Disease relevance of CORT

• Fine mapping of the human preprocortistatin gene (CORT) to neuroblastoma consensus deletion region 1p36.3-->p36.2, but absence of mutations in primary tumors [1].
• Cortistatin inhibits growth hormone release from human fetal and adenoma pituitary cells and prolactin secretion from cultured prolactinomas [2].
• Ghrelin and cortistatin in lung cancer: Expression of peptides and related receptors in human primary tumors and in vitro effect on the H345 small cell carcinoma cell line [3].
• RESULTS: The 2 groups were comparable in demographics, body weight, plasma drug concentration, and behavioral and CORT responses [4].
• To assess whether acute alveolar hypoxia leads to the release of endothelin-1 (ET) in vivo, ET, cortisol (CORT), and lactate (LA) levels were determined in 15 healthy subjects at rest and during exhaustive incremental cycle ergometry on two separate test days [5].

Psychiatry related information on CORT

• METHODS: Prolactin (PRL) and cortisol (CORT) responses to the serotonergic agonist d-fenfluramine (D-fen), clinical psychobehavioral changes, and psychometric measures were evaluated 3 weeks and then 12 months after MDMA discontinuation [6].
• Prolactin (PRL) and Cortisol (CORT) responses to d,l-fenfluramine (FEN) challenge (60 mg) were examined in patients with affective disorders on two occasions under euthymic conditions: drug-free before admission to prophylactic treatment and after about 9 months of medication with lithium or carbamazepine [7].
• 3. Evidence for a role of central 5-HT in parasuicide arises from reduced concentrations of lumbar CSF 5-HIAA, reduced PRL responses to d,l-fenfluramine challenge, and increased CORT responses to 5-HTP challenge [8].
• PSAP aggressive responses positively correlated with catecholamines changes, BDHI 'direct' and 'irritability' scores, MMPI 'psychopathic deviate' scores both in methadone subjects and controls, and with CORT responses only in healthy subjects [9].
• Mechanisms related to the differences in the interaction of natural (e.g. CORT) and synthetic (e.g. PRED) corticosteroids with the central glucocorticoid and mineralocorticoid receptors may explain the different effects upon psychopathology [10].

High impact information on CORT

• Cortistatin is a recently discovered cyclic neuropeptide related to somatostatin that has emerged as a potential endogenous antiinflammatory factor based on its production by and binding to immune cells [11].
• Cortistatin represents a potential multistep therapeutic agent for human septic shock, to be used in combination with other immunomodulatory agents or as a complement to other therapies [11].
• Cortistatin down-regulated the production of inflammatory mediators by endotoxin-activated macrophages [11].
• Cortistatin, a new antiinflammatory peptide with therapeutic effect on lethal endotoxemia [11].
• The administration of cortistatin protected against lethality after cecal ligation and puncture, or injection of bacterial endotoxin or Escherichia coli, and prevented the septic shock-associated histopathology, such as infiltration of inflammatory cells and intravascular disseminated coagulation in various target organs [11].

Chemical compound and disease context of CORT

• Withdrawal symptoms, mood changes, cardiovascular indexes (heart rate, blood pressure), norepinephrine (NE), epinephrine (EPI), adrenocorticotropic hormone (ACTH) and cortisol (CORT) were evaluated during naloxone-naltrexone administration on the second day of detoxification treatment [12].
• However, after she was switched to a regimen of cortisol (CORT) and fludrocortone (FLUD) the psychopathology disappeared [10].
• However, cortistatin also has many properties distinct from somatostatin including induction of slow-wave sleep, apparently by antagonism of the excitatory effects of acetylcholine on the cortex, reduction of locomotor activity, and activation of cation selective currents not responsive to somatostatin [13].
• The results show that the compound with N-terminal proline and C-terminal lysine amide exhibits cortistatin-like biological activities, including reduction of population spike amplitudes in the hippocampal CA1 region, decrease in locomotor activity and enhancement of slow-wave sleep 2 [14].

Biological context of CORT

• In this work we have employed radiation hybrid mapping and BAC physical mapping to map the human preprocortistatin gene (CORT) to chromosome region 1p36.3-->p36.2, close to the genetic marker D1S244 [1].
• Conversely, neither CST nor SRIF affected H345 cell growth, despite the presence of their specific receptors [3].
• PGD and CORT did not have any effect on cell proliferation [15].
• Expressed sequence tags (ESTs) that showed significant homology to rat cortistatin (CST) were found in a human fetal brain cDNA library [16].
• In summary, these results are consistent with the hypothesis that the high-affinity membrane binding site for [3H] CORT is located on a kappa opioid-like receptor [17].

