Pharmacology of the kynurenine pathway

In this review we summarize a possible connection between gut microbiota, melatonin production, and breast cancer. An imbalance in gut bacterial population composition (dysbiosis), or changes in the production of melatonin (circadian disruption) alters estrogen levels. On the one hand, this may be due to the bacterial composition of estrobolome, since bacteria with β-glucuronidase activity favour estrogens in a deconjugated state, which may ultimately lead to pathologies, including breast cancer. On the other hand, it has been shown that these changes in intestinal microbiota stimulate the kynurenine pathway, moving tryptophan away from the melatonergic pathway, thereby reducing circulating melatonin levels. Due to the fact that melatonin has antiestrogenic properties, it affects active and inactive estrogen levels. These changes increase the risk of developing breast cancer. Additionally, melatonin stimulates the differentiation of preadipocytes into adipocytes, which have low estrogen levels due to the fact that adipocytes do not express aromatase. Consequently, melatonin also reduces the risk of breast cancer. However, more studies are needed to determine the relationship between microbiota, melatonin, and breast cancer, in addition to clinical trials to confirm the sensitizing effects of melatonin to chemotherapy and radiotherapy, and its ability to ameliorate or prevent the side effects of these therapies.

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UHPLC-ESI-MS/MS Quantification of Relevant Substrates and Metabolites of the Kynurenine Pathway Present in Serum and Peritoneal Fluid from Gastric Cancer Patients—Method Development and Validation

International Journal of Molecular Sciences ◽

10.3390/ijms22136972 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6972

Author(s):

Ilona Sadok ◽

Katarzyna Jędruchniewicz ◽

Karol Rawicz-Pruszyński ◽

Magdalena Staniszewska

Keyword(s):

Gastric Cancer ◽

Cancer Patients ◽

Peritoneal Fluid ◽

Method Development ◽

Solid Phase ◽

Kynurenine Pathway ◽

Serum Samples ◽

Esi Ms ◽

Gastric Cancer Patients ◽

Development And Validation

Metabolites and enzymes involved in the kynurenine pathway (KP) are highly promising targets for cancer treatment, including gastrointestinal tract diseases. Thus, accurate quantification of these compounds in body fluids becomes increasingly important. The aim of this study was the development and validation of the UHPLC-ESI-MS/MS methods for targeted quantification of biologically important KP substrates (tryptophan and nicotinamide) and metabolites(kynurenines) in samples of serum and peritoneal fluid from gastric cancer patients. The serum samples were simply pretreated with trichloroacetic acid to precipitate proteins. The peritoneal fluid was purified by solid-phase extraction before analysis. Validation was carried out for both matrices independently. Analysis of the samples from gastric cancer patients showed different accumulations of tryptophan and its metabolites in different biofluids of the same patient. The protocols will be used for the evaluation of tryptophan and kynurenines in blood and peritoneal fluid to determine correlation with the clinicopathological status of gastric cancer or the disease’s prognosis.

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Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and α-Lipoic Acid

International Journal of Molecular Sciences ◽

10.3390/ijms22010403 ◽

2021 ◽

Vol 22 (1) ◽

pp. 403

Author(s):

Fanni Tóth ◽

Edina Katalin Cseh ◽

László Vécsei

Keyword(s):

Neurodegenerative Diseases ◽

Lipoic Acid ◽

Kynurenic Acid ◽

Biological Activities ◽

Neuroprotective Effect ◽

Structural Diversity ◽

Kynurenine Pathway ◽

Glutamate Excitotoxicity ◽

Neuroprotective Agents ◽

Starting Point

The incidence of neurodegenerative diseases has increased greatly worldwide due to the rise in life expectancy. In spite of notable development in the understanding of these disorders, there has been limited success in the development of neuroprotective agents that can slow the progression of the disease and prevent neuronal death. Some natural products and molecules are very promising neuroprotective agents because of their structural diversity and wide variety of biological activities. In addition to their neuroprotective effect, they are known for their antioxidant, anti-inflammatory and antiapoptotic effects and often serve as a starting point for drug discovery. In this review, the following natural molecules are discussed: firstly, kynurenic acid, the main neuroprotective agent formed via the kynurenine pathway of tryptophan metabolism, as it is known mainly for its role in glutamate excitotoxicity, secondly, the dietary supplement pantethine, that is many sided, well tolerated and safe, and the third molecule, α-lipoic acid is a universal antioxidant. As a conclusion, because of their beneficial properties, these molecules are potential candidates for neuroprotective therapies suitable in managing neurodegenerative diseases.

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Capillary Electrochromatography-Mass Spectrometry of Kynurenine Pathway Metabolites

Journal of Chromatography A ◽

10.1016/j.chroma.2021.462294 ◽

2021 ◽

pp. 462294

Author(s):

A.S.M.M.R. Chawdhury ◽

Shahab A. Shamsi ◽

Andrew Miller ◽

Aimin Liu

Keyword(s):

Mass Spectrometry ◽

Capillary Electrochromatography ◽

Kynurenine Pathway

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Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial

Journal of Neuroinflammation ◽

10.1186/s12974-021-02196-x ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Vincent Millischer ◽

Matthias Heinzl ◽

Anthi Faka ◽

Michael Resl ◽

Ada Trepci ◽

...

Keyword(s):

Human Subjects ◽

Picolinic Acid ◽

Plasma Concentrations ◽

Experimental Studies ◽

Placebo Treatment ◽

Kynurenine Pathway ◽

Healthy Male ◽

Systemic Injection ◽

Plasma Tryptophan ◽

Endotoxemia Model

Abstract Background Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects. Methods The present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18–40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models. Results Systemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP. Conclusions Our findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway. Trial registration This study is based on a study registered at ClinicalTrials.gov, NCT03392701. Registered 21 December 2017.

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Addiction and the kynurenine pathway: A new dancing couple?

Pharmacology & Therapeutics ◽

10.1016/j.pharmthera.2021.107807 ◽

2021 ◽

Vol 223 ◽

pp. 107807

Author(s):

Nuria Morales-Puerto ◽

Pablo Giménez-Gómez ◽

Mercedes Pérez-Hernández ◽

Cristina Abuin-Martínez ◽

Leticia Gil de Biedma-Elduayen ◽

...

Keyword(s):

Kynurenine Pathway

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Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells ◽

10.3390/cells10061548 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1548

Author(s):

Mustafa N. Mithaiwala ◽

Danielle Santana-Coelho ◽

Grace A. Porter ◽

Jason C. O’Connor

Keyword(s):

Molecular Mechanisms ◽

Treatment Options ◽

Treatment Strategies ◽

Kynurenine Pathway ◽

Economic Problem ◽

Cns Disease ◽

Therapeutic Implications ◽

Efficacious Treatment ◽

The Central Nervous System ◽

Significant Health

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that ‘fuel the fire’ in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

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