The Experts below are selected from a list of 14565 Experts worldwide ranked by ideXlab platform
David J. Torpy - One of the best experts on this subject based on the ideXlab platform.
-
Corticosteroid-Binding Globulin: acute and chronic inflammation.
Expert review of endocrinology & metabolism, 2017Co-Authors: Emily J. Meyer, John G Lewis, Marni A. Nenke, David J. TorpyAbstract:ABSTRACTIntroduction: Corticosteroid-Binding Globulin (CBG) is the principal transport protein for cortisol binding 80% in a 1:1 ratio. Since its discovery in 1958, CBG’s primary function has been considered to be cortisol transport within the circulation. More recent data indicate a cortisol tissue delivery function, particularly at inflammatory sites. CBG’s structure as a non-inhibitory serine protease inhibitor allows allosteric structural change after reactive central loop (RCL) cleavage by neutrophil elastase (NE) and RCL insertion into CBG’s protein core. Transition from the high to low affinity CBG form reduces cortisol-binding.Areas covered: In acute systemic inflammation, high affinity CBG (haCBG) is depleted proportionate to sepsis severity, with lowest levels seen in non-survivors. Conversely, in chronic inflammation, CBG cleavage is paradoxically reduced in proportion to disease severity, implying impaired targeted delivery of cortisol. CBG’s structure allows thermosensitive release of bound c...
-
corticosteroid binding Globulin cleavage is paradoxically reduced in alpha 1 antitrypsin deficiency implications for cortisol homeostasis
Clinica Chimica Acta, 2016Co-Authors: David J. Torpy, John G Lewis, Marni A. Nenke, Mark Holmes, Wayne RankinAbstract:Abstract High-affinity Corticosteroid-Binding Globulin (haCBG) is cleaved by neutrophil elastase (NE) resulting in permanent transition to the low cortisol-binding affinity form (laCBG), thereby increasing cortisol availability at inflammatory sites. Alpha-1 antitrypsin (AAT) is the major inhibitor of NE. AAT deficiency (AATD) predisposes patients to early-onset emphysema due to increased proteolytic destruction from the inherent proteinase–antiproteinase imbalance. We hypothesized that AATD may result in increased CBG cleavage in vivo. We collected demographic data and blood samples from 10 patients with AATD and 28 healthy controls measuring total CBG and haCBG levels by parallel in-house ELISAs, as well as AAT, total and free cortisol levels. haCBG was higher (median [range]); 329 [210–551] vs. 250 [175–365] nmol/L; P
-
Corticosteroid-Binding Globulin Gene Mutations and Chronic Fatigue/Pain Syndromes: An Overview of Current Evidence
An International Perspective on the Future of Research in Chronic Fatigue Syndrome, 2012Co-Authors: Chinmay S. Marathe, David J. TorpyAbstract:Several lines of evidence suggest that Corticosteroid-Binding Globulin (CBG), long known as a cortisol-transport glycoprotein, may have broader roles in targeted-tissue hormone delivery and the neurobehavioural responses to stress. These include studies of individual kindreds with rare severe CBG gene (SERPINA6) mutations, a study of chronic fatigue patients, a community study of individuals with a relatively high prevalence of two function altering CBG gene mutations in Calabria, Italy, a study of the genetic epidemiology of chronic pain, and, finally, two separate animal CBG gene knockout models.
-
A role for Corticosteroid-Binding Globulin variants in stress-related disorders.
Expert review of endocrinology & metabolism, 2012Co-Authors: Chinmay S. Marathe, David J. TorpyAbstract:Primary stress-related diseases such as chronic fatigue syndrome, fibromyalgia or chronic widespread pain have been associated with altered activity of the hypothalamic–pituitary–adrenal axis due to measured relative hyper- or hypo-cortisolism in basal or experimentally stimulated states. A hereditary risk to development of these diseases has been proposed. Corticosteroid-Binding Globulin (CBG), a plasma transport vehicle for cortisol, may play a more active role in the hypothalamic–pituitary–adrenal axis. Chronically altered hypothalamic–pituitary–adrenal axis has been associated with common medical problems. Hypocortisolism has been observed in kindred studies of rare mutations of the SERPIN A6 (CBG) gene and more common SERPIN A6 polymorphisms associated with reduced CBG levels or CBG:cortisol-binding affinity. Over the last decade, studies of five different CBG gene mutations in humans, human genetic associations and transgenic mouse models have suggested that CBG may have hitherto unexpected roles in...
