transcripts of eleven proteins with specific functions are all detected in human normal cells and tumor cell lines: a possible DNA-->RNA basal constant flow. 872 Oct 92

Tumor necrosis factor (TNF alpha) has been shown to inhibit insulin release and it has been postulated to-be an important effector in islet rejection. We studied the effect of cryopreservation on glucose oxidation rate (GOR), lipid synthesis, hormone secretion (insulin, glucagon, somatostatin, thyrotropin-releasing hormone), and cyclic guanosine 3',5'-monophosphate (cGMP) content of human islets, in the presence or absence of TNF alpha, looking for changes that could explain a different susceptibility to rejection for cryopreserved islets. Islets were isolated from multiple organ donor pancreata by collagenase digestion. The islets were then cultured for 7 days, cryopreserved (-0.25 degrees C/min), and stored in liquid N2. After 24 h of culture, thawed islets were cultured for an other 24 h in the presence or absence of TNF alpha. Islets were then washed to remove the cytokine and incubated in Krebs-Ringer bicarbonate (5 or 20 mM glucose), and both the cGMP content of the islets and the hormone concentration in the medium were determined by radio-immunoassay. GOR was measured as the production of 14CO2 from 5 or 20 mM D-[U-14C]glucose, and de novo lipid synthesis was determined as D-[U-14C]glucose incorporation into different lipidic fractions. Cryopreservation did not significantly modify the hormone response to glucose but it partially reversed the TNF alpha-induced inhibitory effect on insulin release in the presence of 20 mM glucose. In addition, the inhibitory effect of TNF alpha on phosphatidylcholine labeling was attenuated in cryopreserved islets compared with noncryopreserved islets. TNF alpha significantly stimulated islet nitrite production and cGMP accumulation, both effects being of a similar magnitude in cryopreserved and noncryopreserved islets. Our results suggest that cryopreservation can modify the metabolic and hormone response of human islets to TNF alpha. This effect is not mediated by changes in the TNF alpha-induced islet nitric oxide production or cGMP accumulation.
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PMID:Influence of cryopreservation on the sensitivity of human islets to tumor necrosis factor. 878 31

Interferon-alpha (IFN alpha) concentrations are increased in conditions associated with tissue injury. To investigate the endocrine and metabolic actions of IFN alpha in vivo, we studied eight healthy controls on two occasions, once after administration of 5 million units/m2 rhIFN alpha and once after administration of saline (control). Rates of appearance (Ra) of glucose and glycerol in plasma were measured by infusion of [3-3H]glucose and D5-glycerol, respectively. Energy expenditure and substrate oxidation were determined by indirect calorimetry. IFN alpha induced increases in plasma concentrations of norepinephrine (225 +/- 93%; P < 0.02 vs. control), epinephrine (272 +/- 80%; P < 0.05), cortisol (353 +/- 63%; P < 0.02), glucagon (50 +/- 12%; P < 0.05), free fatty acids (223 +/- 61%; P < 0.02), and glycerol (68 +/- 21%; P < 0.02) and in resting energy expenditure (36 +/- 50%; P < 0.03). The Ra of glycerol (169 +/- 39%; P < 0.02) and fat oxidation (104 +/- 23%, P < 0.02) were also increased after IFN alpha treatment. The Ra of glucose was higher at the end of the recombinant human IFN alpha treatment day than in the control experiment (12.83 +/- 1.08 vs. 9.34 +/- 0.46 mumol/kg.min; P < 0.03). It is concluded that IFN alpha administration induces, directly or indirectly, major endocrine and metabolic changes and is probably part of the cytokine network mediating the endocrine and catabolic reactions to tissue injury.
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PMID:Endocrine and metabolic effects of interferon-alpha in humans. 878 81

IL-1, a cytokine produced predominantly by cell from the macrophage lineage, can affect multiple neuroendocrine and metabolic functions. We report here effects of this cytokine in obese, diabetic Zucker fa/fa rats. These animals are modestly hyperglycemic, hyper-lipemic, and markedly hyperinsulinemic. Changes in the levels of glucose, lactate, triglycerides, free fatty acids, insulin, glucagon, and corticosterone were detected following a single intraperitoneal or intravenous injection of IL-1 into fa/fa rats. No comparable changes were observed following administration of insulin. In fa/fa rats, the diabetic status is particularly manifested by an abnormal glucose tolerance. Administration of a bolus injection of IL-1 normalized the response of diabetic fa/fa rats to a glucose load. These rats not only returned to their basal glucose levels quicker, but reached glucose concentrations in blood which were comparable to, or even lower than those of Fa/? rats. Although the mechanism underlying the effects of IL-1 in fa/fa rats are presently not clear, the results obtained suggest that this cytokine tends to normalize glucose homeostasis and stimulate fat mobilization in these animals.
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PMID:Metabolic and endocrine effects of interleukin-1 in obese, diabetic Zucker fa/fa rats. 888 49

