237 research outputs found
Epigenetic Mechanisms Modulated by Glucocorticoids With a Focus on Cushing Syndrome
In Cushing syndrome (CS), prolonged exposure to high cortisol levels results in a wide range of devastating effects causing multisystem morbidity. Despite the efficacy of treatment leading to disease remission and clinical improvement, hypercortisolism-induced complications may persist. Since glucocorticoids use the epigenetic machinery as a mechanism of action to modulate gene expression, the persistence of some comorbidities may be mediated by hypercortisolism-induced long-lasting epigenetic changes. Additionally, glucocorticoids influence microRNA expression, which is an important epigenetic regulator as it modulates gene expression without changing the DNA sequence. Evidence suggests that chronically elevated glucocorticoid levels may induce aberrant microRNA expression which may impact several cellular processes resulting in cardiometabolic disorders. The present article reviews the evidence on epigenetic changes induced by (long-term) glucocorticoid exposure. Key aspects of some glucocorticoid-target genes and their implications in the context of CS are described. Lastly, the effects of epigenetic drugs influencing glucocorticoid effects are discussed for their ability to be potentially used as adjunctive therapy in CS.</p
Epigenetic Mechanisms Modulated by Glucocorticoids With a Focus on Cushing Syndrome
In Cushing syndrome (CS), prolonged exposure to high cortisol levels results in a wide range of devastating effects causing multisystem morbidity. Despite the efficacy of treatment leading to disease remission and clinical improvement, hypercortisolism-induced complications may persist. Since glucocorticoids use the epigenetic machinery as a mechanism of action to modulate gene expression, the persistence of some comorbidities may be mediated by hypercortisolism-induced long-lasting epigenetic changes. Additionally, glucocorticoids influence microRNA expression, which is an important epigenetic regulator as it modulates gene expression without changing the DNA sequence. Evidence suggests that chronically elevated glucocorticoid levels may induce aberrant microRNA expression which may impact several cellular processes resulting in cardiometabolic disorders. The present article reviews the evidence on epigenetic changes induced by (long-term) glucocorticoid exposure. Key aspects of some glucocorticoid-target genes and their implications in the context of CS are described. Lastly, the effects of epigenetic drugs influencing glucocorticoid effects are discussed for their ability to be potentially used as adjunctive therapy in CS.</p
Octreotide
A peptide inhibiting the release of growth hormone was originally detected accidentally during studies of the distribution of growth hormone–releasing factor in the hypothalamus of rats. This peptide, called somatostatin, proved to be a cyclic peptide consisting of 14 amino acids. Subsequent work has considerably expanded this initially simple concept of somatostatin as a peptide whose main function is the regulation of growth hormone secretion. Today, somatostatin is best regarded as a phylogenetically ancient, multigene family of peptides with two important bioactive products: somatostatin-14 and somatostatin-28, the latter a congener of somatostatin-14 extended at the N-terminal
Somatostatin receptors in gastroentero-pancreatic neuroendocrine tumours
Five somatostatin receptor (sst) subtype genes, sst(1), sst(2), sst(3),
sst(4) and sst(5), have been cloned and characterised. The five sst
subtypes all bind natural somatostatin-14 and somatostatin-28 with high
affinity. Endocrine pancreatic and endocrine digestive tract tumours also
express multiple sst subtypes, but sst(2) predominance is generally found.
However, there is considerable variation in sst subtype expression between
the different tumour types and among tumours of the same type. The
predominant expression of sst(2) receptors on pancreatic endocrine or
carcinoid tumours is essential for the control of hormonal hypersecretion
by the octapeptide somatostatin analogues such as octreotide and
lanreotide. Somatostatin and its octapeptide analogues are also able to
inhibit proliferation of normal and tumour cells. The high density of
sst(2) or sst(5) on pancreatic endocrine or carcinoid tumours further
allows the use of radiolabelled somatostatin analogues for in vivo
visualisation. The predominant expression of sst(2) receptors in these
tumours and the efficiency of sst(2) receptors to undergo agonist-induced
internalisation is also essential for the application of radiolabelled
octapeptide somatostatin analogues. Currently,
[(111)In-DTPA(0)]octreotide, [(90)Y-DOTA(0),Tyr(3)]octreotide,
[(177)Lu-DOTA(0)Tyr(3)]octreotate, [(111)In-DOTA(0)]lanreotide and
[(90)Y-DOTA(0)]lanreotide can be used for this purpose
Internalization of the radioiodinated somatostatin analog [125I-Tyr3]octreotide by mouse and human pituitary tumor cells: increase by unlabeled octreotide
Recently, we developed a technique that allows the in vivo visualization
in man of somatostatin receptor-positive neuroendocrine tumors after i.v.
injection of [125I-Tyr3]octreotide or [111In-DTPA-D-Phe1]octreotide.
