Search Results (100)

The kynurenine (KYN) metabolic pathway sits at the crossroads of immunity, metabolism, and neurobiology, yet its clinical translation remains fragmented. Emerging spatial omics, wearable chronobiology, and synthetic microbiota studies reveal that tryptophan (Trp) metabolism is regulated by distinct cellular “checkpoints” along the gut–brain axis, finely modulated by sex differences, circadian rhythms, and microbiome composition. However, current interventions tackle single levers in isolation, leaving a key gap in the precision control of Trp’s fate. To address this, we drew upon an extensive body of the primary literature and databases, mapping enzyme expression across tissues at single-cell resolution and linking these profiles to clinical trials investigating dual indoleamine 2,3-dioxygenase 1 (IDO1)/tryptophan 2,3-dioxygenase (TDO) inhibitors, engineered probiotics, and chrono-modulated dosing strategies. We then developed decision-tree algorithms that rank therapeutic combinations against biomarker feedback loops derived from real-time saliva, plasma, and stool metabolomics. This synthesis pinpoints microglial and endothelial KYN hotspots, quantifies sex-specific chronotherapeutic windows, and identifies engineered Bifidobacterium consortia and dual inhibitors as synergistic nodes capable of reducing immunosuppressive KYN while preserving neuroprotective kynurenic acid. Here, we highlight a framework that couples lifestyle levers, bio-engineered microbes, and adaptive pharmaco-regimens into closed-loop “smart protocols.” By charting these intersections, this study offers a roadmap for biomarker-guided, multidisciplinary interventions that could recalibrate KYN metabolic activity across cancer, mood, neurodegeneration, and metabolic disorders, appealing to clinicians, bioengineers, and systems biologists alike. Full article

Skeletal muscle atrophy is a critical health issue affecting the quality of life of elderly individuals and patients with chronic diseases. These conditions induce dysregulation of glucocorticoid (GC) secretion. GCs play a critical role in maintaining homeostasis in the stress response and glucose metabolism. However, prolonged exposure to GC is directly linked to muscle atrophy, which is characterized by a reduction in muscle size and weight, particularly affecting fast-twitch muscle fibers. The GC-activated glucocorticoid receptor (GR) decreases protein synthesis and facilitates protein breakdown. Numerous antagonists have been developed to mitigate GC-induced muscle atrophy, including 11β-HSD1 inhibitors and myostatin and activin receptor blockers. However, the clinical trial results have fallen short of the expected efficacy. Recently, several emerging pathways and targets have been identified. For instance, GC-induced sirtuin 6 isoform (SIRT6) expression suppresses AKT/mTORC1 signaling. Lysine-specific demethylase 1 (LSD1) cooperates with the GR for the transcription of atrogenes. The kynurenine pathway and indoleamine 2,3-dioxygenase 1 (IDO-1) also play crucial roles in protein synthesis and energy production in skeletal muscle. Therefore, a deeper understanding of the complexities of GR transactivation and transrepression will provide new strategies for the discovery of novel drugs to overcome the detrimental effects of GCs on muscle tissues. Full article

Recent preclinical and clinical studies have confirmed the essential role of interferons in the host’s immune response against malignant cells. Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer strongly associated with Merkel cell polyomavirus (MCPyV). Despite progress in understanding MCC pathogenesis, the role of innate immune signaling, particularly interferon-γ (IFN γ) and its downstream pathways, remains underexplored. This review summarizes recent findings on IFN-γ in MCC, highlighting its dual role in promoting both antitumor immunity and immune evasion. IFN-γ enhances cytotoxic T cell responses, upregulates MHC class I/II expression, and induces tumor cell apoptosis. Transcriptomic studies have shown that IFN-γ treatment upregulates immune-regulatory genes including PD-L1, HLA-A/B/C, and IDO1 by over threefold; it also activates APOBEC3B and 3G, contributing to antiviral defense and tumor editing. Clinically, immune checkpoint inhibitors (ICIs) such as pembrolizumab and avelumab yield objective response rates of 30–56% and two-year overall survival rates exceeding 60% in advanced MCC. However, approximately 50% of patients do not respond, in part due to IFN-γ signaling deficiencies. This review further discusses IFN-γ’s crosstalk with the STAT1/3/5 pathways and emerging combination strategies aimed at restoring immune sensitivity. Understanding these mechanisms may inform personalized immunotherapeutic approaches and guide the development of IFN-γ–based interventions in MCC. Full article

