Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excessive oxidative stress and associated macromolecular damage are considered to be key features of aging, and appear to contribute to the age-related decline in steroid hormone production in adrenal and testicular Leydig cells. The current studies were initiated to examine the potential mechanism by which excessive oxidative stress during aging attenuates the functional expression of the oxidant-responsive transcription factor Activator protein-1. Chronic oxidative stress was induced in vivo by maintaining groups of rats on a diet deficient in vitamin E for 6 months. Plasma, liver, and adrenal tissues from vitamin E-deficient animals had negligible levels of this vitamin and showed high susceptibility to in vitro lipid peroxidation. Synthesis and secretion of corticosterone in response to corticotropin (ACTH), dibutyryl-cAMP, or 20alpha-hydroxycholesterol in vitro was significantly reduced in adrenocortical cells prepared cells from rats deficient in vitamin E. AP-1 DNA-binding activity was diminished approximately 55 % in adrenal extracts from vitamin E-deficient rats with no corresponding change in the binding activity of SP-1. The vitamin E deficiency-mediated loss of AP-1 activity was not due to an alteration in the dimeric composition of constituent proteins, but rather to a general down-regulation of steady-state levels of members of the Fos and Jun families of proteins. Interestingly, vitamin E deficiency also reduced the expression of the redox-regulated Ref-1 protein. Collectively these data demonstrate that chronic oxidative stress specifically down-regulates essential components of the AP-1 transcription factor complex, and suggest that aberrancies in AP-1 expression may adversely affect processes crucial for intracellular cholesterol transport and steroid hormone production.
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PMID:Suppression of steroidogenesis and activator protein-1 transcription factor activity in rat adrenals by vitamin E deficiency-induced chronic oxidative stress. 1506 14

Tuberoinfundibular corticotropin-releasing hormone (CRH) neurones are the principal regulators of the hypothalamic-pituitary-adrenal (HPA)-axis. Vasopressin is primarily a neurohypophysial hormone, produced in magnocellular neurones of the hypothalamic paraventricular and supraoptic nuclei, but parvocellular CRH neurones also coexpress vasopressin, which acts as a second 'releasing factor' for adrenocorticotropic hormone along with CRH. All stress inputs converge on these hypothalamic neuroendocrine neurones, and the input signals are integrated to determine the output secretion of CRH and vasopressin. Aminergic, cholinergic, GABAergic, glutamatergic and a number of peptidergic inputs have all been implicated in the regulation of CRH/vasopressin neurones. Glucocorticoids inhibit the HPA-axis activity by negative feedback. Interleukin-1 stimulates CRH and vasopressin gene expression, and is implicated in immune-neuroendocrine regulation. cAMP-response element-binding protein phosphorylation may mediate transcriptional activation of both CRH and vasopressin genes, but the roles of AP-1 and other transcription factors remain controversial. Expression profiles of the CRH and vasopressin genes are not uniform after stress exposure, and the vasopressin gene appears to be more sensitive to glucocorticoid suppression.
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PMID:Regulatory mechanisms of corticotropin-releasing hormone and vasopressin gene expression in the hypothalamus. 1508 73

Corticosteroids were proposed for the treatment of sepsis as early as 1940. Several RCTs cast serious doubts on the usefulness of high dose corticosteroids and doubt still persists regarding the efficacy of replacement therapy. Adrenal insufficiency (non-responders to the 250 microg corticotropin test: increase in cortisol < 9 microg/dl) is present in about half of patients with septic shock and is associated with higher rates of refractory hypotension and mortality. Peripheral glucocorticoid resistance, which may even occur more frequently, can be easily assessed at bedside using skin tests. Cortisol antagonizes the migration of inflammatory cells, the synthesis or action of virtually all proinflammatory mediators, promotes virtually all anti-inflammatory components and enhances humoral immunity by means of transcriptional interference between its receptor and both AP-1 and NF-kappaB. Cortisol mediates cardiovascular tolerance to endotoxin and the maintenance of vascular sensitivity to catecholamines. Low doses (about 300 mg daily for 5 days or more) of hydrocortisone increase vasoconstrictor response to catecholamines in animals, in healthy volunteers challenged with LPS and in several RCTs. Hydrocortisone also increases arterial pressure and decreases the duration of shock. A meta-analysis of all available clinical controlled studies showed a reduction in 28 days, all-cause mortality with glucocorticoids (RR = 0.88, 95% CI: 0.78 - 1.00; p = 0.04). However, there was a significant heterogeneity across the trials (p = 0.006). On the other hand, analysis of studies where low doses of glucocorticoids were given for prolonged periods showed a 24% reduction in the risk of all-cause mortality at 28 days in treated patients (RR = 0.76, 95% CI: 0.64 - 0.90; p = 0.002) without heterogeneity across the trials (p = 0.28). In conclusion, in severe sepsis, high doses of corticosteroids should not be given. Septic shock should be treated with a replacement dose of hydrocortisone.
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PMID:Glucocorticoid treatment in patients with septic shock: effects on vasopressor use and mortality. 1696 Nov 59

