Epidermal growth factor, like glucagon, exerts a short-term stimulation of alanine transport in rat hepatocytes.
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ABSTRACT:
SUBMITTER: Moule SK
PROVIDER: S-EPMC1148393 | biostudies-other | 1987 Oct
REPOSITORIES: biostudies-other
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Project description:The short-term protein-synthesis-independent stimulation of alanine transport in hepatocytes was further investigated. Cyclic AMP increased the Vmax. of alanine transport. Amino acid transport via systems A, ASC and N was stimulated. A good correlation was found between the initial rate of transport and the cell membrane potential as calculated from the distribution of Cl-. Cyclic AMP increased the rate of alanine transport, stimulated Na+/K+ ATPase (Na+/K+-transporting ATPase) activity and caused membrane hyperpolarization. The time courses and cyclic AMP dose-dependencies of all three effects were similar. Ouabain abolished the effect of cyclic AMP on Cl- distribution and on transport of alanine. The effect of cyclic AMP on alanine transport and Cl- distribution was mimicked by the antibiotic nigericin; the effect of nigericin was also abolished by ouabain. It is concluded that the effect of cyclic AMP on transport is mediated via membrane hyperpolarization. It is suggested that the primary action of cyclic AMP is to increase the activity of an electroneutral Na+/K+-exchange system in the liver cell plasma membrane, thus hyperpolarizing the membrane by stimulating the electrogenic Na+/K+ ATPase.
| S-EPMC1147625 | biostudies-other
Project description:Stimulation of growth hormone (GH) and adrenocorticotropic hormone (ACTH) secretion by glucagon is a standard procedure to assess pituitary dysfunction but the pathomechanism of glucagon action remains unclear. As arginine vasopressin (AVP) may act on the release of both, GH and ACTH, we tested here the role of AVP in GST by measuring a stable precursor fragment, copeptin, which is stoichiometrically secreted with AVP in a 1:1 ratio. ACTH, cortisol, GH, and copeptin were measured at 0, 60, 90, 120, 150, and 180 min during GST in 79 subjects: healthy controls (Group 1, n = 32), subjects with pituitary disease, but with adequate cortisol and GH responses during GST (Group 2, n = 29), and those with overt hypopituitarism (Group 3, n = 18). Copeptin concentrations significantly increased over baseline 150 and 180 min following glucagon stimulation in controls and patients with intact pituitary function but not in hypopituitarism. Copeptin concentrations were stimulated over time and the maximal increment correlated with ACTH, while correlations between copeptin and GH were weaker. Interestingly, copeptin as well as GH secretion was significantly attenuated when comparing subjects within the highest to those in the lowest BMI quartile (p < 0.05). Copeptin is significantly released following glucagon stimulation. As this release is BMI-dependent, the time-dependent relation between copeptin and GH may be obscured, whereas the close relation to ACTH suggests that AVP/copeptin release might be linked to the activation of the adrenal axis.
| S-EPMC4824796 | biostudies-literature
Project description:Epidermal growth factor receptor (EGFR) resistance to tyrosine kinase inhibitors can cause low survival rates in mutation-positive non-small cell lung cancer patients. It is necessary to predict new mutations in the development of more potent EGFR inhibitors since classical and rare mutations observed were known to affect the effectiveness of the therapy. Therefore, this research aimed to perform alanine mutagenesis scanning on ATP binding site residues without COSMIC data, followed by molecular dynamic simulations to determine their molecular interactions with ATP and erlotinib compared to wild-type complexes. Based on the result, eight mutations were found to cause changes in the binding energy of the ATP analogue to become more negative. These included G779A, Q791A, L792A, R841A, N842A, V843A, I853A, and D855A, which were predicted to enhance the affinity of ATP and reduce the binding ability of inhibitors with the same interaction site. Erlotinib showed more positive energy among G779A, Q791A, I853A, and D855A, due to their weaker binding energy than ATP. These four mutations could be anticipated in the development of the next inhibitor to overcome the incidence of resistance in lung cancer patients.
