Nanodelivery Optimization of IDO1 Inhibitors in Tumor Immunotherapy: Challenges and Strategies.

Tryptophan (Trp) metabolism plays a vital role in cancer immunity. Indoleamine 2.3-dioxygenase 1 (IDO1), is a crucial enzyme in the metabolic pathway by which Trp is degraded to kynurenine (Kyn). IDO1-mediated Trp metabolites can inhibit tumor immunity and facilitate immune evasion by cancer cells; thus, targeting IDO1 is a potential tumor immunotherapy strategy. Recently, numerous IDO1 inhibitors have been introduced into clinical trials as immunotherapeutic agents for cancer treatment. However, drawbacks such as low oral bioavailability, slow onset of action, and high toxicity are associated with these drugs. With the continuous development of nanotechnology, medicine is gradually entering an era of precision healthcare. Nanodrugs carried by inorganic, lipid, and polymer nanoparticles (NPs) have shown great potential for tumor therapy, providing new ways to overcome tumor diversity and improve therapeutic efficacy. Compared to traditional drugs, nanomedicines offer numerous significant advantages, including a prolonged half-life, low toxicity, targeted delivery, and responsive release. Moreover, based on the physicochemical properties of these nanomaterials (eg, photothermal, ultrasonic response, and chemocatalytic properties), various combination therapeutic strategies have been developed to synergize the effects of IDO1 inhibitors and enhance their anticancer efficacy. This review is an overview of the mechanism by which the Trp-IDO1-Kyn pathway acts in tumor immune escape. The classification of IDO1 inhibitors, their clinical applications, and barriers for translational development are discussed, the use of IDO1 inhibitor-based nanodrug delivery systems as combination therapy strategies is summarized, and the issues faced in their clinical application are elucidated. We expect that this review will provide guidance for the development of IDO1 inhibitor-based nanoparticle nanomedicines that can overcome the limitations of current treatments, improve the efficacy of cancer immunotherapy, and lead to new breakthroughs in the field of cancer immunotherapy.

Tryptophan regulates the expression of IGFBP1 in bovine endometrial epithelial cells in vitro via the TDO2-AHR pathway.

BACKGROUND: This study aimed to identify the roles of L-tryptophan (Trp) and its rate-limiting enzymes on the receptivity of bovine endometrial epithelial cells. Real-time PCR was conducted to analyze the differential expression of genes between different groups of bovine endometrial epithelial cells. Western blot was performed to detect Cyclooxygenase-2 (COX2) expression after treatment with Trp or kynurenine (the main metabolites of Trp). The kynurenine assay was used to examine if Trp or prostaglandin E2 (PGE2) can increase the production of kynurenine in the bovine endometrial epithelial cells. RESULTS: Trp significantly stimulates insulin growth factor binding protein 1 (IGFBP1) expression, a common endometrial marker of conceptus elongation and uterus receptivity for ruminants. When bovine endometrial epithelial cells are treated with Trp, tryptophan hydroxylase-1 remains unchanged, but tryptophan 2,3-dioxygenase 2 (TDO2) is significantly increased, suggesting tryptophan is mainly metabolized through the kynurenine pathway. Kynurenine significantly stimulates IGFBP1 expression. Furthermore, Trp and kynurenine significantly increase the expression of aryl hydrocarbon receptor (AHR). CH223191, an AHR inhibitor, abrogates the induction of Trp and kynurenine on IGFBP1. PGE2 significantly induces the expression of TDO2, AHR, and IGFBP1. CONCLUSIONS: The regulation between Trp / kynurenine and PGE2 may be crucial for the receptivity of the bovine uterus.

4-Vinylpyridine copolymers for improved LC-MS tryptophan and kynurenine determination in human serum.