Radiotherapy of such tumors using somatostatin analogs coupled to alpha-
or beta-emitting radionuclides has been proposed as an application for
radiolabeled somatostatin analogs. To develop this concept further, it is
of importance to know whether the above-mentioned radiolabeled
somatostatin analogs are internalized by the tumor cells, and whether it
might be possible to manipulate the degree of internalization. In the
present study we investigated the internalization of a stable somatostatin
analog, [125I-Tyr3]octreotide, by mouse AtT20/D16V pituitary tumor cells
and primary cultures of human GH-secreting pituitary tumor cells.
Treatment of the cells with low pH was used to distinguish between
membrane-bound (acid-releasable) and internalize (acid-resistant)
radioligand. [125I-Tyr3]octreotide showed a time-dependent increasing
accumulation in AtT20 cells; after 4 h of incubation, values up to 6-8% of
the dose of radioligand added were obtained. Binding and internalization
of [125I-Tyr3]octreotide were temperature dependent and inhibited by
pertussis toxin. Inhibitors of lysosomal degradation did not increase the
amount of internalized radioligand. After 4 h of incubation, 88% of the
radioactivity present in the cells was still peptide bound, suggesting a
low intracellular breakdown of this radioligand. Six of seven human
GH-secreting adenoma cell cultures also internalized [125I-Tyr3]octreotide
(variation between 0.24-4.98% of the dose radioligand added). Displacement
of binding and internalization of [125I-Tyr3]octreotide by unlabeled
octreotide showed a bell-shaped curve in AtT20 cells. At low
concentrations (0.1 and 1 nM), binding and internalization were increased,
whereas at higher concentrations, saturation occurred. In contrast to
this, binding of [125I-Tyr3]octreotide to a broken cell preparation of
AtT20 cells was displaced in a dose-dependent manner by unlabeled
octreotide, with an IC50 of 0.1 nM. Similar observations were made in the
human GH-secreting adenoma cell cultures. In conclusion, a high amount of
[125I-Tyr3]octreotide is internalized in a specific-, time-, temperature-,
and pertussis toxin-sensitive GTP-binding protein-dependent manner by
mouse AtT20 and human GH-secreting pituitary tumor cells. In the presence
of a low concentration of unlabeled octreotide, a rapid increase in the
amount of [125I-Tyr3]octreotide internalized by AtT20 cells and by the
majority of the human GH-secreting adenoma cell cultures was
found.(ABSTRACT TRUNCATED AT 400 WORDS
Inhibin alpha-subunit (INHA) expression in adrenocortical cancer is linked to genetic and epigenetic INHA promoter variation
Adrenocortical carcinoma (ACC) is a rare, but highly malignant tumor of unknown origin. Inhibin α-subunit (Inha) knockout mice develop ACCs following gonadectomy. In man, INHA expression varies widely within ACC tissues and its circulating peptide inhibin pro-αC has been described as a novel tumor marker for ACC. We investigated whether genetic and epigenetic changes of the INHA gene in human ACC cause loss or variation of INHA expression. To this end, analyses of INHA sequence, promoter methylation and mRNA expression were performed in human adrenocortical tissues. Serum inhibin pro-αC levels were also measured in ACC patients. INHA genetic analysis in 37 unique ACCs revealed 10 novel, heterozygous rare variants. Of the 3 coding bases affected, one variant was synonymous and two were missense variants: S72F and S184F. The minor allele of rs11893842 at -2124 bp was observed at a low frequency (24%) in ACC samples and was associated with decreased INHA mRNA levels: 4.7±1.9 arbitrary units for AA, compared to 26±11 for AG/GG genotypes (P = 0.034). The methylation of four proximal INHA promoter CpGs was aberrantly increased in five ACCs (47.763.9%), compared to normal adrenals (18.4±0.6%, P = 0.0052), whereas the other 14 ACCs studied showed diminished promoter methylation (9.8±1.1%, P = 0.020). CpG methylation was inversely correlated to INHA mRNA levels in ACCs (r =-0.701, p = 0.0036), but not associated with serum inhibin pro-aC levels. In conclusion, aberrant methylation and common genetic variation in the INHA promoter occur in human ACCs and are associated with decreased INHA expression