-
Plasma free cortisol fraction reflects levels of functioning Corticosteroid-Binding Globulin.
Clinica Chimica Acta, 2005Co-Authors: John G Lewis, Anthony W. Bachmann, Christopher J Bagley, Peter A Elder, David J. TorpyAbstract:Abstract Background In normal plasma free cortisol accounts for less than 6% of the total with 80–90% bound to Corticosteroid-Binding Globulin (CBG) and the remainder associated albumin. However little is known about the distribution of free cortisol in plasma where CBG is inactivated or in congenital CBG deficiency. Methods and results Here we describe ligand binding experiments revealing that while free cortisol in unstressed individuals is less than 6% of total cortisol this rises markedly to 25% when CBG is totally inactivated by heat. Similar elevations of the free cortisol fraction were noted in a patient with a rare genetically determined complete lack of CBG (mean 32% on frequent circadian sampling). Following heat inactivation of CBG or in the congenital absence of CBG, there is a shift in cortisol binding from CBG to albumin. That this shift occurs is further supported by experiments adding [ 3 H]-cortisol to physiological human serum albumin solutions, where 25% of cortisol remained in the free fraction. Conclusion Taken together the data provide strong evidence that when CBG is inactivated or congenitally absent then more than 25% of the total cortisol appears in the free fraction with the remainder associated with albumin. The proportion of free cortisol measured in plasma thus reflects a simple measure of functional Corticosteroid-Binding Globulin.
Geoffrey L Hammond - One of the best experts on this subject based on the ideXlab platform.
-
Naturally Occurring Mutations of Human Corticosteroid-Binding Globulin
The Journal of clinical endocrinology and metabolism, 2015Co-Authors: Marc Simard, John G Lewis, Lesley A. Hill, Geoffrey L HammondAbstract:Context: Corticosteroid-Binding Globulin (CBG) is encoded by SERPINA6. It is the major plasma binding protein of glucocorticoids and regulates plasma cortisol levels and bioavailability in humans. Several proteases target CBG and disrupt its steroid-binding properties. To date, most genetic deficiencies that alter plasma CBG levels or function have been identified in patients presenting with a variety of clinical conditions. Objective: The objective of the study was to test 32 previously uncharacterized nonsynonymous, single-nucleotide polymorphisms in SERPINA6 for their ability to alter CBG production and/or function. Design: Human CBG mutants were produced in Chinese hamster ovary cells for ELISA, cortisol-binding activity measurements, and Western blotting as well as assays of their protease sensitivities. Results: Eight naturally occurring CBG mutants with abnormal production and/or function were identified. Cortisol-binding affinity was markedly reduced for CBG H14Q and CBG H89Y, moderately decreased...
-
novel corticosteroid binding Globulin variant that lacks steroid binding activity
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Ilias Perogamvros, Geoffrey L Hammond, Caroline Underhill, David Henley, Stafford L. Lightman, Kristen D Hadfield, William G Newman, David W Ray, Peter J TrainerAbstract:Background: Corticosteroid-Binding Globulin (CBG) is the principal carrier for glucocorticoids in the circulation and a regulator of their bioavailability. Inherited CBG deficiencies are rarely reported, and only three causative mutations in four families have been described. Patients, Methods, and Results: In a 26-yr-old female with hypotension, fatigue, and undetectable total serum cortisol at presentation, we have identified a novel homozygous c.776g>t transversion in exon 3 of the CBG (SERPINA6) gene. This results in a p.Gly237Val substitution that is predicted to influence the positioning of two β-sheets that constitute part of the CBG steroid-binding site. Two siblings were also homozygous for the variant, whereas her mother and an unaffected sibling were heterozygous. No other symptomatic family members were identified apart from the proband. Individuals homozygous for the variant had serum CBG levels below the reference range when measured by RIA, but CBG was unmeasurable in cortisol-binding capac...
