International Journal of Tryptophan Research最新文献

Meat-eating was a game changer for human evolution. We suggest that the limiting factors for expanding brains earlier were scarcities of nicotinamide and tryptophan. In humans and some other omnivores, lack of meat causes these deficiencies. Nicotinamide adenine dinucleotide (NADH) is necessary to synthesize adenosine triphosphate (ATP) via either glycolysis or via the mitochondrial respiratory chain. NAD consumption is also necessary for developmental and repair circuits. Inadequate supplies result in "de-evolutionary" brain atrophy, as seen with pellagra. If trophic nicotinamide/tryptophan was a "prime mover" in building bigger brains, back-up mechanisms should have evolved. One strategy may be to recruit extra gut symbionts that produce NADH precursors or export nicotinamide (though this may cause diarrhea). We propose a novel supplier TB that co-evolved early, which did not originally and does not now inevitably cause disease. TB has highly paradoxical immunology for a pathogen, and secretes and is inhibited by nicotinamide and its analogue, isoniazid. Sharp declines in TB and diarrhea correlated with increased meat intake in the past, suggesting that dietary vitamin B3 and tryptophan deficiencies (also associated with poor cognition and decreased lifespans) are still common where meat is unaffordable.

The pathogenesis of morphea and other cutaneous sclerosing disorders remain poorly understood. Although they are considered to be autoimmune disorders, abnormal tryptophan metabolism may be involved. Current therapy is directed to supressing the autoimmune response. Demonstration of a therapeutic response to manipulation of the kynurenine pathway would both support a role for abnormal tryptophan metabolism and offer additional targets for therapy. Tranilast is a 3-hydroxyanthranilic acid derivative known to target the kynurenine pathway. The aim of this study was to see if tranilast lowered the urinary excretion of the kynurenine metabolites kynurenic and quinolinic acid under condition of L tryptophan loading in a volunteer. Mean baseline value for kynurenic acid and quinolinic acid were 1.1 and 2.1 mmol/mol creatinine, respectively. This rose to 5.6 and 3.8 mmol/mol creatinine respectively under conditions of L tryptophan loading 2 grams daily. Adding 1 g of tranilast daily lowered the values to 2.0 and 2.9 mmol/mol creatinine, respectively. These data suggest that tranilast acts as a competitive inhibitor of either indoleamine 2, 3-dioxygenase (IDO), tryptophan 2, 3-di-oxygenase (TDO) or both. As it involved only 1 subject, the results may not be representative of the larger population and must be considered preliminary.

The kynurenine pathway (KP) is the main catabolic pathway of the essential amino acid tryptophan. The KP has been identified to play a critical role in regulating immune responses in a variety of experimental settings. It is also known to be involved in several neuroinflammatory diseases including Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. This review considers the current understanding of the role of the KP in stem cell biology. Both of these fundamental areas of cell biology have independently been the focus of a burgeoning research interest in recent years. A systematic review of how the two interact has not yet been conducted. Several inflammatory and infectious diseases in which the KP has been implicated include those for which stem cell therapies are being actively explored at a clinical level. Therefore, it is highly relevant to consider the evidence showing that the KP influences stem cell biology and impacts the functional behavior of progenitor cells.

This review provides information on the most recent findings concerning presence, origin, and role of kynurenic acid (KYNA), a tryptophan metabolite, in the digestive system. KYNA is an antagonist of both the ionotropic glutamate receptors and the alpha7 nicotinic acetylcholine receptor, as well as an agonist of G-protein coupled GPR35 receptor. Since the GPR35 receptor is mainly present in the gastrointestinal tract, researchers have concentrated on the digestive system in recent years. They have found that KYNA content increases gradually and significantly along the gastrointestinal tract. Interestingly, the concentration of KYNA in the lumen is much higher than in the wall of intestine. It has been documented that KYNA may have a positive influence on the number of pathologies in the gastrointestinal tract, in particular ulcers, colon obstruction, or colitis. Future studies might determine whether it is advisable to supplement KYNA to a human organism.

