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

Because the immune response appears important in the pathogenesis of MS, anti-inflammatory and immunomodulatory drugs and agents are used as a palliative treatment. Azathioprine alone is minimally efficacious and probably not worth the bother and risk. Cyclophosphamide alone is too toxic. Although cyclosporine A may slow the rate of deterioration in chronic progressive MS, adverse effects may limit its use outside major centers. Gamma interferon provokes exacerbations and should not be used. We do not recommend copolymer-1, alpha or beta interferon, monoclonal antibodies, plasmapheresis, and total lymphoid irradiation except in well-designed experimental protocols. Combination therapy of adrenal cortical steroids (ACS) with other immunosuppressants (cyclophosphamide or cyclosporine) merits further study. We think "pulse" synthetic ACS therapy has advantages over corticotropin and will become the "standard of care" for exacerbations. We also would try it for chronic progression. Even then, with the pulse treatment we still must determine the optimum dose, route, duration, and need for "taper."
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PMID:The peculiar difficulties of therapeutic trials for multiple sclerosis. 169 Aug 38

The concentration of immunoreactive beta-endorphin (IR-BE) in the anterior pituitary (AP) and the neurointermediate lobe of the pituitary (NIL) was elevated in old as compared to young male rats. Treatment of old male rats with the dopamine precursor, L-DOPA, did not affect the concentration of IR-BE in the AP and produced a significant reduction in the concentration of IR-BE in the NIL. By contrast, administration of the serotonergic neurotoxin, p-CPA, significantly diminished the concentration of IR-BE in the AP of old male rats, while the concentration of IR-BE in the NIL remained unchanged. Hypothalamic IR-BE was decreased in old male rats and was not influenced by administration of L-DOPA or p-CPA. Chromatographic analysis indicated that in the AP of old animals the amount of beta-endorphin relative to beta-lipotropin was increased and was diminished slightly by the treatments. Alterations in IR-BE in the NIL and hypothalamus were represented solely by beta-endorphin. These data suggest that in old male rats, a decrease in dopaminergic activity contributes to the increase in IR-BE levels in the NIL, and an increase in serotonergic function, at least in part, is responsible for the elevation in the level of IR-BE in the AP.
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PMID:The elevation of immunoreactive beta-endorphin in old male rats is related to alterations in dopamine and serotonin. 236 54

The efficacies of corticosteroids and azathioprine (part 1) and of cyclophosphamide, immune globulin, cyclosporine, interferons, copolymer 1, and cladribine (part 2) in patients with multiple sclerosis (MS) are reviewed. MS is an inflammatory, demyelinating disease of the CNS that commonly affects young adults. The involvement of various immune mechanisms in MS suggests a role for immunomodulating therapy. The goals of immunotherapy vary with the clinical stage of the disease and include (1) improving recovery from exacerbations, (2) decreasing the number or severity of relapses, (3) preventing the development of chronic progressive disease from a relapsing-remitting course, and (4) decreasing further progression in patients with chronic progressive disease. In clinical trials, corticotropin and corticosteroids have been found to accelerate recovery from exacerbations. Tapering is often effective after high-dose induction therapy. Long-term maintenance regimens do not alter disease progression and are not recommended. Azathioprine produces modest benefits with respect to relapse rates and disease progression after two or more years of treatment; adverse effects are mild to moderate. Azathioprine should not be used in patients with aggressive disease who may approach severe disability in 6-18 months. Cyclophosphamide, because of its modest impact on disease progression and its potentially severe adverse effects, including cancer, should be reserved for patients with aggressive relapsing-remitting or chronic progressive disease in whom other treatments have failed to work; maintenance therapy is necessary after induction. Intravenous immune globulin may benefit patients with severe relapses; however, its efficacy remains unproven. Cyclosporine also cannot be recommended because of its modest efficacy, marked adverse effects, and high cost. Interferon beta-1b is a more specific immunotherapy that has been found to decrease the number and severity of relapses. This treatment should be considered in patients with relapsing-remitting disease who are having two or more exacerbations per year. Copolymer 1 and cladribine have shown some promising early results. Although various immunotherapeutic drugs can provide relief in patients with MS, none is capable of reversing disease progression, and some can cause serious adverse effects. Better understanding of the immunologic basis of MS may lead to more specific immunotherapies with more lasting benefits.
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PMID:Immunotherapy in multiple sclerosis, Part 1. 852 66