-
corticosteroid binding Globulin a structural basis for steroid transport and proteinase triggered release
Journal of Biological Chemistry, 2007Co-Authors: Michael A Klieber, Geoffrey L Hammond, Caroline Underhill, Yves A MullerAbstract:Abstract Corticosteroid-Binding Globulin (CBG) is a serine proteinase inhibitor (serpin) family member that transports glucocorticoids in blood and regulates their access to target cells. The 1.9A crystal structure of rat CBG shows that its steroid-binding site resembles the thyroxin-binding site in the related serpin, thyroxin-binding Globulin, and mutagenesis studies have confirmed the contributions of key residues that constitute the steroid-binding pocket. Unlike thyroxin-bound thyroxin-binding Globulin, the cortisol-bound CBG displays an “active” serpin conformation with the proteinase-sensitive, reactive center loop (RCL) fully expelled from the regulatory β-sheet A. Moreover, the CBG structure allows us to predict that complete insertion of the proteolytically cleaved RCL into the serpin fold occurs in concert with a displacement and unwinding of helix D that would disrupt the steroid-binding site. This allosteric coupling between RCL positioning and occupancy of the CBG steroid-binding site, which resembles the ligand (glycosamino-glycan)-dependent activation of the thrombin inhibitory serpins heparin cofactor II and anti-thrombin RCLs, ensures both optimal recognition of CBG by target proteinases and efficient release of steroid to sites of action.
-
N-glycans are not the signal for apical sorting of corticosteroid binding Globulin in MDCK cells.
FEBS letters, 1999Co-Authors: Jakob Eg Larsen, Geoffrey L Hammond, George V. Avvakumov, Lotte K. VogelAbstract:It has been suggested that N-glycans act as a general sorting signal for secretory proteins in MDCK cells [Scheiffele et al. (1995) Nature 378, 96–98]. Human corticosteroid binding Globulin contains six consensus sites for N-glycosylation and is known to be secreted to the apical side of MDCK cells. Our results show that wild-type corticosteroid binding Globulin is N-glycosylated when it is recombinantly expressed in MDCK cells. Six mutants, each lacking one of the N-glycosylation sites, and a mutant lacking all six N-glycosylation sites were also secreted to the apical side of MDCK cells in a polarized manner. Thus, the N-glycans on corticosteroid binding Globulin do not act as an apical sorting signal in MDCK cells.
-
Corticosteroid-Binding Globulin (CBG) in fetal development
The Journal of Steroid Biochemistry and Molecular Biology, 1995Co-Authors: John R. G. Challis, Treena M. Jeffray, E. T. M. Berdusco, Kaiping Yang, Geoffrey L HammondAbstract:In fetal sheep the prepartum increase in plasma cortisol concentration is associated with an increase in high affinity corticosteroid binding activity in plasma. This appears to reflect an increase in Corticosteroid-Binding Globulin (CBG) biosynthesis from the fetal liver, and evidence is presented that hepatic CBG gene expression is increased by exposure to glucocorticoids in the fetus. Immunoreactive CBG is found in other fetal tissues, and CBG mRNA is present in fetal pituitary. CBG reduces the ability of cortisol to exert negative feedback on basal or CRH-stimulated ACTH output by fetal sheep pituitary cells in culture. We suggest that CBG interacts with cortisol in a manner that maintains a low negative feedback on the pituitary, and perhaps hypothalamus. This constitutes a component of the cascade of events that is associated with hypothalamic-pituitary-adrenal activation in the late gestation fetus, and with the onset of parturition.
John G Lewis - One of the best experts on this subject based on the ideXlab platform.
-
Corticosteroid-Binding Globulin: acute and chronic inflammation.
