Both alopecia areata (AA) and vitiligo are distinct, heterogenous, and complex disease entities, characterized by nonscarring scalp terminal hair loss and skin pigment loss, respectively. In AA, inflammatory cell infiltrates are in the deep reticular dermis close to the hair bulb (swarm of bees), whereas in vitiligo the inflammatory infiltrates are in the epidermis and papillary dermis. Immune privilege collapse has been extensively investigated in AA pathogenesis, including the suppression of immunomodulatory factors (e.g., transforming growth factor-β (TGF-β), programmed death-ligand 1 (PDL1), interleukin-10 (IL-10), α-melanocyte-stimulating hormone (α-MSH), and macrophage migration inhibitory factor (MIF)) and enhanced expression of the major histocompatibility complex (MHC) throughout hair follicles. However, immune privilege collapse in vitiligo remains less explored. Both AA and vitiligo are autoimmune diseases that share commonalities in pathogenesis, including the involvement of plasmacytoid dendritic cells (and interferon-α (IFN- α) signaling pathways) and cytotoxic CD8+ T lymphocytes (and activated IFN-γ signaling pathways). Blood chemokine C-X-C motif ligand 9 (CXCL9) and CXCL10 are elevated in both diseases. Common factors that contribute to AA and vitiligo include oxidative stress, autophagy, type 2 cytokines, and the Wnt/β-catenin pathway (e.g., dickkopf 1 (DKK1)). Here, we summarize the commonalities and differences between AA and vitiligo, focusing on their pathogenesis.

UNASSIGNED: Lung adenocarcinoma is a common malignant tumor, and its early diagnosis and treatment are key to improving patient survival rates. However, due to the non-specific early symptoms, many patients are already at an advanced stage when diagnosed. Non-targeted metabolomics analysis, as a method for comprehensive analysis of metabolites in the body, has been shown to have potential in the early diagnosis of cancer. This study aims to identify early-stage lung adenocarcinoma-specific biomarkers using non-targeted metabolomics analysis in an established mouse model. The intervention mechanism of indoleamine 2,3-dioxygenase (IDO) inhibitor in early-stage lung adenocarcinoma is explored to provide evidence for clinical disease treatment.
UNASSIGNED: Twenty specific-pathogen-free-grade female Kunming mice were divided into control group, experimental group, Epacadostatlow group, and Epacadostathigh group. After modeling, immune therapy intervention (epacadostat) was administered to the mice, and plasma and urine samples were collected from all mice on day 7 and day 28. Ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) analysis was performed to identify potential biomarkers for diagnosing early-stage lung adenocarcinoma. Cluster analysis and correlation analysis were used to explore the differential expression patterns of metabolites in different samples. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was used to identify enriched pathways of differentially expressed metabolites.
UNASSIGNED: A total of 348 metabolites were identified after merging the positive and negative ion modes. Among them, organic acids and derivatives (16.954%) and lipids and lipid-like molecules (15.517%) were the two major classes of metabolites in the early-stage lung adenocarcinoma mice. Anthranilic acid (vitamin L1), 1-methylhistidine, 12(R)-HETE, and hippuric acid were the major differentially expressed metabolites on both day 7 and day 28, and they showed correlations with each other. Metabolic pathway analysis revealed multiple dysregulated pathways in lung adenocarcinoma mice.
UNASSIGNED: UPLC-QTOF-MS analysis is a feasible method for identifying biomarkers of lung adenocarcinoma. Epacadostat, a novel and promising IDO inhibitor, may exert its therapeutic effect by modulating 1-methylhistidine and anthranilic acid (vitamin L1).

Indoleamine 2,3-dioxygenase (IDO) has been studied as a promising target for cancer immunotherapy. IDO catalyzes the oxidation of tryptophan into kynurenine, which subsequently activates regulatory T cells, thereby promoting an immunosuppressive microenvironment in the tumor tissue. Due to its overexpression in tumor cells, IDO itself could be a tumor-specific stimulus for targeted cancer therapy. Toward this objective, we developed IDO-triggered swellable micelles for targeted cancer immunotherapy. The micelles are prepared by the self-assembly of amphiphilic polymers containing polymerized tryptophan as a hydrophobic block. The micelles exhibited IDO-responsive behavior via solubility conversion of the hydrophobic core triggered by the oxidation of tryptophan residues into kynurenine. The micelles were internalized into tumor cells and disassembled by overexpressed IDO. Loaded with IDO inhibitor, the micelle presented enhanced therapeutic antitumor effect, and effector T-cells were recruited into the tumor tissue. We demonstrated that overexpressed IDO in cancer cells could be utilized as a tumor-specific stimulus, and utilizing an IDO-responsive drug delivery system holds great promise for targeted cancer therapy and immunomodulation.

