Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035078 (renal failure)
 31,970 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although xanthinuria is nonfatal in human, xanthine oxidoreductase knockout (Xor-KO) mice have only a short lifespan. Hypoxanthine phosphoribosyltransferase activity (HPRT) in human and wild mice is higher than in laboratory mice. The aim of this study was to investigate the underlying mechanisms that give rise to the longer lifespan of high-HPRT/Xor-KO mice. Before Xor-KO mice die, urinary excretion of hypoxanthine increased with a corresponding decrease in excretion of xanthine. The switch of excretion from xanthine to hypoxanthine might be a cause of death for Xor-KO mice, suggesting inhibition of NAD+-dependent IMP dehydrogenase. Because hypoxanthine inhibits the synthesis of nicotinamide mononucleotide (NMN), a precursor of NAD+, the accumulation of hypoxanthine in Xor-KO mice may cause a depletion in the levels of NAD+. Moreover, urinary excretion of urate in high-HPRT/Uox-KO/Xor-KO mice means urate derived from gut microbiota is absorbed by the intestine. Likewise, over excretion of oxypurine in mice may be caused by intestinal absorption of oxypurine. For NAD+ replenishment, oral supplementation with 1% L-tryptophan, an alternative precursor of NAD+, resulted in a recovery of body weight gain in high-HPRT/Uox-KO/Xor-KO mice. In conclusion, the death of Xor-KO mice by renal failure seems to be caused by a depletion in NAD+ levels due to the intracellular accumulation of hypoxanthine. NAD+ replenishment by oral supplementation of NMN or tryptophan was complicated by the effect of gut microbiota and failed to rescue high-HPRT/Xor-KO mice. The attenuation of intestinal absorption of oxypurines seems to be necessary to avoid hypoxanthine accumulation and over excretion of oxypurine.
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PMID:Xanthine oxidoreductase knockout mice with high HPRT activity were not rescued by NAD+ replenishment. 3212 84

Chronic glomerulonephritis (CGN) as the culprit of kidney failure can increase the mortality of critically ill patients and seriously threatens people's health all over the world. This study using metabolomics strategy is to reveal the potential therapeutic mechanism-related targets to evaluate the effects of rhein (RH) on CGN rats. Changes of serum metabolites and pathways were analyzed by non-targeted metabolomic method based on liquid chromatography-mass spectrometry (LC-MS) combined with ingenuity pathway analysis. In addition, the levels of biochemical indicators were also detected. A total of 25 potential biomarkers were identified to express serum metabolic turbulence in CGN animal model, and then 16 biomarkers were regulated by RH trending to the normal states. From metabolite enrichment and pathway analysis, pharmacological activity of RH on CGN were mainly involved in six vital metabolic pathways including phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, arachidonic acid metabolism, tricarboxylic acid cycle (TCA cycle), alanine, aspartate, and glutamate metabolism, arginine and proline metabolism. It suggested CGN treatment with RH, which may be mediated via interference with metabolic pathway such as amino acid metabolism, arachidonic acid metabolism, and TCA cycle to regulating inflammation, oxidation response and immune regulation against CGN. It showed that metabolomics method offer deeply insight into the therapeutic mechanisms of natural product.
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PMID:Functional Metabolomics Analysis Elucidating the Metabolic Biomarker and Key Pathway Change Associated With the Chronic Glomerulonephritis and Revealing Action Mechanism of Rhein. 3310 Oct 21


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