Expert review of endocrinology & metabolism, 2017Co-Authors: Emily J. Meyer, John G Lewis, Marni A. Nenke, David J. TorpyAbstract:ABSTRACTIntroduction: Corticosteroid-Binding Globulin (CBG) is the principal transport protein for cortisol binding 80% in a 1:1 ratio. Since its discovery in 1958, CBG’s primary function has been considered to be cortisol transport within the circulation. More recent data indicate a cortisol tissue delivery function, particularly at inflammatory sites. CBG’s structure as a non-inhibitory serine protease inhibitor allows allosteric structural change after reactive central loop (RCL) cleavage by neutrophil elastase (NE) and RCL insertion into CBG’s protein core. Transition from the high to low affinity CBG form reduces cortisol-binding.Areas covered: In acute systemic inflammation, high affinity CBG (haCBG) is depleted proportionate to sepsis severity, with lowest levels seen in non-survivors. Conversely, in chronic inflammation, CBG cleavage is paradoxically reduced in proportion to disease severity, implying impaired targeted delivery of cortisol. CBG’s structure allows thermosensitive release of bound c...
-
corticosteroid binding Globulin cleavage is paradoxically reduced in alpha 1 antitrypsin deficiency implications for cortisol homeostasis
Clinica Chimica Acta, 2016Co-Authors: David J. Torpy, John G Lewis, Marni A. Nenke, Mark Holmes, Wayne RankinAbstract:Abstract High-affinity Corticosteroid-Binding Globulin (haCBG) is cleaved by neutrophil elastase (NE) resulting in permanent transition to the low cortisol-binding affinity form (laCBG), thereby increasing cortisol availability at inflammatory sites. Alpha-1 antitrypsin (AAT) is the major inhibitor of NE. AAT deficiency (AATD) predisposes patients to early-onset emphysema due to increased proteolytic destruction from the inherent proteinase–antiproteinase imbalance. We hypothesized that AATD may result in increased CBG cleavage in vivo. We collected demographic data and blood samples from 10 patients with AATD and 28 healthy controls measuring total CBG and haCBG levels by parallel in-house ELISAs, as well as AAT, total and free cortisol levels. haCBG was higher (median [range]); 329 [210–551] vs. 250 [175–365] nmol/L; P
-
Naturally Occurring Mutations of Human Corticosteroid-Binding Globulin
The Journal of clinical endocrinology and metabolism, 2015Co-Authors: Marc Simard, John G Lewis, Lesley A. Hill, Geoffrey L HammondAbstract:Context: Corticosteroid-Binding Globulin (CBG) is encoded by SERPINA6. It is the major plasma binding protein of glucocorticoids and regulates plasma cortisol levels and bioavailability in humans. Several proteases target CBG and disrupt its steroid-binding properties. To date, most genetic deficiencies that alter plasma CBG levels or function have been identified in patients presenting with a variety of clinical conditions. Objective: The objective of the study was to test 32 previously uncharacterized nonsynonymous, single-nucleotide polymorphisms in SERPINA6 for their ability to alter CBG production and/or function. Design: Human CBG mutants were produced in Chinese hamster ovary cells for ELISA, cortisol-binding activity measurements, and Western blotting as well as assays of their protease sensitivities. Results: Eight naturally occurring CBG mutants with abnormal production and/or function were identified. Cortisol-binding affinity was markedly reduced for CBG H14Q and CBG H89Y, moderately decreased...
-
Plasma free cortisol fraction reflects levels of functioning Corticosteroid-Binding Globulin.
Clinica Chimica Acta, 2005Co-Authors: John G Lewis, Anthony W. Bachmann, Christopher J Bagley, Peter A Elder, David J. TorpyAbstract:Abstract Background In normal plasma free cortisol accounts for less than 6% of the total with 80–90% bound to Corticosteroid-Binding Globulin (CBG) and the remainder associated albumin. However little is known about the distribution of free cortisol in plasma where CBG is inactivated or in congenital CBG deficiency. Methods and results Here we describe ligand binding experiments revealing that while free cortisol in unstressed individuals is less than 6% of total cortisol this rises markedly to 25% when CBG is totally inactivated by heat. Similar elevations of the free cortisol fraction were noted in a patient with a rare genetically determined complete lack of CBG (mean 32% on frequent circadian sampling). Following heat inactivation of CBG or in the congenital absence of CBG, there is a shift in cortisol binding from CBG to albumin. That this shift occurs is further supported by experiments adding [ 3 H]-cortisol to physiological human serum albumin solutions, where 25% of cortisol remained in the free fraction. Conclusion Taken together the data provide strong evidence that when CBG is inactivated or congenitally absent then more than 25% of the total cortisol appears in the free fraction with the remainder associated with albumin. The proportion of free cortisol measured in plasma thus reflects a simple measure of functional Corticosteroid-Binding Globulin.