The tryptophan-kynurenine (TRP-KYN) pathway is involved in several biological functions, including immunosuppression, inflammatory response, and tumor suppression. Six TRP-KYN pathway-related genes, tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 2 (IDO2), aminoadipate aminotransferase (AADAT), glutamate oxaloacetate transaminase 2 (GOT2), kynurenine monooxygenase (KMO), and kynureninase (KYNU) have been identified and cloned from the jawless vertebrate lamprey (Lampetra japonica) to gain insights into their evolution and characterization. Expression distribution showed that the key gene Lj-TDO was highly expressed in the oral gland. Real-time quantitative PCR showed that TRP-KYN pathway-related genes were significantly overexpressed after multi-stimulation. RNA interference showed that Lj-IDO2 knockdown regulated the expression of inflammatory factors. In conclusion, our study successfully clarified the ancestral features and functions of the TRP-KYN pathway, while providing valuable insights into the involvement of this pathway in the immune responses of a jawless vertebrate.

The pathogenesis of chronic pain entails a series of complex interactions among the nervous, immune, and endocrine systems. Defined as pain lasting or recurring for more than 3 months, chronic pain is becoming increasingly more prevalent among the US adult population. Pro-inflammatory cytokines from persistent low-grade inflammation not only contribute to the development of chronic pain conditions, but also regulate various aspects of the tryptophan metabolism, especially that of the kynurenine pathway (KP). An elevated level of pro-inflammatory cytokines exerts similar regulatory effects on the hypothalamic-pituitary-adrenal (HPA) axis, an intricate system of neuro-endocrine-immune pathways and a major mechanism of the stress response. As the HPA axis counters inflammation through the secretion of endogenous cortisol, we review the role of cortisol along with that of exogenous glucocorticoids in patients with chronic pain conditions. Considering that different metabolites produced along the KP exhibit neuroprotective, neurotoxic, and pronociceptive properties, we also summarize evidence rendering them as reliable biomarkers in this patient population. While more in vivo studies are needed, we conclude that the interaction between glucocorticoid hormones and the KP poses an attractive venue of diagnostic and therapeutic potential in patients with chronic pain.

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme belonging to the kynurenine pathway. IDO activity has been suggested as a potential biomarker for early diagnosis of chronic kidney disease (CKD). The aim of this study was to perform coincident association analysis to gain genetic insights into the correlation between IDO activity and CKD. This study evaluated the association between IDO activity and CKD using the Korea Association REsource (KARE) cohort. Logistic and linear regression were used to analyze CKD and quantitative phenotypes such as IDO and estimated glomerular filtration rate (eGFR). Our results identified 10 single nucleotide polymorphisms (SNPs) that were coincidently associated with both IDO and CKD (p < 0.001). Among them, rs6550842, rs77624055, and rs35651150 were selected as potential candidates after excluding SNPs with insufficient evidence for having an association with IDO or CKD. Further expression quantitative trait loci (eQTL) analysis for variants at selected loci showed that rs6550842 and rs35651150 significantly affected the expression of NKIRAS1 and SH2D4A genes in human tissues, respectively. Additionally, we highlighted that the NKIRAS1 and BMP6 genes were correlated with IDO activity and CKD through signaling pathways associated with inflammation. Our data suggest that NKIRAS1, SH2D4A, and BMP6 were potential causative genes affecting IDO activity and CKD through integrated analysis. Identifying these genes could aid in early detection and treatment by predicting the risk of CKD associated with IDO activity.

The kynurenine pathway of tryptophan catabolism can modulate inflammatory responses inducing immunotolerance or immunosuppressive effects. Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in this pathway. Early aberrant inflammation is implicated in severe dengue, and herein we investigate and characterize the expression of IDO pathway genes in severe dengue patients. We use a SyBR green-based qPCR to evaluate the leukocyte expression levels of IDO1, IDO2, AhR, TGF-β, ARG1, IFNγ, and IFNα in a dengue patient cohort (n = 51). Twenty-two cases were identified as severe dengue using the WHO case classification (2009) criteria. Principal component analysis (PCA) was employed to examine the relationships of gene expression profiles with disease severity and laboratory markers of clinical severity. We find that two principal components describe most of the variance (65.3%) in the expression patterns of the cohort. Reduced expression of IDO1, TGF-β, and AhR, represented by low Component 2 scores, was significantly associated with disease severity, thrombocytopenia, and leukopenia. Higher expression levels of IDO2, IFNγ, and IFNα positively correlated with Component 1 scores, and were significantly associated with elevated ALT (p = 0.018) and AST (p = 0.017) enzymes. Our results suggest that profiling the baseline expression patterns of the IDO pathway genes may aid in the identification of dengue patients most at risk of severe disease.

