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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. [ABSTRACT FROM AUTHOR]

Background: The identification of clinical factors affecting the gray-scale median (GSM) and determination of GSM diagnostic utility for differentiating between symptomatic and asymptomatic internal carotid artery (ICA) stenosis. Methods: This study included 45 patients with asymptomatic and 40 patients with symptomatic ICA stenosis undergoing carotid endarterectomy (CEA). Echolucency of carotid plaque was determined using computerized techniques for the GSM analysis. Study groups were compared in terms of clinical risk factors, coexisting comorbidities, and used pharmacotherapy. Results: Mean GSM values in the symptomatic group were significantly lower than in the asymptomatic group (p < 0.001). Both in the univariate as well as in the multiple regression analysis, GSM was significantly correlated with D-dimers and fasting plasma glucose levels and tended to correlate with β-adrenoceptor antagonist use in the symptomatic group. In asymptomatic patients, GSM was associated with the presence of grade 2 and grade 3 hypertension, and tended to correlate with the use of metformin, sulfonylureas, and statin. Independent factors for GSM in this group remained as grade 3 hypertension and statin's therapy. The receiver operating characteristic (ROC) analysis revealed that GSM differentiated symptomatic from asymptomatic ICA stenosis with sensitivity and specificity of 73% and 80%, respectively. Conclusion: The completely diverse clinical parameters may affect GSM in symptomatic and asymptomatic patients undergoing CEA, whose clinical characteristics were similar in terms of most of the compared parameters. GSM may be a clinically useful parameter for differentiating between symptomatic and asymptomatic ICA stenosis. [ABSTRACT FROM AUTHOR]

Background: Tryptophan metabolism via the kynurenine pathway is considered the link between the immune and endocrine systems. Dysregulation of serotonergic transmission can stem from the direct influence of interferon-[alpha] on the activity of serotonergic receptors 5-[HT.sub.1A] and 5-[HT.sub.2A], and from its indirect effect on tryptophan metabolism. Induction of the kynurenine pathway increases the concentration of neurotoxic kynurenine metabolites, and the activity of kynurenine derivatives is linked to the onset of depression. The aim of our study was to evaluate the relationships between depressive symptoms and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, indolamine 2,3-dioxygenase (IDO) activity and tryptophan availability to the brain. Methods: The study followed a prospective longitudinal cohort design. We evaluated 101 patients with chronic hepatitis C who were treated with pegylated interferon-[alpha]2a, and 40 controls who were awaiting treatment. We evaluated the relationships between total score on the Montgomery-Asberg Depression Rating Scale and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, IDO activity and tryptophan availability to the brain. A logistic regression model was adapted for the diagnosis of major depressive disorder at each time point, taking into account changes in parameters of the kynurenine pathway between a given time point and the baseline measurement. Results: Of the treated patients, 44% fulfilled the criteria for major depressive disorder at least once during the 24 weeks of treatment. Anthranilic acid concentrations were significantly increased compared to baseline for all time points except week 2. Tryptophan availability showed a significant decrease ([beta] = -0.09, p = 0.01) only in week 12 of treatment. Over time, kynurenine, tryptophan and anthranilic acid concentrations, as well as IDO activity and tryptophan availability to the brain, were significantly associated with total score on the Montgomery-Asberg Depression Rating Scale. A logistic regression model revealed that participants with decreased tryptophan availability to the brain at 12 weeks of treatment and participants with increased anthranilic acid concentrations at week 24 of treatment were at increased risk for diagnosis of major depressive disorder (odds ratios 2.92 and 3.59, respectively). Limitations: This study had an open-label design in a population receiving naturalistic treatment. Conclusion: The present study provides the first direct evidence of the role of anthranilic acid in the pathogenesis of inflammation-induced major depressive disorder during treatment for hepatitis C with pegylated interferon-[alpha]2a., Introduction Tryptophan is an essential amino acid that must be supplied from external sources. Four biosynthetic pathways originate from tryptophan: synthesis of proteins, synthesis of serotonin, synthesis of tryptamine and [...]