Tryptophan (an essential amino acid) and its clinically important metabolite-kynurenine contribute to several fundamental biological processes and methods that allow their determination in biological samples are in demand. The novelty of the work was a demonstration of the utility of two polymers: 4-vinylpyridine crosslinked with trimethylolpropane trimethacrylate (poly(4VP-co-TRIM)) or 1,4-dimethacryloyloxybenzene (poly(4VP-co-14DMB))-in terms of human serum clean-up for simultaneous LC-MS determination of tryptophan and kynurenine. The goal was to achieve a reduction of the matrix effect, which is responsible for signal suppression, with minimal capture of analytes. The adsorption properties of the polymeric beads were studied by evaluating the adsorption kinetics and isotherms in model matrices. Therefore, the adsorption capacities of both molecules were not efficient, the tested 4-vinylpyridine-based copolymers have shown great promise (especially poly(4VP-co-TRIM)) as sorbents for serum clean-up. In the model human serum matrix, poly(4VP-co-TRIM) provided good recoveries of tryptophan and kynurenine (76% and 87%, respectively) and allowed for the reduction of the matrix effect. Performances of both copolymers were compared to those of commercially available sorbents (octadecylsilane, activated charcoal, and primary secondary amine).

Kynurenine pathway in type 2 diabetes: Role of metformin.

The Kynurenine pathway (KP) which is involved in the synthesis of nicotinamide adenine dinucleotide (NAD) from tryptophan (Trp) is intricate in the development of insulin resistance (IR) and type 2 diabetes (T2D). Inflammatory reactions in response to cardiometabolic disorders can induce the development of IR through the augmentation of KP. However, kynurenine (KYN), a precursor of kynurenic acid (KA) is increased following physical exercise and involved in the reduction of IR. Consequently, KP metabolites KA and KYN have anti-diabetogenic effects while other metabolites have diabetogenic effects. KP modulators, either inhibitors or activators, affect glucose homeostasis and insulin sensitivity in T2D in a bidirectional way, either protective or detrimental, that is not related to the KP effect. However, metformin through inhibition of inflammatory signaling pathways can reduce the activation of KP in T2D. These findings indicated a strong controversy regarding the role of KP in T2D. Therefore, the objectives of this mini review were to clarify how KP induces the development of IR and T2D. In addition, this review aimed to find the mechanistic role of antidiabetic drug metformin on the KP, and how KP modulators affect the pathogenesis of T2D.

Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies.

Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer's disease (AD), with recent proteomic studies highlighting disrupted glial metabolism in AD. We report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. Activation of astrocytic IDO1 by amyloid ß and tau oligomers increases KYN and suppresses glycolysis in an aryl hydrocarbon receptor-dependent manner. In amyloid and tau models, IDO1 inhibition improves hippocampal glucose metabolism and rescues hippocampal long-term potentiation in a monocarboxylate transporter-dependent manner. In astrocytic and neuronal cocultures from AD subjects, IDO1 inhibition improved astrocytic production of lactate and uptake by neurons. Thus, IDO1 inhibitors presently developed for cancer might be repurposed for treatment of AD.

Alzheimer's and metabolism wed with IDO1.

Kynurenine pathway inhibition reverses deficits in Alzheimer's mouse models.

Mechanistic conformational and substrate selectivity profiles emerging in the evolution of enzymes via parallel trajectories.

Laboratory evolution studies have demonstrated that parallel evolutionary trajectories can lead to genetically distinct enzymes with high activity towards a non-preferred substrate. However, it is unknown whether such enzymes have convergent conformational dynamics and mechanistic features. To address this question, we use as a model the wild-type Homo sapiens kynureninase (HsKYNase), which is of great interest for cancer immunotherapy. Earlier, we isolated HsKYNase_66 through an unusual evolutionary trajectory, having a 410-fold increase in the kcat/KM for kynurenine (KYN) and reverse substrate selectivity relative to HsKYNase. Here, by following a different evolutionary trajectory we generate a genetically distinct variant, HsKYNase_93D9, that exhibits KYN catalytic activity comparable to that of HsKYNase_66, but instead it is a "generalist" that accepts 3'-hydroxykynurenine (OH-KYN) with the same proficiency. Pre-steady-state kinetic analysis reveals that while the evolution of HsKYNase_66 is accompanied by a change in the rate-determining step of the reactions, HsKYNase_93D9 retains the same catalytic mechanism as HsKYNase. HDX-MS shows that the conformational dynamics of the two enzymes are markedly different and distinct from ortholog prokaryotic enzymes with high KYN activity. Our work provides a mechanistic framework for understanding the relationship between evolutionary mechanisms and phenotypic traits of evolved generalist and specialist enzyme species.

The role of kynurenines in migraine-related neuroimmune pathways.