The efficacies of corticosteroids and azathioprine (part 1) and of cyclophosphamide, immune globulin, cyclosporine, interferons, copolymer 1, and cladribine (part 2) in patients with multiple sclerosis (MS) are reviewed. MS is an inflammatory, demyelinating disease of the CNS that commonly affects young adults. The involvement of various immune mechanisms in MS suggests a role for immunomodulating therapy. The goals of immunotherapy vary with the clinical stage of the disease and include (1) improving recovery from exacerbations, (2) decreasing the number or severity of relapses, (3) preventing the development of chronic progressive disease from a relapsing-remitting course, and (4) decreasing further progression in patients with chronic progressive disease. In clinical trials, corticotropin and corticosteroids have been found to accelerate recovery from exacerbations. Tapering is often effective after high-dose induction therapy. Long-term maintenance regimens do not alter disease progression and are not recommended. Azathioprine produces modest benefits with respect to relapse rates and disease progression after two or more years of treatment; adverse effects are mild to moderate. Azathioprine should not be used in patients with aggressive disease who may approach severe disability in 6-18 months. Cyclophosphamide, because of its modest impact on disease progression and its potentially severe adverse effects, including cancer, should be reserved for patients with aggressive relapsing-remitting or chronic progressive disease in whom other treatments have failed to work; maintenance therapy is necessary after induction. Intravenous immune globulin may benefit patients with severe relapses; however, its efficacy remains unproven. Cyclosporine also cannot be recommended because of its modest efficacy, marked adverse effects, and high cost. Interferon beta-1b is a more specific immunotherapy that has been found to decrease the number and severity of relapses. This treatment should be considered in patients with relapsing-remitting disease who are having two or more exacerbations per year. Copolymer 1 and cladribine have shown some promising early results. Although various immunotherapeutic drugs can provide relief in patients with MS, none is capable of reversing disease progression, and some can cause serious adverse effects. Better understanding of the immunologic basis of MS may lead to more specific immunotherapies with more lasting benefits.
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PMID:Immunotherapy in multiple sclerosis, Part 2. 853 45

The present study was designed to examine the possible involvement of supraspinal CTX- and PTX-sensitive G-proteins in an opioid-induced antinociception in the formalin test. Morphine (1 microg) and beta-endorphin (1 microg) given i.c.v. displayed near-maximal inhibitory effects against the formalin response in the first (0-5 min) and the second (20-40 min) phases. CTX (0.1-0.5 microg) pretreated i.c.v. produced antinociceptive effects in both phases of the formalin responses. Its effect was more pronounced in the first phase. However, PTX (0.05-0.5 microg) injected i.c.v produced the antinociceptive effect only in the first, but not the second, phase. Both CTX (0.5 microg) and PTX (0.5 microg), at the dose which had no intrinsic effect, significantly reversed the beta-endorphin-induced antinociceptive effect observed during the second, but not the first, phase. However, the antinociceptive effect by morphine failed to be affected by the same dose of treatment with CTX or PTX. Our results indicate that, at the supraspinal level, CTX- and PTX-sensitive G-proteins appear to be involved in the modulation of antinociception induced by supraspinally administered beta-endorphin, but not morphine, in the formalin pain model.
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PMID:Pretreatment with cholera or pertussis toxin differentially modulates morphine- and beta-endorphin-induced antinociception in the mouse formalin test. 1203 Aug 2