β-lapachone is a naturally occurring 1,2-naphthoquinone-based compound that has been advanced into clinical trials based on its tumor-selective cytotoxic properties. Previously, we focused on the related 1,4-naphthoquinone pharmacophore as a basic core structure for developing a series of potent indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitors. In this study, we identified IDO1 inhibitory activity as a previously unrecognized attribute of the clinical candidate β-lapachone. Enzyme kinetics-based analysis of β-lapachone indicated an uncompetitive mode of inhibition, while computational modeling predicted binding within the IDO1 active site consistent with other naphthoquinone derivatives. Inhibition of IDO1 has previously been shown to breach the pathogenic tolerization that constrains the immune system from being able to mount an effective anti-tumor response. Thus, the finding that β-lapachone has IDO1 inhibitory activity adds a new dimension to its potential utility as an anti-cancer agent distinct from its cytotoxic properties, and suggests that a synergistic benefit can be achieved from its combined cytotoxic and immunologic effects.

Excess L-tryptophan (L-Trp) in the diet decreases fetal body weight. However, the relationship between L-Trp concentration and its effects on maternal, placental, and fetal growth are not well-understood. We investigated the effects of excess L-Trp intake on maternal, placental, and fetal growth. Female mice were fed a 20% casein diet (control diet) or control diet plus 2% or 5% L-Trp during gestation. Pup weights did not differ between the control (L-Trp intake: 0.04 g/kg body weight (BW)/day) and 2% L-Trp groups (L-Trp intake: 3.3 g/kg BW/day), but were significantly lower in the 5% L-Trp group (L-Trp intake: 7.0 g/kg BW/day) than in the control and 2% L-Trp groups. These results show that less than 3.3 g/kg BW/day L-Trp intake in pregnant mice during gestation does not affect fetal growth or L-Trp homeostasis in the placenta or fetus.

The kynurenine pathway (KP) and one of its end-products, the excitotoxin quinolinic acid (QUIN), are involved in the pathogenesis of several major neuroinflammatory brain diseases. A relevant animal model to study KP metabolism is now needed to assess whether intervention in this pathway may improve the outcome of such diseases. Humans and macaques share a very similar genetic makeup. In this study, we characterized the KP metabolism in macaque primary macrophages of three different species in comparison to human cells. We found that the KP profiles in simian macrophages were very similar to those in humans when challenged with inflammatory cytokines. Further, we found that macaque macrophages are capable of producing a pathophysiological concentration of QUIN. Our data validate the simian model as a relevant model to study the human cellular KP metabolism in the context of inflammation.

A tryptophan catabolite, kynurenic acid, is involved in schizophrenia and uremia; there is little information on the mechanism of its disposition. Recently, our laboratory showed that kynurenic acid is a good substrate of human organic anion transporters hOAT1 and hOAT3. In this study, we performed uptake experiment using Xenopus laevis oocytes to characterize the transport of kynurenic acid by rat homologs of the transporters, rOAT1, and rOAT3. These transporters stimulated the uptake of kynurenic acid into oocytes, and transport by rOAT3 was marked. The Km values of the transport were estimated to be 8.46 μM for rOAT1 and 4.81 μM for rOAT3, and these values are comparable to their human homologs. The transport activity of kynurenic acid by rOAT1 was about one quarter of that of p-aminohippurate, although they were at the similar levels in hOAT1. A comparative experiment with hOAT1 was added in this study, showing that uptake amounts of kynurenic acid by hOAT1-expressing oocytes were 4 times greater than rOAT1-expressing oocytes. rOAT3 transported kynurenic acid as efficiently as estrone sulfate; this phenomenon was also observed in hOAT3. In conclusion, transport of kynurenic acid by rOAT1 and rOAT3 was shown. The characteristics of rOAT3 were similar to hOAT3, but low transport activity of kynurenic acid by rOAT1 was exhibited compared with hOAT1.

L-Tryptophan (tryptophan) is an essential amino acid in humans. It has important roles as a precursor of different bioactive compounds. Based on previous studies in which tryptophan has been shown to be present in fresh cherries, the aim of the present work was to analyze the tryptophan content of a Jerte Valley cherry-based product. A previously optimized method of analysis of tryptophan was used, ie, high-performance liquid chromatography with fluorescence detection (HPLC/FL). As expected, HPLC/FL technique permitted to detect and quantify the tryptophan content in a different matrix rather than fresh cherries. In fact, the Jerte Valley cherry-based product contained 69.54 ± 10.64 ppm of tryptophan, thereby showing that this product is a good source of tryptophan. In summary, it has been proven that the Jerte Valley cherry-based product is rich in tryptophan and may be indicated as a supply of this essential amino acid as well as having potential health benefits for conditions where tryptophan is necessary.