| S-EPMC9784575 | biostudies-literature
Project description:ObjectiveTo investigate local short-term neuroplasticity elicited by subthalamic, thalamic, and pallidal deep brain stimulation (DBS) for movement disorders.MethodsDuring DBS surgery, we delivered pairs of stimulus pulses with both circular and directional leads across 90 interstimulus intervals in 17 participants and recorded local field potentials from unused contacts on the implanted electrode array. We removed the stimulus artifact, validated the neural origin of the underlying signals, and examined short-term plasticity as a function of interstimulus interval and DBS target, using linear mixed effects models.ResultsDBS evokes short latency local field potentials that are readily detected with both circular and directional leads at all stimulation targets (0.31 ± 0.10 msec peak latency, mean ± SD). Peak amplitude, area, and latency are modified strongly by interstimulus interval (P < 0.001) and display absolute and relative refractory periods (0.56 ± 0.08 and 2.94 ± 1.05 msec, respectively). We also identified later oscillatory activity in the subthalamic-pallidal circuit (4.50 ± 1.11 msec peak latency) that displays paired pulse facilitation (present in 5/8 subthalamic, 4/5 pallidal, and 0/6 thalamic trajectories, P = 0.018, Fisher's exact test), and correlates with resting beta frequency power (P < 0.001), therapeutic DBS frequencies, and stimulation sites chosen later for therapy in the ambulatory setting (P = 0.031).InterpretationPaired DBS pulses synchronize local circuit electrophysiology and elicit short-term neuroplasticity in the subthalamic-pallidal circuit. Collectively, these responses likely represent the earliest detectable interaction between the DBS pulse and local neuronal tissue in humans. Evoked subcortical field potentials could serve as a predictive biomarker to guide the implementation of next-generation directional and adaptive stimulation devices.
| S-EPMC8108424 | biostudies-literature
Project description:Patterns of responses in the cerebral cortex can vary, and are influenced by pre-existing cortical function, but it is not known how rapidly these variations can occur in humans. We investigated how rapidly response patterns to electrical stimulation can vary in intact human brain. We also investigated whether the type of functional change occurring at a given location with stimulation would help predict the distribution of responses elsewhere over the cortex to stimulation at that given location. We did this by studying cortical afterdischarges following electrical stimulation of the cortex in awake humans undergoing evaluations for brain surgery. Response occurrence and location could change within seconds, both nearby to and distant from stimulation sites. Responses might occur at a given location during one trial but not the next. They could occur at electrodes adjacent or not adjacent to those directly stimulated or to other electrodes showing afterdischarges. The likelihood of an afterdischarge at an individual site after stimulation was predicted by spontaneous electroencephalographic activity at that specific site just prior to stimulation, but not by overall cortical activity. When stimulation at a site interrupted motor, sensory or language function, afterdischarges were more likely to occur at other sites where stimulation interrupted similar functions. These results show that widespread dynamic changes in cortical responses can occur in intact cortex within short periods of time, and that the distribution of these responses depends on local brain states and functional brain architecture at the time of stimulation. Similar rapid variations may occur during normal intracortical communication and may underlie changes in the cortical organization of function. Possibly these variations, and the occurrence and distribution of responses to cortical stimulation, could be predicted. If so, interventions such as stimulation might be used to alter spread of epileptogenic activity, accelerate learning or enhance cortical reorganization after brain injury.