Migraine, a primary headache disorder whose mechanism remains incompletely understood, appears to involve the activation of the trigeminovascular system (TS) during attacks. Research suggests that inflammatory processes mediated by the immune system may play a role in migraine pathophysiology. Neuroinflammation is often associated with migraine attacks, with cytokines serving as crucial mediators in the process. Elevated levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), have been observed in the blood and cerebrospinal fluid of individuals experiencing migraine attacks. These cytokines have the capacity to sensitize pain pathways in the brain, thereby increasing sensitivity to pain stimuli. This phenomenon, known as central sensitization, is believed to contribute to the intensity and persistence of migraine pain. Kynurenines, endogenous mediators of glutamatergic mechanisms, can significantly influence the pathophysiology of primary headache disorders. The kynurenine system is collectively known as the kynurenine pathway (KP), which can act on multiple receptors, such as glutamate receptors, aryl hydrocarbon receptors (AhRs), G protein-coupled receptors 35 (GPR35), and α-7 nicotinic acetylcholine (α7 nACh) receptors. These receptors are also found on various cells of the immune system, so the role of the KP in the pathomechanism of primary headaches may also be mediated through them. In this review, our goal is to show a possible link between the receptors of the KP and immune system in the context of inflammation and migraine. Migraine research in recent years has focused on neuropeptides, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as potential pathogenic factors and possible therapeutic approaches. These peptides share many similarities in their characteristics and roles. For instance, they exhibit potent vasodilation, occur in both the peripheral and central nervous systems, and play a role in transmitting nociception and neurogenic inflammation. The investigation of potential connections between the aforementioned neuropeptides and the kynurenine pathway could play a significant role in uncovering the pathomechanism of migraine and identifying new drug candidates.

Kynurenines as a Novel Target for the Treatment of Inflammatory Disorders.

This review discusses the potential of targeting the kynurenine pathway (KP) in the treatment of inflammatory diseases. The KP, responsible for the catabolism of the amino acid tryptophan (TRP), produces metabolites that regulate various physiological processes, including inflammation, cell cycle, and neurotransmission. These metabolites, although necessary to maintain immune balance, may accumulate excessively during inflammation, leading to systemic disorders. Key KP enzymes such as indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), tryptophan 2,3-dioxygenase (TDO), and kynurenine 3-monooxygenase (KMO) have been considered promising therapeutic targets. It was highlighted that both inhibition and activation of these enzymes may be beneficial, depending on the specific inflammatory disorder. Several inflammatory conditions, including autoimmune diseases, for which modulation of KP activity holds therapeutic promise, have been described in detail. Preclinical studies suggest that this modulation may be an effective treatment strategy for diseases for which treatment options are currently limited. Taken together, this review highlights the importance of further research on the clinical application of KP enzyme modulation in the development of new therapeutic strategies for inflammatory diseases.

Associations of gut microbiota features and circulating metabolites with systemic inflammation in children.

OBJECTIVE: Gut microbes and microbe-dependent metabolites (eg, tryptophan-kynurenine-serotonin pathway metabolites) have been linked to systemic inflammation, but the microbiota-metabolite-inflammation axis remains uncharacterised in children. Here we investigated whether gut microbiota features and circulating metabolites (both microbe-dependent and non-microbe-dependent metabolites) associated with circulating inflammation markers in children. METHODS: We studied children from the prospective Gen3G birth cohort who had data on untargeted plasma metabolome (n=321 children; Metabolon platform), gut microbiota (n=147; 16S rRNA sequencing), and inflammation markers (plasminogen activator inhibitor-1 (PAI-1), monocyte chemoattractant protein-1, and tumour necrosis factor-α) measured at 5-7 years. We examined associations of microbial taxa and metabolites-examining microbe-dependent and non-microbe-dependent metabolites separately-with each inflammatory marker and with an overall inflammation score (InfSc), adjusting for key confounders and correcting for multiple comparisons. We also compared the proportion of significantly associated microbe-dependent versus non-microbe-dependent metabolites, identified a priori (Human Microbial Metabolome Database), with each inflammation marker. RESULTS: Of 335 taxa tested, 149 were associated (qFDR<0.05) with at least one inflammatory marker; 10 of these were robust to pseudocount choice. Several bacterial taxa involved in tryptophan metabolism were associated with inflammation, including kynurenine-degrading Ruminococcus, which was inversely associated with all inflammation markers. Of 1037 metabolites tested, 315 were previously identified as microbe dependent and were more frequently associated with PAI-1 and the InfSc than non-microbe dependent metabolites. In total, 87 metabolites were associated (qFDR<0.05) with at least one inflammation marker, including kynurenine (positively), serotonin (positively), and tryptophan (inversely). CONCLUSION: A distinct set of gut microbes and microbe-dependent metabolites, including those involved in the tryptophan-kynurenine-serotonin pathway, may be implicated in inflammatory pathways in childhood.