-
Plasma free cortisol fraction reflects levels of functioning Corticosteroid-Binding Globulin.
Clinica chimica acta; international journal of clinical chemistry, 2005Co-Authors: John G Lewis, Anthony W. Bachmann, Christopher J Bagley, Peter A Elder, David J. TorpyAbstract:In normal plasma free cortisol accounts for less than 6% of the total with 80-90% bound to Corticosteroid-Binding Globulin (CBG) and the remainder associated albumin. However little is known about the distribution of free cortisol in plasma where CBG is inactivated or in congenital CBG deficiency. Here we describe ligand binding experiments revealing that while free cortisol in unstressed individuals is less than 6% of total cortisol this rises markedly to 25% when CBG is totally inactivated by heat. Similar elevations of the free cortisol fraction were noted in a patient with a rare genetically determined complete lack of CBG (mean 32% on frequent circadian sampling). Following heat inactivation of CBG or in the congenital absence of CBG, there is a shift in cortisol binding from CBG to albumin. That this shift occurs is further supported by experiments adding [3H]-cortisol to physiological human serum albumin solutions, where 25% of cortisol remained in the free fraction. Taken together the data provide strong evidence that when CBG is inactivated or congenitally absent then more than 25% of the total cortisol appears in the free fraction with the remainder associated with albumin. The proportion of free cortisol measured in plasma thus reflects a simple measure of functional Corticosteroid-Binding Globulin.
Dominique Garrel - One of the best experts on this subject based on the ideXlab platform.
-
No detrimental effect from chronic exposure to buprenorphine on Corticosteroid-Binding Globulin and corticosensitive immune parameters.
Clinical immunology (Orlando Fla.), 2003Co-Authors: Michele D’elia, Dominique Garrel, Julie Patenaude, Claudine Hamelin, Jacques BernierAbstract:D'Elia M, Patenaude J, Hamelin C, Garrel DR, Bernier J. Opioid drugs reportedly regulate the immune system via their effects on the hypothalamic- pituitary-adrenal (HPA) axis. The present study was carried out to assess the effects of chronic exposure to buprenorphine on HPA axis activation, Corticosteroid-Binding Globulin (CBG), the main glucocorticoid (GC) carrier, and the immune system. Results show that buprenorphine, delivered by osmotic pump subcutaneously in C57BL/6 male mice during (...)
-
Decreased Corticosteroid-Binding Globulin in burn patients: relationship with interleukin-6 and fat in nutritional support.
Critical care medicine, 1998Co-Authors: Jacques Bernier, Nathalie Jobin, Agnès Emptoz-bonneton, Michel Pugeat, Dominique GarrelAbstract:ObjectivesTo analyze the effect of low-fat nutritional solutions, with or without fish oil, on serum interleukin (IL)-6, and to explore the relationships between IL-6, Corticosteroid-Binding Globulin (CBG; the main cortisol carrier in plasma), and protein metabolism in severely burned adult patients
-
Corticosteroid-Binding Globulin during Inflammation and Burn Injury: Nutritional Modulation and Clinical Implications
Hormone research, 1996Co-Authors: Dominique GarrelAbstract:Corticosteroid-Binding Globulin (CGB) is the main carrier of glucocorticoids in mammals. Serum CBG shows little physiological variation with the exception of pregnancy. Experimental inflammation and b
Anthony W. Bachmann - One of the best experts on this subject based on the ideXlab platform.
-
Plasma free cortisol fraction reflects levels of functioning Corticosteroid-Binding Globulin.
