Kynurenines in the Pathogenesis of Peripheral Neuropathy During Leprosy and COVID-19.

Inflammatory disorders are associated with the activation of tryptophan (TRYP) catabolism via the kynurenine pathway (KP). Several reports have demonstrated the role of KP in the immunopathophysiology of both leprosy and coronavirus disease 19 (COVID-19). The nervous system can be affected in infections caused by both Mycobacterium leprae and SARS-CoV-2, but the mechanisms involved in the peripheral neural damage induced by these infectious agents are not fully understood. In recent years KP has received greater attention due the importance of kynurenine metabolites in infectious diseases, immune dysfunction and nervous system disorders. In this review, we discuss how modulation of the KP may aid in controlling the damage to peripheral nerves and the effects of KP activation on neural damage during leprosy or COVID-19 individually and we speculate its role during co-infection.

Kynurenine pathway in Coronavirus disease (COVID-19): Potential role in prognosis.

BACKGROUND: It is known that inflammatory responses play an important role in the pathophysiology of COVID-19. AIMS: In this study, we aimed to examine the role of kynurenine (KYN) metabolism on the severity of COVID-19 disease AQ5. MATERIALS & METHODS: Seventy COVID-19 patients of varying severity and 30 controls were included in the study. In addition to the classical laboratory parameters, KYN, tryptophan (TRP), kynurenic acid (KYNA), 3 hydroxykynurenine (3OHKYN), quinolinic acid (QA), and picolinic acid (PA) were measured with mass spectrometry. RESULTS: TRP, KYN, KYN:TRP ratio, KYNA, 3OHKYN, PA, and QA results were found to be significantly different in COVID-19 patients (p < 0.001 for all). The KYN:TRP ratio and PA of severe COVID-19 patients was statistically higher than that of mild-moderate COVID-19 patients (p < 0.001 for all). When results were examined, statistically significant correlations with KYN:TRP ratio, IL-6, ferritin, and procalcitonin were only found in COVID-19 patients. ROC analysis indicated that highest AUC values were obtained by KYN:TRP ratio and PA (0.751 vs 0.742). In determining the severity of COVID-19 disease, the odd ratios (and confidence intervals) of KYN:TRP ratio and PA levels that were adjusted according to age, gender, and comorbidity were determined to be 1.44 (1.1-1.87, p = 0.008) and 1.06 (1.02-1.11, p = 0.006), respectively. DISCUSSION & CONCLUSION: According to the results of this study, KYN metabolites play a role in the pathophysiology of COVID-19, especially KYN:TRP ratio and PA could be markers for identification of severe COVID-19 cases.

Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease. Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls. Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine. ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A (p = 0.018), FABP-2 (p = 0.002), and 3-hydroxykynurenine (p = 0.037) and lower levels of kynurenine (p = 0.012) and serotonin (p = 0.045) than controls. Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively. No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease. Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism. Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.

Tryptophan: A Unique Role in the Critically Ill.

Tryptophan is an essential amino acid whose metabolites play key roles in diverse physiological processes. Due to low reserves in the body, especially under various catabolic conditions, tryptophan deficiency manifests itself rapidly, and both the serotonin and kynurenine pathways of metabolism are clinically significant in critically ill patients. In this review, we highlight these pathways as sources of serotonin and melatonin, which then regulate neurotransmission, influence circadian rhythm, cognitive functions, and the development of delirium. Kynurenines serve important signaling functions in inter-organ communication and modulate endogenous inflammation. Increased plasma kynurenine levels and kynurenine-tryptophan ratios are early indicators for the development of sepsis. They also influence the regulation of skeletal muscle mass and thereby the development of polyneuromyopathy in critically ill patients. The modulation of tryptophan metabolism could help prevent and treat age-related disease with low grade chronic inflammation as well as post intensive care syndrome in all its varied manifestations: cognitive decline (including delirium or dementia), physical impairment (catabolism, protein breakdown, loss of muscle mass and tone), and mental impairment (depression, anxiety or post-traumatic stress disorder).

Immunotherapy of COVID-19 with poly (ADP-ribose) polymerase inhibitors: starting with nicotinamide.