Neuropeptides are generally produced from precursor proteins by selective cleavage at specific sites, usually involving basic amino acids. Enzymes such as the prohormone convertases and carboxypeptidase E are highly specific for these basic amino acid-containing sites. In addition to this "traditional" pathway, several neuropeptides are known to be cleaved at non-basic sites, and the enzymes responsible for these cleavages have not been conclusively identified. In a recent search for novel members of the metallocarboxypeptidase family, we found three human genes. One of these, named "CPA-5," has a specificity for C-terminal hydrophobic amino acids and mRNA expression in brain, pituitary, and testis. To test whether CPA-5 protein has a distribution pattern in pituitary that is consistent with a role for this enzyme in the non-basic processing of proopiomelanocortin-derived peptides such as beta-endorphin and adrenocorticotropin, we examined the distribution of CPA-5 using immunocytochemistry. In the pituitary, CPA-5 is detected in the neurointermediate lobe and in scattered cells in the anterior lobe. In the AtT-20 corticotroph cell line, CPA-5 has a perinuclear distribution. Taken together, these results are consistent with a role for CPA-5 in the intracellular processing of proopiomelanocortin-derived peptides at non-basic sites.
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PMID:Neuropeptide-processing carboxypeptidases. 1280 87

The aim of the present study was to investigate the direct effects and action mechanisms of digitalis on the production of corticosterone in rat adrenocortical cells. Male rats were challenged with digoxin (1 microg ml(-1) kg(-1)) in the presence or absence of adrenocorticotropin (ACTH, 5 microg ml(-1) kg(-1)) administered by intravenous injection to the right jugular vein. Blood samples were collected at 0, 30, 60, and 120 min following the challenge. The concentration of corticosterone in the rat plasma samples was measured by radioimmunoassay. Zona fasciculata-reticularis (ZFR) cells in male rats were prepared and then incubated with or without digoxin or digitoxin in the presence or absence of ACTH (10(-9) m), forskolin (10(-7) m), 8-bromo-cyclic 3' : 5'-adenosine monophosphate (10(-4) m), cyclopiazonic acid (CPA, 10(-5) m), trilostane (10(-6) m), 25-OH-cholesterol (10(-5) m), pregnenolone (10(-5) m), progesterone (10(-5) m), or deoxycorticosterone (10(-5) m) at 37 degrees C for 1 h before collection of the media. Corticosterone or pregnenolone levels were measured by radioimmunoassay. A single injection of digoxin did not alter the basal level of plasma corticosterone, but did inhibit the level of plasma corticosterone released in response to ACTH in vivo. Administration of digoxin or digitoxin decreased both spontaneous and ACTH-stimulated release of corticosterone in vitro. Digoxin (10(-7)-10(-5) m) and digitoxin (10(-7)-10(-5) m), but not ouabain (10(-7)-10(-5) m), dose-dependently inhibited corticosterone production in response to forskolin and 8-Br-cyclic AMP in rat ZFR cells. Both digoxin (10(-6)-10(-5) m) and digitoxin (10(-6)-10(-5) m) attenuated corticosterone production in response to CPA. Digoxin (10(-5) m) or digitoxin (10(-5) m) inhibited cytochrome P450 side-chain cleavage enzyme (cytochrome P450scc) activity (catalyses conversion of cholesterol to pregnenolone in the presence of trilostane) in rat ZFR cells. The enzyme activity of 11 beta-hydroxylase (catalyses conversion of deoxycorticosterone to corticosterone) in ZFR cells was also inhibited by the administration of digoxin (10(-5) m) or digitoxin (10(-5) m).10 These results together suggest that digoxin and digitoxin decrease the release of corticosterone by acting directly on ZFR cells via a Na+, K+-ATPase-independent mechanism involving the inhibition of the activities of adenylyl cyclase, cytochrome P450scc and 11 beta-hydroxylase, as well as the functioning of cyclic AMP and intracellular calcium.
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PMID:Inhibitory effects of digoxin and digitoxin on corticosterone production in rat zona fasciculata-reticularis cells. 1524 23

