scholarly journals The Function of the Kynurenine Pathway in the Placenta: A Novel Pharmacotherapeutic Target?

2021 ◽  
Vol 18 (21) ◽  
pp. 11545
Author(s):  
Michelle Broekhuizen ◽  
A. H. Jan Danser ◽  
Irwin K. M. Reiss ◽  
Daphne Merkus
Keyword(s):  
Pregnancy Complications ◽  
De Novo ◽  
Recurrent Miscarriage ◽  
Fetal Loss ◽  
Kynurenine Pathway ◽  
Vascular Regulation ◽  
Exact Function ◽  
Nad Synthesis ◽  
Pregnant Mice ◽  
Rate Limiting

(L-)tryptophan is metabolized via the kynurenine pathway into several kynurenine metabolites with distinct functions. Dysfunction of the kynurenine pathway can lead to impairments in vascular regulation, immune regulation, and tolerance. The first and rate limiting enzyme of this pathway, indoleamine 2,3-dioxygenase (IDO), is highly expressed in the placenta and reduced in placentas from complicated pregnancies. IDO is essential during pregnancy, as IDO inhibition in pregnant mice resulted in fetal loss. However, the exact function of placental IDO, as well as its exact placental localization, remain controversial. This review identified that two isoforms of IDO; IDO1 and IDO2, are differently expressed between placental cells, suggesting spatial segregation. Furthermore, this review summarizes how the placental kynurenine pathway is altered in pregnancy complications, including recurrent miscarriage, preterm birth, preeclampsia, and fetal growth restriction. Importantly, we describe that these alterations do not affect maternally circulating metabolite concentrations, suggesting that the kynurenine pathway functions as a local signaling pathway. In the placenta, it is an important source of de novo placental NAD+ synthesis and regulates fetal tryptophan and kynurenine metabolite supply. Therefore, kynurenine pathway interventions might provide opportunities to treat pregnancy complications, and this review discusses how such treatment could affect placental function and pregnancy development.

scholarly journals Inhibition of Kynurenine Metabolism and Its Effect in Mitochondrial Function in Hepatocellular Carcinoma

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 124-125
Author(s):  
Raul Castro-Portuguez ◽  
Samuel Freitas ◽  
George Sutphin
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mitochondrial Function ◽  
De Novo ◽  
Principal Component ◽  
Kynurenine Pathway ◽  
The Cancer Genome Atlas ◽  
Wilcoxon Test ◽  
Nad Synthesis ◽  
Significant Difference ◽  
Kynurenine Metabolism

Abstract Hepatocellular carcinoma (HCC) is the most prevalent cancer in the liver. The majority of ingested tryptophan is processed in the liver through the kynurenine pathway, the endpoint of which is de novo NAD+ biosynthesis. Dysregulation of tryptophan-kynurenine metabolism and NAD+ synthesis may promote mitochondrial malfunction, tumor reprogramming, and carcinogenesis. Using a publicly available gene expression dataset from liver hepatocellular carcinoma (LIHC) samples available through The Cancer Genome Atlas (TCGA; n = 371), we employed Principal Component Analysis (PCA), hierarchical clustering, gene-pattern expression profiling, and survival analysis to cluster patients and determine overall survival. Our analysis of genes encoding kynurenine pathway enzymes determined that patients with high QPRT expression had a poor prognosis with decreased median survival, with no effect on the maximum survival. There is a significant difference in the survival between patients with high QPRT expression relative to patients with high HAAO/AFMID expression (HR = 1.2, [95% CI 0.5-1.8] P = 0.0181, Gehan-Breslow-Wilcoxon Test). Patients with high QPRT expression have higher survival rates compared with low QPRT expression (HR = 1.4, [95% CI 0.9-2.2] P = 0.0344, Gehan-Breslow-Wilcoxon Test). To test the consequences of kynurenine-pathway inhibition in mitochondrial function and morphology we use 4-Cl-3HAA, an irreversible HAAO inhibitor, and observed a small increase in mitochondrial fragmentation in HepG2 cells after 24 hours of treatment. We conclude that kynurenine metabolism may be useful as a biomarker to predict patient prognosis among HCC patients. In ongoing work, we are testing QPRT inhibitors in cell culture as a potential adjuvant for chemotherapies.

Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia

2011 ◽  
Vol 105 (02) ◽  
pp. 295-301 ◽  
Author(s):  
Jantien Visser ◽  
Veli-Matti Ulander ◽  
Frans Helmerhorst ◽  
Katja Lampinen ◽  
Laure Morin-Papunen ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Live Birth ◽  
Pregnancy Complications ◽  
Birth Rate ◽  
Neonatal Outcome ◽  
Recurrent Miscarriage ◽  
Fetal Loss ◽  
Live Birth Rate ◽  
First Trimester ◽  
Significant Difference

SummaryRecurrent miscarriage affects 1–2% of women. In more than half of all recurrent miscarriage the cause still remains uncertain. Thrombophilia has been identified in about 50% of women with recurrent miscarriage and thromboprophylaxis has been suggested as an option of treatment. A randomised double-blind (for aspirin) multicentre trial was performed among 207 women with three or more consecutive first trimester (<13 weeks) miscarriages, two or more second trimester (13–24 weeks) miscarriages or one third trimester fetal loss combined with one first trimester miscarriage. Women were analysed for thrombophilia. After complete work-up, women were randomly allocated before seven weeks’ gestation to either enoxaparin 40 mg and placebo (n=68), enoxaparin 40 mg and aspirin 100 mg (n=63) or aspirin 100 mg (n=76). The primary outcome was live-birth rate. Secondary outcomes were pregnancy complications, neonatal outcome and adverse effects. The 0.92–1.48] was found for enoxaparin and placebo and 65% [RR 1.08, 95% CI 0.83–1.39] for enoxaparin and aspirin when compared to aspirin alone (61%, reference group). In the whole study group the live birth rate was 65% (95% CI 58.66–71.74) for women with three or more miscarriages (n=204). No difference in pregnancy complications, neonatal outcome or adverse effects was observed. No significant difference in live birth rate was found with enoxaparin treatment versus aspirin or a combination of both versus aspirin in women with recurrent miscarriage.

scholarly journals Genomic Analysis Of NAD+ Synthesis Pathways Involved In Aging and Cancer

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 668-669
Author(s):  
Jeremy Meyers ◽  
Raul Castro-Portuguez ◽  
Luis Espejo ◽  
George Sutphin
Keyword(s):  
Mammalian Cells ◽  
De Novo ◽  
Sequence Data ◽  
Kynurenine Pathway ◽  
Metabolic Reprogramming ◽  
Apparent Contradiction ◽  
Continuous Growth ◽  
C Elegans ◽  
Age Related ◽  
Nad Synthesis

Abstract Cancer cells have elevated energy demands to sustain continuous growth and other malignant processes and undergo extensive metabolic reprogramming to meet these demands. One element of this reprogramming in many cancer subtypes is elevated synthesis of nicotinamide adenine dinucleotide (NAD+), a critical co-enzyme that supports energy production through both glycolysis and the TCA cycle. The kynurenine metabolic pathway is the evolutionarily conserved means by which cells produce NAD+ de novo from tryptophan. NAD+ levels drop with age, a contributing factor to many forms of age-related disease. While interventions that increase NAD+ have been shown to extend lifespan, previous work from our lab demonstrates that knockdown of several kynurenine pathway enzymes, thus decreasing de novo NAD+ production, results in increased longevity of Caenorhabditis elegans by 20-30%. To address this apparent contradiction, we propose that kynurenine pathway inhibition may produce metabolic feedback that results in upregulation of NAD+ recycling. Eukaryotic cells recycle NAD+ from nicotinamide (NAM) through one of two pathways: the Salvage pathway in mammalian cells and the Preiss-Handler pathway in C. elegans and related invertebrates species. We are using tools in C. elegans and human cell culture to examine the interaction between kynurenine/de novo NAD+ synthesis and NAD+ recycling through Salvage and Preiss-Handler. In particular, we are interested in how combining interventions between these pathways will influence activity throughout the NAD+ metabolic networks (measured via mass spectrometry), physiological phenotypes, and transcriptomic changes (via RNA sequence data) involved in aging and age-associated disease.

