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At least 397 records · Page 22Linked to original sources
PubMed2003

Down-regulation of 14-3-3 eta gene expression by IGF-I in mouse cerebellum during postnatal development.

Insulin-like growth factor I (IGF-I) overexpression in the postnatal cerebellum of transgenic (Tg) mice results in remarkable cerebellar overgrowth characterized by a near doubling of granule cell number that is predominantly due to inhibition of apoptosis. Using this Tg model we set out to investigate IGF-I anti-apoptotic mechanisms by defining the influence of IGF-I on gene expression. Using a cDNA array technique, we screened a total of 243 mouse apoptosis-related genes, and found that 14-3-3 eta gene expression was significantly reduced in the cerebella of Tg mice compared with their wild-type (Wt) littermates. Using Northern blot analysis to corroborate our microarray finding, we showed that 14-3-3 eta mRNA abundance was decreased from postnatal day P5 through P17. Nonetheless, the expression pattern of 14-3-3 eta in Tg mice followed the same pattern observed in Wt mice, and was indistinguishable from that in Wt mice at P20 and P23. 14-3-3 eta protein abundance, as determined by Western immunoblot analyses, showed similar decreases in the cerebella of Tg mice. In situ hybridization demonstrated that 14-3-3 eta was predominantly, if not exclusively, expressed and regulated in Purkinje cells. 14-3-3 proteins have multiple functions, including participation in pathways that favor cell survival. Our finding of IGF-I-induced down-regulation of 14-3-3 eta expression in Purkinje cell at a time when IGF-I promotes granule cell survival leads us to speculate that down-regulation of 14-3-3 eta may: (a) serve a negative feedback role to modulate Purkinje cell survival, i.e. limit Purkinje cell number, and/or (b) function as part of a distinct signaling mechanism, perhaps one that augments the capacity of Purkinje cells to promote granule cell survival.

14-3-3 Proteins↗
PubMed2002

Acute effects of acephate and methamidophos and interleukin-1 on corticotropin-releasing factor (CRF) synthesis in and release from the hypothalamus in vitro.

Acute effects of Ace, Meth and IL-1 on AChE activity, ACh and CRF mRNA levels in, and CRF-release from the hypothalamus were studied in vitro. The hypothalamus samples were dissected from the rat brain and were incubated in vitro with IL-1, Ace or Meth in the presence or absence of Dex, Atrop, PTL, PROP and GABA. Ace and Meth, but not IL-1, inhibited AChE activity, while all three compounds; (1) increased ACh and CRF mRNA levels in and CRF release from; (2) activated the CRE promoter region of CRF-gene in: and (3) increased cFos binding to the AP-1 region of the CRF-gene in the hypothalamus. Dex suppressed the effects of IL-1, possibly by inducing the nGRE regulatory sites of the CRF-gene. Dex, however, did not modulate the effects of Ace and Meth on the hypothalamus, which may be attributed to the failure of Dex to modulate the CRF-gene's nGRE regulatory sites. Atrop caused 80-90% inhibition of the effects of IL-1, but caused only 50-65% inhibition of the effects of Ace or Meth on CRF mRNA levels in and CRF release from the hypothalamus. PTL did not affect, while PROP slightly attenuated the effects of IL-1 and the insecticides on the hypothalamus. GABA attenuated the effects of the insecticides but not the effects of IL-1 on the hypothalamus. This suggests that the IL-1-induced augmentation of CRF synthesis in and release from the hypothalamus is mediated through a cholinergic pathway, while the insecticide-induced augmentation of CRF synthesis in and release from the hypothalamus is mediated through the cholinergic and GABAergic pathways. The insecticides, but not IL-1, disrupt feedback regulation of CRF synthesis in and release from the hypothalamus.

Acetylcholine↗
PubMed2006

Ablation of the glucagon receptor gene increases fetal lethality and produces alterations in islet development and maturation.

Although glucagon (GLU) plays a pivotal role in glucose homeostasis, its role in the regulation of fetal growth and maturation is poorly understood. These issues were examined in a line of mice with a global deletion of the GLU receptor (Gcgr-/-), which are characterized by lower blood glucose levels and by alpha- and delta-cell hyperplasia in adults. Ablation of Gcgr was deleterious to fetal survival; it delayed beta-cell differentiation and perturbed the proportion of beta- to alpha-cells in embryonic islets. In adults, the mutation inhibited the progression of alpha-cells to maturity, affected the expression of several beta-cell-specific genes, and resulted in an augmentation of the alpha-, beta-, and delta-cell mass. This increase was due to an augmentation in both islet number and in the rate of proliferation of cells expressing GLU or insulin. These findings suggest that GLU participates in a feedback loop that regulates the proportion of the different endocrine cell types in islets, the number of islets per pancreas, and development of the mature alpha-cell phenotype.