Cyclophosphamide (CP)-induced cystitis is often used as an animal model of visceral pain. Various neuropeptides in the hypothalamic and amygdaloid nuclei are implicated in pain-induced responses. However, little information is available regarding the regulation of the neuropeptides in response to visceral pain. In the present study, we examined the effects of CP-induced cystitis on the levels of mRNAs encoding galanin, corticotropin-releasing hormone (CRH), substance P, and enkephalins in the hypothalamic and limbic nuclei using in situ hybridization histochemistry in mouse. Galanin mRNA levels in CP-treated group increased significantly in the arcuate nucleus and the paraventricular nucleus (PVN) but not in the medial preoptic area after the intraperitoneal administration of CP (200 mg/kg body weight) in comparison to those in saline-treated group. CRH mRNA levels in CP-treated group also increased significantly in the central amygdala as well as the PVN after the CP administration. In contrast, CP-induced cystitis failed to upregulate the preprotachykinin-A and preproenkephalin genes which encode substance P and enkephalins, respectively in the hypothalamic and limbic nuclei at any of the time points examined. These results suggest that visceral nociception may upregulate both galanin and CRH gene expression in the hypothalamic and limbic nuclei.
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PMID:Up-regulation of galanin and corticotropin-releasing hormone mRNAs in the key hypothalamic and amygdaloid nuclei in a mouse model of visceral pain. 1733 20

Membranous nephropathy (MN) is a glomerular disease characterized by proteinuria, usually in a nephrotic range, and variable natural course. The etiology is unknown in many cases, while in some patients, MN may be secondary to infection, to other diseases, or to exposure to drugs and toxic substances. In idiopathic MN, the antigens are probably located at the base of podocytes, and the glomerular lesions occur by the local formation of immune complexes, with consequent activation of complement and inflammation triggered by the membrane attack complex C5b-9. Patients with severe proteinuria, those with advanced tubulointerstitial changes at renal biopsy and those with increased serum creatinine at presentation have a poorer prognosis, while patients showing complete or even partial remission of proteinuria have a favorable prognosis. The indications for and types of treatment are controversial. There is no good evidence in favor of therapies based on corticosteroids alone. Cyclophosphamide and chlorambucil may increase the probability of remission, but the prolonged use of these agents may cause disquieting adverse effects. Good results have been obtained by alternating corticosteroids and a cytotoxic agent every other month for 6 months. Other potential treatments are represented by cyclosporine, synthetic adrenocorticotropic hormone (ACTH), mycophenolate mofetil, rituximab and intravenous immunoglobulins. Further studies addressed to recognizing the responsible antigen(s), and interventions directed to interfere with the specific antibodies, with regulators of glomerular permeability, and/or with factors regulating the complement activity might allow us to better understand the physiopathology of MN and to organize more specific and effective treatments in the near future.
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PMID:Membranous nephropathy. 1755 60

Adrenal adenomas producing both aldosterone and cortisol (A/CPAs) have been described in only a few cases. Correct subtype classification is necessary for making therapeutic decisions in primary aldosteronism (PA). Therefore, we studied in detail the clinical, hormonal and histological features of this entity in two patients with A/CPAs. We describe two patients with A/CPA and present their endocrine evaluations at baseline, after suppression with fludrocortisone and dexamethasone, after therapy with spironolactone and after unilateral adrenalectomy. Moreover, the expression of corticotropin (MC2R) and angiotensin II type 1 (AT1R) receptors and 17alpha-hydroxylase in the tumors of these two patients was analyzed by immunohistochemistry. Aldosterone, 18-hydroxycorticosterone (18-OH-B) and 18-hydroxycortisol (18-OH-F) were not suppressible with fludrocortisone in either patient and were partly suppressible with dexamethasone in one of the patients. Adrenal insufficiency developed in both patients after operation and lasted for more than 6 months. Aldosterone and hybrid corticosteroids returned to normal 8 weeks after adrenalectomy. In both cases, immunostaining showed weak expression of AT1R and MC2R but strong expression of 17alpha-hydroxylase. The most common germline mutations in the aldosterone synthase gene and the aldosterone synthase/11beta-hydroxylase hybrid gene were absent. These two cases document the fact that sporadic A/CPA is a subtype of PA. The presence of an A/CPA should be considered if a patient has both PA and hypercortisolism.
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PMID:Sporadic solitary aldosterone- and cortisol-co-secreting adenomas: endocrine, histological and genetic findings in a subtype of primary aldosteronism. 2018 51


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