Simple Summary: This review aims to present current evidence on the potential use of low-dose naltrexone (LDN) in cancer therapy. Low-dose naltrexone exhibits an inhibitory effect on cancer cell proliferation by blocking the opioid growth factor–receptor axis and enhancing the immune response against cancer cells. Data from existing studies indicate that low-dose naltrexone has a high anti-cancer potential, especially as an adjuvant in conventional chemotherapy and immunotherapy schemes. Naltrexone (NTX) is a non-selective antagonist of opioid receptors, primarily used in the therapy of opioid and alcohol dependence. Low-dose naltrexone (LDN) exhibits antagonistic action against the opioid growth factor receptor (OGFr), whose signaling is associated with the survival, proliferation, and invasion of cancer cells. The mechanism of action of LDN depends on the dose and duration of the OGFr blockade, leading to a compensatory increase in the synthesis of the opioid growth factor (OGF), which has an inhibitory effect on carcinogenesis. Numerous studies on in vitro and in vivo models provide evidence of LDN's positive impact on inhibiting the OGF–OGFr axis in cancers. LDN's unique mechanism of action on cancer cells, lack of direct cytotoxic effect, and immunomodulating action form the basis for its use as an adjuvant in chemotherapy and immunotherapy of cancerous lesions. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the rapid development of medicine, the appropriate selection of anticancer drugs in breast cancer is still not optimized. To address personalized medicine, we propose a simple diagnostic and therapeutic pathway, called the ONCOBREAST-TEST, which aims to select drugs against which a patient's cancer cells, taken during a biopsy, show the greatest sensitivity. Our research showed that simple, inexpensive, and quick tests such as the assessment of cell viability, morphology, and lactate dehydrogenase activity are sufficient tools for selecting drugs with the highest anticancer efficacy. The conducted in vitro studies showed a high probability of accurate drug selection based on the proposed testing techniques. ONCOBREAST-TEST is a diagnostic and therapeutic procedure that is part of the comprehensive care of a patient with breast cancer.: Chemosensitivity of cancer cells was assessed using the MTT test, morphological assessment of cells, LDH activity in the culture medium, and flow cytometry technique (apoptosis, proliferation, CD24, CD44, GATA3, cytokeratin, Ki-67). Diagnostic tools included panels of simple tests which could be used to accurately predict the chemosensitivity of tumor cells previously isolated from a patient, even before actual chemotherapy. The proposed procedure allows for a simple (based on MTT results, cell morphology, LDH concentration), minimally invasive, quick, and accurate assessment of the sensitivity of breast cancer cells to the drugs used and, to select the most effective treatment plan as part of personalized therapy. In a patient with NOS G3, the most promising therapy will be docetaxel with cyclophosphamide and in the case of a patient with NOS G1, paclitaxel alone and in combination with trastuzumab. The implementation of such a procedure would undoubtedly increase the effectiveness of chemotherapy, reduce side effects by excluding drugs that are ineffective before using them, protect the patient's health, and shorten the treatment time, bringing economic and social benefits. [ABSTRACT FROM AUTHOR]

Simple Summary: The discovery of the involvement of the kynurenine pathway in carcinogenesis has prompted significant changes in pharmacotherapy strategies. One such approach involves the simultaneous targeting of an ongoing process in cancer cells and inhibiting the abovementioned pathway. Based on this approach, we investigated the anticancer effect of combining a 1,2,4-triazine derivative, MM-129, together with an inhibitor of the kynurenine pathway, indoximod, in a colon cancer model. The obtained results support the efficacy of this strategy, providing a basis for future in-depth analyses. (1) Background: The purpose of the given study was to examine the antitumor activity of the simultaneous administration of MM-129, a 1,2,4-triazine derivative, and indoximod (IND), the kynurenine pathway inhibitor, toward colon cancer. (2) Methods: The efficiency of the co-administration of the studied compounds was assessed in xenografted zebrafish embryos. Then, the effects of the combined administration of compounds on cellular processes such as cell viability, apoptosis, and intracellular signaling pathways were evaluated. In vitro studies were performed using two colorectal cancer cell lines, namely, DLD-1 and HT-29. (3) Results: The results indicated that the simultaneous application of MM-129 and indoximod induced a stronger inhibition of tumor growth in zebrafish xenografts. The combination of these compounds intensified the process of apoptosis by lowering the mitochondrial potential, enhancing the externalization of phosphatidylserine (PS) and activation of caspases. Additionally, the expression of protein kinase B (AKT) and indoleamine 2,3-dioxygenase-(1IDO1) was disrupted under the applied compound combination. (4) Conclusions: Simultaneous targeting of ongoing cell signaling that promotes tumor progression, along with inhibition of the kynurenine pathway enzyme IDO1, results in the enhancement of the antitumor effect of the tested compounds against the colon cancer cells. [ABSTRACT FROM AUTHOR]

Psoriasis is an important disease in dermatological practice and, despite many studies, its pathogenesis is still not fully understood. Gasdermin C (GSDMC; melanoma-derived leucine zipper-containing extranuclear factor, MLZE) is a member of the gasdermin protein family. The study enrolled 60 patients with active plaque-type psoriasis and 30 volunteers without dermatoses. GSDMC concentration was assessed in serum and urine samples of all participants using ELISA. GSDMC tissue expression was assessed by immunohistochemistry. The GSDMC concentration was significantly higher in serum of patients than in controls (p < 0.001). A urinary GSDMC/creatinine ratio was significantly lower in patients than in controls (p < 0.05). Psoriatic lesions exhibited a significantly higher expression of GSDMC than nonlesional patients' skin or controls' skin (p < 0.001 , p < 0.01 , respectively). There was a positive correlation between the GSDMC serum concentration and the age of patients (R = 0.31, p = 0.015) and a negative correlation between GSDMC and RBC (R = −0.37; p = 0.0038), HGB (R = −0.26; p = 0.047), and urea concentration (R = −0.36; p = 0.04). Our study shows the potential involvement of GSDMC in psoriasis. An increased serum GSDMC and a decreased urinary GSDMC/creatinine ratio could be considered noninvasive psoriasis biomarkers, especially of local hypoxia or cell proliferation. [ABSTRACT FROM AUTHOR]