In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, a series of imidazothiazole-based hydroxamic acid derivatives were designed based on the pharmacophore fusion strategy and evaluated as potent IDO1 and HDAC6 dual inhibitors. Among these inhibitors, the most potent compound 3-(4-Bromophenyl)-N-{4-[(7-(hydroxyamino)-7-oxoheptyl)amino]phenyl}imidazo[2,1-b]thiazole-5-carboxamide (10e) showed considerable IDO1 inhibitory activity and a good selectivity profile for HDAC6 over the other HDAC isoforms. The intracellular inhibition of HDAC6 by 10e was validated by Western blot analysis. Docking studies illustrated that the possible binding modes of compound 10e interacted with IDO1 and HDAC6. Moreover, compound 10e was found to arrest the cell cycle at the G2/M phase in HCT-116 cells. In particular, compound 10e also exhibited potent in vivo antitumor efficacy in CT26 tumor-bearing BALB/c mice models, with no significant toxicity. Collectively, this work provides a promising lead compound that serves as IDO1/HDAC6 dual inhibitor for the development of novel antitumor agents. Full article

Background and Objectives: Acute ulcerative colitis is characterized by excessive mucosal inflammation and epithelial disruption, often driven by dysregulated cytokine and immune signaling. Indoximod (1-methyl-DL-tryptophan), although not a direct enzymatic inhibitor, modulates the indoleamine 2,3-dioxygenase (IDO) pathway and has been reported to exert immunoregulatory effects in various models of inflammation. This study aimed to evaluate the protective effects of Indoximod in an acetic acid-induced colitis model in rats, focusing on histopathological changes and inflammatory mediators. Materials and Methods: Thirty male Wistar albino rats were randomly assigned to three groups (n = 10 per group): Group 1 (Control) received 0.9% saline oral gavage; Group 2 (Colitis) received intrarectal 4% acetic acid to induce colitis and were then treated with saline; Group 3 (Colitis + Indoximod) received 4% acetic acid followed by oral gavage administration of Indoximod (30 mg/kg) for 15 consecutive days. Histopathological evaluation of colonic tissues was performed using hematoxylin and eosin (H&E) staining. Colonic expression of Toll-like receptor 4 (TLR4) and plasma levels of tumor necrosis factor-alpha (TNF-α), pentraxin-3 (PTX-3), and platelet-activating factor (PAF) were quantified using enzyme-linked immunosorbent assay (ELISA). Results: Acetic acid-induced colitis significantly increased mucosal damage, TLR4 expression, and circulating levels of TNF-α, PTX-3, and PAF compared with controls (p < 0.001). Indoximod treatment markedly reduced histological injury and significantly suppressed TLR4 and TNF-α levels (p < 0.01), along with partial reductions in PTX-3 (p < 0.05). However, PAF levels remained elevated despite treatment, indicating limited efficacy in PAF-associated pathways. Conclusions: Indoximod exhibited anti-inflammatory effects in this acute colitis model, likely by downregulating key proinflammatory mediators. Full article

Background: An accurate and rapid analysis of human indoleamine 2,3-dioxygenase (hIDO) is crucial for the development of anticancer pharmaceuticals because of the role of hIDO in promoting tumoral immune escape. However, the conventional assay of hIDO is limited by interference from reductants, which are used to reduce the heme iron to begin the hIDO catalytic reaction. Methods: A direct electrochemical method was applied to drive the hIDO reaction. Results: The nanostructured gold electrode enabled the electrochemical reduction of the heme iron of hIDO1. In the presence of substrates (tryptophan and oxygen), a bioelectrocatalytic current was observed, confirming an electrochemically driven hIDO reaction. A well-known inhibitor of hIDO, epacadostat, hindered this catalytic signal according to its concentration, demonstrating the rapid evaluation of its inhibition activity for the hIDO reaction. Through an in silico study using the proposed electrochemical assay system, we discovered a strong inhibitor candidate with a half-maximal inhibitory concentration of 10 nM. Conclusions: An accurate and rapid assay system in drug discovery for hIDO and kynureine pathway-targeted immunotherapy has been developed. Full article

