Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucose turnover and blood metabolites were measured in eight adult female beagles in the fed state, at 1 day of fasting, and at 7, 14, and 21 days of fasting. Glucose utilization decreased significantly from 1 to 7 days of fasting, but remained constant from 7 to 21 days, while blood ketones and plasma free fatty acids rose significantly during the same period. Plasma alanine, serine, and glycine fell with fasting, with the greatest decrease in alanine levels occurring between 7 to 14 days. Plasma branched chain amino acids rose significantly with fasting. It was concluded that the shifts in plasma metabolites and decreased glucose utilization could be indicative of decreased energy demands of the fasting dogs and/or a shift in substrate utilization with progressive fasting.
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PMID:Influence of prolonged fasting in the dog on glucose turnover and blood metabolites. 86 15

The anti-fatigue effect of phosphoserine, L-serine and a mixture of sodium phosphate and L-serine has been studied in rats. Phosphoserine orally administered induced a statistically significant anti-fatigue effect in rats of both sexes submitted to a training test by rotarod, with 14 sessions in 3 days. Furthermore, phosphoserine was utilized better than the mixture of sodium phosphate and L-serine, whereas L-serine alone induced no effect. Therefore the effect of phosphoserine seems to be due to the phosphoryl bond.
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PMID:Influence of phosphoserine on the performance of rats on the rotarod. 95 8

Interferon-beta-serine (IFN-beta-ser) is a muteine, recombinant IFN that is tolerated at a dose fivefold to 10-fold higher than IFN-alfa and interacts with the same cell membrane receptor as IFN-alfa. We hypothesized that at high doses IFN-beta-ser might induce a higher response rate than IFN-alfa in metastatic renal cell carcinoma. We undertook a phase II trial of IFN-beta-ser in patients with metastatic renal cell carcinoma. Patients were treated three times each week by a 2-hour intravenous infusion. Doses were escalated weekly (.25 to 5.5 mg, 1 mg = 180,000,000 U) until the maximum-tolerated treatment dose (MTTD) was determined. The MTTD is defined as one dose level less than that which caused grade 3 toxicity and was subsequently administered three times weekly for at least 4 weeks. Twenty-nine patients were entered, and 25 were assessable for response and toxicity. The performance status was 0-1 in all patients and only one patient received previous chemotherapy. The MTTD dose was 2.5 mg (range, 0.5 to 5.5 mg per treatment), although in 10 patients, doses were later deescalated because of cumulative toxicity. Initial dose-limiting toxicity and cumulative toxicity were fatigue, malaise, and fever in most patients. Hepatic transaminitis, neutropenia, and elevation of serum creatinine were also observed but were not dose-limiting. There was one complete response (CR) and four partial responses (PRs). All responses but one occurred in pulmonary metastases. The median time to response was 26 days (range, 17 to 102 days). These data demonstrate that IFN-beta-ser given in high doses exhibits significant antitumor activity in renal cell carcinoma; however, the objective response rate is 20%. This is no higher than previous IFN studies; therefore, we reject the hypothesis than IFN-beta-ser at high doses may induce a greater response rate than IFN-alfa. However, we did observe more responses than were seen in a similar trial undertaken with lower dose IFN-beta serine in renal cell carcinoma.
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PMID:Phase II trial of interferon-beta-serine in metastatic renal cell carcinoma. 233 72

The uremic syndrome is multifactorial, and affects most tissues and organs. Disturbances in protein and amino acid metabolism may play important roles, especially in chronic uremia, either directly or by production of toxic metabolites, with resultant negative nitrogen (N) balance, muscle wasting, reduced protein synthesis, and characteristically abnormal intracellular free amino acid concentrations. There are also grossly abnormal amino acid levels in the plasma of uremic patients, e.g., increases in conjugated amino acids, high levels of several nonessential and low levels of essential amino acids. The ratios of tyrosine/phenylalanine and of valine/glycine are decreased. The low tryptophan levels may contribute to encephalopathy as a result of an imbalance in neurotransmitter synthesis. Citrulline is found in excess; the explanation is unresolved. There are elevated concentrations of the sulfur-containing amino acids: cystine, taurine, cystathionine, and homocysteine. Excess of the latter is implicated in the atherogenesis of renal failure. Disturbed metabolism and interorgan exchange of amino acids in the uremic state explains some of the abnormalities in tissue and plasma concentrations of individual amino acids. Enzymatic defects are involved in the disturbed metabolism of branched chain amino acids (BCAA), with possible antagonism among them, which impairs growth and amino acid utilization. Carbohydrate intolerance, associated with insensitivity of peripheral tissues to insulin and hyperinsulinemia, elicits decreased plasma BCAA. Protein synthesis rates in normal and pathological conditions are more closely related to the intracellular amino acid pool than to plasma amino acid levels. Concentrations of individual amino acids in the plasma pool are poor indicators of their intracellular concentrations. Muscle contains the largest pool of protein and free amino acids in the body. In chronic renal failure patients, the intracellular concentrations of valine, threonine, lysine, and carnosine are low. With low protein diets and in hemodialysis, serine, tyrosine, and taurine often are also low. The low taurine may be related to fatigue and to uremic cardiomyopathies. The commonly used amino acid supplements generally fail to correct the intracellular amino acid deficits. A "New Formula" has been developed to correct these intracellular amino acid abnormalities, and to supplement a low protein diet. It provides more valine than leucine, increased tyrosine and threonine, and less histidine, leucine, isoleucine, lysine, methionine, and phenylalanine than in formulas customarily used for patients with chronic renal failure. It is uncertain whether other ap
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PMID:Amino acid metabolism in uremia. 267 58

