Clinical significance of plasma tryptophan,kynurenine, and kynurenine/tryptophan ratio in rheumatoid arthritis patients

BackgroundThe catabolism of tryptophan (Trp) in the kynurenine (Kyn) pathway is thought to have a critical immunosuppressive effect.Aim of the workTo evaluate plasma Trp and metabolite levels to identify their diagnostic potential in rheumatoid arthritis (RA).Patients and methods50 RA patients and 41 control were included in this study. The Trp and Kyn were analyzed and the KynTrp ratio was calculated to estimate Indolamine 2,3 dioxygenase (IDO) enzyme activity involved in Trp degradation.ResultsThe 50 patients had a mean age of 58·5 ± 10·6 years; 37 females and 13 males, F:M 2.8:1 and median disease duration was 10·1 (7–16) years. Rheumatoid factor was positive in 64 %. The median Trp value was significantly lower in RA (11120·7; 3259–16352 ng/ml) compared to control (12372·3; 7217–31,936 ng/ml) (p = 0·001). Kyn/Trp was significantly higher in RA (4·04; 2·5-12·3) compared to control (3.2; 2·1-4·7) (p < 0·0001). The median Kyn value was higher in RA (451·02; 264–1292 ng/ml) than in control (391·4; 236–1494 ng/ml) (p = 0·04). Trp significantly inversely correlated with the morning stiffness (r = ?0·32, p = 0·025), Kyn significantly correlated with the C-reactive protein (CRP) (r = 0·31, p = 0·028) and erythrocyte sedimentation rate (ESR) (r = 0·41, p = 0·003) and the Kyn/Trp ratio correlated with the morning stiffness, CRP and ESR (r = 0·26, p = 0·045; r = 0·32, p = 0·025 and r = 0.32, p = 0·024 respectively). Kyn/Trp, Kyn and Trp significantly predicted RA at a cut-off value of 4.72, 589.1 ng/ml and 9921.1 ng/ml (p < 0.0001, p = 0.04 and p = 0.001 respectively).ConclusionOur study showed that there is a significant relationship between RA and Kyn and Trp levels and IDO enzyme activity.     

Molecular cloning, partial genomic structure and functional characterization of succinic semialdehyde dehydrogenase genes from the parasitic insects Lucilia cuprina and Ctenocephalides felis

The enzyme succinic semialdehyde dehydrogenase (SSADH; EC1.2.1.24) is a component of the gamma-aminobutyric acid degradation pathway in mammals and is essential for development and function of the nervous system. Here we report the identification, cDNA cloning and functional expression of SSADH from the parasitic insects Lucilia cuprina and Ctenocephalides felis. The recombinant proteins possess potent NAD+-dependent SSADH activity, while their catalytic efficiency for other aldehyde substrates is lower. A genomic copy of the L. cuprina SSADH gene contains two introns, while a genomic gene version of C. felis is devoid of introns. In contrast to the single copy SSADH genes in Drosophila melanogaster and mammals, in L. cuprina and C. felis, multiple SSADH gene copies are present in the genome.     

IVIg selectively and rapidly decreases circulating pathogenic autoantibodies in pemphigus vulgaris

Background: Intraveneous immunoglobulin (IVIg) is increasingly used to treat pemphigus vulgaris (PV). The mechanism by which it does so is not known. The following study was conducted to confirm the effectiveness of IVIg for the acute control of active PV and to elucidate the mechanism by which it does.

Methods: Twelve patients with active and severe PV unresponsive to conventional therapy with high doses of systemic steroids together with or without a cytotoxic drug were treated with a single dose of IVIg (400 mg/kg/day for 5 days). All patients were concurrently given cyclophosphamide or azathioprine of not already on one of these two drugs. The primary end-points were healing of skin lesions, changes in serum levels of intercelular (IC) autoantibodies and in steroid doses one to 3 weeks after initiation of IVIg.

Results: Within 1 week of initiating IVIg the activity of PV was controlled in most cases. Within 3 weeks the average baseline dose of systemic steroid was reduced by 40%. Serum levels of IC antibodies rapidly declined by an average of 59% within 1 week of initiating IVIg and by 70% within 2 weeks. The decrease was selective, as the average serum levels of antibody to varicella-herpes zoster did not decrease in the 4 patients in whom they were measured. The decrease in IC antibodies was inversely related to serum levels of total inmmunoglobulin (IgG). The decrease in IC antibodies was not due to blocking factors in the IVIg preparation and was too rapid to be due to suppression of IgG synthesis, suggesting that it resulted from increased catabolism.