Background: CY1-4, 9-nitropyridine [2′,3′:4,5] pyrimido [1,2-α] indole -5,11- dione, is an indoleamine 2,3-dioxygenase (IDO) inhibitor and a poorly water-soluble substance. It is very important to increase the solubility of CY1-4 to improve its bioavailability and therapeutic effect. In this study, the mesoporous silica nano-skeleton carrier material Sylysia was selected as the carrier to load CY1-4, and then the CY1-4 nano-skeleton drug delivery system (MSNM@CY1-4) was prepared by coating the hydrophilic polymer material Hydroxypropyl methylcellulose (HPMC) and the lipid material Distearoylphosphatidyl-ethanolamine-poly(ethylene glycol)₂₀₀₀ (DSPE-PEG₂₀₀₀) to improve the anti-tumor effect of CY1-4. Methods: The solubility and dissolution of MSNM@CY1-4 were investigated, and its bioavailability, anti-tumor efficacy, IDO inhibitory ability and immune mechanism were evaluated in vivo. Results: CY1-4 was loaded in MSNM@CY1-4 in an amorphous form, and MSNM@CY1-4 could significantly improve the solubility (up to about 200 times) and dissolution rate of CY1-4. In vivo studies showed that the oral bioavailability of CY1-4 in 20 mg/kg MSNM@CY1-4 was about 23.9-fold more than that in 50 mg/kg CY1-4 suspension. In B16F10 tumor-bearing mice, MSNM@CY1-4 significantly inhibited tumor growth, prolonged survival time, significantly inhibited IDO activity in blood and tumor tissues, and reduced Tregs in tumor tissues and tumor-draining lymph nodes to improve anti-tumor efficacy. Conclusions: The nano-skeleton drug delivery system (MSNM@CY1-4) constructed in this study is a potential drug delivery platform for improving the anti-tumor effect of oral poorly water-soluble CY1-4. Full article

Amelanotic melanoma (AM) is a subtype of hypomelanotic or completely amelanotic melanoma. AM is a rare subtype of melanoma that exhibits a higher recurrence rate and aggressiveness as well as worse surveillance than typical melanoma. AM shows a dysregulation of melanin production, cell cycle control, and apoptosis pathways. Knowing these pathways has an application in medicine due to targeted therapies based on the inhibiting elements of the abovementioned pathways. Therefore, we summarized and discussed AM biochemical and molecular induction pathways and personalized medicine approaches, clinical management, and future directions due to the fact that AM is relatively rare. AM is commonly misdiagnosed. Hence, the role of biomarkers is becoming significant. Nonetheless, there is a shortage of biomarkers specific to AM. BRAF, NRAS, and c-KIT genes are the main targets of therapy. However, the role of BRAF and KIT in AM varied among studies. BRAF inhibitors combined with MAK inhibitors demonstrate better results. Immune checkpoint inhibitors targeting CTLA-4 combined with a programmed death receptor 1 (PD-1) show better outcomes than separately. Fecal microbiota transplantation may overcome resistance to immune checkpoint therapy of AM. Immune-modulatory vaccines against indoleamine 2,3-dioxygenase (IDO) and PD ligand (PD-L1) combined with nivolumab may be efficient in melanoma treatment. Full article

Background: Tryptophan is widely present in foods such as peanuts, milk, and bananas, playing a crucial role in maintaining metabolic homeostasis in health and disease. Tryptophan metabolism is involved in the development and progression of immune, nervous, and digestive system diseases. Although some excellent reviews on tryptophan metabolism exist, there has been no systematic scientometric study as of yet. Methods: This review provides and summarizes research hotspots and potential future directions by analyzing annual publications, topics, keywords, and highly cited papers sourced from Web of Science spanning 1964 to 2022. Results: This review provides a scientometric overview of tryptophan metabolism disorder-triggered diseases, mechanisms, and therapeutic strategies. Conclusions: The gut microbiota regulates gut permeability, inflammation, and host immunity by directly converting tryptophan to indole and its derivatives. Gut microbial metabolites regulate tryptophan metabolism by activating specific receptors or enzymes. Additionally, the kynurenine (KYN) pathway, activated by indoleamine-2, 3-dioxygenase (IDO) and tryptophan 2, 3-dioxygenase, affects the migration and invasion of glioma cells and the development of COVID-19 and depression. The research and development of IDO inhibitors help to improve the effectiveness of immunotherapy. Tryptophan metabolites as potential markers are used for disease therapy, guiding clinical decision-making. Tryptophan metabolites serve as targets to provide a new promising strategy for neuroprotective/neurotoxic imbalance affecting brain structure and function. In summary, this review provides valuable guidance for the basic research and clinical application of tryptophan metabolism. Full article