COVID-19 induces a proinflammatory environment that is stronger in patients requiring intensive care. The cytokine components of this environment may determine efficacy or otherwise of glucocorticoid therapy. The immunity modulators, the aryl hydrocarbon receptor (AhR) and the nuclear NAD+-consuming enzyme poly (ADP-ribose) polymerase 1 (PARP 1) may play a critical role in COVID-19 pathophysiology. The AhR is overexpressed in coronaviruses, including COVID-19 and, as it regulates PARP gene expression, the latter is likely to be activated in COVID-19. PARP 1 activation leads to cell death mainly by depletion of NAD+ and adenosine triphosphate (ATP), especially when availability of these energy mediators is compromised. PARP expression is enhanced in other lung conditions: the pneumovirus respiratory syncytial virus (RSV) and chronic obstructive pulmonary disease (COPD). I propose that PARP 1 activation is the terminal point in a sequence of events culminating in patient mortality and should be the focus of COVID-19 immunotherapy. Potent PARP 1 inhibitors are undergoing trials in cancer, but a readily available inhibitor, nicotinamide (NAM), which possesses a highly desirable biochemical and activity profile, merits exploration. It conserves NAD+ and prevents ATP depletion by PARP 1 and Sirtuin 1 (silent mating type information regulation 2 homologue 1) inhibition, enhances NAD+ synthesis, and hence that of NADP+ which is a stronger PARP inhibitor, reverses lung injury caused by ischaemia/reperfusion, inhibits proinflammatory cytokines and is effective against HIV infection. These properties qualify NAM for therapeutic use initially in conjunction with standard clinical care or combined with other agents, and subsequently as an adjunct to stronger PARP 1 inhibitors or other drugs.

Diverse chemical space of indoleamine-2,3-dioxygenase 1 (Ido1) inhibitors.

Indoleamine-2,3-dioxygenase 1 (IDO1) catalyses the first and rate limiting step of kynurenine pathway accounting for the major contributor of L-Tryptophan degradation. The Kynurenine metabolites are identified as essential cofactors, antagonists, neurotoxins, immunomodulators, antioxidants as well as carcinogens. The catalytic active site of IDO1 enzyme consists of hydrophobic Pocket-A positioned in the distal heme site and remains connected to a second hydrophobic Pocket-B towards the entrance of the active site. IDO1 enzyme also relates directly to the modulation of the innate and adaptive immune system. Various studies proved that the over expression of IDO1 enzyme play a predominant role in the escape of immunity during cancer progression. Recently, there has been considerable interest in evaluating the potential of IDO1 inhibitors to mobilize the body's immune system against solid tumours. In the last two decades, enormous attempts to advance new IDO1 inhibitors are on-going both in pharmaceutical industries and in academia which resulted in the discovery of a diverse range of selective and potent IDO1 inhibitors. The IDO1 inhibitors have therapeutic utility in various diseases and in the near future, it may have utility in the treatment of COVID-19. Despite various reviews on IDO1 inhibitors in last five years, none of the reviews provide a complete overview of diverse chemical space including naturally occurring and synthetic IDO1 inhibitors with detailed structure activity relationship studies. The present work provides a complete overview on the IDO1 inhibitors known in the literature so far along with the Structure-Activity Relationship (SAR) in each class of compounds.

Increased kynurenine-to-tryptophan ratio in the serum of patients infected with SARS-CoV2: An observational cohort study.

Immune dysregulation is a hallmark of patients infected by SARS-CoV2 and the balance between immune reactivity and tolerance is a key determinant of all stages of infection, including the excessive inflammatory state causing the acute respiratory distress syndrome. The kynurenine pathway (KP) of tryptophan (Trp) metabolism is activated by pro-inflammatory cytokines and drives mechanisms of immune tolerance. We examined the state of activation of the KP by measuring the Kyn:Trp ratio in the serum of healthy subjects (n = 239), and SARS-CoV2-negative (n = 305) and -positive patients (n = 89). Patients were recruited at the Emergency Room of St. Andrea Hospital (Rome, Italy). Kyn and Trp serum levels were assessed by HPLC/MS-MS. Compared to healthy controls, both SARS-CoV2-negative and -positive patients showed an increase in the Kyn:Trp ratio. The increase was larger in SARS-CoV2-positive patients, with a significant difference between SARS-CoV2-positive and -negative patients. In addition, the increase was more prominent in males, and positively correlated with age and severity of SARS-CoV2 infection, categorized as follows: 1 = no need for intensive care unit (ICU); 2 ≤ 3 weeks spent in ICU; 3 ≥ 3 weeks spent in ICU; and 4 = death. The highest Kyn:Trp values were found in SARS-CoV2-positive patients with severe lymphopenia. These findings suggest that the Kyn:Trp ratio reflects the level of inflammation associated with SARS-CoV2 infection, and, therefore, might represent a valuable biomarker for therapeutic intervention.