Conclusions: IVIg can rapidly control active PV unresponsive to conventional therapy by causing a selective and very rapid decline in the autoantibodies that mediate the disease. We believe it does so by increasing the catabolism of all serum IgG antibodies, and that this results in a selective decrease in only abnormal autoantibodies as catabolized normal anti bodies are replaced by those present in the IVIg preparation. IVIg is the first treatment that achieves the ideal therapeutic goal in auto-antibody diseases, the selective removal of the pathogenic antibodies without affecting the level of normal antibodies.     

Cardiac Output in Normal Subjects Under Standard Basal Conditions the Repeatability of Measurements by the Fick Method

For analysis of radioactive histamine metabolites in human urine a simple ion exchange chromatographic method is described. The method is compared with the isotope dilution method developed by Schayer. The advantages of the new method are rapidity and a greater possibility to account for all the radioactive histamine metabolites excreted in the urine. Data also suggest that the histamine metabolite imidazoleacetic acid riboside is partly lost in the isotope dilution method because of adsorption to urinary constituents during hydrolysis. The catabolism of intravenously and orally given [¹⁴C]histamine was studied in one healthy subject. The general metabolic pattern of histamine was confirmed. In addition, it was found that histaminol might be a minor metabolite of injected histamine. It is believed that the chromatographic method will be useful in several metabolic studies in the histamine field.     

Increased expression of the ubiquitin-proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-kappaB

Proteolysis-inducing factor (PIF), isolated from a cachexia-inducing murine tumour, has been shown to stimulate protein breakdown in C(2)C(12) myotubes. The effect was attenuated by the specific proteasome inhibitor lactacystin and there was an elevation of proteasome 'chymotrypsin-like' enzyme activity and expression of 20S proteasome alpha-subunits at concentrations of PIF between 2 and 16 nM. Higher concentrations of PIF had no effect. The action of PIF was attenuated by eicosapentaenoic acid (EPA) (50 microM). At a concentration of 4 nM, PIF induced a transient decrease in IkappaBalpha levels after 30 min incubation, while no effect was seen at 20 nM PIF. The level of IkappaBalpha, an NF-kappaB inhibitory protein, returned to normal after 60 min. Depletion of IkappaBalpha from the cytosol was not seen in myotubes pretreated with EPA, suggesting that the NF-kappaB/IkappaB complex was stabilised. At concentrations between 2 and 8 nM, PIF stimulated an increased nuclear migration of NF-kappaB, which was not seen in myotubes pretreated with EPA. The PIF-induced increase in chymotrypsin-like enzyme activity was also attenuated by the NF-kappaB inhibitor peptide SN50, suggesting that NF-kappaB may be involved in the PIF-induced increase in proteasome expression. The results further suggest that EPA may attenuate protein degradation induced by PIF, at least partly, by preventing NF-kappaB accumulation in the nucleus.     

Gene roles in the prn cluster of Aspergillus nidulans

Summary The roles of the four genes of the prn gene cluster involved in L-proline catabolism in Aspergillus nidulans have been investigated. prnD and prnC encode, respectively, proline exidase and ^I-pyrroline-5-carboxylate (P5C) dehydrogenase. prnB is almost certainly the structural gene for the proline-inducible major proline permease. The prnA product has no structural role in these activities but is a positive acting regulatory molecule necessary for the expression of prnD, prnC and, to a lesser extent, prnB. Evidence favouring de novo synthesis of P5C dehydrogenase upon induction in the presence of a functional prnA allele is also presented.     

