UMLS:C0002736 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Post-traumatic stress-induced disorders are still the focus of interest and most recently discussions are under way whether stress-induced cortisol excess leads to atrophy of the brain. In investigation on carcinogenesis the first reports were published on the use of antisense-oligonucleotides during inhibition of the development of tumours by a humoral mechanism and on the gene-based neuroendocrine differentiation of the lungs, perhaps associated with the basis for the development of small cell carcinoma. The oncogenic action of superoxides has also humoral mediators. Interest in nitrogen oxide is focused on two areas: inflammations and hypertension. Intraluminal NO concentrations increase in asthma 2-10x, in cystitis 30-100x, in Crohn's disease 20-200x. Humoral mechanisms in asthma offer new drugs--inhibitors of the development or action of leucotrienes. The basal NO production is reduced in "essential" hypertension but it is not known whether it is the cause or consequence. IGF-I increases the formation of NO in the vascular wall and thus perhaps reduces vascular contractility. As far as IGF is concerned, it is obvious that if recombinant preparations will be available, they will be tested in amyotrophic lateral sclerosis, myotonic dystrophy, multiple sclerosis, catabolic conditions, osteoporosis, in renal failure and to promote wound healing. STH may also prove useful in cardiac failure, in particular in cardiac cachexia. That TRH has receptors in the gut is not surprising, it acts, however, even there via TSH. Thrombopoietin is being tested in clinical trials. Neocytolysis is a new phenomenon: when erythropoietin secretion declines new erythrocytes disappear and only old ones remain in the blood stream. Alpha-adducin is a renal tubular protein, regulating the sodium balance.
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PMID:[Endocrinology 1996-1997]. 965 Mar 40

The IGFs are believed to be important in pregnancy and are implicated in the pathophysiology of pre-eclampsia. In adults the IGFs circulate primarily with IGF-binding protein-3 (IGFBP-3) and an acid-labile glycoprotein (ALS) in a 140 kDa complex which limits IGF bioavailability. Less than 10% of IGFBP-3 is in lower molecular weight forms. We have investigated the developmental regulation of the IGF/IGFBP system in normal and pre-eclamptic pregnancies with particular emphasis on the IGFBP-3 ternary complex. Circulating levels of IGF-I, IGFBP-3 and ALS, and their degree of association in the ternary complex in the fetus increased with gestational age. In neonatal serum from deliveries <35 weeks' gestation IGFBP-3 was predominantly in 30-50 kDa form(s) and ALS was a limiting factor for ternary complex formation. In serum from deliveries >35 weeks both ALS and IGFs were limiting but approximately 25% of IGFBP-3 was unable to form the ternary complex even in the presence of excess ALS and IGF-I. Serum IGFBP-1, -2 and -6 concentrations tended to decrease with increasing gestational age. In pre-eclamptic pregnancies, amniotic fluid IGFBP-2, -3 and -6 levels decreased with gestational age while IGFBP-1 levels did not show the normal decline. We speculate that the endocrine IGF system develops in the fetus during the third trimester of pregnancy when ALS levels increase.
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PMID:Regulation of insulin-like growth factor-binding protein-3 ternary complex formation in pregnancy. 979 67

The growth hormone (GH)-insulin-like growth factor (IGF) axis and insulin are major anabolic effectors in promoting weight gain and linear growth. These two anabolic systems are interlinked at many levels, thus abnormalities in one of these systems effect the other causing disordered metabolic homeostasis. Insufficient portal insulinization in insulin dependent diabetes mellitus (IDDM) results in hepatic GH resistance and increased production of IGF-binding proteins-1 (IGFBP-1) and IGFBP-2. GH resistance is reflected by decreased hepatic IGF-I production. In addition, changes in other GH-dependent proteins are also observed in IDDM. Increased proteolysis of IGFBP-3 results in reduction of intact IGFBP-3. Serum ALS levels are also slightly diminished in untreated diabetic patients. Hepatic resistance to GH is, at least in part, caused by diminished GH receptors as reflected by diminished circulating GHBP levels. In addition, there is also evidence from experimental and human studies suggesting post-receptor defect(s) in GH action. As a result of these changes, circulating total and free IGF-I levels are decreased during insulinopenia. Lack of negative feed-back effect of IGF-I on GH secretion causes GH hypersecretion which increases hyperglycemia by decreasing sensitivity to insulin. GH hypersecretion in poorly controlled diabetic patients may play a role in the pathogenesis of diabetic vascular complications. Most of these abnormalities in the GH-IGF axis in diabetes are reversed by effective insulinization of the patient. Addition of IGF-I treatment to insulin in adolescents with IDDM allows correction of GH hypersecretion, improves insulin sensitivity and glycemic control, and decreases insulin requirements. The effect of IGF-I treatment on diabetic complications has yet to be seen.
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PMID:Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus. 1022 99

Insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) play an important role in cell growth and differentiation. Clinical and epidemiological studies have indicated that measuring IGFs and IGFBPs in blood has potential implications in assessing growth-related abnormalities and risks of certain types of cancer. To facilitate the application, we reported a large collection of reference ranges of IGFs and IGFBPs in normal population and evaluations of these molecules in serum and plasma as well as the impact of freeze-thaw cycles on the measurement. IGF-I, IGFBP-3 andALS showed a similar pattern of change associated with age. Levels of these molecules were low at birth and increased with age through puberty. After puberty the levels declined slowly with age. Overall, IGF-I, IGFBP-3 and ALS were slightly higher in females than in males. Free IGF-I accounted for about 1% of the total IGF-I and its variation with age was similar to total IGF-I. IGF-II levels were also increased with age from birth to puberty, but became stable after puberty. There was little difference in IGF-II levels between genders. IGFBP-2 levels declined with age from birth to puberty. Levels of IGFBP-6 in contrast were increased with age. These IGF binding proteins were higher in males than in females. IGFs, IGFBP-3 and ALS were 5-10% higher in serum than in plasma. IGFBP-2 and IGFBP-6 differed substantially between serum and plasma. Freeze-thaw treatment up to five cycles had little impact on plasma levels of IGFs and IGFBP-3. Our observations suggest that levels of IGFs and their binding proteins are varied with age, gender, and types of specimen and that these variations need to be taken into consideration when IGFs and their binding proteins are utilized in clinic and research.
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PMID:Insulin-like growth factors (IGF-I, free IGF-I and IGF-II) and insulin-like growth factor binding proteins (IGFBP-2, IGFBP-3, IGFBP-6, and ALS) in blood circulation. 1041 96

The ability of trophic factors to regulate developmental neuronal survival and adult nervous system plasticity suggests the use of these molecules to treat neurodegeneration associated with human diseases, such as Alzheimer's, Huntington's and Parkinson's disease, of amyotrophic lateral sclerosis and peripheral sensory neuropathies. Recent biological data on the neutrotrophins NGF and BDNF, on GDNF, CNTF and IGF-I are discussed together with first results from clinical trials. Literature is presented on the three-dimensional structures of these trophic factors and on models proposed for ligand-receptor interactions. Substantial progress has been made in the understanding of the mechanisms of apoptosis. The cascade consisting of interaction of apoptosis-inducing ligands with death receptors, the coupling of this complex to adaptor proteins via death domains, the further recruitment of procaspases via death effector or caspase recruitment domains and the execution of cell death via the effector caspases is briefly outlined.
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PMID:Receptors in neurodegenerative diseases. 1081 65

The production by the liver of the three subunits of the growth hormone (GH)-dependent 150 kDa complex (IGF-I, IGF-binding protein-3 and acid-labile subunit or ALS) is primarily under the control of GH. Recent data have shown that, besides GH, endotoxin (LPS) and cytokines may regulate the liver IGF-I gene. To investigate the potential regulation of ALS by LPS, we measured serum ALS by immunoblot, 5 and 10 h after IP injection of LPS (250 or 750 microg/100 g BW vs saline), in 4-week-old female Wistar rats (four per group). Ten hours after injection, serum ALS levels were reduced by 57% (delta%) with the lower dose (P<0.05) and by 81% with the higher dose (P<0.01) by comparison with saline-treated rats. The decrease in ALS levels in response to LPS was not prevented by exogenous GH. To investigate the role of interleukin (IL)-1beta in the regulation of ALS, primary cultured rat hepatocytes were exposed to increasing concentrations of IL-1beta. Cell exposure to IL-1beta markedly decreased both basal and GH-stimulated ALS levels (-70%; P<0.01) in a dose-dependent fashion, with the half-maximal inhibitory effect at concentrations of 0.1 ng/ml. Our results show that endotoxin induces a rapid decline in circulating ALS that is potentially mediated through IL-1beta. By limiting the formation of the 150 kDa complex, this reduction in circulating ALS might contribute to the rapid decline in serum IGF-I observed in sepsis.
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PMID:Decreased acid-labile subunit (ALS) levels by endotoxin in vivo and by interleukin-1beta in vitro. 1098 10

Serum levels of insulin and insulin-like growth factors and their binding proteins (IGFs and IGFBPs, respectively) are changed in human neurodegenerative diseases of very different etiology, such as Alzheimer's disease, amyotrophic lateral sclerosis, or cerebellar ataxia. However, the significance of these endocrine disturbances is not clear. We now report that in two very different inherited neurodegenerative conditions, ataxia-telangiectasia (AT) and Charcot-Marie-Tooth 1A (CMT-1A) disease, serum levels of IGFs are also altered. Both types of patients have increased serum IGF-I and IGFBP-2 levels, and decreased serum IGFBP-1 levels, while only AT patients have high serum insulin levels. Furthermore, serum IGFs are also changed in three different animal models of neurodegeneration: neurotoxin-induced motor discoordination, diabetic neuropathy, and hereditary cerebellar ataxia. In these three models, serum insulin levels are significantly decreased, serum IGF-I and IGFBP-1, -2, and -3 are decreased in diabetic and neurotoxin-injected rats, while serum IGFBP-1 is increased in hereditary ataxic rats. Altogether, these observations indicate that a great variety of neurodegenerative diseases show endocrine perturbations, resulting in changes in serum IGFs levels. These perturbations are disease-specific and are probably due to metabolic and endocrine derangements, nerve cell death, and sickness-related disturbances associated to the neurodegenerative process. Our observations strongly support the need to evaluate serum IGFs in other neurodegenerative conditions.
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PMID:Neurodegeneration is associated to changes in serum insulin-like growth factors. 1111 63