| S-EPMC2408939 | biostudies-literature
Project description:Fasting is associated with increased susceptibility to hypoglycemia in people with type 1 diabetes, thereby making it a significant health risk. To date, the relationship between fasting and insulin-induced hypoglycemia has not been well characterized, so our objective was to determine whether insulin-independent factors, such as counterregulatory hormone responses, are adversely impacted by fasting in healthy control individuals. Counterregulatory responses to insulin-induced hypoglycemia were measured in 12 healthy people during 2 metabolic studies. During one study, participants ate breakfast and lunch, after which they underwent a 2-hour bout of insulin-induced hypoglycemia (FED). During the other study, participants remained fasted prior to hypoglycemia (FAST). As expected, hepatic glycogen concentrations were lower in FAST, and associated with diminished peak glucagon levels and reduced endogenous glucose production (EGP) during hypoglycemia. Accompanying lower EGP in FAST was a reduction in peripheral glucose utilization, and a resultant reduction in the amount of exogenous glucose required to maintain glycemia. These data suggest that whereas a fasting-induced lowering of glucose utilization could potentially delay the onset of insulin-induced hypoglycemia, subsequent reductions in glucagon levels and EGP are likely to encumber recovery from it. As a result of this diminished metabolic flexibility in response to fasting, susceptibility to hypoglycemia could be enhanced in patients with type 1 diabetes under similar conditions.
| S-EPMC10371233 | biostudies-literature
Project description:Background:Spinal cord stimulation (SCS) exerts neuroprotective effects in animal models of Parkinson's disease (PD). Conventional stimulation techniques entail limited stimulation time and restricted movement of animals, warranting the need for optimizing the SCS regimen to address the progressive nature of the disease and to improve its clinical translation to PD patients. Objective:Recognizing the limitations of conventional stimulation, we now investigated the effects of continuous SCS in freely moving parkinsonian rats. Methods:We developed a small device that could deliver continuous SCS. At the start of the experiment, thirty female Sprague-Dawley rats received the dopamine (DA)-depleting neurotoxin, 6-hydroxydopamine, into the right striatum. The SCS device was fixed below the shoulder area of the back of the animal, and a line from this device was passed under the skin to an electrode that was then implanted epidurally over the dorsal column. The rats were divided into three groups: control, 8-h stimulation, and 24-h stimulation, and behaviorally tested then euthanized for immunohistochemical analysis. Results:The 8- and 24-h stimulation groups displayed significant behavioral improvement compared to the control group. Both SCS-stimulated groups exhibited significantly preserved tyrosine hydroxylase (TH)-positive fibers and neurons in the striatum and substantia nigra pars compacta (SNc), respectively, compared to the control group. Notably, the 24-h stimulation group showed significantly pronounced preservation of the striatal TH-positive fibers compared to the 8-h stimulation group. Moreover, the 24-h group demonstrated significantly reduced number of microglia in the striatum and SNc and increased laminin-positive area of the cerebral cortex compared to the control group. Conclusions:This study demonstrated the behavioral and histological benefits of continuous SCS in a time-dependent manner in freely moving PD animals, possibly mediated by anti-inflammatory and angiogenic mechanisms.
| S-EPMC7309445 | biostudies-literature
Project description:Epidermal growth factor (EGF) mimicked the effect of insulin to activate glycogen synthase and stimulate glycogen synthesis in isolated rat hepatocytes. Both agents required glucose (greater than 5 mM) and had similar time courses of action. The maximum effect of EGF was approx. 70% of that of insulin, and the half-maximally effective concentrations were 9 nM and 4 nM respectively. Combinations of the two agents produced additive responses. EGF also resembled insulin in its ability to inhibit the effects of 0.1-1.0 nM-glucagon on cyclic AMP and glycogen phosphorylase in hepatocytes. The maximum effect of EGF was approx. 70% of that of insulin, and the half-maximally effective concentrations were approx. 5 nM and 0.5 nM respectively. EGF and insulin inhibited phosphorylase activation by exogenous cyclic AMP, and inhibited cyclic AMP accumulation induced by forskolin. They also inhibited phosphorylase activation provoked by phenylephrine, but not by vasopressin. EGF added alone rapidly activated phosphorylase and increased cytosolic [Ca2+], but the effects were no longer apparent at 5 min and were smaller than those of vasopressin. Insulin did not induce these changes. In hepatocytes previously incubated with myo-[3H]inositol, EGF did not significantly increase myo-inositol 1,4,5-trisphosphate. However, its ability to increase cytosolic [Ca2+] was blocked by neomycin, an inhibitor of phosphatidylinositol bisphosphate hydrolysis. It is concluded that some, but not all, of the effects of EGF in liver are strikingly similar to those exerted by insulin, suggesting that these agents may have some similar mechanisms of action in this tissue.