L-ornithine transaminase synthesis in Saccharomyces cerevisiae: Induction by allophanate,intermediate and inducer of the urea degradative pathway adds to arginine induction

Summary Yeast ornithine transaminase is known to be induced by arginine and ornithine, through the action of regulatory elements common to arginase induction. We show here that it is subject to a second induction circuit, that which is responsible for urea amidolyase and urea permease induction by allophanate and defined by the regulatory mutants durL ^– and durM ^–     

Differences in 25-Hydroxyvitamin D Clearance by eGFR and Race: A Pharmacokinetic Study

BackgroundConversion of 25-hydroxyvitamin D (25[OH]D) to the active form of vitamin D occurs primarily in the kidney. Observational studies suggest 25(OH)D clearance from the circulation differs by kidney function and race. However, these potential variations have not been tested using gold-standard methods.MethodsWe administered intravenous, deuterated 25(OH)D₃ (d-25[OH]D₃) in a pharmacokinetic study of 87 adults, including 43 with normal eGFR (≥60 ml/min per 1.73 m²), 24 with nondialysis CKD (eGFR <60 ml/min per 1.73 m²), and 20 with ESKD treated with hemodialysis. We measured concentrations of d-25(OH)D₃ and deuterated 24,25-dihydroxyvitamin D₃ at 5 minutes and 4 hours after administration, and at 1, 4, 7, 14, 21, 28, 42, and 56 days postadministration. We calculated 25(OH)D clearance using noncompartmental analysis of d-25(OH)D₃ concentrations over time. We remeasured 25(OH)D clearance in a subset of 18 participants after extended oral vitamin-D₃ supplementation.ResultsThe mean age of the study cohort was 64 years; 41% were female, and 30% were Black. Mean 25(OH)D clearances were 360 ml/d, 313 ml/d, and 263 ml/d in participants with normal eGFR, CKD, and kidney failure, respectively (P=0.02). After adjustment for age, sex, race, and estimated blood volume, lower eGFR was associated with reduced 25(OH)D clearance (β=−17 ml/d per 10 ml/min per 1.73 m² lower eGFR; 95% CI, −21 to −12). Black race was associated with higher 25(OH)D clearance in participants with normal eGFR, but not in those with CKD or kidney failure (P for interaction=0.05). Clearance of 25(OH)D before versus after vitamin-D₃ supplementation did not differ.ConclusionsUsing direct pharmacokinetic measurements, we show that 25(OH)D clearance is reduced in CKD and may differ by race.Clinical Trial registry name and registration numberClearance of 25-hydroxyvitamin D in Chronic Kidney Disease (CLEAR), {"type":"clinical-trial","attrs":{"text":"NCT02937350","term_id":"NCT02937350"}}NCT02937350; Clearance of 25-hydroxyvitamin D3 During Vitamin D3 Supplementation (CLEAR-PLUS), {"type":"clinical-trial","attrs":{"text":"NCT03576716","term_id":"NCT03576716"}}NCT03576716     

TNF单抗阻断烫伤大鼠蛋白质高分解代谢的实验研究

目的：探讨烧(烫)伤后骨骼肌蛋白质分解代谢的规律及肿瘤坏死因子(TNF)与TNF单克隆抗体(TNF-McAb)的可能作用及其意义。方法：实验大鼠分为正常对照组、烫伤组、正常重组人TNF(rHu-TNF)注射组、烫伤TNF—McAb注射组。于伤后1周内动态观察骨骼肌蛋白质分解速率与TNF含量的变化，以及外源性TNF和TNF单克隆抗体对烫伤大鼠骨骼肌蛋白质分解代谢的影响。结果：烫伤后各时相点大鼠比目鱼肌酪氨酸净释放量均明显高于正常，且伤肢显著高于未伤肢。烫伤大鼠血清中TNF水平的变化随时间递增。烫伤大鼠比目鱼肌中TNF含量增高，伤肢高于未伤肢。比目鱼肌TNF含量与酪氨酸释放量呈显著正相关。rHu--TNF注射组比目鱼肌酪氨酸净释放量显著增加。TNF-McAb注射组比目鱼肌酪氨酸净释放量显著低于未注射组。结论：伤后骨骼肌蛋白质分解增强；局部高浓度的TNF是蛋白质分解代谢增强的重要原因之一；外源性TNF单抗可阻断内源性TNF的作用。     

Incorporation of 15N from L-leucine into isoleucine by rat brain cerebral cortex slices.

The fate of leucine nitrogen in the central nervous system was investigated by incubating rat cerebral cortex slices in the presence of 0.5 mM each of L-[15N]-leucine, L-isoleucine, and L-valine. Analysis of the slices and incubation media for free amino acids by gas chromatography-mass spectrometry revealed that the 15N from leucine is incorporated into isoleucine only. No 15N was detected in valine or any other amino acid. These results suggest that leucine, valine, and their corresponding aminotransferases may be compartmentalized in brain cerebral cortex.