Pro-inflammatory cytokines affect pancreatic carcinoma cell. Endothelial cell interactions
OBJECTIVES: The potential role of surgery-induced pro-inflammatory\n cytokines on the development of tumor recurrence in pancreatic cancer was\n investigated. MAIN OUTCOME MEASURES: The adhesion of 3 human pancreatic\n carcinoma cell lines, PanC1, MiaPaCa and BxPC3 to monolayers of\n microvascular endothelial cells after pre-incubation with 0.1 or 10 ng/mL\n IL-1beta, TNF-alpha or IL-6 was assessed in a reproducible human in vitro\n assay. Untreated monolayers served as controls. RESULTS: Pre-incubation of\n microvascular endothelial cells with IL-1beta or TNF-alpha, but not IL-6,\n increased adhesion of all three tumor cell lines as compared to adhesion\n in the control group. Maximally stimulated adhesion for PanC1 reached\n 159%, for MiaPaCa 204% and for BxPC3 155% (all vs. the control, P<0.001).\n Pre-incubation of microvascular endothelial cells with IL-1beta or\n TNF-alpha resulted in a significant up-regulation of E-selectin, ICAM-1\n and VCAM-1 expression. The addition of anti-E-selectin, anti-ICAM-1 or\n anti-VCAM-1 monoclonal antibodies did not decrease adhesion to\n microvascular endothelial cells pre-incubated with IL-1beta. Therefore,\n enhanced tumor cell binding seems to be independent of these adhesion\n molecules. CONCLUSIONS: Pro-inflammatory cytokines derived from surgical\n trauma may enhance tumor cell adhesion to microvascular endothelial cells\n and thus bring about more successful tumor cell implantation resulting in\n an increased risk of metastasis formation
Acute effect of pegvisomant on cardiovascular risk markers in healthy men: implications for the pathogenesis of atherosclerosis in GH deficiency
Cardiovascular risk is increased in GH deficiency (GHD). GHD adults are
frequently abdominally obese and display features of the metabolic
syndrome. Otherwise healthy abdominally obese subjects have low GH levels
and show features of the metabolic syndrome as well. We investigated in
healthy nonobese males the effect of the GH receptor antagonist
pegvisomant in different metabolic conditions. This is a model for acute
GHD without the alterations in body composition associated with GHD. We
compared the effect of pegvisomant with that of placebo before and after 3
d of fasting. In addition, we investigated the effect of pegvisomant under
normal, i.e. fed, conditions. Three days of fasting as well as pegvisomant
alone decreased serum free IGF-I levels (1.0 +/- 0.15 vs. 0.31 +/- 0.05
ng/ml and 0.86 +/- 0.23 vs. 0.46 +/- 0.23 ng/ml, respectively). Fasting in
combination with pegvisomant also decreased serum free IGF-I levels (1.0
+/- 0.15 vs. 0.31 +/- 0.07 ng/ml). Treatment with pegvisomant had no
additional influence on the decline of free IGF-I induced by fasting.
Pegvisomant alone had no influence on insulin sensitivity. The increase in
insulin sensitivity induced by fasting was comparable to the increase in
insulin sensitivity induced by fasting combined with pegvisomant. Among
serum lipid concentrations, only serum triglycerides increased
significantly as a result of pegvisomant alone (1.0 +/- 0.2 vs. 1.6 +/-
0.4 mmol/liter). The changes in lipid concentrations induced by fasting
alone or pegvisomant were not different from those induced by pegvisomant
alone. von Willebrand factor antigen levels declined significantly under
the influence of pegvisomant alone (1.1 +/- 0.07 vs. 0.8 +/- 0.06 U/ml).
In conclusion, in different metabolic conditions the GH receptor
antagonist pegvisomant induces no significant acute changes in the major
risk markers for cardiovascular disease. These data suggest that the
secondary metabolic changes, e.g. abdominal obesity or inflammatory
factors, that develop as a result of long-standing GHD are of primary
importance in the pathogenesis of atherosclerosis in patients with GHD
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