Procoagulant Microparticles: New Insights and Opportunities in Pregnancy Loss?

2001 ◽  
Vol 85 (01) ◽  
pp. 3-4 ◽  
Author(s):  
Ian Greer
Keyword(s):  
Pregnancy Complications ◽  
Pregnancy Loss ◽  
Recurrent Miscarriage ◽  
Fetal Loss ◽  
Medical Intervention ◽  
Coagulation System ◽  
Antiphospholipid Antibody ◽  
Antiphospholipid Antibody Syndrome ◽  
Intrauterine Death ◽  
Increased Risk

SummaryIn recent years, prothrombotic states have been not only associated with an increased risk of venous thrombosis, but also with pregnancy complications. In particular there is good evidence linking antiphospholipid antibody syndrome, which is associated with increased thrombin generation (1), to recurrent miscarriage. The importance of procoagulant changes in the pathophysiology of recurrent miscarriage is emphasised by the fact that treatment with heparin and low dose aspirin will substantially improve the likelihood of a successful pregnancy (2). Essentially, this is the only successful medical intervention in the treatment of miscarriage. There are also data now accumulating that link congenital thrombophilia to pregnancy complications such as miscarriage, pre-eclampsia, intra-uterine growth restriction, abruption and intrauterine death (3, 4). Furthermore, recent data have shown that acquired changes in the coagulation system, such as the acquired activated protein C resistance of pregnancy is also associated with an increased risk of pre-eclampsia (5). These data collectively suggest that procoagulant changes in general, rather than congenital or acquired thrombophilia in particular are associated with the development of pregnancy complications including fetal loss. However, in the majority of cases of fetal loss no cause is found and we cannot easily link these events to a procoagulant problem in the mother. In this issue of the Thrombosis and Haemostasis, Laude et al. (6) report, for the first time, the association between circulating procoagulant microparticles and pregnancy loss so providing a new insight into potential mechanisms.

scholarly journals Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets

2021 ◽  
Vol 22 (24) ◽  
pp. 13497
Author(s):  
Artur Wnorowski ◽  
Sylwia Wnorowska ◽  
Jacek Kurzepa ◽  
Jolanta Parada-Turska
Keyword(s):  
Inflammatory Bowel Disease ◽  
Successful Treatment ◽  
Bowel Disease ◽  
Drug Targets ◽  
De Novo ◽  
Meta Analysis ◽  
Kynurenine Pathway ◽  
Infliximab Treatment ◽  
Nad Synthesis ◽  
Inflammatory Bowel

A meta-analysis of publicly available transcriptomic datasets was performed to identify metabolic pathways profoundly implicated in the progression and treatment of inflammatory bowel disease (IBD). The analysis revealed that genes involved in tryptophan (Trp) metabolism are upregulated in Crohn’s disease (CD) and ulcerative colitis (UC) and return to baseline after successful treatment with infliximab. Microarray and mRNAseq profiles from multiple experiments confirmed that enzymes responsible for Trp degradation via the kynurenine pathway (IDO1, KYNU, IL4I1, KMO, and TDO2), receptor of Trp metabolites (HCAR3), and enzymes catalyzing NAD+ turnover (NAMPT, NNMT, PARP9, CD38) were synchronously coregulated in IBD, but not in intestinal malignancies. The modeling of Trp metabolite fluxes in IBD indicated that changes in gene expression shifted intestinal Trp metabolism from the synthesis of 5-hydroxytryptamine (5HT, serotonin) towards the kynurenine pathway. Based on pathway modeling, this manifested in a decline in mucosal Trp and elevated kynurenine (Kyn) levels, and fueled the production of downstream metabolites, including quinolinate, a substrate for de novo NAD+ synthesis. Interestingly, IBD-dependent alterations in Trp metabolites were normalized in infliximab responders, but not in non-responders. Transcriptomic reconstruction of the NAD+ pathway revealed an increased salvage biosynthesis and utilization of NAD+ in IBD, which normalized in patients successfully treated with infliximab. Treatment-related changes in NAD+ levels correlated with shifts in nicotinamide N-methyltransferase (NNMT) expression. This enzyme helps to maintain a high level of NAD+-dependent proinflammatory signaling by removing excess inhibitory nicotinamide (Nam) from the system. Our analysis highlights the prevalent deregulation of kynurenine and NAD+ biosynthetic pathways in IBD and gives new impetus for conducting an in-depth examination of uncovered phenomena in clinical studies.