Animals↗
PubMed1976

The insulinotropic effect of endogenous gastric inhibitory polypeptide in normal subjects.

Intravenously administered porcine GIP is insulinotropic in man. This study was designed to investigate the effects of simultaneous fat ingestion, a potent stimulus for GIP release, and intravenous glucose infusion upon endogenous serum GIP and insulin concentrations in normal subjects. Seven normal volunteers were studied on three separate occasions following: a) the ingestion of 67 grams of emulsified corn oil, b) constant intravenous infusion of glucose, and c) simultaneous administration of corn oil and glucose as in parts (a) and (b) of the study. Serum glucose, insulin (IRI), and GIP concentrations were measured at intervals between 15 and 180 minutes following each stimulus. With corn oil, mean serum GIP concentrations increased from a fasting level of 290 +/- 40 (SE) pg/ml to 1936 +/- 402 pg/ml at 60 minutes without a significant change in serum IRI or glucose concentrations. The infusion of intravenous glucose alone was associated with no rise in serum GIP levels despite a substantial increase in serum IRI and glucose concentrations. With the combined stimuli, mean serum GIP increased less (P is less than .05) between 30 and 90 minutes, and total integrated incremental GIP was significantly less (P is less than .025) than that after corn oil ingestion alone. Following the combined stimuli, incremental insulin levels were higher (P is less than .05) between 15 and 90 minutes, total integrated incremental insulin was greater (P is less than .025), and glucose homeostasis was significantly enhanced (P is less than .05) at 120 and 180 minutes compared with the effects on insulin of glucose infusion alone. We conclude that the potentiation of glucose-stimulated insulin secretion induced by the ingestion of fat is associated with serum GIP levels that are within the insulinotropic range. The augmented secretion of insulin may be mediated partially or completely by endogenous GIP. The lower serum GIP concentrations observed following the combined stimuli suggest a feedback inhibition of GIP release which is perhaps mediated by insulin.

Adult↗
PubMed1975

Effects of lithium chloride on parameters biosynthetic capacity for 5-hydroxytryptamin in rat brain.

Administration of lithium chloride to rats resulted in a biphasic, temporally related alteration in the brain's biosynthetic capacity for 5-hydroxytryptamine (5-HT). After 3 to 5 days of drug administration, the Vmax of the high affinity uptake of [14-C]tryptophan into striate nerve ending synaptosomes increased to 140% of control values. The stimulated uptake of radioactive precursor apparently resulted in an augmentation of tryptophan-to-5-HT conversion activity of the same magnitude in these synaptosomes. These events were succeeded by an apparently compensatory decrease in the Vmax of midbrain cell body and nerve-ending solubilized tryptophan-5-hydroxylase (EC 1.99.1.4). After 21 days of drug administration, [14-C]tryptophan uptake remained above control levels, but striate synaptosomal conversion activity had returned to control levels. In contrast, soluble midbrain and solubilized striate synaptosomal enzyme activity remained significantly below control values. In vitro lithium chloride at 10 or 53 mM had no effect on soluble tryptophan hydroxylase activity, but either concentration of lithium chloride significantly enhanced the uptake of [14-C]tryptophan into striate synaptosomes, and consequently also the synaptosomal conversion of tryptophan to 5-HT. Increasing tryptophan levels either by preincubation of synaptosomes with L-tryptophan or by administration of L-tryptophan loads (20-60 mg/kg) resulted in augmented [14-C]tryptophan uptake and conversion activity. The sequence of events that we observed after lithium treatment is consistent with receptor-mediated neuronal feedback regulation of tryptophan hydroxylase activity after stimulation of tryptophan uptake and conversion of 5-HT.

Animals↗
PubMed1990

Endothelial cell platelet-activating factor primes neutrophil responses: amplification of endothelial activation by neutrophil products.