Twelve patients with advanced malignant disease were entered onto a Phase I study of escalating doses of beta-interferon serine given by 4-h i.v. infusion twice a wk. Three patients each were entered at starting doses of 0.01, 1, 10, and 30 million units (MU)/m2. Doses escalation within individual patients was allowed to a maximum dose of 400 MU/m2. Fever, chills, fatigue, and acral cyanosis were commonly seen and increased in frequency at higher doses. Myalgia, nausea, diarrhea, headache, and confusion were seen at lesser frequencies. Mild leukopenia, paresthesia, infusion site erythema, and hypotension were each seen in one patient. No conventional maximal tolerated dose could be defined, since several patients underwent escalation to the highest allowable dose and seemed to develop tolerance to acute toxicities. However, a maximal starting dose of 10 MU/m2 was identified, such that those begun at this level or below tolerated semiweekly dose escalation, while those begun at 30 MU/m2 could not tolerate continued therapy. Detectable serum interferon levels were noted during treatment at 10 and 30 MU/m2, the levels at which significant toxicity also first appeared. A maximal starting dose of 10 MU/m2, with gradual escalation as tolerance to side effects develops, is suggested if therapy with high-dose beta-interferon serine is given by 4-h infusion.
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PMID:Phase I study of recombinant beta-interferon given by four-hour infusion. 380 98

The cytoskeleton plays a pivotal role in lectin-induced lymphocyte blastogenesis. Microtubule disrupting agents, many of which are sulfhydryl (SH) reagents, interfere with cytoskeletal-dependent cell functions including lymphocyte blastogenesis and agglutination. For example, hydroquinone (HQ) and N-ethylmaleimide (NEM) inhibit lectin-stimulated lymphocyte blastogenesis and agglutination at concentrations (10(-5)M) that do not reduce cell viability or ATP production. Indicative of the SH-specificity of these effects, only L-cysteine protects against HQ or NEM inhibition of blastogenesis and agglutination. Other compounds, including L-serine, DL-lysine and imidazole, have no protective effect. These and other findings previously reported suggest a selective interaction of HQ, or its oxidation product, p-benzoquinone (p-BQ) with SH groups critical to early G1 events associated with lymphocyte activation. These compounds show similar SH specificity in inhibiting microtubule assembly in vitro. The subcellular target specificity (cytoskeleton) exhibited by these compounds was compared to that of Adriamycin (ADR), a complex polycyclic quinone with known immunotoxic activity. ADR inhibited microtubule assembly in vitro and inhibited lymphocyte blastogenesis, however, these effects were not correlated with a loss of agglutination nor was toxicity protected against by the addition of SH compounds. The combination of cell culture methods together with application of techniques to measure microtubule assembly in vitro provides an effective means to discriminate between agents that selectively interfere with cytoskeletal-dependent function and those producing non-specific effects associated with cell death, such as decreased energy production or increased membrane permeability.
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PMID:Alteration of lymphocyte function by quinones through a sulfhydryl-dependent disruption of microtubule assembly. 665 42

The age and gender related differences in serum amino acid concentrations have been assessed in 72 (23-92 years) medically screened healthy men and women who were divided into three male and three female groups according to age. Free-time physical activity and food intake were analysed from the 5-day diaries. The subjects were instructed to eat according to their normal dietary habits and to avoid any clinical complementary nutritional products or other products that could increase protein or energy intake. The blood samples (5 ml) taken from the antecubital vein after an over-night fast were analysed for their amino acid contents by chromatography. In total nutrient intake of energy (P < 0.001), protein (P < 0.001), alcohol (P < 0.05), water (P < 0.01), sodium (P < 0.001) and fiber P < 0.001) decreased significantly with age. The concentration of total amino acids (P < 0.01), essential amino acids (P < 0.001), non-essential amino acids (P < 0.05) and branched-chain amino acids (P < 0.05) decreased, whereas citrulline (P < 0.001) and cysteine (P < 0.001) were the only amino acids, which increased with aging. In addition, men had significantly higher concentrations than women of essential amino acids (P < 0.001), branched-chain amino acids (P < 0.001), and 10 of the 22 individual amino acids assayed (P < 0.01). Women had significantly higher concentrations of aspartate (P < 0.05), glycine (P < 0.01), serine (P < 0.001) and taurine (P < 0.01) than men. It is concluded that the decrease in serum total amino acid concentration is associated with decreased energy and protein intake with aging and men have higher essential amino acid concentration in serum than women.
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PMID:Serum amino acid concentrations in aging men and women. 1276 4