The application of intracerebroventricular injection of streptozotocin (ICV-STZ) is considered a useful animal model to mimic the onset and progression of sporadic Alzheimer’s disease (sAD). In rodents, on day 7 of the experiment, the animals exhibit depression-like behaviors. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn), is closely related to depression and AD. The present study aimed to investigate the pathophysiological mechanisms of preliminary depression-like behaviors in ICV-STZ rats in two distinct cerebral regions of the medial prefrontal cortex, the prelimbic cortex (PrL) and infralimbic cortex (IL), both presumably involved in AD progression in this model, with a focus on IDO-related Kyn pathways. The results showed an increased Kyn/Trp ratio in both the PrL and IL of ICV-STZ rats, but, intriguingly, abnormalities in downstream metabolic pathways were different, being associated with distinct biological effects. In the PrL, the neuroprotective branch of the Kyn pathway was attenuated, as evidenced by a decrease in the kynurenic acid (KA) level and Kyn aminotransferase II (KAT II) expression, accompanied by astrocyte alterations, such as the decrease in glial fibrillary acidic protein (GFAP)-positive cells and increase in morphological damage. In the IL, the neurotoxicogenic branch of the Kyn pathway was enhanced, as evidenced by an increase in the 3-hydroxy-kynurenine (3-HK) level and kynurenine 3-monooxygenase (KMO) expression paralleled by the overactivation of microglia, reflected by an increase in ionized calcium-binding adaptor molecule 1 (Iba1)-positive cells and cytokines with morphological alterations. Synaptic plasticity was attenuated in both subregions. Additionally, microinjection of the selective IDO inhibitor 1-Methyl-DL-tryptophan (1-MT) in the PrL or IL alleviated depression-like behaviors by reversing these different abnormalities in the PrL and IL. These results suggest that the antidepressant-like effects linked to Trp metabolism changes induced by 1-MT in the PrL and IL occur through different pathways, specifically by enhancing the neuroprotective branch in the PrL and attenuating the neurotoxicogenic branch in the IL, involving distinct glial cells. Full article

Glioma is characterized by strong immunosuppression and excessive angiogenesis. Based on existing reports, it can be speculated that the resistance to anti-angiogenic drug vascular endothelial growth factor A (VEGFA) antibody correlates to the induction of novel immune checkpoint indoleamine 2,3-dioxygenase 1 (IDO1), while IDO1 has also been suggested to be related to tumor angiogenesis. Herein, we aim to clarify the potential role of IDO1 in glioma angiogenesis and the mechanism behind it. Bioinformatic analyses showed that the expressions of IDO1 and angiogenesis markers VEGFA and CD34 were positively correlated and increased with pathological grade in glioma. IDO1-overexpression-derived-tryptophan depletion activated the general control nonderepressible 2 (GCN2) pathway and upregulated VEGFA in glioma cells. The tube formation ability of angiogenesis model cells could be inhibited by IDO1 inhibitors and influenced by the activity and expression of IDO1 in condition medium. A significant increase in serum VEGFA concentration and tumor CD34 expression was observed in IDO1-overexpressing GL261 subcutaneous glioma-bearing mice. IDO1 inhibitor RY103 showed positive anti-tumor efficacy, including the anti-angiogenesis effect and upregulation of natural killer cells in GL261 glioma-bearing mice. As expected, the combination of RY103 and anti-angiogenesis agent sunitinib was proved to be a better therapeutic strategy than either monotherapy. Full article

With the aim to advance the understanding of immune regulation in MCL and to identify targetable T-cell subsets, we set out to combine image analysis and spatial omic technology focused on both early and late differentiation stages of T cells. MCL patient tissue (n = 102) was explored using image analysis and GeoMx spatial omics profiling of 69 proteins and 1812 mRNAs. Tumor cells, T helper (T_H) cells and cytotoxic (T_C) cells of early (CD57−) and late (CD57+) differentiation stage were analyzed. An image analysis workflow was developed based on fine-tuned Cellpose models for cell segmentation and classification. T_C and CD57+ subsets of T cells were enriched in tumor-rich compared to tumor-sparse regions. Tumor-sparse regions had a higher expression of several key immune suppressive proteins, tentatively controlling T-cell expansion in regions close to the tumor. We revealed that T cells in late differentiation stages (CD57+) are enriched among MCL infiltrating T cells and are predictive of an increased expression of immune suppressive markers. CD47, IDO1 and CTLA-4 were identified as potential targets for patients with T-cell-rich MCL TIME, while GITR might be a feasible target for MCL patients with sparse T-cell infiltration. In subgroups of patients with a high degree of CD57+ T_C-cell infiltration, several immune checkpoint inhibitors, including TIGIT, PD-L1 and LAG3 were increased, emphasizing the immune-suppressive features of this highly differentiated T-cell subset not previously described in MCL. Full article