We have shown that platelet-activating factor (PAF) primes neutrophil (PMN) responses and enhances their ability to damage endothelial cells. Furthermore, thrombin-stimulated endothelial cells which produce PAF can augment and prime PMN superoxide production, elastase release and adhesion to endothelium. We wondered whether these marginated neutrophils (PMN) themselves, or their release products, might feedback and further amplify endothelial cell activation. To measure cellular activation, we assessed changes in endothelial cell intracellular calcium [( Ca2+]i) in endothelial monolayers loaded with Fura-2, and PAF production by [3H]acetate incorporation into phospholipid. Resting PMNs induced no change in [Ca2+]i, while N-formyl-L-methionine-L-leucyl-L-phenylalanine stimulated PMN and their lysosomal products caused a 25% increase in endothelial cell calcium. Sonicates of PMN produced a much larger increase in [Ca2+]i than activated PMN; the effect of PMN sonicates could in part be reduced by the serine protease inhibitor, alpha 1 antitrypsin. In contrast, purified neutrophil elastase did not alter endothelial cell [Ca2+]i. Despite hydrogen peroxide's ability to increase [Ca2+]i, catalase failed to inhibit the PMN-induced rise in [Ca2+]i. Since polyanionic heparin inhibited the PMN sonicate rise in calcium, a cationic protein released by PMN was thought to be responsible. The cationic primary granule enzyme, cathepsin G, duplicates the rise in [Ca2+]i seen with PMN sonicates. Furthermore, PAF production increased threefold in response to neutrophil sonicates. Thus, during inflammation, when coagulation and inflammatory cells are activated the endothelium responds by priming PMNs and promoting margination.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium↗
PubMed1989

Augmented pituitary corticotropin response to a threshold dosage of human corticotropin-releasing hormone in depressives pretreated with metyrapone.

We studied pituitary corticotropin response to exogenous corticotropin-releasing hormone infusion and attempted to control for the confounding effect of variable serum cortisol levels between depressed and control subjects. If metyrapone was given during the time of day when hypothalamic pituitary adrenal activity was otherwise low, the relative increase in the corticotropin concentration was small. Pituitary response to exogenous corticotropin-releasing hormone can be defined under conditions in which the amount of glucocorticoid-mediated negative feedback present at the level of the pituitary gland is equal in all subjects. When the ambient cortisol level was equalized (and suppressed) in all subjects at the time of study with a threshold dosage of corticotropin-releasing hormone, we found an augmented response to corticotropin-releasing hormone in depressives. This raises the possibility that either increased pituitary sensitivity to corticotropin-releasing hormone or an increased intracellular pool of corticotropin is available for release in subjects with major depressive illness.

Adrenocorticotropic Hormone↗
PubMed1998

The control of sequential goal-directed movement: learning to use feedback or central planning?

Fifteen participants practiced a two-target sequential aiming movement with either full vision of the movement environment, vision during flight, or vision while in contact with the first target. After 100 acquisition trials, participants performed a retention test in their own condition and then were transferred to each of the other two vision conditions. Both performance and kinematic data indicated that rather than becoming less dependent on visual information with practice, subjects learned to adjust their movement trajectories to use the visual information available in their particular vision condition. Although transfer to a degraded vision condition disrupted performance, when vision was augmented participants quickly adjusted their aiming trajectories to use the added information. The findings suggest that at least part of learning involves the development of rapid and efficient procedures for processing afferent information, including visual response-produced feedback.

Adolescent↗
PubMed1981

Feedback modulation of glucose-induced insulin secretion by arachidonic acid metabolites: possible molecular mechanisms and relevance to diabetes mellitus.

Recent evidence suggests that glucose stimulation of insulin release may trigger a classic negative feedback loop involving local release of an inhibitor of beta cell function. One or more metabolite of arachidonic acid could comprise such putative system. Several metabolic events triggered by glucose-induced stimulus-secretion coupling (such as calcium influx, membrane turnover, augmented reduced pyridine nucleotide or glutathione levels, and alterations in toxic oxygen radical availability) would be expected to alter arachidonic acid release and subsequent metabolism via the lipoxygenase or cyclo-oxygenase pathways. At lease one arachidonate derivative (prostaglandin E) inhibits insulin secretion, and several inhibitors of prostaglandin synthesis augment glucose-induced insulin release in normal subjects and type II diabetics. Development of more selective inhibitors of arachidonate metabolism could represent a new approach to therapeutic manipulation of beta cell function.

Arachidonic Acid↗
PubMed1999

Jointly amplified basal and pulsatile growth hormone (GH) secretion and increased process irregularity in women with anorexia nervosa: indirect evidence for disruption of feedback regulation within the GH-insulin-like growth factor I axis.