The process of wound healing represents a series of complex physicochemical reactions requiring different nutritional microcomponents at each stage. In patients with extremely grave diseases and injuries the course of wound healing is impaired because of a hypermetabolic reaction to stress, leading to protein catabolism. The hypothalamus responds to cytokine stimulation by changes of thermoregulation (increase of heat production) and increased production of stress hormones (catecholamines, hydrocortisone, and glucagon). In turn, stress hormones trigger the thermogenous (unproductive) metabolic cycle and the lipolysis and proteolysis processes. Hyperproduction of glucose at the expense of skeletal muscle tissue degradation leads to the formation of amino acid substrate for liver glyconeogenesis. Additional nutrients are obligatory for wound healing in such patients. Protein catabolism cannot be arrested by amino, acids alone partly because amino acid transport is impaired; it can be normalized by anabolics, such as growth hormone and insulin-like growth factor 1. Treatment with growth hormone yields a dramatic positive effect in severely burned children. Proteins and vitamins, specifically arginine and vitamins A, B, and C provide the optimal nutritive support during wound treatment.
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PMID:[The utilization of nutrient substances during wound healing]. 902 51

Down-regulation of the mitogenic activity of the rodent liver carcinogen cyproterone acetate (CPA) and of epidermal growth factor (EGF) were compared in cultured rat hepatocytes. Both hepatomitogens produce an increase in the expression of proliferating cell nuclear antigen (PCNA) and in [3H]thymidine incorporation in a dose-dependent manner. In combination, the two mitogens induced an additive mitogenic response. Concomitant exposure to the growth inhibitory cytokine transforming growth factor beta1 (TGF-beta1) resulted in a differential dose-dependent down-regulation of PCNA-expressing cells. The corresponding down-regulation of CPA-induced PCNA expression required a 3- to 5-fold higher TGF-beta1 concentration than for EGF-induced expression. In contrast, CPA-exposed hepatocytes become vulnerable to and EGF-exposed cells protected against the apoptosis-inducing activity of TGF-beta1 (>0.1 ng/ml). Under culture conditions that mimicked a pericentral-equivalent microenvironment (low oxygen tension, low glucagon concentration), PCNA expression was 3-fold lower and CPA-specific resistance was no longer detectable. It is concluded that EGF and CPA induce their growth stimuli preferentially in the periportal area of the liver but in different hepatocyte sub-populations, which differ in their down-regulation of premitotic events by TGF-beta1. At low TGF-beta1 concentrations, EGF-stimulated cells shift back into a resting cell cycle phase, whereas CPA-treated hepatocytes are eliminated by apoptosis at higher TGF-beta1 concentrations.
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PMID:EGF- and CPA-induced mitogenic stimuli are differentially down-regulated by TGF-beta1 in cultured rat hepatocytes. 916 75

In cultured rat hepatocytes, the gluconeogenic key enzyme, phosphoenolpyruvate carboxykinase (PCK), is induced by glucagon via elevation of cyclic 3',5' adenosine monophosphate (cAMP). The proinflammatory cytokine, interleukin-6 (IL-6), which in the liver together with IL-1beta and tumor necrosis factor alpha triggers the acute-phase response, had been shown to attenuate the glucagon-induced increase in PCK gene transcription, messenger (mRNA) levels, and enzyme activity. The molecular mechanism of this inhibition was investigated in the present study. Glucagon increased cyclic cAMP and PCK mRNA levels to a transient maximum twofold and fivefold, respectively. The increases were attenuated by IL-6. Forskolin, which stimulates adenylate cyclase activity, increased cAMP and PCK mRNA levels 1.6-fold and fivefold, respectively. However, IL-6 attenuated the forskolin-stimulated increase in PCK mRNA but not the increase in cAMP. This showed that IL-6 inhibited PCK mRNA increase in part by the attenuation of cAMP increase, but also beyond cAMP formation. This was confirmed in experiments in which PCK mRNA levels were increased by the nonhydrolyzable cAMP-analogue, chlorophenylthio (CPT)-cAMP. The increase in PCK mRNA was again attenuated by IL-6. In pertussis toxin- and in isobutylmethylxanthine-treated hepatocytes, IL-6 still inhibited the glucagon-stimulated increase in cAMP, indicating that IL-6 did not activate an inhibitory G-protein or phosphodiesterase, which could cause the impairment of cAMP increase. To demonstrate whether the inhibition of PCK gene expression by IL-6 beyond cAMP might be caused by the inhibition of the activation of the PCK gene promoter by cAMP, cultured rat hepatocytes were transfected with a luciferase reporter gene construct under the control of a PCK gene promoter fragment (base -979 to base +32). Luciferase activity was determined after stimulation of the cells with CPT-cAMP in the absence or presence of IL-6. CPT-cAMP increased luciferase activity by 1.7-fold, which was inhibited in the presence of IL-6. It is concluded that IL-6 had a dual inhibitory effect on the stimulation of PCK gene expression by glucagon. It inhibited the increase in cAMP at a site before cAMP formation by adenylate cyclase and at a site after cAMP formation, the activation of the PCK gene promoter by cAMP.
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PMID:Mechanism of the impairment of the glucagon-stimulated phosphoenolpyruvate carboxykinase gene expression by interleukin-6 in rat hepatocytes: inhibition of the increase in cyclic 3',5' adenosine monophosphate and the downstream cyclic 3',5' adenosine monophosphate action. 921 54


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