Scientific interest in tryptophan metabolism via the kynurenine pathway (KP) has increased in the last decades. Describing its metabolites helped to increase their roles in many diseases and disturbances, many of a pro-inflammatory nature. It has become increasingly evident that KP can be considered an important part of emerging mediators of diabetes mellitus and metabolic syndrome (MS), mostly stemming from chronic systemic low-grade inflammation resulting in the aggravation of cardiovascular complications. An electronic literature search of PubMed and Embase up to March 2021 was performed for papers reporting the effects of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), xanthurenic acid (XA), anthranilic acid (AA), and quinolinic acid (QA), focusing on their roles in carbohydrate metabolism and the cardiovascular system. In this review, we discussed the progress in tryptophan metabolism via KP research, focusing particular attention on the roles in carbohydrate metabolism and its complications in the cardiovascular system. We examined the association between KP and diabetes mellitus type 2 (T2D), diabetes mellitus type 1 (T1D), and cardiovascular diseases (CVD). We concluded that tryptophan metabolism via KP serves as a potential diagnostic tool in assessing cardiometabolic risk for patients with T2D.

Hypertension is a serious condition that can lead to many health problems. The mechanisms underlying this process are still not fully understood. The kynurenine pathway may be involved in the occurrence and progression of hypertension. The purpose of this study was to examine the activity of peripheral kynurenine pathway in rats with renovascular hypertension in Goldblatt 2K1C model. Hypertension was induced in the experimental groups by constricting the renal artery of the left kidney of the rats. Determination of tryptophan (Trp) and kynurenine pathway metabolites was assessed by high-performance liquid chromatography in plasma and tissues obtained at 4, 8, and 16 weeks after the surgical intervention or sham surgery. Levels of Ang II were evaluated using commercial immuno-enzymatic ELISA kits. Surgical treatment led to increased values of mean blood pressure and systolic blood pressure, whereas Trp concentrations were decreased in experimental animals compared to appropriate controls. Simultaneously, the considerable increment of kynurenine pathway components and a significant increase in the activity of tryptophan 2,3-dioxygenase were observed in rats with developed hypertension in comparison with controls. There were no differences between Ang II levels in controls and experimental groups. The inverse relationship was between plasma Trp and both SBP and Ang II values, and Trp independently affected Ang II concentrations in hypertensive rats. In contrast, tryptophan 2,3-dioxygenase activity and plasma kynurenine metabolites positively correlated with blood pressure values as well as with Ang II levels in these animals. Moreover, kynurenine was independently connected with MBP. Renovascular hypertension influences kynurenine pathway and leads to an imbalance in Trp and its metabolite levels. Tryptophan 2,3-dioxygenase and part of the kynurenine metabolites in plasma and tissues positively correlated with blood pressure values and Ang II levels. Although the mechanisms underlying this phenomenon are unclear, our experiment showed a link between renovascular hypertension and activation of kynurenine pathway.Impact statement: As hypertension is a major health problem, our research has focused on the connection between the kynurenine pathway and hypertension. We assessed the levels of the main metabolites of dietary tryptophan and analyzed its levels in terms of high blood pressure. The results of our work indicated that in the renovascular rat’s model of hypertension, an alteration of the kynurenine pathway occurred. According to our knowledge, this is the first study that has investigated in a comprehensive manner the alteration of the kynurenine pathway under the condition of elevated blood pressure. On the one hand, the work supports a better understanding of pathophysiological basics of the occurrence of hypertension, and on the other hand it provides potential opportunities to treat this disease.

Triple-Negative Breast Cancer is a subtype of breast cancer characterized by the lack of expression of estrogen receptors, progesterone receptors, as well as human epidermal growth factor receptor 2. This cancer accounts for 15–20% of all breast cancers and is especially common in patients under 40 years of age, as well as with the occurring BRCA1 mutation. Its poor prognosis is reflected in the statistical life expectancy of 8–15 months after diagnosis of metastatic TNBC. So far, the lack of targeted therapy has narrowed therapeutic possibilities to classic chemotherapy. The idea behind the use of humanized monoclonal antibodies, as inhibitors of immunosuppressive checkpoints used by the tumor to escape from immune system control, is to reduce immunotolerance and direct an intensified anti-tumor immune response. An abundance of recent studies has provided numerous pieces of evidence about the safety and clinical benefits of immunotherapy using humanized monoclonal antibodies in the fight against many types of cancer, including TNBC. In particular, phase three clinical trials, such as the IMpassion 130, the KEYNOTE-355 and the KEYNOTE-522 resulted in the approval of immunotherapeutic agents, such as atezolizumab and pembrolizumab by the US Food and Drug Administration in TNBC therapy. This review aims to present the huge potential of immunotherapy using monoclonal antibodies directed against immunosuppressive checkpoints—such as atezolizumab, avelumab, durvalumab, pembrolizumab, nivolumab, cemiplimab, tremelimumab, ipilimumab—in the fight against difficult to treat TNBCs as monotherapy as well as in more advanced combination strategies.

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.