Human skin is constantly exposed to UV light, the most ubiquitous environmental stressor. Here, we investigated the expression and regulation of Nrf1-3, transcription factors crucially involved in protection against oxidative stress in human skin cells in vitro, ex vivo, and in situ. In particular, we examined whether alpha-MSH, a UV-induced peptide, is capable of modulating Nrf2 and Nrf-dependent gene expression. Nrf1, -2, and -3 were found to be expressed in various cutaneous cell types in vitro. Surprisingly, UVB irradiation at physiological doses (10 mJ/cm(2)) reduced Nrf2 and Nrf-dependent gene expression in normal keratinocytes and melanocytes in vitro as well as ex vivo in skin organ cultures. alpha-MSH alone significantly increased Nrf2 as well as Nrf-dependent heme oxygenase-1, gamma-glutamylcysteine-synthetase, and glutathione-S-transferase Pi gene expression in both keratinocytes and melanocytes. This effect of alpha-MSH occurred at physiological doses and was due to transcriptional induction, mimicked by the artificial cAMP inducer forskolin, and blocked by protein kinase A pathway inhibition. In silico promoter analysis of Nrf2 further identified several putative binding sites for activator protein 1 and cAMP response element-binding protein, transcription factors typically activated by alpha-MSH. Importantly, alpha-MSH prevented or even overcompensated the UVB-induced suppression of Nrf2 and Nrf-dependent genes not only in normal keratinocytes and melanocytes in vitro but also in skin organ cultures. These findings, for the first time, show regulation of Nrf2 and Nrf-dependent genes by alpha-MSH. Our data also highlight a novel facet in the cytoprotective and antioxidative effector mechanisms of alpha-MSH and perhaps of related melanocortin peptides.
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PMID:Alpha-melanocyte-stimulating hormone counteracts the suppressive effect of UVB on Nrf2 and Nrf-dependent gene expression in human skin. 1928 78

Opioids are widely used for the treatment of severe pain. However, it is also known that opioids, in particular morphine, cause immunosuppression. Therefore, their use may complicate treatment of persons with an already impaired immune system, e.g., patients suffering from cancer or AIDS. We investigated the mechanisms of opioid-induced immunosuppression in primary human T lymphocytes and the human T cell line Jurkat. We demonstrated that morphine and the endogenous opioid beta-endorphin inhibited the transcription of IL-2 in activated human T lymphocytes as well as the activation of the transcription factors AP-1, NFAT, and NF-kappaB, which transactivate IL-2. In addition, the TCR-induced calcium flux and MAPK activation were inhibited by the opioids, as well as proximal signaling events, such as the phosphorylation of the linker for activation of T cells and Zap70. A more detailed characterization of the mechanism revealed that incubation of T cells with the opioids caused a marked increase in cAMP. This in turn activated protein kinase A, which augmented the kinase activity of C-terminal Src kinase bound to phosphoprotein associated with glycosphingolipid-enrich microdomains, resulting in a further enhancement of the tonic inhibition of the leukocyte-specific protein tyrosine kinase Lck, thereby blocking the initiation of TCR signaling. These effects were mediated by mu opioid receptors. Our findings contribute to the understanding of immunosuppressive side effects of morphine. Since beta-endorphin is expressed and secreted by immune effector cells, including T cells, and up-regulated in these cells by various stimuli, our data also suggest an inhibitory role for beta-endorphin in the physiological regulation of T cell activation.
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PMID:Mechanisms of opioid-mediated inhibition of human T cell receptor signaling. 1956 Nov 13


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