Anorexia nervosa (AN) is associated with multiple endocrine alterations. In the majority of AN patients, basal and GHRH-stimulated serum GH levels are increased. The metabolic effects of GH are known to be related to its pulsatile secretory pattern. The present study was performed to examine GH pulsatility in AN using the techniques of deconvolution analysis and approximate entropy, which quantify secretory activity and serial irregularity of underlying hormone release not reflected in peak occurrence or amplitudes. To this end, 24-h GH profiles were obtained by continuous blood sampling aliquoted at 20-min intervals in 8 nonfasting patients with AN [body mass index (BMI), 14.2 +/- 0.8 kg/m2; mean +/- SEM) and in 11 age-matched healthy women (BMI, 20.3 +/- 0.5 kg/m2). The deconvolution-estimated half-life of GH was not altered in the AN patients. The pituitary GH secretory burst frequency, burst mass, and burst duration were each significantly increased in women with AN compared to those in normal weight women. A 4-fold increase in daily pulsatile GH secretion was accompanied by a 20-fold increase in basal (nonpulsatile) GH secretion. There were significant negative correlations between BMI and the basal as well as pulsatile GH secretion rates. Moreover, AN patients exhibited significantly greater GH approximate entropy scores than the controls, denoting marked irregularity of the GH release process. In contrast to previous reports in healthy fasting subjects, cortisol levels in AN patients were positively correlated to GH secretion rates. Leptin levels were significantly inversely correlated to the pulsatile, but not the basal, GH secretion rate. The present data demonstrate augmented basal as well as pulsatile GH secretion with disruption of the orderliness of the GH release process in AN. Accordingly, GH secretion in AN probably reflects altered neuroendocrine feedback regulation, e.g. associated with increased hypothalamic GHRH discharge superimposed on reduced hypothalamic somatostatinergic tone.

Activity Cycles↗
PubMed1999

Effects of angiotensin II on sodium potassium pumps, endogenous ouabain, and aldosterone in bovine zona glomerulosa cells.

Angiotensin (Ang) II stimulates secretions of aldosterone and an endogenous ouabain-like steroid (EO) from bovine adrenal zona glomerulosa (BAG) cells. The BAG cell sodium pump, a possible target of EO, affects aldosterone secretion although little is known about this pump. Here, we describe the effects of Ang II on the characteristics of this transporter and steroid secretions. Under serum-free conditions, 3H-ouabain bound to a single class of sites on BAG cells. Binding of label was time and concentration dependent, was sensitive to extracellular potassium ions, and was displaced by ouabain and digoxin with EC50 of approximately 218 and approximately 232 nmol/L, respectively. Sodium pump-mediated 86Rb uptake was inhibited by ouabain (EC50 approximately 301 nmol/L). Ang II dose dependently augmented secretions of EO and aldosterone, increased ouabain-sensitive 86Rb uptake and 3H-ouabain binding, and increased the affinity for 3H-ouabain binding (Kd, from 205 to 80 nmol/L) with no change in the maximal number of sodium pumps (5.45x10(6)) per cell. Losartan blocked all effects of Ang II except EO secretion, which was inhibited by PD123319. We conclude that BAG cells express sodium pumps in high density and bind ouabain to a single class of low-affinity sites. The characteristics of the sodium pumps protect BAG cells from EO autotoxicity but may exclude them from mediating feedback inhibition of EO secretion. The effects of Ang II on sodium pump activity, ouabain binding affinity, and aldosterone secretion are mediated via Ang II type 1 receptors, whereas Ang II type 2 receptors augment EO secretion. The role of the Ang II-mediated increase in the ouabain sensitivity of BAG cell sodium pumps in the secretions of aldosterone and EO remains to be elucidated.

Aldosterone↗
PubMed2003

Intrarenal angiotensin II and hypertension.

Elevations in intrarenal angiotensin II (Ang II) cause reductions in renal function and sodium excretion that contribute to progressive hypertension and lead to renal and vascular injury. Augmentation of intrarenal Ang II occurs by several processes, leading to levels much greater than can be explained from the circulating levels. In Ang II-dependent hypertension, Ang II is internalized via an AT1 receptor mechanism, but there is also sustained intrarenal production of Ang II. Ang II exerts a positive feedback action on intrarenal angiotensinogen (AGT) mRNA and protein. The increased intrarenal AGT production is associated with increased intrarenal and intracellular Ang II contents and urinary AGT excretion rates. The increased urinary AGT indicates spillover of AGT into distal nephron segments supporting enhanced distal Ang II formation and sodium reabsorption. The augmentation of intrarenal Ang II provides the basis for sustained actions on renal function, sodium excretion, and maintenance of hypertension.

Angiotensin II↗
PubMed2003

Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors.