Clinica Chimica Acta, 2005Co-Authors: John G Lewis, Anthony W. Bachmann, Christopher J Bagley, Peter A Elder, David J. TorpyAbstract:Abstract Background In normal plasma free cortisol accounts for less than 6% of the total with 80–90% bound to Corticosteroid-Binding Globulin (CBG) and the remainder associated albumin. However little is known about the distribution of free cortisol in plasma where CBG is inactivated or in congenital CBG deficiency. Methods and results Here we describe ligand binding experiments revealing that while free cortisol in unstressed individuals is less than 6% of total cortisol this rises markedly to 25% when CBG is totally inactivated by heat. Similar elevations of the free cortisol fraction were noted in a patient with a rare genetically determined complete lack of CBG (mean 32% on frequent circadian sampling). Following heat inactivation of CBG or in the congenital absence of CBG, there is a shift in cortisol binding from CBG to albumin. That this shift occurs is further supported by experiments adding [ 3 H]-cortisol to physiological human serum albumin solutions, where 25% of cortisol remained in the free fraction. Conclusion Taken together the data provide strong evidence that when CBG is inactivated or congenitally absent then more than 25% of the total cortisol appears in the free fraction with the remainder associated with albumin. The proportion of free cortisol measured in plasma thus reflects a simple measure of functional Corticosteroid-Binding Globulin.
-
Plasma free cortisol fraction reflects levels of functioning Corticosteroid-Binding Globulin.
Clinica chimica acta; international journal of clinical chemistry, 2005Co-Authors: John G Lewis, Anthony W. Bachmann, Christopher J Bagley, Peter A Elder, David J. TorpyAbstract:In normal plasma free cortisol accounts for less than 6% of the total with 80-90% bound to Corticosteroid-Binding Globulin (CBG) and the remainder associated albumin. However little is known about the distribution of free cortisol in plasma where CBG is inactivated or in congenital CBG deficiency. Here we describe ligand binding experiments revealing that while free cortisol in unstressed individuals is less than 6% of total cortisol this rises markedly to 25% when CBG is totally inactivated by heat. Similar elevations of the free cortisol fraction were noted in a patient with a rare genetically determined complete lack of CBG (mean 32% on frequent circadian sampling). Following heat inactivation of CBG or in the congenital absence of CBG, there is a shift in cortisol binding from CBG to albumin. That this shift occurs is further supported by experiments adding [3H]-cortisol to physiological human serum albumin solutions, where 25% of cortisol remained in the free fraction. Taken together the data provide strong evidence that when CBG is inactivated or congenitally absent then more than 25% of the total cortisol appears in the free fraction with the remainder associated with albumin. The proportion of free cortisol measured in plasma thus reflects a simple measure of functional Corticosteroid-Binding Globulin.
-
Familial Corticosteroid-Binding Globulin Deficiency Due to a Novel Null Mutation: Association with Fatigue and Relative Hypotension
The Journal of clinical endocrinology and metabolism, 2001Co-Authors: David J. Torpy, Anthony W. Bachmann, Jeffrey E. Grice, Stephen P. Fitzgerald, Patrick J. Phillips, Judith A. Whitworth, Richard V. JacksonAbstract:Corticosteroid-Binding Globulin is a 383-amino acid glycoprotein that serves a hormone transport role and may have functions related to the stress response and inflammation. We describe a 39-member Italian-Australian family with a novel complete loss of function (null) mutation of the Corticosteroid-Binding Globulin gene. A second, previously described, mutation (Lyon) segregated independently in the same kindred. The novel exon 2 mutation led to a premature termination codon corresponding to residue −12 of the proCorticosteroid-Binding Globulin molecule (c.121G→A). Among 32 family members there were 3 null homozygotes, 19 null heterozygotes, 2 compound heterozygotes, 3 Lyon heterozygotes, and 5 individuals without Corticosteroid-Binding Globulin mutations. Plasma immunoreactive Corticosteroid-Binding Globulin was undetectable in null homozygotes, and mean Corticosteroid-Binding Globulin levels were reduced by approximately 50% at 18.7 ± 1.3 μg/ml (reference range, 30–52 μg/ml) in null heterozygotes. Morn...
