Browsing by Subject "Purines"

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    Homeostatic imbalance of purine catabolism in first-episode neuroleptic-naïve patients with schizophrenia.
    (PLoS One, 2010-03-03) Yao, Jeffrey K; Dougherty, George G; Reddy, Ravinder D; Keshavan, Matcheri S; Montrose, Debra M; Matson, Wayne R; McEvoy, Joseph; Kaddurah-Daouk, Rima
    BACKGROUND: Purine catabolism may be an unappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. Accumulating evidence suggests a pivotal role of oxidative stress in schizophrenia pathology. METHODOLOGY/PRINCIPAL FINDINGS: Using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system, we compared 6 purine metabolites simultaneously in plasma between first-episode neuroleptic-naïve patients with schizophrenia (FENNS, n = 25) and healthy controls (HC, n = 30), as well as between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. Significantly higher levels of xanthosine (Xant) and lower levels of guanine (G) were seen in both patient groups compared to HC subjects. Moreover, the ratios of G/guanosine (Gr), uric acid (UA)/Gr, and UA/Xant were significantly lower, whereas the ratio of Xant/G was significantly higher in FENNS-BL than in HC. Such changes remained in FENNS-4w with exception that the ratio of UA/Gr was normalized. All 3 groups had significant correlations between G and UA, and Xan and hypoxanthine (Hx). By contrast, correlations of UA with each of Xan and Hx, and the correlation of Xan with Gr were all quite significant for the HC but not for the FENNS. Finally, correlations of Gr with each of UA and G were significant for both HC and FENNS-BL but not for the FENNS-4w. CONCLUSIONS/SIGNIFICANCE: During purine catabolism, both conversions of Gr to G and of Xant to Xan are reversible. Decreased ratios of product to precursor suggested a shift favorable to Xant production from Xan, resulting in decreased UA levels in the FENNS. Specifically, the reduced UA/Gr ratio was nearly normalized after 4 weeks of antipsychotic treatment. In addition, there are tightly correlated precursor and product relationships within purine pathways; although some of these correlations persist across disease or medication status, others appear to be lost among FENNS. Taken together, these results suggest that the potential for steady formation of antioxidant UA from purine catabolism is altered early in the course of illness.
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    JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids.
    (JCI insight, 2022-06) Nystrom, Sarah E; Li, Guojie; Datta, Somenath; Soldano, Karen L; Silas, Daniel; Weins, Astrid; Hall, Gentzon; Thomas, David B; Olabisi, Opeyemi A
    COVID-19 infection causes collapse of glomerular capillaries and loss of podocytes, culminating in a severe kidney disease called COVID-19-associated nephropathy (COVAN). The underlying mechanism of COVAN is unknown. We hypothesized that cytokines induced by COVID-19 trigger expression of pathogenic APOL1 via JAK/STAT signaling, resulting in podocyte loss and COVAN phenotype. Here, based on 9 biopsy-proven COVAN cases, we demonstrated for the first time, to the best of our knowledge, that APOL1 protein was abundantly expressed in podocytes and glomerular endothelial cells (GECs) of COVAN kidneys but not in controls. Moreover, a majority of patients with COVAN carried 2 APOL1 risk alleles. We show that recombinant cytokines induced by SARS-CoV-2 acted synergistically to drive APOL1 expression through the JAK/STAT pathway in primary human podocytes, GECs, and kidney micro-organoids derived from a carrier of 2 APOL1 risk alleles, but expression was blocked by a JAK1/2 inhibitor, baricitinib. We demonstrate that cytokine-induced JAK/STAT/APOL1 signaling reduced the viability of kidney organoid podocytes but was rescued by baricitinib. Together, our results support the conclusion that COVID-19-induced cytokines are sufficient to drive COVAN-associated podocytopathy via JAK/STAT/APOL1 signaling and that JAK inhibitors could block this pathogenic process. These findings suggest JAK inhibitors may have therapeutic benefits for managing cytokine-induced, APOL1-mediated podocytopathy.
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    Wee1-regulated apoptosis mediated by the crk adaptor protein in Xenopus egg extracts.
    (J Cell Biol, 2000-12-25) Smith, JJ; Evans, EK; Murakami, M; Moyer, MB; Moseley, MA; Vande Woude, G; Kornbluth, S
    Many of the biochemical reactions of apoptotic cell death, including mitochondrial cytochrome c release and caspase activation, can be reconstituted in cell-free extracts derived from Xenopus eggs. In addition, because caspase activation does not occur until the egg extract has been incubated for several hours on the bench, upstream signaling processes occurring before full apoptosis are rendered accessible to biochemical manipulation. We reported previously that the adaptor protein Crk is required for apoptotic signaling in egg extracts (Evans, E.K., W. Lu, S.L. Strum, B.J. Mayer, and S. Kornbluth. 1997. EMBO (Eur. Mol. Biol. Organ.) J. 16:230-241). Moreover, we demonstrated that removal of Crk Src homology (SH)2 or SH3 interactors from the extracts prevented apoptosis. We now report the finding that the relevant Crk SH2-interacting protein, important for apoptotic signaling in the extract, is the well-known cell cycle regulator, Wee1. We have demonstrated a specific interaction between tyrosine-phosphorylated Wee1 and the Crk SH2 domain and have shown that recombinant Wee1 can restore apoptosis to an extract depleted of SH2 interactors. Moreover, exogenous Wee1 accelerated apoptosis in egg extracts, and this acceleration was largely dependent on the presence of endogenous Crk protein. As other Cdk inhibitors, such as roscovitine and Myt1, did not act like Wee1 to accelerate apoptosis, we propose that Wee1-Crk complexes signal in a novel apoptotic pathway, which may be unrelated to Wee1's role as a cell cycle regulator.