Besides the free radical hypothesis raised by the identification of Superoxide Dismutase I mutations in a subset of familiar Amyotrophic Lateral Sclerosis (ALS) patients, three etiopathogenic hypotheses for sporadic ALS, namely autoimmune, neurofilament, and glutamate toxicity, have attracted interest in the last few years. The role of autoimmunity in ALS has been seriously questioned. The excitotoxic hypothesis for ALS spurred two clinical trials with riluzole. The results of both studies showed a modest benefit in prolonging survival that was statistically significant. Riluzole was the first drug made available for ALS patients. It began a new era in both basic and clinical research. Various human recombinant neurotrophic molecules (CNTF, BDNF, IGF-I) were administered to ALS patients. IGF-I slowed the progression of functional impairment in patients with ALS with no adverse effects. The recent demonstration of the specific viral echovirus 7 RNA sequences in the spinal cord of ALS patients refocused research on the viral hypothesis of the disease and antiviral drugs are ready to be used in clinical settings. New treatment strategies are today under study: intrathecal infusion with BDNF, intrathecal capsules for neurotrophic factor secretion or in vivo gene therapy using viral vectors. New research findings are, more than for other diseases, immediately transferred to clinical ground for the desperate need of a curative treatment of the patients affected by ALS.
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PMID:The pathogenesis of ALS: implications for treatment strategies. 1173 78

Peroxisome proliferator-activated receptor alpha (PPARalpha) plays a central role in glucose and lipid homeostasis. Mice lacking PPARalpha(-/-) have a sexually dimorphic phenotype. We have characterized the IGF system in wild type and PPARalpha-/- mice. In normal mice fasting IGF-I and the IGFBP-3 ternary complex were 2-fold higher in males than in females. PPARalpha influenced the IGF/IGFBP response to feeding, particularly in males. Compared to wild type, male PPARalpha-/- mice had 40% lower total fasting IGF-I concentrations, decreased ALS and less IGFBP-3 ternary complex formation, but within 4 h of refeeding there was an increase in IGF-I and IGFBP-3 ternary complex to values similar to controls. Circulating IGFBP protease activity was induced in male PPARalpha-/- mice during refeeding. IGFBP-1 and insulin concentrations were higher in males than females, and were increased by PPARalpha knockout, suggesting significant hepatic insulin resistance. We speculate that gender differences in the IGF system contribute to the PPARalpha-/- phenotype.
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PMID:Responses of insulin-like growth factor (IGF)-I and IGF-binding proteins to nutritional status in peroxisome proliferator-activated receptor-alpha knockout mice. 1173 49

Indirect evidence suggests a link between factors produced during the inflammatory response and stunted growth. The demonstration of this link was provided by the observation that mice transgenic for the inflammatory cytokine interleukin-6 (IL-6), expressing high circulating levels of IL-6 since birth, show a marked decrease in growth rate leading to adult mice 50-70% the size of wild-type littermates. The growth defect is completely abolished by neutralization of IL-6. In these mice the production of GH is normal, while circulating levels of IGF-I are markedly decreased. Administration of IL-6 to wild-type mice results in a marked decrease in IGF-I levels. These observations show that in vivo high levels of IL-6 are associated with low levels of IGF-I. However, IL-6 does not directly affect IGF-I production both in vitro and in vivo. In contrast, markedly decreased levels of IGFBP-3 are present in the IL-6 transgenic mice and administration of IL-6 to wild-type mice results in a marked decrease in IGFBP-3 levels. In these mice the decrease in IGFBP-3 levels is associated with impaired formation of the 150 kD ternary complex, even in the presence of normally functional ALS. As a consequence, IL-6 transgenic mice show increased clearance of circulating IGF-I, suggesting that IL-6 decreases IGF-I levels by increased clearance. Proteolytic degradation of IGFBP-3 occurs in the IL-6 transgenic mice, suggesting that the decrease in IGFBP-3 could be at least in part due to proteolysis. The abnormalities of the IGF-I system observed in the IL-6 transgenic mice are similar to those found in patients with systemic juvenile idiopathic arthritis, one of the chronic inflammatory diseases characterized by stunted growth and prominent production of IL-6. The IL-6 transgenic mice represent a faithful animal model of the growth impairment associated with chronic inflammation and may therefore provide information relevant to the understanding and treatment of this complication of inflammatory diseases.
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PMID:Role of interleukin-6 in growth failure: an animal model. 1237 10

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