scholarly journals Autism Spectrum Disorder in a Girl with aDe NovoX;19 Balanced Translocation

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Marcelo Razera Baruffi ◽  
Deise Helena de Souza ◽  
Rosana Aparecida Bicudo da Silva ◽  
Ester Silveira Ramos ◽  
Danilo Moretti-Ferreira
Keyword(s):  
X Chromosome ◽  
De Novo ◽  
Recurrent Miscarriage ◽  
Chromosomal Rearrangements ◽  
Position Effect ◽  
Autism Spectrum ◽  
Balanced Translocation ◽  
Replication Banding ◽  
Conventional Cytogenetic Analysis ◽  
Gonadal Dysfunction

Balanced X-autosome translocations are rare, and female carriers are a clinically heterogeneous group of patients, with phenotypically normal women, history of recurrent miscarriage, gonadal dysfunction, X-linked disorders or congenital abnormalities, and/or developmental delay. We investigated a patient with ade novoX;19 translocation. The six-year-old girl has been evaluated due to hyperactivity, social interaction impairment, stereotypic and repetitive use of language with echolalia, failure to follow parents/caretakers orders, inconsolable outbursts, and persistent preoccupation with parts of objects. The girl has normal cognitive function. Her measurements are within normal range, and no other abnormalities were found during physical, neurological, or dysmorphological examinations. Conventional cytogenetic analysis showed ade novobalanced translocation, with the karyotype 46,X,t(X;19)(p21.2;q13.4). Replication banding showed a clear preference for inactivation of the normal X chromosome. The translocation was confirmed by FISH and Spectral Karyotyping (SKY). Although abnormal phenotypes associated withde novobalanced chromosomal rearrangements may be the result of disruption of a gene at one of the breakpoints, submicroscopic deletion or duplication, or a position effect, X; autosomal translocations are associated with additional unique risk factors including X-linked disorders, functional autosomal monosomy, or functional X chromosome disomy resulting from the complex X-inactivation process.

scholarly journals Exploitation of the IDO Pathway in the Therapy of Rheumatoid Arthritis

2013 ◽  
Vol 6s1 ◽  
pp. IJTR.S11737 ◽  
Author(s):  
Richard O. Williams
Keyword(s):  
Rheumatoid Arthritis ◽  
Anthranilic Acid ◽  
Kynurenine Pathway ◽  
Gene Encoding ◽  
Rate Limiting Step ◽  
Tryptophan Metabolites ◽  
Synthetic Derivative ◽  
Rate Limiting ◽  
Kinetics Of ◽  
Draining Lymph Nodes

Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting step along the kynurenine pathway and is thought to play a key role in immune homeostasis through depletion of tryptophan and accumulation of kynurenines. In this review we summarize recent research into the possibility of harnessing the IDO pathway for the therapy of rheumatoid arthritis. Inhibition of IDO activity, or knockout of the gene encoding IDO, was shown to cause an increase in the severity of collagen-induced arthritis, an animal model of rheumatoid arthritis. The increased severity of disease was associated with elevated numbers of pathogenic Th1 and Th17 cells in the joints and draining lymph nodes. In another study, analysis of the kinetics of expression of downstream kynurenine pathway enzymes during the course of arthritis revealed a potential role for tryptophan metabolites in resolution of arthritis. Furthermore, the therapeutic administration of L-kynurenine or [3,4-dimethoxycinnamonyl]-anthranilic acid (a synthetic derivative of 3-hydroxy-anthranilic acid) significantly reduced both clinical and histological progression of experimental arthritis. These findings raise the possibility of exploiting the IDO pathway for the therapy of autoimmune disease.

Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency

2000 ◽  
Vol 349 (1) ◽  
pp. 353-356 ◽  
Author(s):  
Cynthia J. MEININGER ◽  
Rebecca S. MARINOS ◽  
Kazuyuki HATAKEYAMA ◽  
Raul MARTINEZ-ZAGUILAN ◽  
Jose D. ROJAS ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
De Novo ◽  
Diabetic Rats ◽  
Bb Rat ◽  
No Production ◽  
Gtp Cyclohydrolase I ◽  
Gtp Cyclohydrolase ◽  
Bb Rats ◽  
Metabolic Basis ◽  
Rate Limiting

Endothelial cells (EC) from diabetic BioBreeding (BB) rats have an impaired ability to produce NO. This deficiency is not due to a defect in the constitutive isoform of NO synthase in EC (ecNOS) or alterations in intracellular calcium, calmodulin, NADPH or arginine levels. Instead, ecNOS cannot produce sufficient NO because of a deficiency in tetrahydrobiopterin (BH4), a cofactor necessary for enzyme activity. EC from diabetic rats exhibited only 12% of the BH4 levels found in EC from normal animals or diabetes-prone animals which did not develop disease. As a result, NO synthesis by EC of diabetic rats was only 18% of that for normal animals. Increasing BH4 levels with sepiapterin increased NO production, suggesting that BH4 deficiency is a metabolic basis for impaired endothelial NO synthesis in diabetic BB rats. This deficiency is due to decreased activity of GTP-cyclohydrolase I, the first and rate-limiting enzyme in the de novo biosynthesis of BH4. GTP-cyclohydrolase activity was low because of a decreased expression of the protein in the diabetic cells.

Regulation of ornithine decarboxylase by hypoxia in pulmonary artery smooth muscle cells

1996 ◽  
Vol 271 (1) ◽  
pp. L31-L37 ◽  
Author(s):  
K. S. Harrod ◽  
J. W. Olson ◽  
M. N. Gillespie
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Mrna Stability ◽  
De Novo ◽  
Hypoxic Exposure ◽  
Polyamine Synthesis ◽  
Mrna Content ◽  
Pulmonary Artery Smooth Muscle ◽  
Rate Limiting

The polyamines are a family of low-molecular-weight organic cations that play essential intracellular regulatory roles in cell growth and differentiation. Elevations in cellular polyamine contents necessary for most physiological and pathological events in the lung appear to be driven by increase de novo synthesis. In contrast, increases in lung cell polyamines required for hypoxic pulmonary vascular disease can be attributed to augmented transmembrane polyamine transport which may, in turn, be the result of hypoxia-related decreases in the activity of the initial and generally rate-limiting enzyme in de novo polyamine synthesis, ornithine decarboxylase (ODC). To begin to define the unusual mechanism whereby hypoxia governs polyamine regulatory pathways, the present study examined the impact of varying severity and durations of hypoxic exposure on ODC activity and mRNA content in cultured bovine main pulmonary artery smooth muscle cells (PASMC). The effect of hypoxia on the activity of another rate-limiting enzyme in polyamine synthesis, S-adenosylmethionine decarboxylase (AdoMet-DC), also was examined. Hypoxia caused time-dependent decreases in ODC and AdoMet-DC activities that were related to the severity of hypoxic exposure. Similarly, ODC mRNA content also was depressed by hypoxic exposure. The relationship between the decline in ODC activity and mRNA content was roughly linear. To determine whether hypoxia impairs ODC mRNA stability, two different inhibitors of transcription and Northern analyses were used to follow the decay in ODC mRNA abundance in hypoxic and normoxic PASMC. Densitometric scanning of Northern analysis indicated that ODC mRNA stability did not differ between hypoxic and normoxic PASMC. These results suggest that the reduction in ODC activity provoked by hypoxia in cultured bovine PASMC can be ascribed in part to a diminished transcriptional rate rather than to alterations in mRNA stability.

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