Muscular inactivity leads to atrophy, weakness, and decreased fatigue resistance. In order to provide a window into the dynamic processes that underlie muscle atrophy, we performed global gene expression analysis of rat soleus muscles using Affymetrix GeneChips at 1, 4, 7 and 14 days of hindlimb unloading. Expression of 309 known genes was significantly changed by at least 2-fold (212 upregulated, 97 downregulated). K-means clustering was used to divide these genes into co-regulated clusters based on the similarity of temporal expression patterns. This allowed the development of a timeline of the atrophy process with respect to the behaviour of genes in a broad array of functional categories. Regulatory genes were often upregulated early, in either a transient or sustained manner, but they also populated clusters with later patterns of activation, suggesting different phases of molecular adaptations. Other early events were the activation of ubiquitination genes and downregulation of protein chaperones. In comparison, clusters representing slightly delayed activation patterns included genes involved in fast contraction, glycolysis, translational inhibition, oxidative stress, protein degradation, and amino acid catabolism. Downregulated genes exhibited fewer unique expression patterns and included structural and regulatory genes of the extracellular matrix and cytoskeleton, and genes that define a slow-oxidative phenotype. Other novel findings include the tight co-activation of proteasome subunit and ubiquitination genes, differential regulation of serine proteases and serine protease inhibitors, and the identification of transcriptional, signalling, growth and cell cycle genes that probably play a role in the atrophy process. The present work has uncovered temporal patterns of gene expression that highlight the molecular processes that underlie muscle atrophy and provide new avenues for study.
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PMID:Global analysis of gene expression patterns during disuse atrophy in rat skeletal muscle. 1284 9

Chronic fatigue syndrome (CFS) is characterized by idiopathic fatigue of greater than 6 months' duration with postexertional exacerbation and many other symptoms. A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized that CBG gene polymorphisms may act as a genetic risk factor for CFS. A total of 248 patients with CFS defined by Centers for Disease Control criteria, and 248 controls were recruited. Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G-->T, Ala-Ser224). Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies. A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted, compared with controls (chi2 = 5.31, P = 0.07). Immunoreactive-CBG (IR-CBG) levels were higher in Serine/Alanine (Ser/Ala) than Ala/Ala subjects and higher again in Ser/Ser subjects, this effect was strongest in controls; Ser/Ser: 46.1+/-1.8 (n = 31, P = 0.03) vs. Ser/Ala: 42.4+/-1.0 (n = 56, P = 0.05) vs. Ala/Ala: 40.8+/-1.7 microg/mL (n = 21). Despite higher CBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients, total cortisol: Ser/Ser: 13.3+/-1.4 (n = 34) vs. Ser/Ala: 14.0+/-0.7 (n = 66) vs. Ala/Ala: 15.4+/-1.0 (n = 23). Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions.
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PMID:Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism. 1555 58

Previous work by others have suggested the occurrence of one or more chemical or metabolic 'markers' for ME/CFS including specific amino acids and organic acids and a number of unidentified compounds (CFSUM1, CFSUM2). We have shown elsewhere that CFSUM1 is partially derivatised pyroglutamic acid and CFSUM2 partially derivatised serine and have suggested and demonstrated that the analytical methods used were unsuitable to identify or to accurately quantify urinary metabolites. We have now made a detailed analysis of plasma and urinary amino acids and of urinary organic acids from patients with ME/CFS and from three control groups. Fasting blood plasma and timed urine samples were obtained from 31 patients with CFS, 31 age and sex-matched healthy controls, 15 patients with depression and 22 patients with rheumatoid arthritis. Plasma and urinary amino acids and urinary organic acids were determined using established and validated methods and data compared by statistical analysis. None of the previously reported abnormalities in urinary amino acids or of organic acids could be confirmed. Results however provide some evidence in patients with ME/CFS for underlying inflammatory disease and for reduced intramuscular collagen with a lowered threshold for muscle micro-injury. These factors in combination may provide a basis for the fatigue and muscle pain that are the major symptoms in these patients.
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PMID:Urinary and plasma organic acids and amino acids in chronic fatigue syndrome. 1599 88


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