Anatomical context of CORT

• On the basis of these observations, we hypothesize a role for CST as an endogenous ligand of at least the sst2 receptor in the human immune system, rather than SS itself [18].
• This is the first extensive study demonstrating that human lymphoid tissues and immune cells express different levels of CST mRNA and that its expression can be regulated [18].
• Expression of CST mRNA was up-regulated during differentiation of monocytes into macrophages and dendritic cells and could be up-regulated by lipopolysaccharide stimulation [18].
• CST mRNA was clearly expressed in the immune cells, lymphoid tissues, and bone marrow [18].
• Thus, our findings show the presence of CST in the human endocrine pancreas [19].

Associations of CORT with chemical compounds

• Neither SRIF nor CST modified glucose levels [20].
• While the binding of 125I-Tyr-Ala-hexarelin to pituitary membranes was completely displaced by unlabelled hexarelin, ghrelin and CST, none of the SRIH fragments tested inhibited this binding [21].
• Baseline prolactin (PRL) and cortisol (CORT) and hormonal responses to d-FEN and placebo were measured at hourly intervals over a 4-hour period [4].
• In contrast, CORT responses in MDMA users were restored after 12 months of abstinence, with significantly higher responses to D-fen, in comparison with 3-week responses (p < .05) [6].
• CORT restored responses to D-fen at 12 months, and the correlation of neuroendocrine changes with MDMA exposure suggest that the neuroendocrine impairment may be due to a partially reversible neurotoxic action of MDMA on the human brain [6].

Physical interactions of CORT

• CST binds all 5 SRIF receptors, as well the GH secretagogue (GHS)/ghrelin receptors [19].
• CONTEXT: Cortistatin binds all somatostatin receptor subtypes but also has particular central actions; moreover, a specific cortistatin receptor has also been discovered [22].
• Given these findings, the ability of CST to bind the GHS-R1a is of particular relevance because somatostatin and its fragments do not bind the same receptor [23].

Regulatory relationships of CORT

• CST-14 or CST-17 (10 nm) inhibited basal GH secretion in six of the 13 GH-cell adenomas and two of the three GH-PRL mixed adenomas [2].
• Both SRIF and CST similarly inhibited (p < 0.01) circulating ghrelin levels of about 55% [20].
• The GH response to GHRH was similarly inhibited (P < 0.01) by either CST-14 or SS-14 [24].
• We investigated the influence of CORT on pyridostigmine-induced GH responses by testing subjects at 9.00 and 14.00 h [25].
• The results indicate that a glucocorticoid hormone (CORT) enhances INS induced stimulation of TO activity, as evidenced by enhanced enzyme activity [26].

Other interactions of CORT

• Cortistatin (CST)-14, a neuropeptide with high homology with somatostatin (SS)-14, binds all sst subtypes but, unlike SS, also ghrelin's receptor [24].
• The GH-releasing activity of ghrelin seems partially resistant to CST-14 as well as SS-14 [24].
• Our data demonstrate for the first time that cortistatin, a natural peptide related to SRIH, binds to GHS-R and suggest that this factor may play a role in modulating the activity of these receptors [21].
• Both SRIF and CST similarly inhibited (p < 0.01) glucagon levels of about 40% [20].
• It bound to all human somatostatin receptor (SSTR) subtypes in almost the same manner as rat CST-14 [16].

Analytical, diagnostic and therapeutic context of CORT

• Using autoradiography, we showed that CST displaced [125I-Tyr3]octreotide binding with relatively high affinity on human thymic tissue and sst2-expressing cells [18].
• By in situ hybridization, CST mRNA was localized in the pancreatic islets, but not in the exocrine pancreas [19].
• RESEARCH METHODS: CST-14 and SS-14 in doses of 1nMol, 10nMol, and 100nMol were added after 48 hrs of pituitary cell culture, and the medium was collected 30, 60, 120, 240 min thereafter. rGH was measured with RIA kits provided by Linco [27].
• Prolactin (PRL) and cortisol (CORT) responses to a single oral administration (1.0 mg/kg) of the indirect serotonin agonist dl-fenfluramine were assessed in unmedicated prepubertal and adolescent males with disruptive behavior disorders (DBD) [28].
• Using a neuroendocrine challenge paradigm, this study investigates whether subjects characterized by blunted cortisol (CORT) responses after ipsapirone (IPS) relate to different subfactors of HA from those characterized by blunted prolactin (PRL) responses after treatment with d-fenfluramine (D-FEN) [29].

References