Background: Indoleamine 2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase (TDO) are the two principals enzymes involved in the catabolization of tryptophan (Trp) into kynurenine (Kyn). Despite their well-established role in the immune escape, their involvement in angiogenesis remains uncertain. We aimed to characterize TDO and IDO1 in human umbilical venular endothelial cells (HUVECs) and human endothelial colony-forming cells (ECFCs). Methods: qRT-PCR and immunofluorescence were used for TDO and IDO1 expression while their activity was measured using ELISA assays. Cell proliferation was examined via MTT tests and in in vitro angiogenesis by capillary morphogenesis. Results: HUVECs and ECFCs expressed TDO and IDO1. Treatment with the selective TDO inhibitor 680C91 significantly impaired HUVEC proliferation and 3D-tube formation in response to VEGF-A, while IDO1 inhibition showed no effect. VEGF-induced mTor phosphorylation and Kyn production were hindered by 680C91. ECFC morphogenesis was also inhibited by 680C91. Co-culturing HUVECs with A375 induced TDO up-regulation in both cell types, whose inhibition reduced MMP9 activity and prevented c-Myc and E2f1 upregulation. Conclusions: HUVECs and ECFCs express the key enzymes of the kynurenine pathway. Significantly, TDO emerges as a pivotal player in in vitro proliferation and capillary morphogenesis, suggesting a potential pathophysiological role in angiogenesis beyond its well-known immunomodulatory effects. Full article

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs. Full article

In the last few years, nivolumab has become the standard of care for advanced-stage lung cancer patients. Unfortunately, up to 60% of patients do not respond to this treatment. In our study, we identified variations in gene expression related to primary resistance to immunotherapy. Bronchoscopy biopsies were obtained from advanced non-small cell lung cancer (NSCLC) patients previously characterized as responders or non-responders after nivolumab treatment. Ten tumor biopsies (from three responders and seven non-responders) were analyzed by the differential expression of 760 genes using the NanoString nCounter platform. These genes are known to be involved in the response to anti-PD1/PD-L1 therapy. All the patients were treated with nivolumab. Examining the dysregulated expression of 24 genes made it possible to predict the response to nivolumab treatment. Supervised analysis of the gene expression profile (GEP) revealed that responder patients had significantly higher levels of expression of CXCL11, NT5E, KLRK1, CD3G, GZMA, IDO1, LCK, CXCL9, GNLY, ITGAL, HLA-DRB1, CXCR6, IFNG, CD8A, ITK, B2M, HLA-B, and HLA-A than did non-responder patients. In contrast, PNOC, CD19, TP73, ARG1, FCRL2, and PTGER1 genes had significantly lower expression levels than non-responder patients. These findings were validated as predictive biomarkers in an independent series of 201 patients treated with nivolumab (22 hepatocellular carcinomas, 14 non-squamous cell lung carcinomas, 5 head and neck squamous cell carcinomas, 1 ureter/renal pelvis carcinoma, 120 melanomas, 4 bladder carcinomas, 31 renal cell carcinomas, and 4 squamous cell lung carcinomas). ROC curve analysis showed that the expression levels of ITK, NT5E, ITGAL, and CD8A were the best predictors of response to nivolumab. Further, 13/24 genes showed an adverse impact on overall survival (OS) in an independent, large series of patients with NSCLC (2166 cases). In summary, we found a strong association between the global GEP of advanced NSCLC and the response to nivolumab. The classification of NSCLC patients based on GEP enabled us to identify those patients who genuinely benefited from treatment with immune checkpoint inhibitors (ICIs). We also demonstrated that abnormal expression of most of the markers comprising the genomic signature has an adverse influence on OS, making them significant markers for therapeutic decision-making. Additional prospective studies in larger series of patients are required to confirm the clinical utility of these biomarkers. Full article