Polymorphonuclear leukocytes (PMNs) are critical effector cells of the innate immune system that protect the host by migrating to inflammatory sites and killing pathogenic microbes. We addressed the role of chemokine receptor desensitization induced by G-protein-coupled receptor kinases (GRKs) in the feedback control of PMN migration. We show that the chemokine macrophage inflammatory protein-2 (MIP-2) induces GRK2 and GRK5 expression in PMNs through phosphoinositide-3-kinase (PI3K)-gamma signaling. We also show that lipopolysaccharide (LPS)-activated signaling through the Toll-like receptor (TLR)-4 pathway transcriptionally downregulates the expression of GRK2 and GRK5 in response to MIP-2. The reduced expression of GRKs lowers chemokine receptor desensitization and markedly augments the PMN migratory response. These data indicate that TLR4 modulation of PMN surface chemokine receptor expression subsequent to the downregulation of GRK2 and GRK5 expression is a critical determinant of PMN migration.

Animals↗
PubMed1991

Possible regulatory functions of protein kinase C-alpha and -epsilon isoenzymes in rat renal mesangial cells. Stimulation of prostaglandin synthesis and feedback inhibition of angiotensin II-stimulated phosphoinositide hydrolysis.

Short-term treatment of mesangial cells with phorbol 12-myristate 13-acetate (PMA) decreases angiotensin II-induced InsP3 formation, but potentiates hormone-stimulated arachidonic acid release and prostaglandin (PG) E2 synthesis. Long-term treatment with PMA augments hormone-stimulated InsP3 generation (after 8 h treatment), but eliminates angiotensin II-induced arachidonic acid release and PGE2 formation (after 24 h treatment). By using specific antibodies it is observed that mesangial cells express two protein kinase C (PKC) isoenzymes, PKC-alpha and -epsilon. No PKC-beta and -gamma isoenzymes are detected. On exposure to PMA a complete depletion of PKC-alpha is observed within 8 h. In contrast, down-regulation of PKC-epsilon to 10-20% of that found in control cells requires a 24 h treatment with PMA. These results may imply that PKC-alpha mediates feedback inhibition of phosphoinositide hydrolysis, whereas PKC-epsilon is a candidate for regulating PG synthesis in mesangial cells.

Amino Acid Sequence↗
PubMed1990

A revised interpretation of postdexamethasone ACTH and cortisol findings in unipolar depressed females.

Baseline 8 a.m. adrenocorticotropic hormone (ACTH) and cortisol levels and the postdexamethasone ACTH/cortisol values at 8 a.m. and 4 p.m. were determined in 86 depressed females diagnosed using DSM-III criteria. Postdexamethasone ACTH and cortisol values were significantly correlated with their baseline levels. We have shown that regression analysis should be used to assess dexamethasone-induced changes as the residual ACTH and cortisol responses, with the relative effects of the baseline data on the hormone responses being partialed out. The residual ACTH and cortisol values were significantly increased in the most severely depressed females as compared to minor depressives. The residual ACTH responses were markedly correlated with the residual cortisol responses. Cortisol nonsuppression during a depressive episode appeared to be determined by an augmented ACTH escape from dexamethasone suppression. The residual ACTH and cortisol responses could prove to be the most sensitive reflection of the disorder in the negative feedback by dexamethasone on the pituitary. In clinical practice, the ratio ln (postdexamethasone ACTH): ln (basal ACTH) can be used, since this ratio is linearly correlated with the residual ACTH responses.

Adrenocorticotropic Hormone↗
PubMed2005

Simultaneous aberrations in Mphi and T cell function adversely affect trauma patients' clinical outcome: a possible faulty IL-13 feedback loop.

Possible defective trauma patients' Mphi-T-cell feedback interactions between T cell IL-13 production and IL-1beta and IL-18 Mphi secretion were assessed. Mphi produced IL-1 and IL-18 augment T cell IL-13, which in turn limits excessive macrophage activation. Immunodepressed patients' T cells (depressed proliferation to alphaCD3 + alphaCD4) had decreased IL-13 production concomitant to aberrant Mphi activities ( upward arrow mTNFalpha, downward arrow IL-10) and consequent multiple organ failure (MOF). Decreased IL-13 levels in patients' T cell and diminished Mphi supernatant augmentation of healthy controls' T cell IL-13 production appeared concomitantly, suggesting patients' aberrant monokine levels might intensify in vivo T cell dysfunction severity. Patients' Mphi supernatants, which failed to augment controls' T cell IL-13 production, had depressed IL-1beta and lower induction of IL-18 than immunocompetent patients' Mphi, but combined addition of IL-1beta and IL-18 restored these Mphis' IL-13 enhancing activity. These data suggest that immunodepressed patients' aberrant monokine and depressed T cell IL-13 production are independent but synergistic contributors to emergence of MOF.

Adolescent↗