| S-EPMC1147318 | biostudies-other
Project description:We have studied the relationship between the effect of epidermal growth factor (EGF) on glycogen metabolism and its effect on glycolysis, in rat hepatocyte suspensions. Although 10 nM glucagon or 10 microM adrenaline increased glycogen degradation by more than 120%, 10 nM EGF increased glycogenolysis by less than 20% in hepatocytes incubated in glucose-free medium. Both glucagon and adrenaline increased phosphorylase a activity by more than 130%; EGF increased this activity by about 30%. Under basal conditions, 65% of the glucosyl residues were released as free glucose and about 30% ended up as C3 molecules (lactate and pyruvate). Both glucagon and adrenaline decreased the proportion of glucosyl units that rendered glycolysis end-products (to 2% for glucagon and 6% for adrenaline) and increased the proportion that ended up as free glucose (to 94% and 88% of the glucosyl residues for glucagon and adrenaline respectively). EGF increased the production of both free glucose and lactate+pyruvate, but the proportion of glucosyl residues that ended up as free glucose or glycolysis end-products was unchanged. In glycogen-depleted hepatocytes incubated in the presence of 25 mM glucose, EGF affected neither glycogen deposition nor glycolysis. EGF increased cytosolic free Ca2+, and neomycin decreased both the Ca2+ signal and the glycogenolytic effect. In conclusion, our results indicate that the effect of EGF on glycolysis is secondary to the Ca(2+)-mediated stimulation of glycogenolysis in rat hepatocyte suspensions.
| S-EPMC1136807 | biostudies-other
Project description:Mouse models of cystic fibrosis (CF) display increased sulfotransferase 1E1 (SULT1E1) activity in hepatocytes of cystic fibrosis transmembrane receptor (CFTR)-deficient animals. SULT1E1 is responsible for the sulfation and inactivation of beta-estradiol (E2) at physiological concentrations. IGF-1 message levels in CFTR(-/-) mouse livers were positively correlated with body weight and negatively correlated with SULT1E1 activity. Growth hormone (GH) is important in the regulation of hepatic IGF-1 expression indicating that E2 levels are involved with GH signaling in hepatocytes. To investigate the effects of E2 and SULT1E1 activity on GH signal transduction in human hepatocytes, SULT1E1 was stably expressed in HepG2 cells. Effects of increased E2 sulfation on the GH signaling pathway and E2-regulated gene expression were examined. Pretreatment of HepG2 cells with 10nM E2 prior to GH stimulation increased STAT5b phosphorylation and IGF-1 expression. In SULT1E1-transfected HepG2 cells, GH-stimulated STAT5b phosphorylation was significantly decreased. E2 treatment had no effect on STAT5b phosphorylation in the absence of GH stimulation. E2 also had no effect on Jak-2 phosphorylation. E2 has an apparent rapid action on increasing GH-stimulated STAT5b phosphorylation that was not attenuated by the estrogen receptor antagonist, ICI 182,780. Physiological levels of E2 in HepG2 cells increase GH stimulation of IGF-1 production apparently through increased phosphorylated STAT5b levels and transcriptional activation of the IGF-1 gene. The enhanced SULT1E1 activity may have a role in inhibiting GH-stimulated STAT5b phosphorylation and IGF-1 synthesis via the sulfation and inactivation of E2.
| S-EPMC2633718 | biostudies-literature