The Complex World of Kynurenic Acid: Reflections on Biological Issues and Therapeutic Strategy.

It has been unequivocally established that kynurenic acid has a number of actions in a variety of cells and tissues, raising, in principle, the possibility of targeting its generation, metabolism or sites of action to manipulate those effects to a beneficial therapeutic end. However, many basic aspects of the biology of kynurenic acid remain unclear, potentially leading to some confusion and misinterpretations of data. They include questions of the source, generation, targets, enzyme expression, endogenous concentrations and sites of action. This essay is intended to raise and discuss many of these aspects as a source of reference for more balanced discussion. Those issues are followed by examples of situations in which modulating and correcting kynurenic acid production or activity could bring significant therapeutic benefit, including neurological and psychiatric conditions, inflammatory diseases and cell protection. More information is required to obtain a clear overall view of the pharmacological environment relevant to kynurenic acid, especially with respect to the active concentrations of kynurenine metabolites in vivo and changed levels in disease. The data and ideas presented here should permit a greater confidence in appreciating the sites of action and interaction of kynurenic acid under different local conditions and pathologies, enhancing our understanding of kynurenic acid itself and the many clinical conditions in which manipulating its pharmacology could be of clinical value.

The Biology and Biochemistry of Kynurenic Acid, a Potential Nutraceutical with Multiple Biological Effects.

Kynurenic acid (KYNA) is an antioxidant degradation product of tryptophan that has been shown to have a variety of cytoprotective, neuroprotective and neuronal signalling properties. However, mammalian transporters and receptors display micromolar binding constants; these are consistent with its typically micromolar tissue concentrations but far above its serum/plasma concentration (normally tens of nanomolar), suggesting large gaps in our knowledge of its transport and mechanisms of action, in that the main influx transporters characterized to date are equilibrative, not concentrative. In addition, it is a substrate of a known anion efflux pump (ABCC4), whose in vivo activity is largely unknown. Exogeneous addition of L-tryptophan or L-kynurenine leads to the production of KYNA but also to that of many other co-metabolites (including some such as 3-hydroxy-L-kynurenine and quinolinic acid that may be toxic). With the exception of chestnut honey, KYNA exists at relatively low levels in natural foodstuffs. However, its bioavailability is reasonable, and as the terminal element of an irreversible reaction of most tryptophan degradation pathways, it might be added exogenously without disturbing upstream metabolism significantly. Many examples, which we review, show that it has valuable bioactivity. Given the above, we review its potential utility as a nutraceutical, finding it significantly worthy of further study and development.

Understanding the kynurenine pathway: A narrative review on its impact across chronic pain conditions.

Chronic pain is a debilitating symptom with a significant negative impact on the quality of life and socioeconomic status, particularly among adults and the elderly. Major Depressive Disorder (MDD) stands out as one of the most important comorbid disorders accompanying chronic pain. The kynurenine pathway serves as the primary route for tryptophan degradation and holds critical significance in various biological processes, including the regulation of neurotransmitters, immune responses, cancer development, metabolism, and inflammation. This review encompasses key research studies related to the kynurenine pathway in the context of headache, neuropathic pain, gastrointestinal disorders, fibromyalgia, chronic fatigue syndrome, and MDD. Various metabolites produced in the kynurenine pathway, such as kynurenic acid and quinolinic acid, exhibit neuroprotective and neurotoxic effects, respectively. Recent studies have highlighted the significant involvement of kynurenine and its metabolites in the pathophysiology of pain. Moreover, pharmacological interventions targeting the regulation of the kynurenine pathway have shown therapeutic promise in pain management. Understanding the underlying mechanisms of this pathway presents an opportunity for developing personalized, innovative, and non-opioid approaches to pain treatment. Therefore, this narrative review explores the role of the kynurenine pathway in various chronic pain disorders and its association with depression and chronic pain.