Dysfunction of the central nervous system are accompanied by changes in tryptophan metabolism, with the kynurenine pathway (KP) being the main route of its catabolism. Recently, KP metabolites, which are collectively called kynurenines, have become an area of intense research due to their ability to directly and indirectly affect a variety of classic neurotransmitter systems. However, the significance of KP in neuropathic pain is still poorly understood. Therefore, we designed several experiments to verify changes in the mRNA levels of KP enzymes in parallel with other factors related to this metabolic route after chronic constriction injury of the sciatic nerve (CCI model) in mice. The analysis revealed an increase in, Kmo, Kynu and Haoo mRNA levels in the spinal cord on the 7th day after CCI, while Kat1, Kat2, Tdo2, Ido2 and Qprt mRNA levels remain unchanged. Subsequent pharmacological studies provided evidence that modulation of KP by single intrathecal administration of 1-D-MT, UPF468 or L-kynurenine attenuates mechanical and thermal hypersensitivity and increases the effectiveness of selected opioids in mice as measured on day 7 after CCI. Moreover, our results provide the first evidence that the injection of L-kynurenine preceded by UPF468 (KMO inhibitor) is more effective at reducing hypersensitivity in animals with neuropathic pain. Importantly, L-kynurenine also exerts an analgesic effect after intravenous injections, which is enhanced by the administration of minocycline, an inhibitor of microglial activation. Additionally, L-kynurenine administered intrathecally and intravenously enhances analgesia evoked by all tested opioids (morphine, buprenorphine and oxycodone). Overall, our results indicate that the modulation of KP at different levels might be a new pharmacological tool in neuropathy management.

Mesenchymal stromal/stem cell (MSC)-based therapy has become a promising approach to periodontal tissue repair. Adipose-derived stromal/stem cells (ASCs), compared with other dental or non-dental MSCs, serve as promising candidates for MSC therapy due to non-invasive acquisition and abundant sources. This study aimed to explore the effects of ASC therapy in experimental periodontitis and the underlying mechanism.
Micro-CT was performed to evaluate the alveolar bone parameters following local injection of ASCs. Immunohistochemistry and immunofluorescence were employed to detect the expression of IL-1β, osteocalcin (OCN), nuclear factor (erythroid-derived 2)-like 2 (NRF2), and surface markers of macrophage polarization. Afterward, multiple reaction monitoring (MRM)-based targeted tryptophan metabolomic analysis was used to examine the ASC metabolites. Chromatin immunoprecipitation (ChIP)-qPCR assay was performed to investigate the direct binding of aryl hydrocarbon receptor (AhR) and NRF2.
Alveolar bone loss was reduced, and the ratio of iNOS+/CD206+ macrophages was significantly decreased after ASC injection in the rat models of periodontitis. ASCs promoted NRF2 expression and activation in macrophages, while NRF2 silencing in macrophages blocked the regulation of ASCs on macrophages. Furthermore, the expression of indoleamine 2,3-dioxygenase (IDO) of ASCs in the inflammatory condition was high. The inhibitor of IDO, 1-methyltryptophan (1-MT), impaired the therapeutic effects of ASCs in experimental periodontitis and regulation of macrophage polarization. Mechanistically, kynurenine (Kyn), a metabolite of ASCs catalyzed by IDO, activated AhR and enhanced its binding to the promoter of NRF2, which stimulated M2 macrophage polarization.
These findings suggested that ASCs can alleviate ligature-induced periodontitis through modulating macrophage polarization by the IDO-dependent Kyn-AhR-NRF2 pathway, uncovering a novel mechanism and providing a scientific basis for ASC-based therapy in experimental periodontitis.

UNASSIGNED: High activity of Indoleamine 2,3-dioxygenase1 (IDO1) in lung cancer patients converts tryptophan (Trp), which is the essential amino acid for T-cell metabolism, to kynurenine (Kyn) and consequently suppresses anti-tumor immune responses. We aimed to track the dynamics of IDO1 activity in stage III non-small cell lung cancer (NSCLC) patients who received first-line radiotherapy (RT) and explore its association with survival outcomes.
UNASSIGNED: Systemic IDO1 activity was calculated by Kyn : Trp ratio. Plasma levels of Kyn and Trp in 113 thoracic RT-received stage III NSCLC patients were measured by high-performance liquid chromatography before the initiation of RT. The dynamic change of IDO1 activity was followed in 24 patients by measuring the Kyn : Trp ratio before, during, and after RT administration.
UNASSIGNED: In 24 patients with dynamic tracking of plasma IDO1 activity, there were no significant alterations observed among the three time points (Friedman test, p = 0.13). The changing pattern of the Kyn : Trp ratio was divided into four groups: decreased consistently during RT, first increased, then decreased, increased consistently, first decreased then increased. Patients whose Kyn : Trp ratio kept decreasing or first increased then decreased were defined as the good-change group. The good-change status was identified as an independent positive factor for overall survival (OS) and progression-free survival (PFS) (p = 0.04; p = 0.01) in multivariate analysis among evaluated parameters. Patients with good change showed significantly superior local control than the bad-change group (p = 0.01, HR = 0.22). In 113 stage III NSCLC patients with pre-radiation Kyn : Trp ratio, a trend that high baseline IDO1 activity was associated with short OS was observed (p = 0.079).
UNASSIGNED: Favorable change in IDO1 activity during RT was associated with superior OS, PFS, and local control. IDO1 activity is a promising biomarker for prognosis in stage III NSCLC patients.