Prognostic relevance of high expression of kynurenine pathway markers in glioblastoma.

Glioblastoma (GBM) continues to exhibit a discouraging survival rate despite extensive research into new treatments. One factor contributing to its poor prognosis is the tumor's immunosuppressive microenvironment, in which the kynurenine pathway (KP) plays a significant role. This study aimed to explore how KP impacts the survival of newly diagnosed GBM patients. We examined tissue samples from 108 GBM patients to assess the expression levels of key KP markers-tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenase (IDO1/2), and the aryl hydrocarbon receptor (AhR). Using immunohistochemistry and QuPath software, three tumor cores were analyzed per patient to evaluate KP marker expression. Kaplan-Meier survival analysis and stepwise multivariate Cox regression were used to determine the effect of these markers on patient survival. Results showed that patients with high expression of TDO2, IDO1/2, and AhR had significantly shorter survival times. This finding held true even when controlling for other known prognostic variables, with a hazard ratio of 3.393 for IDO1, 2.775 for IDO2, 1.891 for TDO2, and 1.902 for AhR. We suggest that KP markers could serve as useful tools for patient stratification, potentially guiding future immunomodulating trials and personalized treatment approaches for GBM patients.

Role of Kynurenine and Its Derivatives in the Neuroimmune System.

In recent years, there has been a growing realization of intricate interactions between the nervous and immune systems, characterized by shared humoral factors and receptors. This interplay forms the basis of the neuroimmune system, the understanding of which will provide insights into the pathogenesis of neurological diseases, in which the involvement of the immune system has been overlooked. Kynurenine and its derivatives derived from tryptophan have long been implicated in the pathogenesis of various neurological diseases. Recent studies have revealed their close association not only with neurological disorders but also with sepsis-related deaths. This review provides an overview of the biochemistry of kynurenine and its derivatives, followed by a discussion of their role via the modulation of the neuroimmune system in various diseases.

Sex-specific associations of kynurenic acid with neopterin in Alzheimer's disease.

BACKGROUND: Sex differences in neuroinflammation could contribute to women's increased risk of Alzheimer's disease (AD), providing rationale for exploring sex-specific AD biomarkers. In AD, dysregulation of the kynurenine pathway (KP) contributes to neuroinflammation and there is some evidence of sex differences in KP metabolism. However, the sex-specific associations between KP metabolism and biomarkers of AD and neuroinflammation need to be explored further. METHODS: Here we investigate sex differences in cerebrospinal fluid concentrations of seven KP metabolites and sex-specific associations with established AD biomarkers and neopterin, an indicator of neuroinflammation. This study included 311 patients with symptomatic AD and 105 age-matched cognitively unimpaired (CU) controls, followed for up to 5 years. RESULTS: We found sex differences in KP metabolites in the AD group, with higher levels of most metabolites in men, while there were no sex differences in the CU group. In line with this, more KP metabolites were significantly altered in AD men compared to CU men, and there was a trend in the same direction in AD women. Furthermore, we found sex-specific associations between kynurenic acid and the kynurenic acid/quinolinic acid ratio with neopterin, but no sex differences in the associations between KP metabolites and clinical progression. DISCUSSION: In our cohort, sex differences in KP metabolites were restricted to AD patients. Our results suggest that dysregulation of the KP due to increased inflammation could contribute to higher AD risk in women.

The improvement effect of exercise on rats with chronic stress-induced depression-like behavior: a discussion based on the kynurenine pathway.

OBJECTIVE: To observe the effects of 4 weeks of voluntary wheel running on depressive-like behavior in a rat chronic stress-induced depression model to explore the anti-depressive mechanism of exercise. METHODS: In this observational study, 36 Sprague-Dawley rats were randomly divided into control, stress model, and stress exercise groups (12 rats/group). The control group received no intervention, and the stress model and stress exercise group rats underwent chronic mild unpredictable stress and isolation. The stress exercise group rats also underwent 4 weeks of voluntary wheel running. Behavioral changes and hippocampal protein and mRNA expression levels were detected. RESULTS: Voluntary wheel running significantly increased horizontal and vertical movements, sucrose intake, and the sucrose preference percentage and reduced immobility time in the forced swimming test in depression model rats. The hippocampal tumor necrosis factor-α, interleukin (IL)-6, IL-1ß, and quinolinic acid levels were significantly decreased, while the IL-4, IL-10, and kynurenic acid levels were significantly increased. Kynurenine-3-monooxygenase and 3-hydroxyanthranilate-3, 4-dioxygenase mRNA levels were downregulated, and kynurenine aminotransferase mRNA was upregulated. CONCLUSION: Voluntary wheel running improved depressive-like behavior in depression model rats. The mechanism may be related to a kynurenine pathway metabolite level imbalance, which has neurotoxic and neuroprotective effects, caused by long-term voluntary wheel running.

Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice.

Tryptophan (Trp) is an essential amino acid, whose metabolism is a key gatekeeper of intestinal homeostasis. Yet, its systemic effects, particularly on atherosclerosis, remain unknown. Here we show that high-fat diet (HFD) increases the activity of intestinal indoleamine 2, 3-dioxygenase 1 (IDO), which shifts Trp metabolism from the production of microbiota-derived indole metabolites towards kynurenine production. Under HFD, the specific deletion of IDO in intestinal epithelial cells leads to intestinal inflammation, impaired intestinal barrier, augmented lesional T lymphocytes and atherosclerosis. This is associated with an increase in serotonin production and a decrease in indole metabolites, thus hijacking Trp for the serotonin pathway. Inhibition of intestinal serotonin production or supplementation with indole derivatives alleviates plaque inflammation and atherosclerosis. In summary, we uncover a pivotal role of intestinal IDO in the fine-tuning of Trp metabolism with systemic effects on atherosclerosis, paving the way for new therapeutic strategies to relieve gut-associated inflammatory diseases.

Gut microbiota dysbiosis is associated with altered tryptophan metabolism and dysregulated inflammatory response in COVID-19.

The clinical course of COVID-19 is variable and often unpredictable. To test the hypothesis that disease progression and inflammatory responses associate with alterations in the microbiome and metabolome, we analyzed metagenome, metabolome, cytokine, and transcriptome profiles of repeated samples from hospitalized COVID-19 patients and uninfected controls, and leveraged clinical information and post-hoc confounder analysis. Severe COVID-19 was associated with a depletion of beneficial intestinal microbes, whereas oropharyngeal microbiota disturbance was mainly linked to antibiotic use. COVID-19 severity was also associated with enhanced plasma concentrations of kynurenine and reduced levels of several other tryptophan metabolites, lysophosphatidylcholines, and secondary bile acids. Moreover, reduced concentrations of various tryptophan metabolites were associated with depletion of Faecalibacterium, and tryptophan decrease and kynurenine increase were linked to enhanced production of inflammatory cytokines. Collectively, our study identifies correlated microbiome and metabolome alterations as a potential contributor to inflammatory dysregulation in severe COVID-19.

Kynurenic Acid/AhR Signaling at the Junction of Inflammation and Cardiovascular Diseases.

Persistent systemic chronic inflammatory conditions are linked with many pathologies, including cardiovascular diseases (CVDs), a leading cause of death across the globe. Among various risk factors, one of the new possible contributors to CVDs is the metabolism of essential amino acid tryptophan. Proinflammatory signals promote tryptophan metabolism via the kynurenine (KYN) pathway (KP), thereby resulting in the biosynthesis of several immunomodulatory metabolites whose biological effects are associated with the development of symptoms and progression of various inflammatory diseases. Some participants in the KP are agonists of aryl hydrocarbon receptor (AhR), a central player in a signaling pathway that, along with a regulatory influence on the metabolism of environmental xenobiotics, performs a key immunomodulatory function by triggering various cellular mechanisms with the participation of endogenous ligands to alleviate inflammation. An AhR ligand with moderate affinity is the central metabolite of the KP: KYN; one of the subsequent metabolites of KYN-kynurenic acid (KYNA)-is a more potent ligand of AhR. Understanding the role of AhR pathway-related metabolites of the KP that regulate inflammatory factors in cells of the cardiovascular system is interesting and important for achieving effective treatment of CVDs. The purpose of this review was to summarize the results of studies about the participation of the KP metabolite-KYNA-and of the AhR signaling pathway in the regulation of inflammation in pathological conditions of the heart and blood vessels and about the possible interaction of KYNA with AhR signaling in some CVDs.